ENDOCRINOLOGY
AND METABOLISM
PRESENTED IN THEIR SCIENTIFIC
AND PRACTICAL CLINICAL ASPECTS
BY NINETY- EIGHT CONTRIBUTORS
EDITED BY
LEWELLYS F. BARKER, M.D. (TORONTO), ,,,
LL.D. (QjJEENS; McGlLL)
PROFESSOR OF MEDICINE, JOHNS HOPKINS UNIVERSITY, 1905-1914 ; PHYSICIAN-IN-CHIF.F, JOHNS HOPKINS
HOSPITAL, 1905-1914; PRESIDENT OF ASSOCIATION OF AMERICAN PHYSICIANS, 1912-1913; PRESIDENT
OP AMERICAN NEUROLOGICAL ASSOCIATION, 1915 ; PRESIDENT OF SOUTHERN MEDICAL ASSOCIA-
TION, 1919 ; PROFESSOR OF CLINICAL MEDICINE, JOHNS HOPKINS UNIVERSITY, 1914-
1921 ; AND VISITING PHYSICIAN, JOHNS HOPKINS HOSPITAL
ASSOCIATE EDITORS
ENDOCRINOLOGY
R. G. HOSKINS
PH.D. (HARVARD), M.D. (JOHNS HOPKINS) }
PROFESSOR OF PHYSIOLOGY, STARLING-OHIO MEDICAL
COLLEGE, 1910-1913 ; ASSOCIATE PROFESSOR OP
PHYSIOLOGY, NORTHWESTERN UNIVERSITY MED-
ICAL SCHOOL, 1913-1916 ; PROFESSOR OP
PHYSIOLOGY, IBID., 1916-1918 ; ASSOCIATE
IN PHYSIOLOGY. JOHNS HOPKINS UNIVER-
SITY, 1920-1921 ; PROFESSOR AND HEAD
OF DEPARTMENT OF PHYSIOLOGY,
OHIO STATE UNIVERSITY, 1921 ;
EDITOR-IN-CHIEF "ENDOCRIN-
OLOGY," 1917-.
METABOLISM
HERMAN O. MOSENTHAL
M.D. (COLUMBIA UNIVERSITY)
ASSOCIATE PHYSICIAN, JOHNS HOPKINS HOSPITAL,
1914-1918 ; ASSOCIATE PROFESSOR OF MEDICINE,
JOHNS HOPKINS UNIVERSITY, 1914-1918 ; AS- .
SOCIATE IN MEDICINE, COLLEGE OF PHYSI-
CIANS AND SURGEONS, COLUMBIA UNI-
VERSITY, 1910-1920 ; ASSOCIATE PRO-
FESSOR AND ATTENDING PHYSICIAN,
NEW YORK POST-GRADUATE MEDICAL
SCHOOL AND HOSPITAL.
VOLUME 3
5-3-
D. APPLETON AND COMPANY
NEW YORK LONDON
1922
COPYRIGHT, 1922, BY
D. APPLETON AND COMPANY
PRINTED IW TUB UNITED STATES OF AMERICA
CONTRIBUTORS TO VOLUME III
Graham Lusk, Ph.D., Sc.D., F.R.S.E.
PROFESSOR OF PHYSIOLOGY, CORNELL UNIVERSITY MEDICAL COLLEGE, SCIENTIFIC DIRECTOR
RUSSELL SAGE INSTITUTE OF PATHOLOGY.
v \ 0 1 / // / ^ v
A. I. Ringer, M.D.
ASSOCIATE PHYSICIAN, MONTEFIORE HOSPITAL, NEW YORK; CONSULTING PHYSICIAN, DIS-
EASES OF METABOLISM, LENOX HILL HOSPITAL, NEW YORK CITY; FORMERLY ASSISTANT
PROFESSOR OF PHYSIOLOGICAL CHEMISTRY, L7NIVERSITY OF PENNSYLVANIA; LECTURER IN
PHYSIOLOGY AT CORNELL UNIVERSITY MEDICAL COLLEGE; PROFESSOR OF CLINICAL MEDICINE
( DISEASES OF METABOLISM ) , FORDHAM UNIVERSITY SCHOOL OF MEDICINE.
Walter Jones, Ph.D.
PROFESSOR OF PHYSIOLOGICAL CHEMISTRY IN THE JOHNS HOPKINS MEDICAL SCHOOL;
MEMBER OF THE NATIONAL ACADEMY OF SCIENCES.
Louis Bauman, M.D.
ASSOCIATE IN MEDICINE, COLUMBIA UNIVERSITY; ASSISTANT VISITING PHYSICIAN, PRES-
BYTERIAN HOSPITAL, NEW YORK.
Walter R. Bloor, M.A., A.M., Ph.D.
ASSISTANT IN BIOLOGICAL CHEMISTRY, HARVARD MEDICAL SCHOOL, 1908-1910; ASSOCIATE
IN BIOLOGICAL CHEMISTRY, WASHINGTON UNIVERSITY, MEDICAL SCHOOL ( ST. LOUIS ) ,
1910-1914; ASSISTANT PROFESSOR OF BIOLOGICAL CHEMISTRY, HARVARD MEDICAL SCHOOL,
1914-1918; PROFESSOR OF BIOCHEMISTRY AND HEAD OF THE DEPARTMENT OF BIOCHEMISTRY
AND PHARMACOLOGY, UNIVERSITY OF CALIFORNIA, 1918-.
Emil J. Baumann, B.S., Ph.D.
IN CHARGE OF DIVISION OF CHEMISTRY AND LABORATORY OF THE MONTEFIORE HOSPITAL;
FORMERLY LECTURER IN BIOCHEMISTRY, UNIVERSITY OF TORONTO.
Philip B. Hawk, M.S., Ph.D.
PROFESSOR OF PHYSIOLOGICAL CHEMISTRY AND TOXICOLOGY, JEFFERSON MEDICAL COLLEGE
AND PHYSIOLOGICAL CHEMIST TO JEFFERSON HOSPITAL.
Harold L. Higgins, A.B., M.D.
ASSISTANT PROFESSOR OF PEDIATRICS, UNIVERSITY OF CINCINNATI; ATTENDING PEDIATRI-
CIAN OF THE CINCINNATI GENERAL HOSPITAL.
iv CONTRIBUTORS TO VOLUME III
Henry A. Mattill, A.M., Ph.D.
JUNIOR PROFESSOR OF BIOCHEMISTRY, UNIVERSITY OF ROCHESTER, ROCHESTER, N. Y. ; PRO-
FESSOR OF PHYSIOLOGY AND PHYSIOLOGICAL CHEMISTRY, UNIVERSITY OF UTAH, SALT LAKE
CITY, UTAH, 1910-1915} ASSISTANT PROFESSOR OF NUTRITION, UNIVERSITY OF CALIFORNIA,
1915-1917.
Helen Isham Matill, Ph.D.
FORMEELY ASSOCIATE IN CHEMISTRY, UNIVERSITY OF ILLINOIS.
Carl Voegtlin, M.D.
PROFESSOR OF PHARMACOLOGY AND CHIEF OF DIVISION OF PHARMACOLOGY, HYGIENIC
LABORATORY, U. S. PUBLIC HEALTH SERVICE, WASHINGTON, D. C.
Isidor Greenwald, Ph.D.
CHEMIST, HARBIMAN RESEARCH LABORATORY, ROOSEVELT HOSPITAL.
Victor Caryl Myers, B.A., M.A., Ph.D.
PROFESSOR OF PATHOLOGICAL CHEMISTRY, NEW YORK POST-GRADUATE MEDICAL SCHOOL
AND HOSPITAL; PATHOLOGICAL CHEMIST TO THE POST-GRADUATE HOSPITAL.
John R. Murlin, Ph.D., Sc.D.
PROFESSOR OF PHYSIOLOGY AND DIRECTOR OF DEPARTMENT OF VITAL ECONOMICS, UNIVER-
SITY OF ROCHESTER, ROCHESTER, N. Y. ; CHAIRMAN, COMMITTEE ON FOOD AND NUTRITION,
NATIONAL RESEARCH COUNCIL.
Arthur Isaac Kendall, B.S., Ph.D., Dr.P.H.
PROFESSOR OF BACTERIOLOGY, NORTHWESTERN UNIVERSITY MEDICAL SCHOOL; DIRECTOR
OF THE PATTEN RESEARCH FOUNDATION.
Henry G. Barbour, A.B., M.D.
PROFESSOR OF PHARMACOLOGY, MC GILL UNIVERSITY, MONTREAL.
Arlie Vernon Bock, M.D.
ASSISTANT IN MEDICINE, HARVARD UNIVERSITY; ASSISTANT IN MEDICINE, MASSACHUSETTS
GENERAL HOSPITAL; ASSISTANT VISITING PHYSICIAN, COLLIS P. HUNTINGTON MEMORIAL
HOSPITAL OF HARVARD UNIVERSITY.
Herbert S. Carter, A.M., M.D.
ASSISTANT PROFESSOR OF MEDICINE, COLUMBIA UNIVERSITY, NEW YORK; ASSOCIATE AT-
TENDING PHYSICIAN TO THE PRESBYTERIAN .HOSPITAL, NEW YORK; CONSULTING PHYSICIAN
TO THE LINCOLN HOSPITAL, NEW YORK.
CONTRIBUTORS TO VOLUME III v
George R. Minot, M.D.
ASSISTANT PROFESSOR OF MEDICINE, HARVARD UNIVERSITY; ASSOCIATE IN MEDICINE,
MASSACHUSETTS GENERAL HOSPITAL; PHYSICIAN TO THE COLLIS P. HUNTINGTON MEMO-
RIAL HOSPITAL OF HARVARD UNIVERSITY.
Thomas Ordway, A.B., A.M., M.D., Sc.D.
DEAN AND ASSOCIATE PROFESSOR OF MEDICINE, ALBANY MEDICAL COLLEGE; ATTENDING
PHYSICIAN, ALBANY HOSPITAL.
Arthur Knudson, A.B., Ph.D.
PROFESSOR OF BIOLOGICAL CHEMISTRY, ALBANY MEDICAL COLLEGE; ATTENDING BIOLOGICAL
CHEMIST, ALBANY HOSPITAL.
E. C. Schneider, B.S., Ph.D., Sc.D.
PROFESSOR OF BIOLOGY, WESLEYAN UNIVERSITY, MIDDLETOWN, CONNECTICUT, AND DIRECTOR
OF THE DEPARTMENT OF PHYSIOLOGY AT THE AIR SERVICE MEDICAL RESEARCH LABORATORY,
MITCHEL FIELD, GARDEN CITY, NEW YORK; MEMBER OF THE ANGLO-AMERICAN PIKE'S PEAK
EXPEDITION IN 1911 AND OTHER ALPINE PHYSIOLOGICAL EXPEDITIONS TO PIKE'S PEAK.
CONTENTS
PAGK
»A HISTORY OF METABOLISM 3
SECTION I
DIETARY CONSTITUENTS AND THEIR DERIVATIVES
»THE PROTEINS AND THEIR METABOLISM A. /. Ringer 81
NUCLEIC ACIDS Walter Jones 135
UROBILIN AND UROBILINOG&N Louis Bauman 163
VCREATIN AND CREATiNiN Louis Bauman 171
^NORMAL FAT METABOLISM Walter R. Bloor 183
-THE CARBOHYDRATES AND THEIR METABOLISM
A. I. Ringer and Emil J. Bauman 213
WATER AS A DIETARY CONSTITUENT Philip B. Hawk 275
THE METABOLISM OF ALCOHOL Harold L. Higgins 297
MINERAL METABOLISM Henry A. Mattill and Helen I. Mattill 303
THE METABOLISM OF VITAMINS Carl Voegtlin 341
SECTION II
A NORMAL DIET Isidor Greenwald 359
SECTION III
BODY TISSUES AND FLUIDS Victor C. Myers 423
SECTION IV
EXCRETIONS Victor C. Myers 481
SECTION V
NORMAL PROCESSES OF ENERGY METABOLISM .... John R. Murlin 515
SECTION VI
BACTERIAL METABOLISM, NORMAL AND ABNORMAL WITHIN THE BODY
Arthur Isaac Kendall 663
SECTION VII
ACTIONS OF DRUGS AND THERAPEUTIC MEASURES
THE EFFECTS OF CERTAIN DRUGS AND POISONS UPON THE METABOLISM
Henry G. Barlour 747
THE INTRAVENOUS INJECTION OF FLUIDS . Arlie V. Bock 787
vii
viii CONTENTS
PAGE
ARTIFICIAL METHODS OF FEEDING Herbert C. Carter 805
TRANSFUSION OF BLOOD George R. Minot and Arlie V. Bock 821
MINERAL WATERS Henry A. Mattill 845
HYDROTHERAPY Henry A. Mattill 855
THE INFLUENCE OF ROENTGEN RAYS, RADIOACTIVE SUBSTANCE*, LIGHT, AND
ELECTRICITY UPON METABOLISM . Thomas Ordway and Arthur Knudson 871
CLIMATE Edward C. Schneider 899
INDEX . , „ „ <> 913
LIST OF ILLUSTRATIONS
A History of Metabolism
GRAHAM LUSK
FIGURE PAGE
1. F.rontispiece of "De medicina statica aphorismi," showing Sanctorius
seated on a chair suspended from a large steelyard 7
2. Priestly 16
3. Scheele's apparatus showing bees in the upper chamber of a glass
apparatus filled with oxygen 18
4. Lavoisier and his wife 20
5. The burning glass of Trudaine 21
6. The closed circuit apparatus of Regnault and Reiset 41
7. Carl Voit 66
8. Max Rubner 76
SECTION I
DIETARY CONSTITUENTS AND THEIR DERIVATIVES
Water as a Dietary Constituent
PHILIP B. HAWK
1. Curve showing pronounced stimulation by water and rapid emptying
of the stomach 282
2. Curve showing moderate stimulation by water 283
3. Curve showing slight stimulation by water in the human stomach . . 283
4. Curves showing immediate stimulation by water and rapid emptying
of the stomach 284
5. Curves showing no glandular fatigue in human stomach .... 285
6. Curves showing comparative stimulatory power of water and bouillon
in the human stomach 285
7. Curves showing comparative stimulatory power of water and coffee
in the human stomach 286
8. Curves showing comparative stimulatory power of water and oatmeal
in the human stomach 287
9. Chart illustrating the evacuation of various fluids from the human
stomach 289
x- SECTION II
A Normal Diet
ISIDOR GREENWALD
CHART PAGE
1. Total food value of the chief world foods expressed in calories . . . 362
2. Per capita consumption of meat 364
3. Neumann's observations on himself of reduced war diet 417
ix
x LIST OF ILLUSTRATIONS
SECTION V
Normal Processes of Energy Metabolism
JOHN R. MURLIN
FIGURE
1. The smaller respiration apparatus of Pettenkofer and Toit .... 517
2. Diagram of the Jaquet-Grafe respiration apparatus used by Krogh
and Lindhard 520
3. Haldane respiration apparatus 521
4. Respiration apparatus of Regnault and Reiset 522
5. Respiration apparatus of Hoppe-Seyler . 523
6. Diagram of the system of ventilation in the closed circuit apparatus of
Atwater and Benedict 524
7. Diagram of the respiration apparatus used by Benedict and Talbot in
their study of the gaseous metabolism of infants 526
8. Respiration incubator 529
9. Micro-respiration apparatus of Winterstein . . . . . . . . 530
10. Mouthpiece of Denayrouse with nose clip attached 532
11. Pneumatic nosepiece of Benedict 533
12. The half mask as used by Boothby 534
13. Air valve of Loven 534
14. Metal air valve of Thiry 535
15. Tissot spirometer with capacity of 50 liters 536
16. Spirometer of Boothby and Sandiford as used in the writer's
laboratory 537
17. Respiration apparatus of Douglas 538
18. Respiration apparatus of Zuntz and Geppert 539
19. The Haldane air analyser as used by Boothby 540
19-a. Henderson modification of Haldane apparatus 541
20. The air analyser of Krogh 542
21. The Benedict universal respiration apparatus as employed by the
writer 545
22. Portable respiration apparatus of Benedict and Collins 547
23. The bomb calorimeter of Riche for use with Berthelot bomb . . . 569
24. The air calorimeter of Lefevre 572
25. Cross section of chair calorimeter of Benedict and Carpenter . . . 574
26. The Sage calorimeter at Bellevue Hospital 575
27. The wiring diagram of the observer's table with the Sage calorimeter . 576
28. Diagram of the Atwater, Rosa, Benedict respiration calorimeter as
prepared by DuBois for the Sage calorimeter 577
29. The small calorimeter at Cornell University Medical College shown
in process of construction 579
30. Richet siphon calorimeter 5g2
31. The second calorimeter of Rubner ...... 583
32. Curves showing the total heat output per minute and corresponding
external muscular work per minute, expressed in calories, for sub-
ject riding with constant load— 1.5 amperes— at varying speeds . 589
LIST OF ILLUSTRATIONS xi
FIGURE PAGE
33. Existence d'une loi geometrique tres simple de la surface du corps de
Fhomme de dimensions quelconques, demontree par une nouvelle
methode 596
33-a. Chart for determining surface area of man in square meters from
weight in kilograms and height in centimeters according to the
formula • 597
34. Showing the K. Q., the total metabolism determined by indirect and
direct calorimetry as well as the nitrogen elimination during hourly
periods after the ingestion of 1200 grams of meat, by a dog . . . 606
35. Variations of basal metabolism with age 613
36. Gross-section of bed calorimeter with which studies on pregnancy
were made by Carpenter and Murlin 623
37. Metabolism during first year of life 645
38. Body-weight, pulse-rate and basal metabolism per 24 hours of a girl
from 5 months to 41 months of age 649
39. Basal heat production of boys from birth to puberty 650
40. Basal heat production of girls from birth to puberty 651
41. Basal heat production of boys from birth to puberty 651
42. Basal heat production of girls from birth to puberty 652
43. Comparison of basal heat production of boys and girls per 24 hours
referred to body-weight 653
44. Basal heat production of boys from birth to puberty 657
45. Metabolism in calories per day of boys from birth to 15 years of age . 659
SECTION VII
ACTIONS OF DRUGS AND THERAPEUTIC MEASURES
The Effects of Certain Drugs and Poisons Upon the Metabolism
HENRY G. BARBOUR
1. Influence of sodium carbonate ingestion on the glycosuria of a diabetic 738
2. Leg bones in osteogenesis imperfecta 751
3. Same case as Fig. 2 after two years of treatment with 1/150 grain
phosphorus twice daily 752
4. Effects of acetyl salicylic acid on patient with tuberculous abscess . . 769
5. Effect of thyroxin in cretinism 783
Hydrotherapy
HENRY A. MATTILL
1. Total nitrogen and sodium chlorid in tenths of grams, creatinin in
hundredths of grams 865
Metabolism
A History of Metabolism Graham Lusk
Introduction — The Dawn of History — The Classical Period — The Dark Ages
—The Eenaissance — The Chemical Revolution — Science After the French
Revolution — The Beginnings of Calorimetry — The Rise of German
Science — Late French Work — Conclusion.
A History of Metabolism
GRAHAM LUSK
NEW YOBK
Introduction
When one considers the history of the development of the science
of nutrition one is impressed with the gradual growth of knowledge upon
the subject. The ideas concerning it are not the products of the work
of supermen. The ideas were not born as was Minerva, who sprang from
the head of Jove. And yet those who furthered science were men pos-
sessing much information and also a sense of appreciation of values.
"JSTot from a vain or shallow thought
His awful Jove young Phidias brought."
Though vain and shallow men may contribute for weal or woe to
political or social life, they have no influence upon science.
This history has been composed with the dominant viewpoint of pre-
senting the subject in the words of the Old Masters themselves. One
would not desire to see an imitation of the Sistine Chapel could one view
the reality itself.
The Dawn of History
It is interesting to note that Voit (d} attributes the higher cultivation
of the peoples living in the temperate zones to the distribution of food. He
says in this regard:
"The ingestion of food is a fundamental condition of our existence
and is indeed one of the most wonderful arrangements of Providence.
To the blinded eyes of man it often appears as a punishment that by the
sweat of his brow he should eat bread. Hunger is the primary and
most powerful spur to work, and only through work come experience
and progress. If we were provided with sufficient available energy for
life we would ever remain in an undeveloped state. In a country where
nature with outstretched arms offers excess of nourishment which is
obtainable without effort, one will seek in vain for independent, driving
progress. Originally, prehistoric man was nomadic, living temporarily
3
4 GRAHAM LUSK
upon the country where he settled. He tamed wild animals for his ser-
vice. He then drifted into the most fruitful land areas and these he
cultivated. Here came the dawn of history.
"In the tropics the development of man is prevented by an enervating
atmosphere. In the polar regions where the greatest exertion results in
obtaining only a small amount of sustenance progress is also limited.
Eskimo and Lapp live as they did a thousand years ago and have no
history. In temperate climes the production of food is not so favored
as in warmer regions, but the other conditions for the maintenance of
an active life are more favorable and therefore civilization will ever have
her home there."
The Classical Period
The Greeks had no classical education but it has been said that they
had the two essential requisites of true education, the capacity to express
themselves in words and a desire to understand their relations with their
environment, of which the latter is science (Prof. E. II. Starling). Epic-
tetus makes the statement and gives the advice which follows : "Socrates
in this way became perfect, in all things improving himself, attending to
nothing except to reason, but you who are not yet a Socrates ought to live
as one who wishes to be a Socrates." This was the general attitude of the
scholars of Greece and Rome.
Socrates (B. C. 470-399) held that the object of food was to replace
the loss of water from the skin and the loss of ponderable heat.
Hippocrates (B. C. 460-364), the Father of Medicine and a con-
temporary of Socrates, believed that the loss of body weight in fasting
was due to the loss of "insensible perspiration" from the skin and to a
loss of heat which he conceived to consist of a fine material. Among the
writings of Hippocrates may be found the following aphorisms :
Aphorism, Sec. I, 14. — Growing bodies have the most innate heat ; they there-
fore require the most food, for otherwise their bodies are wasted. In old persons
the heat is feeble and therefore they require little fuel as it were to the flame,
for it would be extinguished by much. On this account, also, fevers in old per-
sons are not equally acute, because their bodies are cold.
Aphorism 4, Sec. II. — Neither repletion nor fasting nor anything else is
good when more than natural.
Aphorism 38. — An article of food or drink which is slightly worse but more
palatable is to be preferred to such as are better but less palatable.
The Greeks believed that there were four elements, fire, air, earth
and water, and four elemental properties, hot, cold, moist and dry. The
broad viewpoint of Hippocrates thus finds expression:
Whoever having undertaken to speak and write on medicine have first laid
down for themselves some hypothesis to their argument such as hot or cold or
A HISTOEY OF METABOLISM 5
moist or dry or whatever else they choose (thus reducing their subject within
a narrow compass and supposing only one or two original causes of disease or
of death among mankind) are clearly mistaken in much that they say.
Aristotle (B. C. 384-322) created the conception of a functioning
organism in the following celebrated passage :
The animal organism is to be conceived after the similitude of a well gov-
erned commonwealth. When order is once established in it there is no more
need of a separate monarch to preside over each separate task. The individuals
each play their assigned part as it is ordered, and one thing follows another in
its accustomed order. So in animals there is the same orderliness — nature taking
the place of custom — and each part naturally doing his own work as nature has
composed them. There is no need of a soul in each part, but she resides in a
kind of central governing place in the body and the remaining parts live by
continuity of natural structure and play the parts nature would have them play.
Galen (A. D. 131-200}, a physician from Troy who practiced in
Rome six hundred years after Socrates, was unable to add anything to
the ancient doctrines taught by the Greeks. Galen remarks, "The blood
is like the oil, the heart is like the wick and the breathing lungs an
instrument which conveys external motion."
The Dark Ages
For thirteen hundred years after the time of Galen knowledge of nu-
trition did not advance. The alchemists were at work striving to make
gold from the baser metals and endeavoring to produce infallible medi-
cines. But in the absence of a knowledge of the chemistry of living things
there could be no knowledge of the function of food.
Carl Voit(d), possibly with a slight national bias, thus portrays the
events in the dark ages:
One usually regards this period of the world as intellectually barren, during
which only a blind imitation of the old and senseless scholasticism prevailed.
However, one makes a great mistake to condemn the human race as having
been incapable for a thousand years. We should rather understand why a
rapid development was impossible. The conditions for a continued expan-
sion of scientific knowledge were about as unfavorable as imaginable. The
Age of Antiquity reached the highest standard of cultivation possible from the
knowledge of the time and it needed entirely new ideas in order to move
forward, for the cultivation of mankind is not accomplished like a constantly
growing branch, but rather like one which is stimulated anew after having been
formerly ripe. I doubt whether the ancient Greeks and Romans with their pe-
culiar mental temperament had the power further to extend knowledge. The
Empires in which the old Cultivation had flourished went down, and younger
races reigned in their stead. These rough victors eagerly acquired the intellectual
treasures which the conquered people had accumulated in the days of their glory ;
they regarded themselves as pupils and fell for a time into intellectual dependence
6 GRAHAM LUSK
as they devoutly entered into this great heritage. The education of peoples is
like that of an individual. It is some time after education in the schools has
taught one to think that one is capable of independent action, and usually one
seeks first the wrong way before one finds the right. Even so, the change from
the olden to the modern could take place only after prolonged struggle. The
spirit was gradually sharpened but there were not enough new facts to create
new ideas. Satisfaction was sought in acute dialectics. This was only an indi-
cation that the old methods brought no one forward. Finally, the tremendous
events which took place in the fifteenth century changed dutiful scholars into
critics and independent investigators who, through the revelation of heretofore
unknown methods of the mind, were able to open up new pathways.
The Renaissance
The universities of Cambridge (founded in 1229) and Oxford
(founded in 1249) were established at a time when authority was wor-
shiped. After the revival of learning in Italy the original versions of
the ancient classics were brought into France and England and the for-
gotten culture of a bygone civilization was revived.
The Greek idea of medicine persisted after two thousand years and
Chaucer (1340-1400) portrays the physician as follows:
"He knew the cause of every malady,
Were it of cold or hot or moist or dry,
And where engendered and of what humour,
He was a very perfect practisour."
No adequate conception of the nature of nutrition was possible with-
out an understanding of the nature of air. The idea that air was an ele-
mentary substance persisted until comparatively recent times. The grop-
ing of human inquiry into the analysis of the invisible atmosphere con-
stitutes a fascinating chapter.
Leonardo da Vinci (1452-1519), accounted one of the greatest paint-
ers of the Renaissance and who was at the same time mathematician,
physicist and naturalist, said at the end of the fifteenth century that no
animal, whether of the land or of the air, could live in an atmosphere
which could not support a flame (Milne-Edwards I, 377). The broad
mind of Leonardo with won'derful intuition interprets life as follows :
Hast thou marked Nature's diligence? The body of everything that takes
nourishment constantly dies and is constantly reborn ; because nourishment can
only enter, into places where that past nourishment has expired, and if it has
expired it has no more life; and if you do not supply nourishment equal to the
nourishment departed life will fail in vigor; and if you take away this nourish-
ment life is utterly destroyed. But if you restore as much as is consumed day
by day, just so much of life is reborn as is consumed; as the flame of the candle
is fed by the nourishment given by the liquor of the candle, which flame con-
tinually with rapid succor restores from below what above is consumed in
dying; and from a brilliant light is converted into dark smoke; which death
is continuous as the smoke is continuous; and the continuance of the smoke
equals the continued nutriment; and at the same moment all the flame is dead
and regenerated with the movement of its nutriment.
Paracelsus (1493-1591) recognized the analogy between the produc-
tion of heat without flame, both in the body and chemically outside the
body, as had Aristotle and Galen
before him. He imagined the
existence of a spirit, the
Archceus, which lived in the
stomach and which there di-
vided the foods into the good
and the bad, the former being
used by the body and the latter
being eliminated in the excreta
as evil and poisonous.
Sanctorius (1561-1636), a
professor of Padua, published
in 1614 his celebrated "De medi-
cina statica aphorismi," which
was printed in Venice. Sanc-
torius kept careful account of
his body weight, noted also the
weight of foocj and drink taken
and of urine and excrement
passed. He was thus able to
discover that the major evacua-
tion from the body was the
"insensible perspiration." He
determined the considerable loss
in body weight during periods
in which no urine or feces were
passed from the body. Section
III of the Aphorisms treats "of
Meats and Drink" and contains
the following quaint allusions,
as rendered in a translation by John Quincy, published in London in
1712 and printed for William JSTewton in Little Britain.
LXXV. "The Physician who has the Care of the Health of Princes and
and knows not what they daily perspire, deceives them and will never be able
to cure them except by Accident."
LXXVI. "In the first four Hours after Eating a great many perspire a
Pound or near ; and after that to the ninth two Pound ; and from the ninth to
the sixteenth scarce a Pound."
Fig. 1. Frontispiece of "De medicina statica
aphorismi," showing Sanctorius seated on a
chair suspended from a large steelyard.
8 GRAHAM LUSK
VIII. "Mutton easily digests and perspires; or it will waste in a night a
third part of a Pound more than any other usual Food."
XXIII. "Pork and Mushrooms are bad both because they do not Perspire
themselves and because they hinder the Perspiration of other things eat along
with them."
LIX. "If a Supper of eight Pounds corrupts' in the Stomach, the next Day
the Body will be lighter than after a Supper of three Pound which does not do
so."
These aphorisms summarized signify that a well appreciated meat,
such as mutton, increases the perspiration, whereas pork, which very
likely then as now was an unpopular food in Italy, causes "corruption"
and diarrhea and hence no increase in perspiration.
This kind of investigation was continued by Dodart (died 1707) in
France, who devoted thirty-three years of exhaustive labor to the subject.
Then followed the first discovery of carbonic acid gas by Van Hel-
mont in the seventeenth century.
Van Helmont (1577-1644), a member of the ancient princely family
of the Counts of Merode of Belgium, was one who consecrated his life
to his laboratory. He discovered that when charcoal burned or wine
fermented a gas was produced which was as invisible as respired air;
that it is sometimes emitted from the bowels of the earth in mines or
at the Grotto del Carno (near Naples — so called because if a man
enters it accompanied by a dog, the man lives but the dog dies, since
carbon dioxid gas evolved is heavier than air and remains near the
ground) ; that it is present in the waters of Spa and is evolved when
vinegar is poured on chalk. This gaz sylvestre ("wood gas") does not
maintain a flame nor life of animals. It promptly results in their
asphyxiation and death.
Jean Rey, born about the end of the sixteenth century, died 1645, a
physician of Perigord, found in 1630 that tin and lead increased in
weight when calcined, but the significance of these facts was neglected
in the subsequent enthusiasm over phlogiston. Key's work, "Essays sur
la recherche de la cause pour laquelle 1'estain et le plomb augmentent de
poids quand on les calcine," 1630, was reprinted after Lavoisier's dis-
coveries in 1777.
Nicholas Lefevre (died 1674), in his "Traite de Chimie," published
about 1660, says, "In the act of respiration the air does not confine
itself to refreshing the lungs, but by means of the 'universal spirit' it
reacts upon the blood, refining it and volatilizing all its superfluities."
A hundred years later Haller had about the same viewpoint. Lefevre
was one of the founders of the Academie des Sciences and was physician-
in-chief to Louis XIV.
Robert Boyle (1621-1679) in 1660 showed tbat the flame of a candle
or the life of an animal was extinguished after placing them in an air
pump. Between 1668 and 1678 he made numerous experiments with
A HISTORY OF METABOLISM 9
many animals of different species with a view of isolating that part of
the air which was "eminently respirable." Thus he suggests in a sub-
division entitled "Of Air in Reference to Fire and Flame" in his work
on "The General History of the Air" (1680) the following experiments:
The burning of candles under a glass bell.
Tjie burning of spirits of wine under a glass bell.
The keeping of animals in the same instrument whilst the flame is
burning.
In the "Sceptical Chemist," which appeared in 1661, Boyle thus
voices his opinions:
Now a man need not be very conversant in the writings of chemists to ob-
serve in how lax, indefinite and almost arbitrary senses they employ the terms
salt, sulphur and mercury. . . .
But I will not here enlarge upon this subject nor yet will I trouble you
with what I have largely discoursed in the "Sceptical Chemist," to call in ques-
tion the grounds on which chemists assert that all mixed bodies are compounded
of salt, sulphur and mercury.
Boyle lived in the period of the birth of national scientific societies.
The Academie des Sciences was founded in Paris by Louis XIV, who,
after the peace of the Pyrenees in the fullness of his power, felt that his
kingdom needed nothing further than to be fortified by science, industry
and art, and he instructed his minister Colbert to carry out his desires.
The members were given stipends from the state. This was the first
example of state endowment of science. About the same time the Royal
Society of London was established in England, which was the outgrowth
of a gathering of men at first held surreptitiously. This older organiza-
tion, of which Boyle was a member, is still perpetuated as the Royal
Society Club.
Among those influenced by Boyle was one John Mayow.
John Mayow (1640-1679), "descended from a genteel family of his
name living at Bree in Cornwall, was born in the parish of St. Dunstan-
in-the-West, in Fleet Street, London, admitted as a scholar of Wadham
College the 23rd of September, 1659, aged sixteen years," (Beddoes). His
scientific work was accomplished at All Soul's, Oxford. Some of his ex-
periments may be thus recounted :
Camphor placed in a capacious glass vessel inverted over water is
ignited by a burning glass. After cooling, the air is reduced one-thirtieth
in bulk. A second piece of camphor will not burn, "a clear proof that
the combustion has deprived the air of its fire-air particles so as to
have rendered it altogether unfit to support flame."
A mouse was put into a wire trap and this was placed on a three-
legged stool which stood in water and the whoje was covered with a bell
jar. The volume of the air diminished one-fourteenth.
10 GRAHAM LUSK
If a burning candle and an animal be put together in a bell jar
both will go out sooner than one alone because flame is extinguished and
an animal expires for want of nitro-aerial particles.
"Air loses somewhat of its elastic force during its respiration by ani-
mals, as also in combustion. One must believe that animals, like fire, re-
move from air particles of the same nature."
And in another place he writes, "Breathing brings the air into contact
with the blood to which it gives up its nitro-aerial constituent. Again
the motion (of the muscles) results from the chemical action in the
muscle with the combustible matter contained therein."
Niter contains the nitro-aerial particles and hence gunpowder burns
without air. Many authors have written "as if it had been ordained
that niter should make as much noise in philosophy as in war, yet its
properties are still concealed from our knowledge."
Calcined antimony mixed with niter, when acted on by heat from a
burning glass, increases in weight through addition of nitro-aerial par-
ticles.
As to Mayow's death, at the age of thirty-nine it was written :
"He paid his last debt to nature in an apothecary's house bearing
the sign of the Anchor in York Street near Covent-Garden, within the
liberty of Westminster (having been married a little before not alto-
gether to his content), in the month of September, 1679, and was buried
in the Church of St. Paul, Covent-Garden."
Beddoes, his biographer, writes: "Mayow . . . silently and unper-
ceived in the obscurity of the last century discovered if not the whole
sum and substance, yet certainly many of those splendid truths which
adorn the writings of Priestley, Scheele, Lavoisier, Crawford, Goodwyn
and other philosophers of this day."
"Should I ask you who of all your acquaintance is the person least
likely to be overtaken by surprise you would, I think, name a certain
Northern Professor. . . . Yet at the sight of the annexed representation
of Mayow's pneumatic apparatus, this sedate philosopher lifted up his
hands in compleat astonishment." ^
The "sedate philosopher" was undoubtedly Black. Writing in 1790,
however, Beddoes cannot escape from the absurd statement, "He (Mayow)
has clearly presented the notion of phlogiston which rendered the name
of Stahl so celebrated."
Mayow's "Treatise on Respiration" was published in his twenty-eighth
year. Newton invented the calculus when twenty years old ; Black found
"fixed air" at twenty-four; R. Mayer formulated the Law of the Con-
servation of Energy at twenty-six.
Mayer's paper containing the last-named doctrine was refused pub-
lication in Liebig's Annalen! These facts should afford a stimulus to
the young and food for the thought of the more mature.
A HISTORY OF METABOLISM 11
Willis (1621-1675), a contemporary of Boyle, and his pupil Lower,
a colleague of Mayow at Oxford, demonstrated the reddening of blood
by the respiration by admitting and excluding air from an animal.
Stephen Hales (1677-1761) was a parish priest described by Horace
Walpole as "a poor, good, primitive creature." And yet this apparently
unimportant man writes in his "Statical Essays," published in 1727,
"A part of the inspired air is lost in the blood, but it is as yet entirely
dark what its use may be."
Boerhaave (1668-1738), when he published his great work, the
"Elements of Chemistry," in 1724, is believed to have had the work of
Mayow in mind when he wrote: "Who can say whether an air of spe-
cial virtue for the maintenance of the lives of animals and plants does
not exist; whether it may not become exhausted; whether its consump-
tion is not the cause of the death of animals who can no longer possess
it ? Many chemists have announced the existence of a vital element in
the air, but they have never told what it is or how it acts. Happy the
man who discovers it!"
Stahl (1660-1734), the German chemist who in 1716 moved to Berlin
as physician to the King of Prussia, was the originator of the phlogiston
theory of combustion which enthralled the minds of men for nearly a
hundred years. According to this theory all combustible substances con-
tained phlogiston which passed from them when they were burned. What
we now know as oxids of iron or lead 'were those metals which through
burning had lost their phlogiston. Such substances, if calcined with
carbon, a material supposed to be rich in phlogiston, absorbed phlogiston
and became metals once more. This simple theory availed to explain all
the phenomena of combustion and was generally accepted by the scientific
world.
When one halts to consider the general knowledge of nutrition in
the middle of the eighteenth century one finds little to distinguish be-
tween the statements of Sanctorius, 150 years earlier, and Benjamin
Franklin. Sanctorius writes, "Meats which promote Perspiration bring
Joy, but those which obstruct it Sorrow"; and Franklin in 1742, "If
thou art dull and heavy after Meat it is a sign that thou hast exceeded
due measure; for Meat and Drink ought to refresh the Body and make
it cheerful and not to dull or oppress it."
The general opinion of high authorities in the eighteenth century was
voiced by Haller.
Albrecht von Haller (1708-1777), the great physiologist, published
his "Elementa Physiologica" between 1757 and 1765. He asserts "that
fire is contained in the blood is proved by its heat," and he has this
rather hazy conception of the process of respiration: "The secondary
uses of respiration are very numerous. It exhales copiously and removes
from the blood something highly noxious; for by remaining in the air
12 GRAHAM LUSK
it will cause suffocation; and the breath of many people crowded in a
close and small place impregnates the air with a suffocating quality. On
the other hand, it absorbs from the air a thin vapor, of which the use
is not sufficiently known."
And Benjamin Franklin in "Poor Richard," 1746, thus poetically
popularizes the ideas of his time:
"Like cats in air pumps to subsist we strive,
On joys too thin to keep the soul alive."
The dawn of the modern era has been reached, but there is little
to indicate the impending clarification of thought. Before considering
the events which led to the Chemical Revolution one must stop to learn
of a case of self-inflicted human scurvy.
William Stark, M.D. (1740-1770).— The work of Stark was edited
after his death by J. C. Smyth.
In the editor's preface one reads, "His experiments on diet are
the first and will probably long remain the only experiments of the
kind."
It is stated that he began his experiments on diet in 1769, greatly
encouraged by Dr. Franklin, "from whom he received many hints."
Stark thus describes himself: "The person upon whom these ex-
periments are tried is a healthy man about twenty-nine years of age, six
feet high, stoutly made but not corpulent, of a florid complexion, with
red hair."
He reached the following general conclusions: "A very spare and
simple diet has commonly been recommended as most conducive to health,
but it would be more beneficial to mankind if we could shew them that a
pleasant and varied diet was equally consistent with health as the very
strict regimen of Cornaro or the Miller of Essex. These and other ab-
stemious people, who having experienced the great extremities of bad
health, were driven to temperance as their last resource, may run out in
praises of a simple diet, but the probability is that nothing but the dread
of former sufferings could have given them resolution to persevere in so
strict a course of abstinence."
He gives the following reasons for undertaking the investigation:
"Dr. B. Franklin of Philadelphia informed me that he himself when a
journeyman printer lived a fortnight on bread and water at the rate of
ten pounds of bread per week and found himself stout and hearty on
this diet." . . .
"I learned from Dr. Mackenzie that many of the poor people near
Inverness never took any kind of animal food, not even eggs, cheese,
butter or milk."
Mr. Hfewson told him that a ship's crew, having consumed the pro-
visions, lived one part on tobacco, the other part on sugar. The latter
A HISTORY OF METABOLISM 13
generally died of scurvy, while the former remained free from the disease
or soon recovered.
Dr. Cirelli informed him that Neapolitan physicians frequently gave
for periods of forty days no food to patients suffering from fever.
Mr. Slingsby has lived many years on bread, milk and vegetables with-
out animal food or wine and has been free from gout ever since he began
this -regimen.
Stark's experiments of taking bread and water alone may thus be sum-
marized :
Daily diet
oz.
Body weight
at start Period
Ibs.
Period
u
tt
I
II
III
IV
Bread,
Bread,
Bread,
Bread,
20
30
30
38
171
163
161
158
160
2
3
5
1
(at
end)
weeks.
u
days
week
"During the third period I was one day irregular, having ate about
four ounces of meat and drank two or three glasses of wine. At the con-
clusion of it I was perfectly hearty, my head clear, often hungry."
After this, from July 26 to August 24, he took a diet of bread, water
and sugar. On August 11, "I. now perceived small ulcers on the inside
of my cheeks, particularly near a bad tooth; the gums of the upper jaw
of the same side were swelled and red and bled when pressed with the
finger; the right nostril was also internally red or purple and very
painful."
On August 13, having been extremely ill, he took a few ounces of
meat and two or three glasses of wine with his bread. This caused
marked improvement in his condition. On August 22 he dined heartily
on meat and fruit and drank some wine.
From August 24 to September 13, a diet of bread, water and olive
oil. On September 8 he was so weak that he almost fainted when walking
across the floor. The gums were swollen and he "spat in considerable
quantity a very disagreeable, fetid, yellowish fluid." On September 9
he took "a basin of mutton broth" and thereafter lived freely on animal
food, milk and wine until September 18, when "I felt myself quite re-
covered."
On September 18 to October 2, a diet of bread, water and milk. Upon
this diet the gums improved and the offensive smell disappeared.
From October 2 to October 14 the diet consisted of bread, water and
roast goose. He became "hearty and vigorous, both in mind and body."
14 GRAHAM LUSK
October 14 to 19 lived freely on animal food.
October 21 to 28, bread, water and boiled beef. "Never the least
heavy or dull, . . . but had a keenness for study."
October 28 to November 1, diet of bread, water and sugar. The gums
were not affected by the sugar.
November 17 to 20, lean beef, 20 oz. Upon this diet he felt hungry.
November 21 to 25, lean beef, 20 oz., and suet, 7 oz. "I slept longer
and more quietly than formerly and was more disposed to be drowsy
than when I lived on meat alone."
November 26 to December 8, flour, 20 oz. ; suet, 4 to 6 oz. This diet
was arranged in order to compare its value with that of meat. It was
taken in the form of a pudding. He notes an extraordinary gain in
body weight of 8 Ibs., in five days after changing the dietary from meat
to flour, (vide later experiments of Voit, p. 70).
December 9 to 13, flour, 24 oz. Upon this diet he became extremely
hungry.
He finds that flour and beef suet disagree with him, tries to substitute
butter fat for beef suet, but does not return to a normal appetite until
he has enjoyed eating two pounds of figs. In another experiment he has
indigestion after taking for four days puddings made of flour and butter. •
February 4 to 15. Bread and flour with honey. Scorbutic symp-
toms developed on February 12. Honey pudding had a remarkable diu-
retic effect and provoked diarrhea.
On February 15 he was feeble and took an infusion of rosemary.
February 16 and 17. Diet — bread with Cheshire cheese to check the
diarrhea, which it did.
February 18 he omits cheese but continues with the infusion of rose-
mary. His mouth is sore, there are pimples at the corner of his mouth
and many large ones on his body.
This closes his diary.
On February 18 he was bled, but died on February 23, 1770, evi-
dently of acute intestinal infection, the victim of his scientific curiosity.
John Hunter made a report of the findings at the autopsy.
The Chemical Revolution
Out of the misty conclusions of the middle of the eighteenth century
before its close modern chemistry developed. The work of Mayow was
forgotten in the enthusiasm over the phlogiston doctrine of Stahl. The
pioneer discoverer was again an Englishman, Joseph Black. It is quite
probable that had Mayow known of Black's "fixed air" he might have
solved the problem of respiration. And also had Black known of the
existence of Mayow's experiments without having learned of them to his
A HISTORY OF METABOLISM 15
"compleat astonishment", he too might have had the honor reserved for
Lavoisier.
Black (1728-1799) in 1754 published a Latin essay which, in its
English form, is entitled "Experiments on Magnesia Alba, Quicklime
and other Alkaline Substances." In this Black describes the discovery
of "fixed air" or carbonic acid. Black writes of himself as follows :
In the early days of my chymical studies the author whose works made the
most agreeable impression on my mind was Markgraaf (1709-1782) of Berlin; he
contrived and executed his experiments with so much chymical skill that they
were uncommonly instructive and satisfactory; and he described them with so
much modesty and simplicity, avoiding entirely the parade of erudition and
self-importance, with which many other authors encumber their works, that I
was quite charmed with Markgraaf and said to Dr. Cullen that I would rather
be the author of Markgraaf s Essays than of all the chymical works in the library.
The celebrated Reaumur's method of writing appeared to me also uncommonly
pleasing. After three years spent with Dr. Cullen I came to Edinburgh to finish
my education in medicine. Here I attended the lectures of Dr. Monroe, senior,
and the other medical professors until the summer of 1754 when I received the
degree of Doctor of Medicine and printed my inaugural dissertation, "De Humore
Acido a Cibis Orto, et Magnesia Alba."
Black finds that the carbonates yield "fixed air" on ignition and that
caustic alkalis absorb the same air. Magnesia alba loses half its weight
when heated and gives off "fixed air" when treated with acids. Lime
water does not combine with ordinary air but does combine with "fixed
air." Black describes the new found kind of air as one "which is dis-
persed through the atmosphere either in the state of a very subtle powder,
or more probably in that of an elastic fluid. To this I have given the
name of fixed air, and perhaps very improperly; but I thought it better
to use a word already familiar in philosophy than to invent a new name,
before we are more fully acquainted with the nature and properties of
this substance."
This was the pioneer discovery in the field long known as pneumatic
chemistry. "Fixed air" was produced in fermentation, in the combus-
tion of carbon, and was eliminated in the respiration. The next gas to
be discovered was hydrogen.
Cavendish (1731-1810) was a nephew of the third Duke of Devon-
shire. He was a man of wealth and of extremely eccentric character. It
was he who discovered hydrogen in 1766 and gave it the name of "in-
flammable air." He considered hydrogen to be phlogiston. Later, in
1781, he found that when two volumes of "inflammable air" and one
volume of Priestley's "dephlpgisticated air" (oxygen) were united by an
electric spark the airs disappeared and water resulted. Cavendish con-
cluded that dephlogisticated air was water deprived of its phlogiston.
The French have always claimed that Lavoisier was the first to dis-
16
GRAHAM LUSK
cover the composition of water. A discussion of the Water Controversy
is given by Thorpe.
Daniel Rutherford (1749-1819) was a pupil of Black's and the uncle
of Sir Walter Scott. Rutherford in 1772 described "a residual air," or
nitrogen gas, as it is now called. He found that wh^p a candle burned
in an inclosed place until it went out and the "fixed air" was then ab-
sorbed by alkali, there remained a large volume of air which extinguished
life and flame in an instant.
Priestley (1733-1804) in
1771, a year before Ruther-
ford's discovery of nitrogen,
introduced a growing sprig of
mint into an atmosphere in
which a candle had burned out
and after a lapse of several days
found that another candle
burned in it perfectly. Evi-
dently the burning candle filled
the space with phlogiston; the
growing plant absorbed the phlo-
giston and produced "dephlo-
gisticated air." This could again
receive phlogiston when the
second candle burned.
Shortly after this discovery
(1774) Priestley submitted red
oxid of mercury to the heat of
a burning glass and found that
an air was evolved in which a
candle burned very vigorously.
Priestley assumed that this air was pure dephlogisticated air, while com-
mon air was only partly dephlogisticated.
And Priestley writes, "My reader will not wonder that, after having
ascertained the superior goodness of dephlogisticated air by mice living
in it and the other tests above mentioned, I should have the curiosity to
taste it myself. I have gratified that curiosity by breathing it, drawing
it through a glass siphon, and by this means I reduced a large jar full
of it to the standard of common air. The feeling of it to my lungs was
not sensibly different from that of common air; but I fancied that my
breath felt peculiarly light and easy for some time afterward. Who
can tell but that in time this pure air may become a fashionable article
in luxury? Hitherto only two mice and myself have had the privilege
of breathing it."
Priestley explained the presence of Black's "fixed air" in the ex-
Fig. 2. Priestley. From an engraving of
a portrait by Gilbert Stuart.
17
pired air thus : "It will follow that in the precipitation of lime by breath-
ing into lime water the fixed air which incorporates with lime comes not
from the lungs but from the common air, decomposed by the phlogiston
exhaled from them." And Priestley, who was one of the discoverers of
oxygen, was gathered to his fathers at Northumberland, Pennsylvania, in
1804, still believing the phlogiston theory of combustion.
Crawford (1748-1795) was the first individual to publish experiments
on animal calorimetry. In 1777 he found, after burning wax and carbon
or on leaving a live guinea-pig in his water calorimeter, that for every
100 oz. of oxygen used the water was raised the following number of
degrees Fahrenheit:
Wax 2.1
Carbon 1.93
Guinea-pig 1.73
Crawford states, "Animal heat seems to depend upon a process similar
to a chemical elective attraction." However, the theory of phlogiston
renders Crawford's work quite unintelligible and in the second edition
of his "Experiments and Observations — Animal Heat," published in 1788,
one still finds statements like this, "Now it has been proved that when
an animal is surrounded by a medium at a low temperature it phlogisti-
cates a greater quantity of air in a given time than when it is surrounded
by a warm medium."
Scheele (1742-1786). — Independent of Priestley and before him,
Scheele, a Swedish apothecary and eminent chemist, discovered oxygen
by decomposing dioxid of manganese and other substances. Scheele be-
lieved that the atmosphere was composed of "spoiled air" and "fire air."
When a body burned in air it lost its phlogiston, which united with "fire
air." Heat consisted of "fire air" united with phlogiston. It passed
through glass. In this way a portion of air could pass through glass,
In 1771 Scheele (Scheele, 1793) had found that when silver carbonate
was heated in a retort "fixed air" was liberated as well as "fire air,"
while a residue of metallic silver remained. In 1775 he placed silver
carbonate in a small retort connected with a collapsed bladder and then
heated the substance. Two airs were evolved, "fixed air" which he re-
moved with lime water, and "fire air" in which a flame burned brightly.
In the interim between these two experiments he wrote Lavoisier in
Paris a letter dated September 30, 1774, asking him to use his powerful
burning glass upon silver carbonate, then to absorb the "fixed air" in
lime water and observe whether a candle would burn and an animal live
in the remaining air, and he begged Lavoisier to inform him of the
results.
Scheele performed another striking experiment (Scheele, 1777). He
placed two large bees together with a little honey in a small upper chamber
18
<;KAIIAM LUSK
of a glass apparatus which he had devised. This upper chamber was in
communication with a glass cylinder. The glass cylinder he filled with
"fire air" and immersed its lower end in lime water. The volume of the
air within the receptacle diminished day by day and the lime water which
absorbed the carbonic acid rose in the tube. After eight days the bees
were both dead and the lime water almost completely filled the space.
It is evident that Scheele had intro-
duced bees into pure or nearly pure oxygen
gas and that the carbon dioxid which they
produced had been completely absorbed by
the lime water.
Scheele made no direct comment upon
this truly beautiful experiment but in the
general criticism of several experiments
one may read the following hazy general-
ization :
Why do not the blood and lungs change
"fire air" into "acid air"? I take the liberty
to express my opinion concerning this, for
what would such exacting experiments profit
unless through them I had the hope to more
nearly approach my ultimate aim, the truth.
Phlogiston, which combines with most sub-
stances causing them to become more fluid,
Fig. 3. Scheele's apparatus
showing bees in the upper chamber
of a glass apparatus filled with
oxygen.
more mobile and more elastic, must have the same influence upon the blood.
The blood corpuscles must absorb it from the air through delicate openings in
the lungs. Through this combination they are expanded and in consequence
become more fluid. In some part of the circulation they must give off this
absorbed phlogiston and consequently be able to again absorb this fine principle
when they next reach the lungs. Whither the phlogiston goes during the circu-
lation I will leave to others to find out. The affinity of blood for phlogiston
cannot be as great as in the instance of plants and insects which take it from
the air and also the blood cannot convert it into "acid air," but it is changed
into a kind of air which is midway between "fire air" and "acid air"; it is
"spoiled air." For it does not unite with lime water or water as does "fire air,"
though it extinguishes fire as does "acid air."
Scheele's "spoiled air" was nitrogen. The poor struggling apothecary
who had made so many careful and accurate experiments and who was
one of the greatest chemists of his time, was unable to interpret his results
without adherence to the dominant fetish of phlogiston.
We have here the picture of two earnest men, Priestley and Scheele,
both absorbingly interested in chemistry, both contributing important
knowledge and ranking among the greatest scientists of their day, and
yet neither had the philosophical acumen to understand the meaning of
his experiments. Priestley was a Dissenting clergyman, earning his living
by preaching, but in his old age his house was burned by Loyalists and he
A HISTORY OF METABOLISM 19
shortly afterward fled to America. Sclieele, though honored by scientific
men the world over, remained a poor apothecary to the end of his days.
In the current parlance of to-day these two great contributors to human
knowledge would undoubtedly have been known outside their own circles
as "narrow-minded scientists."
This, however, could never have been said of Lavoisier, who repeated
and extended their experiments, overthrew the phlogiston theory and
established modern chemistry.
Lavoisier (1743-1794). — The family of Antoine Laurent Lavoisier
traced its ancestry back seven generations to Antoine Lavoisier, who was a
post-boy* in the stables of the king and who died in 1620. Successive
generations raised the position of the family name to ever higher levels
until it was said of the great Lavoisier that it would require perhaps a
hundred years for the appearance of his equal. Native intelligence, a
fine education, great wealth, combined with the environment of the
searchingly critical atmosphere of the Paris of his day, allowed of the
vivid inspiration which filled his life.
Lavoisier was elected a member of the Academie des Sciences in 1768
at the age of twenty-four. About the same time, desirous of promoting
his personal fortune, he became associated with la ferme generale, through
whose activities the taxes were collected in France. Some of his fellow
academicians looked askance at this undertaking, but the mathematician
Fontaine is reported to have remarked, "Never mind, he will be able to
give us better dinners." (Grimaux, (Ar) 1896.)
In the ferme generale the young man was the subordinate of one
Paulze, a nephew of the then all-powerful Terr ay, Minister of State and
Controller of Finance. At the age of twenty-eight Lavoisier married the
fourteen-year-old daughter of Paulze, His own position and his marriage
brought him great wealth but in no way diminished his tireless activity.
He congratulated himself that his patronage of the instrument makers
of Paris had rendered France independent of Great Britain in the manu-
facture of scientific instruments.
Lavoisier's first paper before the Academie was "On the Nature of
Water and on Those Experiments Which Pretend to Prove Its Trans-
formation Into Earth." In this experiment he placed rain water in a
flask and boiled it for 101 days. Mineral matter appeared in the flask
but the whole did not change in weight and the mineral material which
appeared was shown to be derived from the disintegration of the flask
itself, which lost in weight. Lavoisier used an extremely sensitive (ires
exade) balance, made by the official who was charged with the weighing
of gold.
Here we witness the overthrow of a dogma more than two thousand
years old, accomplished by the introduction of the quantitative method into
20
GRAHAM LFSK
chemistry. One may recall the words of Lavoisier written in his "Ele-
ments of Chemistry" (Robert Kerr, (w) 1799) :
As the usefulness and accuracy of chemistry depend entirely upon the de-
termination of the weights of the ingredients and products both before and after
experiments, too much precision cannot be employed in this part of the subject
and for this purpose we must be provided with good instruments. ... I have
three sets (of balances) of different sizes made by M. Fontin with the utmost
nicety ; and excepting those made by Mr. Kamsden of London I do not think that
any compare with them in precision and sensibility.
Lavoisier had a bal-
ance which could weigh
600 gin. within five mg.
and another which was
sensitive to within a
tenth of a milligram,
which were quite up to
modern standards of ac-
curacy. One may visit
the Conservatoire des
Arts et Metiers in Paris
and see there -a notable
collection of Lavoisier's
apparatus. One sees a
gasometer for the accu-
rate measurement of
gases; there is the cele-
brated ice calorimeter of
Lavoisier and La Place ;
there also afe barom-
eters of finest workman-
ship, set in mahogany
supports decorafed with
gilded Slagree work, re-
minding one of the
choicest furniture.
These treasures were
placed in the cellar of the Conservatoire during the bombardment of Paris
by the Germans in the late war.
Concerning the gasometers, Lavoisier wrote (Lavoisier, (m) 1799) :
It becomes expensive because in many experiments, such as the formation
of water and of nitric acid, it is absolutely necessary to employ two of the same
machines. In the present advanced state of chemistry very expensive and com-
plicated instruments are become indispensably necessary for ascertaining the
analysis and synthesis of bodies with the requisite precision as to quantity and
proportion.
Fig. 4. Lavoisier and his wife.
of a portrait by David.
From an engraving
21
It is strange that Lavoisier's insistence upon the use of accurate,
quantitative measurements through the application of which nearly a
hundred and fifty years ago he brought about the "Chemical Kevolution,"
should appear as new truth when enunciated by some of our ultra modern
scientists.
In the heart of France near Puy-du-Dom, at Chateau de la Carriere,
now owned by Monsieur de Chazelles, there is a veritable museum of
scientific apparatus which formerly belonged to Lavoisier (Truchot, (s)
1879). There are several thermometers of great accuracy and a fine
Fig. 5. The burning glass of Trudaine. From "CEuvres de Lavoisier," Vol. Ill,
PI. IX.
balance, and there are 'three large glass globes, one capable of holding 15
liters of air, another 12 liters and a third 7 liters; also many another
treasure of great historic value. Lavoisier made his experiments before
the days when rubber and cork reduced laboratory expenses. His glass
tubes and receptacles were united with finely polished brass joints.
We may imagine this accomplished Frenchman at work in his labora-
tory, or his library, or receiving information from visitors to the fashion-
able and brilliant capital of France. It is related (Thorpe, (r) 1908) that
Priestley dined with Lavoisier in Paris in October, 1774, and informed
him concerning the production of "pure dephlogisticated air" from oxid
of mercury, and we may also recall that Scheele, on September 30 of the
same year, wrote to Lavoisier, asking him to expose silver carbonate to
22 GRAHAM LUSK
the heat rays of a large burning glass and produce ''fixed air" and "fire air"
from them. Ten days after his conversation with Priestley, and again
during the month of the following March, Lavoisier went to Montigny to
visit his friend Trudaine, who was the owner of an immense burning
glass 42 ins. in diameter, which had cost 15,000 livres (about $3,000),
and he here repeated Priestley's experiments. In the paper read before
the Academic des Sciences at Easter, 1775, Lavoisier (a) stated that he
took the red mercury calx and heated it with carbon and obtained "fixed
air," and when he heated the same without carbon a gas was evolved in
which a flame burned with the splendor of phosphorus in air, and that this
gas was the "air eminently respirable." The loss in weight of the mercury
calx was equal to the weight of the "air eminently respirable" given off.
He concluded that "fixed air" was the result of the union of carbon with
"air eminently respirable." In a subsequent paper he reported that it was
this "air eminently respirable" which was absorbed by phosphorus and
sulphur when they burn with the production of phosphoric and sulphuric
acids (6).
Having discovered these facts, Lavoisier (c) proceeded to determine the
effect of a sparrow upon the content of air in a confined space. In a
brief memoir published in 1777 he enunciated the principles that during
respiration it was only "air eminently respirable" (oxygen) which dis-
appeared from the atmosphere when an animal was put into a confined
space and that this air was supplanted by expired "aeriform calcic acid"
(carbon dioxid) ; that when metals were calcined in air oxygen was
absorbed until its supply was exhausted; that if after an animal had
perished in a confined space and the carbon dioxid in the atmosphere was
absorbed by alkali the "foul air" remaining was the same kind of air as
that found after metals had been calcined in air in an Inclosed space.
All the former qualities of this air could be restored by adding to it "air
eminently respirable."
Three years later Lavoisier and La Place made another step in ad-
vance. (Lavoisier and La Place, (n) 1780.) They noticed that a guinea-
pig produced 224 grains of carbonic acid in ten hours, and that what would
now be called the respiratory quotient was 0.84. Then they put another
guinea-pig in their recently constructed ice calorimeter and found that
the heat given off by the animal melted 13 oz. of ice in a period of 10
hours. Next they calculated that if carbon was oxidized so that 224
grains of carbonic acid were produced, 10.4 oz. of ice would have been
melted. They realized that in the case of the guinea-pig allowances would
have to be made (1) because the legs of the animal became chilled during
the experiment; (2) because the water of respiration was added to that of
the melted ice; and (3) because the influence of cold increased the heat
production of the animal. But tney nevertheless stated that "Since we
have found in the preceding experiments that the two qualities of heat
A HISTOEY OF METABOLISM 23
obtained are nearly the same, we can conclude directly and without
hypothesis that the conservation of animal heat in the animal body is due,
at least in greater part, to the transformation of 'air pur' (oxygen) into
'air fixe' (carbonic acid) during the process of respiration." Here
be it noted that Lavoisier refers to the conservation of animal heat more
than fifty years before the general law of the conservation of energy was
enunciated. He also observed that two sparrows produced about the
same quantity of carbonic acid in the unit of time as did a guinea-pig.
About a year after these experiments (1781) Cavendish in England
found that when "inflammable air" (or hydrogen) and Priestley's "de-
phlogisticated air" were united by an electric spark the airs disappeared
and water resulted.
• It is said that Lavoisier, hearing of these experiments from Blagden,
secretary of the Royal Society of London, repeated them. But the im-
portant point is that Lavoisier (d) was the first really to understand the
phenomenon. In a memoir presented to the Academic des Sciences in
1783 he stated that water is merely a combination of "inflammable air"
and oxygen and that any heat or light produced by their union is
imponderable.
In the same year Lavoisier (e) completely demolished the phlogiston
hypothesis and concluded his memoir "Reflections upon Phlogiston" with
these words :
My object in preparing this memoir has been to record the new developments
of the theory of combustion which I published in 1777, to show that the phlogiston
of Stahl, which he gratuitously supposed existed in metals, sulphur, phosphorus
and all combustible substances, is an imaginary creation. All the phenomena
of combustion and calcination are much more readily explained without phlogis-
ton than with phlogiston. I understand that my ideas will not be suddenly
adopted. The human mind conforms to a certain manner of vision and those
who during a portion of their lives comprehend nature from a given point of
view have difficulty in acquiring new ideas. In good time the opinions I have
set forth will be confirmed or destroyed. In the interim, it is a great satisfaction
for me to see that young, unprejudiced minds among those who are commencing
to study science, such as mathematicians and physicists who have a new sense
of chemical truths, no longer believe in phlogiston as presented by Stahl but
regard the whole doctrine as scaffolding which is more embarrassing than it is
useful for the continuance of the structure of the science of chemistry.
And the wonder of it all is that the great chemists of his time outside
of his own country persisted in their narrow viewpoint. Priestley and
Cavendish refused to be converted. Scheele wrote in 1783, "Is it im-
possible to convince Lavoisier that his system will not find universal
acceptance? The idea of nitric acid from nitrous air and pure air, of
carbonic acid from carbon and pure air, of sulphuric acid from sulphur
and pure air, of lactic acid from sugar and pure air ! ! Can one believe
such things ? Rather will I support the English."
24 GRAHAM LUSK
Only Black, professor of chemistry at Edinburgh and the discoverer
of "fixed air," saw the truth. Lavoisier wrote to Black on November 1-'!,
1790, a letter (Richet, (p) 1887) composed six months after the reading <>f
his last memoir to the Academic des Sciences. He concluded the letter
with the truest French courtesy : "It is only right that you should be the
first to be informed of progress in a field which you opened and in which
we all regard ourselves as your disciples. We do the same kind of
experiments and I have the honour to communicate to you the results of
our recent discoveries. I have the honour to remain, with respectful
attachment, etc."
And to this Black replied in 1791, "The numerous experiments which
you have made on a large scale and which you have so well devised have
been persued with so much care and with such scrupulous attention to
details that nothing can be more satisfactory than the proofs you have
obtained. The system which you have based on the facts is so intimately
connected with them, is so simple and so intelligible, that it must become
more and more generally approved and adopted by a great number of
chemists who have long been accustomed to the old system. . . . Having
for thirty years believed and taught the doctrine of phlogiston as it was
understood before the discovery of your system, I for a long time felt
inimical to the new system which represented as absurd that which I had
hitherto regarded as sound doctrine, but this enmity which springs only
from force of habit has gradually diminished, subdued by the clearness
of your proofs and the soundness of your plan."
In reading of the overthrow of the old doctrine of the fire principle
phlogiston one must feel a throb of the impending horror of the French
Revolution when one considers the statements of Marat written in 1791.
Marat at one time had declared that a flame, when placed in a confined
vessel, went out because the heat of the flame suddenly expanded the air,
causing such a pressure on the flame that it was extinguished. Lavoisier
refuted this doctrine. Marat, "L'Ami du People," under the title "Mod-
ern Charlatans," published the following: "Lavoisier, the putative
father of all the discoveries that are noised about, having no ideas of his
own, snatches at those of others, but having no ability to appreciate
them, he quickly abandons them and changes his theories as he does his
shoes." Certainly words of unqualified, contemporaneous disapproval !
Lavoisier's new system of salts and oxids led him to forecast the
discovery of sodium and potassium, for in his "Elements of Chemistry"
(Lavoisier, (m) 1799) he wrote, "It is quite possible that all the substances
we call earths may be only metallic oxids irreducible by any hitherto
known process." A eulogist of Lavoisier has likened this to the vision of
Copernicus before Galileo's invention of the telescope.
Lavoisier had now progressed so that he was able to lay the funda-
mental basis of modern chemical physiology. Thus, in 1785, he stated
A HISTORY OF METABOLISM
25
that the discrepancy between the quantity of expired carbonic acid and
inspired oxygen, which he had observed in 1780, was accounted for by the
fact that a part of the absorbed oxygen was utilized to oxidize hydrogen
in the lungs. This oxidation would produce additional heat and account
for the discrepancy between the heat directly measured from a guinea-pig
and the heat calculated as being derivable from the oxidation of carbon by
oxygen. It is interesting to recall that eighty years later, in I860,
Bischoff and Voit still calculated the heat value of the metabolism from
the heat which would be produced in burning the carbon and hydrogen
elements of the metabolism.
Respiration experiments on a human being constituted the final con-
tribution in the culmination of this great career. The work is presented
by Seguin and Lavoisier (£) in the memoirs of the Academic des Sciences
during the year 1789. In this paper the authors remark: "This analogy
between combustion and respiration did not escape the attention of the
poets and philosophers of antiquity, of which they were the interpreters
and spokesmen. Fire taken from the heavens, this flame of Prometheus,
not only represents an idea that is ingenious and poetical but it is a true
picture of the operations of nature on behalf of animals who respire ; one
can say with the ancients that the fire is lighted the moment a baby takes
its first respiration and is not extinguished until its death."
Before giving the details of the experiments on man the authors
state that a guinea-pig respired in pure oxygen and in a mixture of oxygen
and hydrogen gas just as it did in ordinary air; respiration, circulation
and the intensity of combustion were uninfluenced. Nitrogen had nothing
to do with respiration.
In the experiments on man Seguin himself was the subject. The
results are given in the accompanying table:
RESULTS OF EXPERIMENTS ON MAN
Condition
Environ-
mental
Tempera-
ture
Degrees
Oxygen Absorbed per
Hour
Pouces
Liters
(1)
(2)
(3)
(4)
(5)
Without food
Without food
With food
26
12
1210
1344
1800-1900
3200
4600
24
27
38
65
91
Work (9,105
Work (9,750
foot pounds ) without food . .
foot pounds ) with food
Here are the basic facts regarding metabolism. The basal metabolism
was increased 10 per cent after exposure to cold; 50 per cent after taking
food; 200 per cent by exercise; and 300 per cent on combining the influ-
ences of food and exercise. We now know more details and we may also
calculate that Lavoisier's determination of 24 liters of oxygen absorbed
26 GRAHAM LI'SK
per hour in this first historical experiment on the basal metabolism was 25
per eent too high. As for the experimental plan, it is as modern as the
work of to-day, and yet it was executed 140 years ago by the first man
who really understood the significance of oxygen. It is only in the last
decade that the summation of the individual stimuli caused by food and
muscular work and noted by Lavoisier has been verified. Lavoisier (/>).
also observed a constant relation between the quantity of oxygen consumed
and the rate of the pulse multiplied by the number of respirations.
How Lavoisier achieved these remarkable results is not known, for
the times in which he lived became too troubled to allow further work in
pure science. We find, however, the following statement in the original
memoir: "It would have been impossible to accomplish these exact
experiments upon respiration before the introduction of a simple, easy
and rapid method of gas analysis. This service M. Seguin has rendered
to chemistry."
If, now, one turns to the report of Seguin (Seguin (g), 1791) one finds
that he states that in his work with Lavoisier he used eudiometers 8 to 10
inches high and an inch in diameter in order to determine the "vital air"
or oxygen in the respired air. The tube was first filled with mercury and
inverted over mercury, a little of the gas to be analyzed was introduced
and then a bit of phosphorus, which phosphorus was later ignited by
bringing a burning ember in the vicinity of the glass. The rest of the
air to be analyzed was gradually admitted and when the tube cooled the
volume of the air remaining could be measured. The loss in volume
represented the quantity of oxygen absorbed. Carbonic acid could then be
absorbed by potash. Seguin stated that the older method, as originally
introduced by Priestley, had twenty sources of error but that his method
merited attention on account of the very great exactitude with which he
could determine the gases which are contained in respired air:
He furthermore truly stated that "if we enter into a room containing a
large number of people we immediately smell a strong, suffocating odor,
but if we use eudiometers to analyze this foul air and compare it with
ordinary atmospheric air we find hardly any difference in the proportions
of gases which are contained in them."
After Lavoisier's death Madame Lavoisier drew from memory the
apparatus used by her husband. The drawings were retouched by David,
Madame Lavoisier's instructor in art. There are two pictures quite dis-
similar. Good reproductions are to be found in Grimaux's "Lavoisier."
In both pictures Seguin sits naked in a chair, breathing through a mask
into a series of globes or bell jars. In both pictures Madame Lavoisier is
shown seated at a table, taking notes of the experiment. In both pictures
the pulse is being counted. In one experiment a weight is placed on
Seguin's instep. The arrangement of the apparatus is quite different in
the two pictures. In the experiment showing Seguin at work it seems as
A HISTORY OF METABOLISM 27
though valves were indicated through which inspired air was received
from the atmosphere while the expired air was driven through a tube
into a bell jar under water. Nysten (Nysten, (o) 1817), working in Paris
in 1811, described the method by which he caused tuberculous and other
patients to respire through valves into a previously collapsed bag for
half a minute and then analyzed the expired air by a method similar to
that of Seguin.
These are the known historical facts about the apparatus used in the
"first respiration experiments on man, but the exact details of the method
by which results were established and which still are the basis of metab-
olism studies are unknown.
In contemplating his results Lavoisier (/) said: "This kind of obser-
vation suggests a comparison of forces concerning which no other report
exists. One can learn, for example, how many pounds of weight lifting
correspond to the effort of one who reads aloud or of a musician who plays
a musical instrument. One might even value in mechanistic terms the
work of a philosopher who thinks, the man of letters who writes, the
musician who composes. These factors, which have been considered
purely moral, have something of the physical and material which this
report allows us to compare with the activities of a man who labors with
his hands. It is not without justice that the French language has united
under the common expression work the effort of the mind with that of
the body, the work at the desk with the work at the shop. . . .
Thus far we have considered respiration only as a consumption of air, the
same kind for the rich as for the poor, for air belongs equally to all and costs
nothing. The laborer who works enjoys indeed in great measure this gift of
nature. But now that experiment has taught us that respiration is a true process
of combustion which every instant consumes a portion of an individual, that this
combustion is greater when the circulation and respiration are accelerated and
is augmented in proportion to the activity of the individual life, a host of moral
considerations suggest themselves from these determinations of physical science.
What fatality ordains that a poor man, who works with his arms and who
is forced to employ for his subsistence all the power given him by nature, con-
sumes more of himself than does an idler, while the latter has less need
of repair? Why the shocking contrast of a rich man enjoying in abundance
that which is not physically necessary for him and which is apparently destined
for the laboring man? Let us take care, however, not to calumniate nature and
accuse her of faults undoubtedly a part of our social institutions and perhaps
inseparable from them. Let us be content to bless the philosophy and humanity
which unite to promote wise institutions which tend to bring about equality of
fortune, to increase the price of labor, to assure to it just recompense, to offer
to all classes of society and especially to the poor more pleasures and greater
happiness. Let us trust, however, that the enthusiasm and exaggeration which
so readily seize men united in large assemblies, that the human passions which
sway the multitude, often against their own interest, and sweep the sage and the
philosopher like other men into their whirlpool, do not reverse an outlook with
such beautiful vistas and do not destroy the hope of the country. . . .
28 GRAHAM LUSK
We end this memoir with a consoling reflection. To merit well of humanity
and to pay tribute to one's country it is not necessary to take part in brilliant
public functions that have to do with the organization and regeneration of em-
pires. The naturalist may also perform patriotic functions in the silence of his
laboratory and at his desk; he can hope through his labors to diminish the mass
of ills which afflict the human race or to increase its happiness and pleasure; and
should he by some new methods which he has opened up prolong the average life
of men by years or even by days he can also aspire to the glorious title of bene-
factor of humanity.
These are words written by the greatest scientist of his day under the
spell of the French Revolution. They are words of an educated, culti-
vated man of middle age spoken in the Academic des Sciences in the
year of the fall of the Bastile and at a time when Edmund Burke from
the other side of the Channel said, "In the groves of their Academy at
the end of every vista you see nothing but the gallows."
Lavoisier and Franklin had been intimate friends, living near each
other in Paris and Franklin dining frequently with the great French
chemist and his wife. In a letter written to Franklin, then in America, on
February 5, 1790, during the early days of the French Revolution,
Lavoisier says: "After having recited what has transpired in chemistry
it is well to speak of our political revolution. We regard it as accom-
plished, well accomplished and beyond recall. There still exists, however,
an aristocratic party which is making vain efforts but is evidently
feeble. . . . We greatly regret at this moment your absence from France.
You could be our guide and mark the limits beyond which we ought not
to pass."
And in 1790 Lavoisier (#) concluded his last scientific communication
to the Academic with these words, "Up to the present time we have learned
only to conjecture as to the cause of a great number of diseases and as to
the means of their cure. Before hazarding a theory we propose to multiply
our observations, to investigate the phenomena of digestion -and to analyze
the blood both in health and in disease. We will draw upon medical
records and the light and experience of learned physicians who are our
contemporaries and it will be only when we are thus completely armed
that we will dare to attack a revered and antique colossus of prejudice
and of error."
No person of understanding can escape a thrill at this vision of modern
medicine expressed by him who had overthrown phlogiston, discovered the
composition of the air and its relation to combustion and to life, who
had created calorimetry and revolutionized the whole of chemical thought.
True to his enthusiasm we find him drawing up the conditions for an
international prize of 5,000 livres offered by the Academic des Sciences
in 1792 to the author of the best experimental treatise on the liver and
the bile (t).
Lavoisier's life outside his laboratory had been that of a public
A HISTORY OF METABOLISM 29
official, a tax gatherer, and he had also been associated with the national
manufacture of gunpowder, the quality of which he had greatly improved.
He purchased a large landed estate and made experiments in scientific
agriculture, doubling the wheat crop, quintupling the number of beasts
on the land and earning thereby the enduring gratitude of the peasants.
However, as before remarked, he had incurred the bitter hatred of Marat
and he was a tax gatherer. In November, 1793, he was arrested at the
Arsenal in his laboratory there, upon which he had spent a large portion
of his fortune. Just a little while before, in August of the same year,
the Academic des Sciences had been closed as inimical to the welfare
of the state. Les amis du peuple are notoriously suspicious of the "intelli-
genzia," and the Academic was abolished.
Just prior to his execution Lavoisier wrote to a friend, "I have had a
sufficiently long career, always a very happy one, and I believe that my
memory will be thought of with some regret and perhaps as having some-
thing of glory. What more could I desire? The circumstances which
surround me would probably lead to an uncomfortable old age. ... It is
certainly true that all the social virtues, important services to the country,
a useful career employed in promoting art and human knowledge, have
not sufficed to save me from a sinister end or to prevent me from perish-
ing as a criminal."
One of the charges against Lavoisier was that he had allowed the
collection of taxes upon the water contained in tobacco. On May 8, 1794,
at the age of fifty years, he was tried and found guilty. Twenty-eight
fermiers-generaux were executed in the Place de la Republique at the
same time. He witnessed the execution of his father-in-law, Paulze, who
was fourth on the list, and he was the fifth upon whom the ax of the
guillotine fell.
Such was the Terror.
His friend Lagrange whispered that night to an intimate, "It took
but an instant to cut off his head; a hundred years will not suffice to
produce one like it !"
Writing a hundred years later, Berthelot (;') (1890) exclaimed, "It is
our right to admire the positive work which he accomplished. The uni-
versal judgment of the civilized world increasingly reveres his establish-
ment of chemistry, one of the fundamental sciences, upon a fixed and
definite basis. There is no grander accomplishment in the history of
civilization and hence the name of Lavoisier will live forever in the
memory of humanity."
It is interesting to consider the differences in the lives of the men
concerned in the great discoveries of the last quarter of the eighteenth
century. Priestley, an indigent clergyman ; Cavendish, of whom it was
said that he was the most wealthy of learned men and the most learned of
the wealthy ; Scheele, a poor Swedish apothecary ; and Lavoisier, a man of
30 GRAHAM LUSK
affairs, a noble of high social position, in receipt of huge personal revenues.
What is it, then, that makes for greatness in science *. Would Lavoisier
have accomplished more had he been on a "full-time" basis with a
restricted income? It is a question of individual opinion, but to most
people it would appear that scientific greatness depends primarily upon
the quality of the intellectual protoplasm of the brain, upon the advantages
offered to the functioning of that brain by a favoring mental environment,
and on the possession of a good conscience.
One may well understand that the clarification of the work of Black,
Rutherford, Cavendish, Priestley and Scheele by the brilliant mind of
Lavoisier might lead others than they to the expression of national
scientific self-consciousness. Thus, Wurtz's "Histoire des doctrines
chimiques," published in Paris in 1861, begins with the proud statement,
"La chimie est une science franchise; elle fut constitute par Lavoisier."
It is needless to state that this caused reverberations of disapproval from
England. The personal opinion of national worth finds still more intense
modern expression in the Manifesto of the Intellectuals (1915), "The
German Mind is, in our opinion, beyond all doubt our one supremely
valuable asset. It is the one priceless possession amongst all our posses-
sions. It alone justifies our people's existence and their impulse to main-
tain and assert themselves in the world ; and to it they owe their superiority
over a41 other peoples."
A historic case in which a generous attitude was taken occurred when
the French Academy in 1806, just prior to a declaration of .war between
France and England, conferred its newly established Volta medal upon
Humphrey Davy. A French delegation went to London to deliver the
medal while the war was in progress and Davy, in acknowledging it, said,
"Science knows no country. If the two countries or governments are at
war, the men of science are not. That would, indeed, be a civil war of the
worst description. We should rather through the instrumentality of men
of science soften the asperities of national hostility."
Perhaps this "old-fashioned" courtesy was a relic of the days of a
bygone chivalry. At any rate, it affords a delightful example of human
behavior.
Science after the French Revolution
Napoleon, during the winter of 1797-1798, attended the regular course
of chemical lectures delivered by Berthollet, who had been an associate
of Lavoisier. At a later date Berthollet and Monge, the mathematician,
organized a company of one hundred scientists to accompany Napoleon to
Egypt. At least the scientific men of France had no cause to complain of
lack of recognition. And perhaps partly in consequence of this one finds
living in Paris in 1823, the year Liebig studied there, such men as La
A HISTORY OF METABOLISM 31
Place, Berthollet, Gay-Lussac, Thenard, Cuvier, Ampere, Laennec and
Magendie.
Thorpe writes of them (1908) :
"That constellation has set —
'The world in vain
Will hope to look upon their like again.' '
The atmosphere for the development of French science reached at
this- time a maximum of power to stimulate. One of the few mistakes
of Lavoisier was his conception that oxidation took place in the lungs.
Lagrange, the illustrious mathematician, a friend and associate of La-
voisier, reflecting that if the heat production took place in the lungs their
temperature must be higher than elsewhere in the body, concluded that
heat was generated wherever the blood circulated, that oxygen dissolved in
the blood, combined with hydrogen and carbon there, and that carbonic
acid was eliminated. This interpretation of Lagrange was published in
1791 before Lavoisier's death by Lavoisier's pupil Hassenfranz (Z), who
agrees that the caloric necessary to maintain animal heat is liberated in the
blood by the combination of carbon and hydrogen with oxygen, with which
the blood is mixed.
Humphrey Davy (1778-1829) was the first to obtain oxygen from
arterial blood by warming it to 93° C. and carbonic acid from the venous
blood by warming it to 45° C. He was apparently not well acquainted
with Lavoisier's work, and his own work, published in 1799, remained long
forgotten. To him oxygen occurred as "phosoxygen," a combination of
heat and light. In his experiment XVII he shows that "phosoxygen" can
be absorbed by venous blood in the dark without the liberation of light,
but with the result that the color of the blood changes from dark red to
bright vermilion.
Experiment XVIII.—
A phial containing about 12 inches, having a pneumatic apparatus affixed to
it, was filled with arterial blood from the carotid artery of a calf. The phial was
placed in a sand bath at a temperature of 96° and the heat gradually and slowly
raised. In about ten minutes the temperature of the bath was 108° and the blood
began to coagulate. At this moment some globules of gas were perceived passing
through the tube. Gas continued to pass in very small quantities for about half
an hour when the temperature of the sand was about 200°; the blood had coagu-
lated perfectly and was now almost black. About 1.8 cu. in. of gas were collected
in the mercurial apparatus; of this 1.1 cu. in. were carbonic acid and the re-
maining 0.7 phosoxygen.
From this experiment it is evident that the arterial blood contains phosoxy-
gen, and we have proved before by synthesis that it is capable of combining with
it directly. We are possessed of a number of experiments which prove that
phosoxygen is consumed in respiration. It has been likewise proved that gases
can penetrate through moist membranes like those of which the vessels of the
lungs are composed. We may therefore conclude that phosoxygen combines
32 GRAHAM LUSK
with the venous blood of the system in the pulmonary vessels. As no light
•was liberated in Experiment XVII there cannot be even a partial decompo-
sition of phosoxygen in respiration.
Davy's interpretations are far from clear, as will be seen in the
following paragraph: "Respiration then is a chemical process, the com-
bination of phosoxygen with the venous blood of the lungs and liberation
of carbonic acid and aqueous gas from it. From the combination and
decomposition arises an increase of repulsive motion which, combined
with that produced by the other chemical processes taking place in the
system and that generated by the reciprocal action of the solids and
fluids, is the cause of animal heat; a heat which the other systems have
supposed to arise chiefly from the decomposition of phosoxygen (oxygen
and caloric)."
About the same time that Davy was experimenting in England Spal-
lanzani in Italy was inquiring into the validity of Lavoisier's ideas.
Spallanzani (1729-1799). — The experiments of Spallanzani were
published in 1804 after his death. His biographer states: "When the
Empress Maria Theresa had reestablished the University of Pavia on a
more extensive plan she wished to render it at once celebrated by the
attainments of its professors; she empowered Count Firmian to invite
Spallanzani to give lectures on natural history."
Spallanzani says that oxygen is transported by the blood to the heart
and is necessary for the heart beat, but he is not convinced that oxygen is
necessary for the production of carbonic acid. He put snails into two
tubes filled, respectively, with atmospheric air and with nitrogen. "On
removing them from the tubes at the end of twelve hours I found the
animals still alive ; I examined the two aeriform fluids and was astonished
to discover that the quantity of carbonic acid' gas was greater in the
azotic gas (nitrogen) than in the common air." He obtained the same
result when he used hydrogen gas and says, "I shall only conclude from
these experiments that it is clearly proved that the carbonic acid gas
produced by the living and dead snails in common air resulted not from
atmospheric oxygen, since an equal or even a greater quantity of it was
obtained in azotic and hydrogen gas."
This is very nearly the same as Davy's conclusion. Of his method
of work Spallanzani says : "Being engaged in similar experiments, it was
natural for me to attend to this part of the subject uninfluenced by the
opinion of those celebrated men, in order that I might observe only
nature herself. This is at least the mode I have always pursued, when
it was possible, with respect to the most universally received opinions,
however respectable the quarter whence they proceeded; I have always
myself examined the facts on. which they were built."
William F. Edwards (1776-1842) confirmed the work of Spallanzani,
finding that frogs when placed in hydrogen gas eliminated in a few hours a
A HISTORY OF METABOLISM 33
volume of carbonic acid equal to their own volume and larger in quantity
than they would have expired had they breathed in air. He concluded
that carbon dioxid was not formed by oxidation in the lungs but must
have been excreted from the blood, and he supports this conclusion by
citing unpublished experiments by Vauquelin in which blood was exposed
to a hvdrogen atmosphere with the result that carbonic acid was given
off.
Magnus (1802-1870) repeated the experiments of Vauquelin, shaking
blood in hydrogen gas, and he also placed blood in a complete vacuum
and 'noticed the elimination of a great volume of gases. There was more
carbonic acid eliminated than could be accounted for by the bicarbonate
present.
Gay-Lussac (1778-1850) criticized these results .and stated that the
quantity of oxygen found in the blood was sixteen times larger than could
be dissolved by water and that no differences appeared in the analyses of
arterial and venous bloods. Magnus (1845) replied that 100 parts of gas
extracted from blood contained :
Arterial Blood Venous Blood
Carbonic acid 62.3 71.6
Oxygen 23.2 15.3
Nitrogen 14.5 13.1
100 100
He found also that when blood was pumped out it could again absorb
sixteen volumes per cent of oxygen.
Berzelius (1779-1848) announced in 1838 that little oxygen could be
added to blood serum freed from corpuscles, but when the serum was mixed
with the coloring matter of the blood it was absorbed in large volume.
Berzelius attributed the affinity of "hematin" for oxygen to its content
of iron.
Dumas in 1846 found that on replacing blood serum with a solution
of sodium sulphate the blood corpuscles suspended therein still changed in
color after shaking with oxygen.
It was Liebig in 1851 who gave expression to modem thought upon
the subject of the respiration in saying, "The absorption of a gas by a
liquid is due to two causes, an external consisting in the pressure exerted
by the gas upon the liquid, and a chemical, an attraction manifested by the
constituent particles of the liquid."
For complete references to this story, consult "Lecons sur la physiolo-
gic," by H. Milne-Edwards, Volume 1, printed in 1857. These volumes
treat the subject of physiology with a thoroughness lately thought to be
exclusively German.
34 GRAHAM LUSK
The Beginnings of Calorimetry
The work of Lavoisier concerning the source of animal heat was in-
sufficiently convincing, and so the French Academy^ of Science offered a
prize to any one who would produce the best thesis on the subject. The
prize was competed for by Despretz and by Dulong. It was awarded in
1823 to the former, although in the light of modern knowledge it would
seem that the latter had a greater insight into the problem.
Despretz (1792-1863) gives the following account (1824) : "Xo
phenomenon in physiology is more capable of attracting attention than
the singular property enjoyed by man and warm-blooded animals of pre-
serving an almost constant temperature, although the temperature with
which they are surrounded is subject to continual variations. All bodies
tend constantly to seek heat equilibrium ; reciprocal exchange tends to
establish a uniform temperature between different bodies.
"Warm-blooded animals, en the contrary, though they are equally
exposed to heat loss occasioned by contact, radiation and the evaporation
of water, possess within themselves a power to produce heat which main-
tains their temperature as a rule at about 39 9 above the melting point
of ice."
The resources of modern science were lacking in the days of Galen,
Boerhaave and Haller. The author cites Lavoisier (n) (1780) and criti-
cizes Crawford's (1779) very imperfect method. He states that Brodie
(1812 Philosophical Transactions) thought the brain produced heatthrough
the nerves, citing the heat loss after decapitation. This was denied by Le
Gallois, who maintained artificial respiration in a decapitated animal.
Type of experiment by Despretz:
Subjects, three guinea-pigs.
Ventilation, 55 to 60 liters per 2 hours, the air being purified by
passing through potash.
Condition of the environmental air, 6 per cent CO2 and water
saturation.
Experiment 1 :
CO2 formed, 2,587 liters.
O2 unaccounted (i. e., not in CO2), 0.709 liter.
The three animals raised the temperature of 23310.5 g.
water 0.63°.
Animal heat as measured, 100 per cent.
Heat due to formation CO2 69.9 per cent.
Heat due to formation water, 19.4 per cent
Total heat as calculated, 89.3 per cent.
A HISTORY OF METABOLISM 35
The modern calculation would be:
O2 CO2 R. Q. Calories Calories
indirect direct
liters liters
3.30 2.59 0.78 15.86 14.68
Or 8 per cent too much calculated heat instead of 11 per cent too
little.
The conclusions of Despretz were :
1. That the respiration is the principal cause of the development of
animal heat ; that assimilation, movement of the blood, friction in different
parts, can easily produce the small residual amount.
2. Although oxygen is employed in forming carbonic acid, a certain
quantity, sometimes considerable in amount, disappears; it is generally
thought that it is used in the combustion of hydrogen.
3. There is an exhalation of nitrogen in the respiration of both
carnivorous and herbivorous animals.
The following animals were used : Ducks, chickens, cocks, young and
old pigeons, gulls, buzzards, owls, magpies, dogs, cats, rabbits and guinea-
pigs.
Dulong (1785-1838) presented the second paper in competition for
the prize of the Academy, of which a resume follows :
The author, who is both physicist and chemist, proposes to determine
if the quantity of oxygen intake is sufficient (in health) to repair the
heat loss by animals under natural conditions of life; in other words,
whether animal heat is entirely due to combustion which takes place
within the animal through respiration.
He calls attention to the fact that Lavoisier used two different guinea-
pigs, one in the calorimeter and another for the determination of the
gaseous exchange. He uses the water calorimeter of Rumford. The
temperature of the water is the same as that of surrounding air at the
start ; at the end, higher. The animals can move at will. Cat, dog, kestrel,
capibara (water-hog), rabbit, and pigeon are used. He finds that in
the cat, dog and kestrel the volume of oxygen inspired is one-third more
than that of the carbonic acid expired, whereas in rabbits, capibara and
pigeons the oxygen is only one-tenth more than the carbonic acid. There-
fore he thinks this difference is due to food or to a difference of animal
organization through food. He finds that nitrogen is exhaled. The heat
from carbonic acid in carnivora is 49 to 55 per cent of the total heat
measured; in herbivora, 65 to 75 per cent. Calculated inclusive of the
heat produced from the oxidation of hydrogen, it equaled 69 to 80 per
cent. The experiments were repeated many times.
One source of error in the calculations of Despretz and of Dulong
36 CKAIIAM LUSK
lay in the fact that the caloric values attributed to the oxidation of carbon
and hydrogen were wrong. One may compare the values used at different
periods as follows:
Favre and
.
Lavoisier Deapretz Silbermann
1780 1823 1852-53
calories calories calories
1 gm. H oxidized yields. . . 22.170 23.640 34.462
1 gm. C oxidized yields... 7.237 7.914 8.080
The agreement between Despretz and Dulong that nitrogen
present in the expired air in an amount larger than that inspired was
accepted for many years by many writers. Magendie, in his "Elements of
Physiology," in 1836, thus expresses the thoughts of his time: "Accord-
ing to the experiments of M. Despretz upon herbivora, the respiration
furnishes only 89 per cent of the animal heat, and in carnivora only 80 per
cent. Therefore, other sources of animal heat must exist in the economy.
It is probable that these occur in the friction of various parts, in the
movement of the blood, the friction of the blood corpuscles upon one
another and finally in nutritive phenomena. This supposition is not
forced, for it is known that most chemical combinations give rise to heat,
and it is doubtless true that combinations of this nature take place in the
organs, both during secretion and digestion."
It is evident that ignorance of the Law of the Conservation of Energy
hampered progress at this time.
Dumas (1800-1884). — In the year 1823 a paper was published by
Prevost and Dumas pointing out the fact that if the kidneys were ex-
tirpated in cats and rabbits, urea rose to high concentration in the blood.
This experiment proved that urea was not formed in the kidney. Rouelle
in 1773 had found urea in the urine.
It was the year 1823, the year of the publication of the work of
Despretz, of Dulong and of Dumas, that Liebig, at the age of twenty,
came to Paris to study. This should be remembered as the story of the
development of the French school is unfolded. The part Liebig played
will be told later.
Dumas was an organic chemist of high repute. Concerning his influ-
ence, the words of Pasteur, spoken in 1882, may be recalled: "My dear
Master, it is indeed forty years since I first had the happiness of knowing
you and since you first taught me to love science.
"I was fresh from the country; after each of your classes I would
leave the Sorbonne transported, often moved to tears. From that moment
your talent as a professor, your immortal labors and your noble character
have inspired me with an admiration which has grown with the maturity
of mv mind,"
A HISTOEY OF METABOLISM 37
Dumas came into frequent intellectual conflict with Liebig and
Wb'hler in Germany and Berzelius in Sweden. In ISSS^Wb'hler produced
urea synthetically from ammonium cyanate, delivering the final death
blow to the doctrine that organic compounds arise only through the inter-
vention of living things.
Magendie (1783-1855) was among the first to differentiate between
various kinds of foods. This distinguished physiologist fed dogs cane
sugar or olive oil or butter and found that death occurred in 34 days
(Magehdie, 1836). He rightly concluded that the nitrogen of the organs
of the body arose only from the nitrogen of the food, that the nitrogen-free
food-stuffs were not transformable into nitrogen-containing food-stuffs.
He rendered great service in pointing out the nitrogen content of rice,
maize and potatoes, foods upon which people live.
Magendie also found that dogs fed with bread alone lived only a
month. The second gelatin commission of the French Academy (Magen-
die, 1841), sitting in 1841 under the presidency of Magendie, determined
that bread and gelatin given together to either dog or man constituted an
insufficient diet.
Boussingault (1802-1887). — Organic analysis, which was founded by
Lavoisier, was further advanced by Gay-Lussac and Thenard (1810-15),
by Berzelius in 1814, and was perfected by Liebig in 1830. This work
led to that of Boussingault, who curiously enough had been previously for
several years in the employ of an English mining company in equatorial
South America.
The experiments of Boussingault in 1839 may be considered to be
prophetic of the future evolution of metabolism studies. Boussingault
compares the quantities of carbon, hydrogen, nitrogen and oxygen in the
fodder constituting a maintenance ration of a milch cow, with the quan-
tities of the same elements eliminated in the urine, feces and milk. The
difference between these quantities would be available for the respiration.
He gives the following account (Boussingault, (&) 1839) :
"It is generally recognized to-day that the food of animals must con-
tain a certain amount of nitrogen. The presence of nitrogen in a large
number of vegetable foods forces the conclusion that herbivora receive
nitrogen in their food, which enters into their constitution.
"In ordinary alimentation an individual does not change his average
weight; this state of affairs exists when an animal takes a maintenance
ration (ration d' entretieri) "
Under these conditions the food of the animal should be found in his
excretions. During growth, or the process of fattening the conditions
would be different.
Cows were given a maintenance ration of known elementary com-
position and the elements recovered in the urine, feces and milk were
subtracted from those in the fodder, with the following results :
38 GRAHAM LUSK
C H 0
Elements in the fodder 4813 595 4035
N
201.5
Salts
889
Elements in the urine, feces and milk. 2602 332 2083
174.5
921
—2211 —263 —1952 —27 +32
Uniting the oxygen of the food with the hydrogen in such a proportion
as to form water, there would remain 19.8 gm. of hydrogen requiring
inspired atmospheric oxygen for its conversion into water. The loss of
carbon equaling 2211 gm., it would require 4052 liters to convert it into
7999 gm. of carbonic acid. A cow would therefore deprive 19 square
meters of air of its oxygen.
Boussingault states that one nitrogen determination is not sufficient
to decide whether nitrogen as a gas enters into the metabolism of
protein.
The same kind of work is done with a horse (Boussingault, (a) 1839).
It is concluded that 4584 liters of oxygen would be required to form the
carbonic acid produced. There were 24 gm. less of nitrogen in the
excreta than in the food. It seems clear that atmospheric nitrogen is not
assimilable by the body.
In a subsequent experiment published in 1843 Boussingault (c) gives
food to a turtle-dove and estimates the carbonic acid elimination as he
had done with the horse, but he also determines directly the carbonic acid
given off. By the first method 0.211 gm. of carbon were estimated to
have been expired and by the second method an average of 0.198 gm.
were actually found. This closely approaches modern technic.
Boussingault and Le Bel (1839) made the first complete analyses
of cow's milk. They conclude from their -work that the nature of the
fodder does not affect the quantity or the chemical composition of the
milk, provided the cow receives the same relative nutritive equivalents in
the fodder.
The nutritive equivalents, however, were based on the nitrogen content
of the fodders, thus 13.5 kg. of hay were accounted the nutritive equiva-
lents of 54 kg. of beets or 27 kg. of potatoes. It is evident that at this
date there was no real understanding of the nature of the different food-
stuffs.
Barral (1819-1884) in 1849 applied the principles of Boussingault's
method to the analysis of the metabolism of human beings. He thus
presents his problem: "Knowing the amount and the elementary com-
position of the food, both solid and liquid, taken each day, determining
the elementary composition of the excreta and perspiration, one may
calculate the gains and losses of the human body."
His experiment on himself lasted five days, with the following results
per day:
A HISTORY OF METABOLISM 39
In
In
the
the
food. . . .
Water
. . 1998.6
Salts
31.3
15.4
Cl
7.8
5.0
C
366.2
30.5
H
57.3
5.4
N
28.0
13.7
0
265.7
16.9
Total
2754.9
1264.7
excreta. .
. . 1177.8
Differei
ices . .
. . — 820.8
— 15.9
02 +
— 2.8
31.1
20.8
335.7
crq Crq dq 1
335.7
H2 =
H2 +
c +
— 51.9
279.9 g.
166.3 g.
895.2 g.
— 14.3
H20
insp.
insp.
— 248.8 —1490.2
O3 = 187.1 g. H,O
O2 = 1230.9 g. CO2
248.8 g.
It is evident that 1061 gm. of oxygen would have been inspired and
1231 gm. of carbonic acid expired, according to this calculation. He
finds that his figures for carbonic acid elimination accord with those of
Andral and Gavarret (see below). He calculates the heat production as
follows :
335.7 g. C X 7.200 calories = 2417.040 calories from C
20.8 g. H X 34.600 " = 719.680 " " HI
Total 3136.720
These calories were calculated for a man from the food partaken
during the winter months.
Barral makes the further analysis of the heat produced by various
individuals in 24 hours:
Total Calories
Subject. calories perkgm.
Barral, in winter (age 29 yrs. ; wgt. 47.5 kgm.) . . . 3,136.720 66.036
Barral, in summer 2,312.000 48.673
BarraFs son (age 6 yrs. ; wgt. 15 kgm.) 1,223.960 81.597
Laboratory servant (age 59 yrs.; wgt. 58.7 kgm.). 2,559.080 43.595^^
Woman (age 32 ; wgt. 61.2 kgm.) : 2,541.100 41.521 -*
The quantity of nitrogen in the food was always greater than that
found in the evacuation, so much so that a part must have been eliminated
in the respiration. This portion was one-third or one-quarter of the
nitrogen taken in the food but was not more than the hundredth part of
the volume of carbonic acid eliminated. The loss of food nitrogen was
estimated as not more than six ten-thousandths of the total volume of air
expired.
Barral did not know that his urinary nitrogen analyses were faulty.
Barral criticizes the contemporary work of Liebig as follows: "Liebig
has attempted the solution of the question which occupies us by the same
method and as concerns man. This skilful chemist was content to measure
the principal foods of a company of the grand ducal guard of Hesse-
Darmstadt and to regard the minor food-stuffs as the approximate equiva-
lent of the material found in the feces and urine so far as carbon content
was concerned. Be also made similar valuations of the food-stuffs of
prisoners at Giessen and at Marienbad and of a family composed of five
40 GRAHAM. LUSK
persons. But this application of the method of BouBfiingault is too im-
perfect to establish definitely incontrovertible results in science."
It might be added at this point that Liebig in 1845 found that nine-
tenths and more of the heat measured by the calorimeters of Dulong and
of Despretz could be accounted for from the oxidation of carbon and
hydrogen calculated according to the method of 'Lavoisier. The more
modern caloric values for hydrogen were here employed as later in 1855
by Gavarret.
Liebig also points out that if one of the dogs experimented upon by
Dulong had really eliminated the quantity of nitrogen gas Dulong had
reported, the animal in seven days would have expired as nitrogen gas
the amount of that element contained in its hair, skin, flesh and blood, and
at the end of the period would have been merely a mass of mineral ash.
Regnault (1810-1878). — Henri \rictor Regnault was born in Aix-la-
chapelle, and in 1840 became professor of physics and chemistry at the
University of Paris. In 1847 he became also chief engineer of mines;
in 1854 was director of the Sevres porcelain manufactory. He was a
strict disciplinarian of students and up to- the outbreak of the war in
1914 his memory was held in tradition as representative of the highest
pedagogical severity.
In 1849 Regnault and Reiset published their celebrated monograph
upon the respiration of animals. The apparatus which they used consisted
of a closed system, from which the carbonic acid produced by an animal
placed within the system could 'be absorbed, and into which oxygen could
be admitted as the atmospheric air was consumed by the animal. This is
the "closed system of Regnault and Reiset," the principle of which is
employed in modern calorimeter work (vide Atwater and Benedict,
1905)*.
The results obtained were usually accurate and their interpretations
were within the compass of the knowledge of the time.
Their main conclusions as they enumerated them, together with some
of trrek^experimental data, are presented in the following abstract :
For anrrna-k. of warm blood, mammals and birds:
1. Normally nourished animals constantly expire nitrogen but the
quantity eliminated is very small, never exceeding two per cent and often
being less than one per cent of the total oxygen consumption.
2. If animals fast they 'frequently absorb nitrogen. The proportion
of nitrogen absorbed varies within the same limits as the exhalation of
nitrogen by animals regularly fed. This absorption of nitrogen takes
place in almost every instance in the case of birds but scarcely ever *in
mammals. . . .
(In experiment 10 performed on a rabbit the quantity of nitrogen
absorbed was 0.08 per cent of the quantity of oxygen absorbed. In the
text of the article they remark that the enormous elimination of nitrogen
A HISTOEY OF METABOLISM
41
reported by Dulong is impossible and that Liebig had pointed out [p. 40]
that when one considered the loss of nitrogen in the urine and feces, an
animal expiring in addition the amount of nitrogen found by Dulong
would thus in a few days liberate all the nitrogen contained in the organic
material of its own body. They also state that the respiration cannot
contain more than extremely small quantities of ammonia.)
4. ... The alternating elimination and absorption of nitrogen found
in the'same animal under various conditions is favorable to the opinions
Fig. 6. The closed circuit apparatus of Regnault and Reiset. From "Annales de
Chimie et 'de Physique," Series 3, Vol. XXVI, PI. III. Water rising in the glass recep-
tacle drives oxygen into the glass bell jar. A pump alternately raises and lowers two
cylinders. The lower cylinder fills with alkali at the expense of the upper one, and
this movement 'of the liquid forces air from one cylinder into the bell jar and draws
a corresponding amount from the bell jar into the other cylinder.*
of Edwards, who believes that an elimination and an absorption of nitro-
gen constantly takes place during respiration, and what one finds is the
resultant of these two contrary processes.
5. The relation between the quantity of oxygen exhaled as carbon
dioxid and the quantity of total oxygen consumed appears to depend more
on the nature of the food than on the species of the animal. This ratio is
higher in the animals which live upon grain and in them it may exceed
unity. When they are given meat, the ratio is less and varies between
0.62 and 0.80. Upon a diet of legumes the ratio is between that found
after giving meat and that after giving bread.
6. This ratio is nearly constant in animals of the same race, such as
dogs when they are given the same diet.
42 GRAHAM. IJ'SK
7. Fasting animals show about the same ratio (R. Q.) as they, do
when fed with meat, though usually a little less than under latter con-
ditions. During inanition fasting animals live off their own flesh, which
is of the same nature as the flesh which they eat. All fasting animals
present the picture of carnivora.
8. The fact that the relation between the volumes of oxygen absorbed
and carbonic acid exhaled varies between 0.62 and 1.04 according to the
kind of food which the animal takes in, destroys the validity of the
hypothesis of Brunner and Valentin (1846), attributing the respiration
to the simple diffusion of gases through membranes according to the laws
of Graham (which calls for a constant ratio of 0.85). In the text they
describe how they placed the bodies of animals (fowls, dogs, rabbits) in
an impermeable rubber sack and found in mammals, as well as in birds,
that the total quantity of carbon dioxid eliminated from the skin and
intestine of these animals was practically negligible, rarely exceeding two
per cent of that found in the pulmonary respiration.
9. Lavoisier tried to prove that the heat of the body came from the
oxidation of carbon and hydrogen. Regnault and Reiset do not doubt
that the heat is in fact derived entirely from chemical reactions in the
body. But they think the reactions are too-complex to be computed on the
basis of the oxygen intake. "The substances which are oxidized are
composed of carbon, nitrogen, hydrogen, and often contain a considerable
amount of oxygen. Though they be completely oxidized in the respiration
process, their own oxygen content contributes to the production of water
and carbonic acid, and the heat which is liberated is necessarily different
from that which would have been evolved by the oxidation of carbon and
hydrogen supposedly liberated. Moreover, the food substances are not
completely destroyed, for portions are converted into other materials
which play a special part in the body's economy and portions are trans-
formed into urea and uric acid. In all the transformation and assimilative
processes which these substances undergo in the organism there is either
liberation or absorption of heat ; but the processes are evidently so complex
that it is very unlikely that one will ever be able to calculate them."
(They found in fowls that the volume of carbon dioxid was often
greater than the volume of oxygen, which rendered the proposition of
estimating the heat production from the oxygen impossible.)
10. The quantity of oxygen varies during different periods of diges-
tion because of muscle work, and numerous other circumstances. In ani-
mals of the same species and the same weight the quantity of oxygen is
larger in young individuals than in adults. It is greater in healthy, thin
animals than in fat ones.
11. The consumption of oxygen absorbed varies greatly in different
animals per unit of body weight. It is ten times greater in sparrows than
in chickens. Since the different species have the same body temperature
• A HISTORY OF METABOLISM 43
and the smaller animals present a relatively larger area to the environ-
mental air, they experience a substantial cooling effect, and it becomes
necessary that the sources of heat production operate more energetically
and that the respiration increases.
14. Awakening marmots consume oxygen in very largely increased
quantity.
17. Reptiles consume much less oxygen per unit of body weight than
do warm-blooded animals, but do not differ from them in the relative
quantities of oxygen and carbon dioxid.
18. Frogs without lungs respire just as well as frogs with lungs.
• 19. Frogs and earthworms show nearly the same metabolism per
kilogram of body substances.
20. The respiration of insects, such as beetles and silkworms, is very
much more active than that of reptiles. For equal body weights they
consume as much oxygen as mammals, and a proportionately large amount
of nourishment. We are comparing insects with animals two to ten
thousand times heavier than they.
A thermometer placed in the midst of a mass of active beetles inclosed
in a sack showed a temperature of two degrees higher than the sur-
rounding air.
The results of the work on these lower forms of life may be thus
summarized :
Weight Oxygen per
gm. R. Q. kg. per hr. Temp.
37 Beetles 37. 0.82 0.962
18 Silkworms . . 42.5 0.79 0.840
25 Chrysalides.. 21. 0.64 0.240
- Earthworms. 112. 0.78 0.101
2 Frogs 127.5 0.75 0.105 19°
21. Animals of different species respire just the same in air con-
taining two to three times the usual quantity of oxygen, and do not per-
ceive the difference in oxygen content. (The air contained 72.6 per cent
of oxygen.)
22. If hydrogen replaces nitrogen of atmospheric air there is very
little difference in the respiration process. (The air contained 77 per t
cent of hydrogen and 21.9 per cent of oxygen.)
There were 104 experiments in all.
Regnault and Reiset exemplify their natural instincts of friendship
and courtesy when they write that experiment 26, in which they varnished
a dog with gelatin, was done at the suggestion of "cet habile physiologiste'
Magendie," and that M. Bernard "dont 1'habilite est bien connue de tons
les physiologistes" had extirpated the lungs of the frogs about half an
hour before placing them in their apparatus.
44 GRAHAM LUSK
In the closing words of this masterpiece the authors write :
We are far from concluding that our work presents a complete study of
respiration. We consider ourselves happy if we have established the principal
facts and if our methods are useful to physiologists who, through their special
learning, may be able to extend them.
The animals were never inconvenienced in any way in the apparatus.
Though single animals were often used in many experiments, there was
never any deleterious effect upon their health.
It will be noticed that there are two regrettable omissions in our work, ex-
periments on the respiration of fish and of man. We have not made experiments
on fish because we knew that Valenciennes was doing this. Regarding the res-
piration of man it was our intention to accomplish this in a special research.
We proposed to study not only healthy men under various conditions of diet
and at rest or at work, but also patients affected with different diseases and we
hoped to associate ourselves in this important work with one of the skilled physi-
cians of the large Paris hospitals. Unfortunately, the new apparatus which was
to have served for this investigation, on account of the special conditions it had
to satisfy, cost more money than we had at our disposal and we had to renounce
our project.
The study of the respiration in man in its various pathological phases ap-
pears to us to be one of the most important subjects that could occupy those
who follow the art of healing the sick ; it can give a precious means of diagnosis
in a great number of diseases and render more evident the transformations
which take place in the organism. . . . Our desires will be fulfilled if our work
provokes study that will be of such great importance to humanity.
The Rise of German Science
Justus von Liebig (1803-1873). — It has already been stated that
Liebig was in Paris during the greatest period of French scientific achieve-
ment. Liebig had been a dunce at school and was laughed, at by his
teacher when, as a boy, he expressed his determination to become a
chemist. Liebig attended the university of Erlangen, where he was duly
educated in the spirit of the phlogiston hypothesis. He heard with im-
patience the lectures of the renowned philosopher Schelling, and found
no satisfaction until, in the autumn of 1822, he went to study in Paris
(see p. 36). Both Liebig and Dumas were introduced into the scientific
circles of Paris by Alexander von Humboldt. Liebig, dedicating a French
edition of one of his books to Thenard, a former master, thus expresses
his appreciation:
"To Monsieur le Baron Thenard,
Member of the Academic des Sciences.
Monsieur :
"In 1823 when you presided over the Academie des Sciences a young foreign
student came to you and begged you to advise him concerning the fulminates
which he was then investigating.
A HISTORY OF METABOLISM 45
"Attracted to Paris by the immense reputation of those celebrated masters
whose glorious researches established the foundations of the sciences and elevated
them into an admirable edifice, he had no other introduction to you except his
love of study and his fixed desire to profit from your teachings.
"You bestowed on him a most encouraging and flattering welcome, you
directed his first researches, and through your influence he had the honor to
communicate them to the Academic.
"It was the session of the 28th of July which decided his future and opened
a career in which for seventeen years he has labored to justify your benevolent
patronage.
"If his labors have been useful, it is to you that science is indebted for
them, and he feels obliged to express publicly to you his ineffaceable sentiments
of -gratitude, esteem and veneration."
JUSTUS LIEBIG.
Giessen, 1 January, 1841.
Through the influence of Alexander von Humboldt, Liebig was ap-
pointed professor of chemistry at Giessen in 1824 at the age of twenty-
one. Wilhelm Ostwald writes in his "Grosse Manner" that this gave
him free water to swim in. Here he built the first modern chemical re-
search laboratory and attracted to it men, many of whom afterward became
distinguished. Liebig's "Thierchemic in Ihrer Anwendung auf Physiol-
ogie und Pathologie" was first published in 1840 and passed through nine
editions. Comparison should be made between it and the publications
of Boussingault already described.
Liebig divided the foodstuffs into protein, fat and carbohydrate, and
stated that protein could take the place of body protein, while carbo-
hydrate and fat could spare body fat. He believed that muscular work
caused the metabolism of protein, while oxygen destroyed fat and car-
bohydrate.
In the introduction he states that in fifty years it will be as impossible
to separate chemistry from physiology as it was then to separate chemistry
from physics; that he had endeavored to bring chemistry and physiology
together in a single book.
In one of his writings Liebig says that the acceptance of principles,
like the application of chemistry to physiology, all depends on the mental
development, that the great Leibnitz refused to accept Newton's doctrine
of gravitation, which is now understood by every schoolboy.
The time was propitious for the writing of Liebig's book. He himself
had been more largely the creator of organic chemistry than any man then
living. Chemical compounds of carbon were becoming known. Scheele
had discovered uric acid and lactic acid in 1776 and glycerin as a com-
ponent of fat in 1778; Fourcroy and Vauquelin in 1779 and Prout in
1803 had analyzed urea; Chevreul announced the chemical constitution of
fat in 1823 and Thenard investigated the composition of bile; Berzelius,
the composition of the secretions in general. In 1828 Wohler prepared
46 GRAHAM LUSK
urea synthetically, and in 1837 Liebig and Wohler, working together,
described the decomposition products of uric acid.
Carl Voit, writing in 1865, thus describes Liebig's services:
All these chemical discoveries, to which Liebig so largely contributed, gave
him his fruitful conceptions concerning the processes* in the animal body. Be-
fore him the observations were like single building-stones without interrelation,
and it required a mind like his to bring them into ordered relation. It is a
service which the physiologists of our own day do not sufficiently recognize. In
order to appreciate this one has only to read physiological papers written before
the publication of his books and afterward in order to witness how his writings
changed the mental attitude toward the processes in the organism. The chemical
discoveries on which he based his conclusions were, in fact, matters of general
knowledge, but it was he who applied them to the processes of living things.
Scientific progress is determined by the establishment of correct interpretations
and the creation thereby of new pathways and problems. A school-boy has a
better knowledge of many things than the wisest man had formerly; and he
laughs at the ignorance of his forefathers because he does not understand the
history of the human mind.
The man of science ought to realize the factors which have given him the
vantage which he holds. But there are textbooks on physiology in which the
chapters on the animal mechanism do not even mention the name of Liebig.
This anomaly is possible only for those who do not understand history, and who
hold only the new to be worthy of consideration. Liebig was the first to establish
the importance of chemical transformations in the body. He stated that the
phenomena of motion and activity which we call life arise from the interaction
of oxygen, food and the components of the body. He clearly saw the relation
between metabolism and activity and that not only heat but all movement was
derived from metabolism. He investigated the chemical processes of life and
followed them step by step to their excretion products.
The following quotations from Liebig's (6) "Thierchemie" appear to be
significant cf his attitude (Cambridge, 1842 ; Braunschweig, 1846) :
It is clear that the number of heat units liberated increases or decreases with
the quantity of oxygen given to the body in a given time through the respiratory
process. Animals which respire rapidly and are therefore able to absorb a great
deal of oxygen can eliminate a larger number of heat units than those which
have the same volume but absorb less oxygen.
Of metabolism in fasting, he writes:
The first action of hunger is a disappearance of fat. This fat is present
neither in the scanty feces nor in the urine, its carbon and hydrogen must
have been eliminated through the lungs in the form of oxygen-compounds. It
is clear that these constituents are related to the respiration.
Oxygen enters every day and takes away a part of the body of the fasting
person with it.
Martell found that a fat pig lived 160 days without food and .lost
120 pounds.
A HISTORY OF METABOLISM 47
In herbivora ten volumes of oxygen absorbed result in nine volumes"
of carbon dioxid eliminated. In carnivora only six or five volumes carbon
dioxid are eliminated (Diilcmg and Despretz).
With the exception of a small amount of sulphur, hydrogen is the only
other combustible substance with which oxygen could combine and it can be
regarded as settled that, whereas in the body of an herbivorous animal one-
tenth of the oxygen is used to form water, in the body of the carnivorous animal
four or five times that quantity are so employed.
In- the exact analysis of the process of respiration it is evident that the
carbon dioxid production is related to water formation and the two cannot be
dissociated. It is therefore self-evident that the determination of the quantity
of 'carbon dioxid expired by an animal within a given time is not a measure
of the respiratory process and that all experiments in which the relation of the
food to the total oxygen intake is not considered have only a relative value.
In starvation it is not alone fat which disappears but also all solids which
are capable of solution. In the completely wasted body of the fasting man the
muscles become thin and soft, lose their contractility ; all parts of the body which
were capable of producing movement have served to protect the rest of the organs
of the body from the destroying influence of the atmosphere. Finally the par-
ticles of the brain become involved in the oxidation process, delirium, madness
and death follow; resistance completely ceases, chemical putrefaction ensues,
and all parts of the body unite with the oxygen of the air.
Liebig speaks of the cleavage of sugar into lactic acid, into alcohol
and carbonic acid, and later into butyric acid, hydrogen and carbonic acid.
He then remarks:
No one will deny that such influences are at work not only in the respiratory
process but also have a part in the processes which take place in the animal body,
and if further investigations demonstrate that the cause of the decomposition
of sugar into alcohol and carbonic acid in alcoholic fermentation is dependent
on the development of a lower order of vegetation, and that the metabolism
of complex molecules with the production of new substances can be caused by
contact with certain particles which are in the state of vital movement, it is
clear that a pathway has been constructed which leads to a vision of the mysteri-
ous processes of nutrition and secretion.
As to the energy production, he says:
The lack of a correct viewpoint regarding energy and activity and their
relation to natural phenomena, has led people to ascribe the production of animal
heat to the nervous system. If one excludes the metabolism within the active
nerves, the above proposition would be merely saying that movement would arise
from nothing. But out of nothing no power or activity can arise.
Liebig asks:
What is the use of fat, butter, milk-sugar, starch, cane-sugar in the diet?
Through these non-nitrogenous food-stuifs a certain amount of carbon and in
the case of butter a certain amount of carbon and hydrogen are added to the
nitrogen-containing materials and form an excess of elementary substances which
cannot be used to generate nitrogen- and sulphur-containing substances, which
latter are contained preformed in the food. Hardly a doubt can be entertained
48 GRAHAM LUSK
that this excess of carbon or of carbon and hydrogen is expended in the pro-
duction of animal heat and serves to protect the organism from being attacked
by atmospheric oxygen.
' Further on he remarks :
In their final forms meat and blood which are consumed yield the greater
part of their carbon to the respiration, their nitrogen *is recovered as urea, and
their sulphur as sulphuric acid. Before this occurs the dead meat and blood
must be converted into living flesh and blood. The food of carnivora is con-
verted into blood which is destined for the reproduction of organized tissue.
We know that the nitrogen-containing products of metabolism are not sus-
ceptible of further change and are eliminated from the blood by the kidney.
Differences in the quantity of urea secreted in these and similar experiments
are explained by the condition of the animal in regard to the amount of the
natural movement permitted. Every movement increases the amount of organ-
ized tissue which undergoes metamorphosis. Thus, after a walk, the secretion
of urine in man is invariably increased.
In the animal body the components of fat are used for the respiration
process and hence for the production of animal heat.
If the condition and the weight of all parts of a carnivorous animal are
to be maintained it must daily receive a certain definite measure of sulphur and
nitrogen-containing food substances as well as of fat.
The difficulties of calculating the metabolism are discussed.
The weight of the ingested materials must be the same as those eliminated
in the forms of uric acid, urea, carbonic acid and water. The weight of the
ingested fat must be the equivalent of the fat eliminated in the form of carbonic
acid and water. From this it follows that the quantity of oxygen absorbed
cannot be a measure of the amount of the living substance destroyed in a given
time.
The oxygen absorption expresses the sum of two factors; one the destruction
of nitrogen-free substances and the other the destruction of nitrogen-containing
substances. It has already been frequently stated that the measure of the latter
can be determined from the nitrogen content of the urine.
He later considers the metabolism of a horse: "A horse preserves
itself in a state of health if he be given 7^ kg. hay and 21/4 kg. oats.
Hay contains 1.5 per cent and oats 2.2 per cent of nitrogen. Assuming
that all the protein in the food is transformed into the fibrin and serum
albumin of the blood, there would be produced daily 4 kg. of blood, con-
taining 20 per cent of water and 140 gm. of nitrogen. The quantity of
carbon combined with the protein and ingested at the same time would
have been 448 gm. Of this only 246 gm. could have served for the respira-
tion, for 95 gm. are eliminated in the form of urea and 109 gm. in the
form of hippuric acid. . . . The experiment of Boussingault which shows
that a horse expires 2450 gm. of carbon in a day cannot be very far
from the truth."
The nitrogen-containing substances of the fodder of the horse do not con-
tain more than one-fifth of the carbon necessary for the maintenance of the
A HISTOKY OF METABOLISM 49
respiration, and we see that the wisdom of the Creator has added to all the
foods the remainder of the carbon in the form of sugar, starch, etc., which is
necessary for the renewal and maintenance of animal heat and for the conversion
of inspired oxygen into carbonic acid. If these substances had not been present
in the food and there had been the same intake of oxygen, then the materials
of the animal's own body would have been used instead.
Liebig says that only a small fraction of the bile is unabsorbed and
cannot contribute greatly to the formation of the feces.
As to the formation of fat, Liebig argues as follows:
A spider, fierce with hunger, sucks the blood of the first fly, but is not to
be' disturbed by a second or third fly. A cat eats the first and perhaps a second
mouse, and will kill but not eat a third. Lions and tigers react the same way,
driven by hunger to devour their prey.
How different with a sheep and a cow in the pasture, which eat almost
without intermission as long as the sun in the heavens shines upon them.
The herbivorous animals eat in such excess that the ingestion of starch is
greater than is necessary for union with oxygen, and hence the animals fatten
through conversion of starch into fat.
Concerning alcohol, he makes the following comments: "Alcohol is
oxidized in the body, the carbon dioxid elimination decreases after alcohol
(Vierordt) because relatively more oxygen unites with hydrogen."
Liebig has been informed that in England all servants are given beer,
or where the Temperance Society is influential the money equivalent of
beer. Under the latter conditions more bread is eaten, so that the beer
is paid for twice, once in money and once in extra food containing the
same carbon and hydrogen equivalents as the beer.
Liebig enters into the calculation of the oxidation of various foods
in the body and gives the following values (p. 106) :
100 Liters of O2 And they warm liters of
combine with water from 0° to 37°
120.2 gm. starch 28.356
48.8 em. fat 27.647
Liebig also calculates the caloric value of meat. He prepares a table
of isodynamic equivalents which are given below, contrasted with the
values given by Rubner (d) later in 1885 (p. 75).
Liebig writes:
Since the capacity of these substances (the respiratory materials) to develop
heat through union with oxygen is dependent on the amount of combustible
elements which equal weights contain, and since the amount of oxygen neces-
sary for their combustion increases in the same proportion, therefore it is pos-
sible to calculate approximately their relative heat producing power or respira-
tory value. The following table contains the respiratory materials arranged in
one possible order. The figures express the relative amount of each substance
which a given amount of oxygen would convert into carbonic acid and water or
50 GRAHAM Ll'SK
approximately how much one must eat in order to maintain the body tempera-
ture at a given level of metabolism during a given time:
Table of Isodynamic Values
Liebig Rubner
in 1846 in 1885
Fat 100 100
Starch 242 232
Cane-sugar 249 234
Dried meat 300 243
This, surely, is a divination of Rubner's subsequently enunciated isody-
namic law.
As regards the oxygen requirement for the combustion of different
foods, comparisons may be made between the findings of Liebig in 1846
and those of Loewy in 1911 :
To oxidize requires O2 in c.c.
Liebig Loewy
Fat, 1 gm 2050 2019
Starch, 1 gm 832 828
It is evident that Liebig clearly understood that it was protein, car-
bohydrate and fat which were oxidized in the -body and that they were
the source of energy and not carbon and hydrogen supposed to be pro-
duced from them.
Liebig divides the foodstuffs of man into two classes, the nitrogenous
and the non-nitrogenous. The first class can be converted into blood ; the
other cannot be. The constituents of organs of the body are built up
from those foods which are convertible into blood. In the state of normal
health the other foodstuffs are used merely for maintaining the respira-
tion process. He calls the nitrogen-containing foods the plastic food-
stuffs and the non-nitrogenous, the respiratory foodstuffs. They are as
follows :
Plastic Foods Respiratory Foods
Plant fibrin Fat
Vegetable albumin Starch
Vegetable casein Gum
Meat and blood of animals Sugars
Pectin
Bassorin,
Beer
Wine
Brandy
A HISTORY OF METABOLISM 51
"It is a fundamental fact, so far without a contradictory experiment,
that the sulphur- and nitrogen-containing constituents of plants have the
same chemical composition as the principal components of the blood. We
know of no nitrogen-containing material of a composition different from
fibrin, albumin and casein which is able to sustain life.
"The animal organism is certainly able to construct its membranes and
cells, nerves and brain, the organic materials of ribs, cartilages and bones
out of. the. constituents of its own blood, but these constituents must be
already constructed in proper form or the production of blood and life
itself is brought to an end.
• "Looking at the matter from this standpoint, it is easily understood
why gelatin is not a builder of blood or a supporter of life, for its com-
position is different from that of the fibrin and albumin of the blood."
Concerning the ultimate disposal of the products of metabolism, Liebig
writes :
The kidneys, skin and lungs cannot be the only ways through which products
of the metabolism are eliminated from the body. The intestinal canal functions
also as an organ of excretion and its relation to the respiration process must
not be misunderstood.
If the quantity of oxygen absorbed in a given unit of time is that which
is exactly necessary to convert the products of metabolism present during the
same period into carbonic acid, urea and water, then the intestinal canal will
contain only indigestible substances.
... In general it must be assumed that all of the nitrogen- and sulphur-
containing constituents of the food of man are completely digestible, are brought
into solution and absorbed into the circulating blood, for a property belonging
to some parts must belong to all. In such cases it is undoubtedly true that the
discovery of nitrogen-containing materials in the feces signifies that they can
only be the products of the metabolism of the intestinal canal itself or products
which have escaped normal metabolism and have been excreted from the blood
by the intestinal wall.
Just before the publication of Liebig's great work Dumas, in glowing
language, pictured similar interpretations without giving Liebig credit
for the ideas. He utilized a formula similar to that given by Liebig
without stating its derivation. Thus, in 1842, Dumas and Cahours pre-
sented the following penetrating conception:
The food of an ordinary maintenance ration contains 16 to 21 gm. nitrogen.
This nitrogen is almost entirely recoverable in the urine in the form of urea.
Ignoring the intermediary phases, protein breaks up as follows:
C48H37N12015 + 100 O = Ca H12N1206 urea
^42 ^84 carbon dioxid
Hoc O0, water
C48H37N120115
The only object in giving this formula is to enable one to calculate the heat of
combustion of protein. Allowing for the daily production of urea from protein,
52 GRAHAM LUSIv
there would remain 50 gin. of carbon and 6 gm. of hydrogen suitable for oxida-
tion ; this would yield 575 calories. Since calculations based on the carbonic
acid elimination and oxygen absorption show that a man produces between 2,500
and 3,000 calories daily, it follows that he needs an additional 200 gm. of carbon
and 10 gm. of hydrogen to complete the required quantity of heat.
The writings of Dumas brought Liebig (6) to the defense of his priority
in an article entitled, "Antwort auf Herrn Dumas' Rechtfertigung wegen
eines Plagiats," published in 1842. He recited how, in the winter of
1840-41, he had lectured to his students upon: (1) the respiration process
in its relation to the bile, (2) the nitrogen-containing substances of the
vegetable kingdom are identical with those of the blood; and (3) sugar
and starch are not food materials but serve for respiration and for fat
production. A young Swiss student of Geneva came to Liebig with a
letter from Dumas, attended the lectures, and afterward carried the in-
formation to Dumas in Paris. With volume 41 of Liebig's Annalen the
name of Dumas as collaborator disappears from the front page. Berzelius
sided with Dumas in this historic controversy, greatly increasing the bit-
terness of Liebig. The feeling between the two men, however, must have
died down, for in a dedication to Dumas of his "Nouvelles lettres sur
la chimie," dated Giessen, 1851, Liebig speaks in the most flattering terms
of his old associate and brilliant antagonist.
Charges of plagiarism are contemporaneous with the progress of hu-
man thought. When two people work together they may find it possible to
make the pleasing statement of Bidder and Schmidt, "As the result of
mutual exchange of ideas and through intellectual metabolism, we find
ourselves in entire agreement." But as regards the controversies regarding
the priority of discoveries, such as grouped themselves around the person
of Lavoisier and the person of Liebig, no such self-abnegation was pos-
sible.
Wb'hler writes to Liebig regarding another matter in the following
words (Moore, 1918) :
To make war upon Marchand (or any one else for that matter) is of no use.
You merely consume yourself, get angry, and ruin your liver and your nerves —
finally with Morrison's Pills. Imagine yourself in the year 1900, when we shall
both have been decomposed again into carbonic acid, water and ammonia, and
the lime of our bones belongs perhaps to the very dog who then dishonors our
grave. Who then will care whether we lived at peace or in strife? Who then
will know anything about your scientific controversies — of your sacrifices of
health and peace for science? No one:, but your good ideas, the new facts you
have discovered, these, purified from all that is unessential, will be known and
recognized in the remotest times. But how do I come to counsel the lion to
eat sugar!
This is the correct interpretation to be placed upon rights of priority.
The influence of an individual is evidently the result of the sum total
of all activities of his life. If he contributes to the ideas of others, the
A HISTOEY OF METABOLISM 53
results may be of three kinds: (1) the donor may be publicly acknowl-
edged; (2) the donor may be honestly forgotten and the recipient may
honestly believe that he has for years held the same views; or (3) the
donor may be well known to the recipient but be deliberately and sys-
tematically ignored. The last-named reaction is the one most difficult to
bear with becoming humility of spirit, but, interpreted in the light of
history, it signifies but little. It matters little to the world at large
whether Bacon wrote Shakespeare or Shakespeare wrote it himself. The
heritage- of. the masterpieces is what matters.
Before Liebig's death he wrote to Wohler concerning the publication
of their correspondence as follows : "When we are dead and gone these
letters which united us in life will be as a token for the memory of man
of a not frequent example of two men who, without jealousy or envy,
strove in the same field and always remained intimately united in friend-
ship."
Liebig's Munich Period. — In 1852, at the age of forty-nine, Liebig
moved to Munich to become professor of chemistry there. His creative
work ceased and a period of literary activity set in. He engaged in
violent polemics with Pasteur, maintaining that alcoholic fermentation
was a purely chemical phenomenon and not one of biological origin. He
gave popular lectures in court circles and, with Richard Wagner, shared
the popular adulation of the town. When Liebig's new gluten bread was
put upon the market the townspeople stood in long lines before the
bakeries to receive the precious product.
It may be of interest to pass here to the viewpoint of Liebig ex-
pressed in 1870 just before he died. In the interim the work of Bidder
and Schmidt, of Bischoff and Voit, of Voit, and of Pettenkofer and Voit,
had appeared, material which is still to be recorded.
Liebig writes as follows : "On the basis of general experience I for-
merly expressed the opinion that the source of mechanical work of the
animal body must be sought in the metabolism, especially in the metab-
olism of the nitrogen-containing constituents of muscle. The capacity
for work in two individuals would therefore depend upon their respective
mass of muscle tissue, and the endurance of each would depend on his
capacity to rebuild the broken-down muscle substance from the inflowing
food material.
"It is well known that hard-working men eat much meat. An em-
ployee (Brauknecht) in Seldmeyer's large beer brewery consumes daily
810 gm. of meat, 600 gm. of bread and 8 liters of beer. One should be
cautious in adopting the popular Bavarian idea that it is the beer which
gives muscular power, for the beer drinkers are also the greatest con-
sumers of meat.
The question regarding the source of muscle power has been confused
through a conclusion which has been shown to be false and for which I am to
54 GRAHAM LUSK
blame. It was an error to assume that, if urea were an end-product of the
oxidative metabolism of muscle, then one could measure the intensity of the
work done by the quantity of urea in the urine.
The first facts contradicting the idea that urea is a measure of muscular
activity were communicated by Bischoff and by Bischoff and Voit of Munich,
which researches are to be considered as the extension of work accomplished in
Giessen. It is hardly necessary to state that these experiments always excited
my keenest interest because they were effected with rriy method of urea determi-
nation. . . .
These experiments firmly establish the fact that, although urea elimination
is a measure of protein ingestion and metabolism, it is not a measure of the
work done by the body.
When one thinks these matters over it is apparent that the facts could
not be otherwise. For if the metabolism of the muscle increased with work a
man could exhaust his entire supply of muscle tissue, because work is directed
by the will.
He criticizes Frankland's comparison of the muscle with a steam
engine, as follows:
It is certain that the wonderful structure of the animal body and of its
parts will long and perhaps forever remain an insoluble riddle. But the proces-
ses within the organs are of chemical and physical nature, and it is incompre-
hensible that oxygen and combustible materials are under the control of nerves
to induce their union. The factor of voluntary nerves upon muscle activity
must be of a different order. . . .
I consider that those investigators who have busied themselves with the
question of the source of muscular power have thought its solution too simple
and that it will be many years before a proper viewpoint leads to clarity in the
solution of this subject. I have no desire to enter into the dispute.
Liebig discusses the activity of the yeast cell as follows:
A close consideration of the behavior of the yeast cell may be desirable in
order to give a more definite idea of what transpires in living muscle.
It is certain that motions occur witKin the yeast cell through which it is
enabled to accomplish external work. This work consists in the cleavage of
carbohydrates and similar substances. This is chemical work; it would be
mechanical work if the yeast were able to split wood, which is likewise carbo-
hydrate.
One part of yeast can destroy sixty parts of its weight in sugar, according
to Pasteur. A gram of yeast can produce the heat equivalent of 148,960 gram
meters of work without the intervention of oxygen.
The cause of all these activities lies in the motions of the contents of the
yeast cells.
In similar manner the motions of life are present in muscle cells, without
muscular contraction resulting. When the movement within the muscle cells
rises above a certain limit, muscular contraction follows.
Liebig enters into a defense of the use of Liebig's extract of meat.
At one time he had regarded it, when mixed with potatoes, as the equiva-
lent of meat. He quotes Hippocrates:
A HISTORY OF METABOLISM 55
"Soup and pap were discovered because experience has taught mankind that
foods which are good for healthy people are not good for the sick."
One need only compare the capacity for work of the German workman, who
lives on bread and potatoes, with the English or American workman, who eats
meat, in order to gain a clear insight into the importance of the kind of food
taken. The partaking of meat raises the capacity, the power and the endurance
for work. Or compare an English statesman who may speak for five hours or
more in a Parliamentary debate, and who in the full possession of youth may
still engage in a strenuous hunt at the age of sixty, with a German professor
of the same age who sparingly conserves the rest of his physical powers and
who is exhausted by a walk of a few hours.
.• Liebig cannot understand the modern expressions, "organized protein"
and "circulating protein" ; they confuse him to such a degree that he
cannot tell his right hand from his left.
It is right to investigate a single phase in order to comprehend the existence
and activity of a whole process, but in order to interpret correctly the results of
investigations one must have a clear picture of the manifold phenomena and
the limitations affecting the entire problem.
I have a general knowledge (Ich weiss so ziemlich) of how to estimate the
importance of experiments and facts, and of their inequality as far as draw-
ing conclusions is concerned. The simple observation of a natural phenomenon
arranged without our assistance is more important and often much more diffi-
cult than the phenomena observed in an experiment produced by our will. In
the first reality is mirrored, while an experiment represents the imperfection of
our understanding.
I remember that many years ago during a walk between Berchtesgaden
and the Konigssee, a very simple observation led me to the conclusion of the
source of carbon in plants. At that time there was great confusion in the
subject, and it was difficult to exclude humus from consideration as a factor.
But on this walk Nature gave the proof that the carbon of the plant could arise
only from carbonic acid. For one finds rocks there which had been dislodged
and had fallen from the higher mountain side, and trees thirty or forty feet
high grow on the rocks, sending their roots between the crevices while the
rocks are covered only with moss and a layer of dust. It was impossible to con-
ceive that humus could have conveyed carbon to vegetation of this sort.
Similar observations can be made in the laws of nutrition if one has but
the good- will to see them.
It appears to me to be almost unthinkable that the high value placed by
the French family upon their "Pot-au-feu" is merely based on custom ; or that
one of the greatest military physicians of the French army, Dr. Baudens (Bau-
dens, 1857) would dare to say "La soupe fait le soldat" unless he was absolutely
convinced of the high potency of meat soup containing the necessary vegetables
which the French soldier often prefers to meat.
Liehig laments the criticism of his extract of beef and quotes Goethe,
"The word of a wise man teaches me that if a person once does a thing
which is good for the world, the world takes pains to see that that person
does not do it a second time."
One may annotate Liebig's opinion of Voit's "circulating protein"
and "organized protein" by citing a letter which Liebig wrote to Wohler
56 GRAHAM LUSK
in 1870, in which he says that he is considering giving up his lectures
during the summer semester upon the subject of animal chemistry and
nutrition and continues, "I find so little to interest me in what others
are doing in this subject I lose all desire to take part in it. They per-
form nothing but small experiments which lead to nothing. Modern
physiologists lack a great idea 'upon which all investigations depend."
Wilhelm Ostwald comments that this is the usual experience of parents
with their children, and is the greater the more capable and important
the children become.
It may be of interest in this connection that I heard Voit tell my
father in 1891 that there were no young, promising physiologists of about
forty in Germany at that date, a generalization which would have in-
cluded Rubner (born 1854), Kossel (bdrn 1853) and Hofmeister (born
1850).
The happy ideas obtained as the result of Liebig's walk between
Berchtesgaden and the Konigssee recalls the statement made. by Helm-
holtz at a festival given in honor of his seventieth birthday, in which
he told that he had never had a great thought come to him at his desk
nor when he was tired nor after taking a glass of wine, but usually when
he was walking in the garden thinking of other things.
All the quotations of Liebig's later views are from writings pub-
lished in the year of the Franco-Prussian. War of 1870. In his "Thier-
chemie" of 1840 and in several other of his publications at that period
occur the following memorable words : "Culture is the economy of power,
the sciences teach how to produce the greatest results by the simplest
means with the least expenditure of energy. Every unnecessary use of
energy, every waste of power in agriculture, industry, science, or in state-
craft is characteristic of crudeness or lack of culture."
Concerning the results of the conflict of 1870, Liebig moralized as
follows: "It was a battle between knowledge and science on one side
and empiricism and routine on the other, in which, as in agriculture,
knowledge won."
Hear this realizing cry of Pasteur (Vallery-Radot, 1902) which fol-
lowed the defeat of France in 1870 concerning the "forgetfulness, dis-
dain even, that France had had for great intellectual men, especially in
the realm of exact science." He says, "Whilst Germany was multiplying
her universities, establishing between them the most salutary emulation,
bestowing honors and consideration on the masters and the doctors, cre-
ating vast laboratories amply supplied with the most perfect instruments,
France, enervated by revolutions, ever vainly seeking the best form of
government, was giving but careless attention to her establishments for
higher education.
"The cultivation of science in its highest expression is perhaps even
more necessary to the moral condition of a nation than to its material
prosperity."
A HISTORY OF METABOLISM 57
Nor was the development of German science ignored in England, for
Matthew Arnold wrote in 1868: "Petty towns have a university whose
teaching is famous throughout Europe, and the King of Prussia and
Count Bismarck resist the loss of a great savant from Prussia as they
would resist a political check."
Let us not forget the environmental conditions under which men like
Liebig may be fostered and developed.
Bidder, F. W. (1810-1894) and Schmidt, C. (born 1822).— In order
to complete the story of Liebig's life this history has been diverted from
its chronological sequence, and it is now necessary to tell of the activity
of the period essentially coincident with the date of the publications of
Regnault and Eeiset. At the same time that these men were at work
in Paris, Bidder and Schmidt (a) were active in the German university
established at Dorpat in Russia. In 1852 they published their book,
"Die Verdauungssafte und der Stoffwechsel." Voit often referred to
this book as a veritable mine of information. The book, however, has
never been as well known as it should be. The statement still found
in textbooks on physiology that the influence of food upon the bile flow
has never been investigated finds its refutation in this volume, published
in the middle of the last century. Here, also, one finds the method of
computing the metabolism used by those who employed the Pettenkofer-
Voit respiration apparatus.
Bidder and Schmidt were much more profoundly influenced by the
doctrines of Liebig than were Regnault and Reiset. Had the methods of
the four investigators been combined, much of value would probably have
been rapidly uncovered. But Reiset's publication of 1868 on the metabol-
ism of farm animals shows no knowledge of the publication of Bidder and
Schmidt. To promote science one must know of contemporaneous activi-
ties in many lands, as well as of the older historical happenings.
C. Schmidt, who had been a pupil of Liebig and Wohler, began work
six years before (1845) the completion of the combined work of Bidder
and Schmidt. Schmidt had planned an experimental critique of the
metabolism of the higher vertebrates. His idea was to study in a few
typical forms the following main factors : oxygen absorption, carbonic acid
and urea elimination and the energy statistics of fasting animals, ac-
complished upon the same individual under identical conditions. Having
accumulated this mass of observations concerning the typical intensity of
the respiration and the protein consumption on the more prominent types
of vertebrates, it was planned to investigate in similar fashion the size
of the intermediary metabolism, the effect of external temperature and
the effect of partaking of protein, fat and carbohydrate, and then to
reduce the sum total of all the observations to a systematic whole.
It was beyond the power of a single individual to accomplish this
plan. A preliminary investigation established the specificity of the
58 GRAHAM LUSK
enzymes, that yeast can act only on sugar and produces only alcohol and
carbonic acid, emulsin acts only on amygdalin, converting it into hydro-
cyanic acid, benzyaldehyd and sugar; the same principle follows as re-
gards the digestive enzymes. The determination of the characteristic
metabolism, including the respiratory exchange, the analysis of urine and
feces and record of the body temperature upon a "single animal, each ob-
servation continuing over several weeks, required such unremitting at-
tention by a single observer that even one provided with a powerful
constitution found it almost beyond his power of accomplishment.
Bidder, who had become interested in the lymph flow as a possible
measure of the intermediary metabolism, united his work to that of
Schmidt and they decided to work together. Bidder edited the part
about the digestive juices and Schmidt "that about the metabolism and,
"as the result of mutual exchange of ideas and intellectual metabolism, we
are in entire agreement."
The intermediary metabolism is practically terra incognita. To in-
vestigate this the authors seek especially to determine the bile excretion
in relation to the total ingesta and excreta of the body.
They ask, "Is bile an excrement or not?" Schwann first described
bile fistula1. In at least six of his dogs the cause of their death could
have been attributed only to the removal of the bile (1844).
Blondlot disputed as to this being the cause of death (1846).
They note that the bile solids eliminated daily constitute a three-hun-
dredth part of the solids of the body and they inquire into the question
of the quantity of bile reabsorbed by the intestine, as follows: "We in-
vestigated the content of bile in the feces of a dog weighing 8 kg. during
a five-day period. In order to obtain exactly the quantity of feces be-
longing to this period the animal was given only meat during the experi-
mental period, and before and after the experiment he received a diet
of "Schwartzbrod," which yields an extraordinarily voluminous feces,
greatly resembling the bread itself and therefore easily recognizable. The
fecal material between these two portions must have been derived from
the meat diet or from the residues of the bile excreted into the intestine."
The feces following meat ingestion weighed 97.3 gm. and contained
40.9 gm. of dry solids. "Since this fecal matter contained only traces of
bile constituents, and since the quantity of bile solids flowing into the
intestine must have aggregated 39.52 gm. or nearly the quantity of the
entire feces, it necessarily follows that the larger part of the bile must
have been reabsorbed. Still more convincing is the fact that 39.5 gm. of
bile solids must have contained 2.37 gm. of sulphur, whereas the entire
sulphur content of the feces was only 0.384 gm., more than half of which
must have been derived from hair, for, excluding the hair in the feces,
only 0.154 gm. of sulphur were found. Almost all the biliary sulphur
must have been absorbed into the blood and we are therefore convinced
A HISTOKY OF METABOLISM 59
that the larger part, perhaps seven-eighths of the biliary solids return to
the blood and undergo further metabolic transformations before they are
removed from the body by other channels."
When Bidder and Schmidt operated on about a dozen cats by the
method of Schwann they all died of peritonitis in tavo or three days, but
in dogs only two of eleven died of peritonitis.
Liebig had stated that the bile was reabsorbed and was used as a
"respirat'ion stuff." It was formed in the body and then later, when re-
absorbed, was oxidized to carbon dioxid, being an example of the steps
in the metamorphosis of organic substance during life. To what an extent
does this process" take place?
A cat excreted 0.6 gm. bile containing 0.033 gm. solids per kilogram
of animal in the third hour after a meal.
There was no increase in the flow of the bile after giving fat. The
quantity was the same as that after 48 hours fasting. But the ingestion
of meat increased the volume of the flow and the weight of the solid
constituents.
In dogs with bile fistulse, the secretion of the bile cannot be very far
from normal because of the complete digestion of the foodstuffs, of the
effect of these upon the bile flow and of the perfectly normal condition
of the liver and its vascular supply.
This fate of the bile does not exclude its having certain functions,
while it is present in the gastro-intestinal tract. They can confirm the
recent work of Hoffmann regarding the antiseptic action of the bile on
the intestinal contents. For they observed that dogs whose bile is con-
ducted away through a fistula pass feces which have an extremely foul,
almost carrion-like, odor, and that there is flatulence induced by a gas of
evil odor. However, when bread alone was given the feces and fecal
gas had no odor.
Much more important is the question whether the bile has a digestive
action in making materials more fluid. When meat is given to dogs
with biliary fistula?, it is perfectly digested and absorbed and no particles
of undigested meat can be microscopically detected in the dog's
feces. This was true even when large quantities of meat were given.
However, when 113.6 gm. of fat were ingested, 72.2 gm. of fat substances
appeared in the feces. When black or white bread was given no starch
granules were present in the feces and the dog even gained weight. But
when fat was given there was very poor absorption ; in one case only one-
tenth was absorbed. Hence a normal dog absorbs much more fat than
one with a bile fistula.
They find, also, that there is much less fat in the chyle of the thoracic
duct of a dog which had been provided with a biliary fistula than in that
of a normal animal. The action of the bile is evidently upon fat or
upon the absorbing intestinal surface.
60 GRAHAM LUSK
Neutral fat in a melted state penetrates the epithelia of the intestinal
wall provided the same is covered with bile in a living animal, whereas
it is impermeable to fat when it is not covered with bile. There is a
greater attraction for fat in the former case. If two capillary tubes be
taken and one be soaked in fresh bile, the other in water or normal
saline, and then both be dipped in oil, the fat will rise much higher in
the tube dipped in bile than in the other tube (we moderns would call
this a diminution of the surface tension).
They state that when the bile is drawn off through a biliary fistula
there is an increased intake of other food to compensate for the losses
through the bile.
Is the absorbed bile eliminated through the kidneys or through the
lungs ? The nitrogen content is too small to contribute much to the
nitrogen content of the urine, and hence Liebig concluded that bile was
a respiratory material (material fit for respiration), yielding carbon
dioxid and water as end products. Certainly, all the carbon of the respi-
ration does not have to pass through the bile prior to oxidation, for the
total bile contains only 0.5 gm. of carbon, the expired air 8.6 gm. of
carbon per kilogram of body weight in the dog in twenty-four hours.
However, the 0.035 gm. of nitrogen eliminated in the bile per kilogram of
body weight might readily be that quantity which was liberated as free
nitrogen and was expired in the respiration.
Bidder and Schmidt describe what is now known as "basal metabol-
ism," as follows : "For every species of animal there is a typical minimum
of necessary metabolism which is apparent in experiments when no food
is given (im niichternen Zustande). The excess over and above this
necessary measure of typical metabolism can be termed luxury con-
sumption, although the well-being and the energy of all the functions of
life are considerably increased through this increased activity of
metabolism."
Bidder and Schmidt now attempt the first computation of the total
metabolism, as calculated from the respiratory as well as from the urinary
and fecal pathways of elimination. They say, "To give the total figures
would involve too much printing." The following was an experiment of
June, 1847, accomplished on a pregnant dog.
In the first place they give the following elementary analysis of dry
meat free from ash : ,:
C 53.01 per cent
H 7.02
N 16.11
O 22.86
S 1.00
100.00
61
During an eight-day period they give to a dog 1866.7 gm. of meat
of the above-mentioned constitution, together with 27.4 gm. of fat. In
the urine and feces of this period they find 62.36 gm. of nitrogen, which
would correspond to a destruction of 387.09 gm. of dry flesh or 1695.5
gm. of living tissue of the dog.
The balance would therefore read:
Grams
Flesh destroyed 1695.5
Flesh ingested 1866.7
Flesh retained 171.2
Add fat retained . . 27.4
Total maximum assimilation 198.6
The gain in body weight was 337 gm., the excess was attributable to
water retention.
Not only was the elementary composition of the urine and feces de-
termined (as in the method of Boussingault), but on seven different occa-
sions the carbon dioxid in the respiration was determined in periods
lasting one hour each. After this fashion Bidder and Schmidt were able
to estimate the quantity of the carbon metabolism, which they express
as follows:
C in
grams
387.09 gm. of muscle metabolized contain 205.20
In the excreta were eliminated 194.02
Retained in the body 11.08
Since the total carbon elimination in the urine, feces and respiration
was less than that derivable from the flesh metabolized, it was evident
that the ingested fat could not have participated in the metabolic process,
but must have been absorbed and stored in the body. Analysis of the
feces showed the almost complete absorption of fat.
This method of determining the total metabolism is in principle that
used by Pettenkofer and Voit a decade later.
The authors strike the following balance, showing the fate of 100 gm.
of meat protein :
C H N O S
100 gm. meat protein 53.01 7.02 16.11 22.86 1.00
In 34.52 gm. urea 6.91 2.30 16.11 9.20
In 65.48 gm. rest for respiration
and bile production 46.10 4.72 13.66 1.00
62 GRAHAM LUSK
A very small quantity of carbon, hydrogen and oxygen (3 to 5 per
cent) and a lesser portion of the sulphur as sulphid of iron were elimi-
nated in the feces, but the greater portion of the sulphur was eliminated
in the urine in the form of sulphuric acid.
From the data available they calculate the oxygen necessary for the
oxidation of the materials metabolized by the- dog. They note that
Regnault and Reiset obtained a relatively greater volume of oxygen ab-
sorbed than volume of carbon dioxid given off and attribute this to the
fasting condition of the animals, since fat contains relatively more hydro-
gen than protein and therefore more water was produced at the expense
of oxygen absorbed than in the case of a protein diet. Bidder and Schmidt
estimate the respiratory quotient of a meat-fed dog to be 0.84.
They further estimate that five per cent of the total carbonic acid ex-
pired passes through a stage of intermediary metabolism by way of the
bile.
In a fasting cat Bidder and Schmidt determined daily for eighteen
days the water eliminated in the urine and feces, the urea, sulphuric and
phosphoric acids in the urine, the expired carbonic acid and (for ten
days) the dried solids of the bile. From the nitrogen excreted they cal-
culated the quantity of carbon attributable to the protein metabolism of
the time. Subtracting this protein carbon elimination from the total
carbon elimination in the urine, feces and respiration, they were able to
calculate the quota of respiratory carbon attributable to fat metabolism
and from this the quantity of fat metabolized during the fasting period.
This is again the method followed by Pettenkofer and Voit.
They make the following table to represent the starvation period
(eighteen days) :
From the metabolism of C H. N O S P2O5
204.43 gm. protein ... 102.24 13.43 30.81 43.81
132.75 gm. fat 103.72 15.59 13.45
Total 205.96 29.02 30.81 57.26 2.167 3.761
Excreted by lungs, urine
and feces . . 205.96 4.67 30.81 18.42 1.127 3.565
Rest (to be expired as
water) 24.35 38.84
O2 Gm.
190.78 gm. expired C require to produce CO2 ... 508.74
24.347 gm. " H " " " " H2O . . 194.78
703.52
Less O2 contained in the products of metabolism. . . . 38.84
Oxygen which must have been used 664.68
A HISTOEY OF METABOLISM 63
What one now calls the "respiratory quotient" was 0.765, whereas
Regnault and Reiset had found 0.744.
After this fashion the metabolism was also estimated for each day.
The oxygen consumption fell from 44 gm. on the second day to 31 gin. on
the sixteenth day, just before the premortal fall in body temperature.
At the death of the animal the body was sectioned and the various
parts we-re weighed when fresh and their dry weights and fat contents
were later obtained. A normal cat was then killed and similarly analyzed.
The 'first cat before fasting had weighed 2572 gm., and at death 1241.2 gm.
The- original composition of the organs of the cat, when it began to fast,
was computed on the basis of the analysis of the normal cat. The loss
of weight of different organs in starvation could then be computed.
This is the historical forerunner of several similar extremely laborious
experiments.
In 1852 we might have read this modern statement:
The extent of the respiration, like every other component of the metabolism
process, is to be regarded as a function of one variable, the food taken, and one
constant, a distinctly typical metabolism (Respirationsgrosse) which varies with
the age and sex of the individual. This factor characterizes every animal of a
given race, size,, age and sex. It is just as constant and characteristic as the
anatomical structure and the corresponding mechanical arrangements of the
body. It is in the main determined by the heat consumption in the organism;
that is to say, the replacement quota for heat lost to the body through radiation
and conduction to the environment in a given unit of time. It may therefore
be used to determine this, or in case the factor of heat loss is known, one can
deduce the extent of the metabolism.
This typical metabolism ... is that of the fasting animal. It must be
nearly the same in animals having the same body volume, surface and tempera-
ture; the larger the body surface, the body volume and temperature remaining
constant, or the higher the body temperature with surface and volume constant,
the higher will be the metabolism as determined by the laws of static heat.
Of course a sharp mathematical treatment of this phenomenon can be
thought of only after very numerous and exact experimental determination upon
animals of most varied form, size and temperature.
A footnote states : "This is an extensive program and may require
many decades for its solution." It is suggested that experimenters divide
the investigations into the animal kingdom after the fashion that astron-
omers have divided portions of the heavens among themselves for ob-
servations. Bidder and Schmidt state that, acting with this intent, they
have dealt almost exclusively with the cat.
"Animals cannot maintain the typical metabolism over a prolonged
fasting period."
They define a "typical food minimum' as that quantity of assimilable
food upon which the body maintains its weight over a long period of
time. A slightly lesser quantity than this causes the body to lose weight.
After giving much meat "there is a double Luxus consumption : ex-
64 GRAHAM LUSK
pressed ( 1 ) by excessive oxidation, heat production, by increased evapora-
tion of water, and (2) by the cleavage of one-eighth of the carbon and one-
third of the hydrogen of protein in the form of urea. Only the smallest
quantity of this urea production is necessary for the maintenance of the
animal; it arises from the cleavage of the metabolized body protein itself.
The larger part is eliminated in order to yield tne carbon, hydrogen and
oxygen containing rest in a form suitable for respiration and not injuri-
ous to the body. Protein nitrogen cannot be eliminated through the
lungs, for nitrogen scarcely combines with blood and if liberated would
fill the capillaries with gas, nor can ammonia be produced for this destroys
the blood corpuscles."
The greater the quantity of fat given,, the smaller is the Luxus consump-
tion in carnivora. Among herbivora it is usually very slight because here
protein is taken in conjunction with an excessive quantity of carbohydrates and
is almost entirely used in replacement (Wiederersatz) of the body protein neces-
sarily destroyed — which latter is the typical (minimum) protein metabolism.
They find that following fat ingestion the feces contain magnesium
and calcium soaps, as shown by Boussingault.
The authors suggest that protein may be composed of taurin, glyco-
coll and a carbohydrate, a "respirations "rest," they call it. One hundred
grams of protein would contain:
Taurin 6.2 gm.
Glycocoll 79.3 gm.
"Respirations rest" 28.3 gm.
Taurin and glycocoll would yield 33.2 gm. of urea and 49.8 gm. of
carbohydrate.
They add, "It is not possible to formulate a well-grounded hypothesis
concerning the formation of urea because of the present uncertainty of
our knowledge of the composition of protein."
At the end of the book there is a beautiful chart showing the metabol-
ism of the fasting cat and giving the bile secretion as intermediary
metabolism.
Max von Pettenkofer (1818-1901). — Pettenkofer, who is well known
as the man who first raised hygiene into a science of sufficient dignity to
be provided with an independent laboratory of its own, was not only
responsible for the modern drainage system of the town of Munich,
which converted it from the "pestilential city of Europe" into one which
was extraordinarily healthful, but he also made notable contributions to
the physiology of nutrition.
He noted that a child with St. Vitus' dance, who partook of an in-
ordinate amount of apple parings, voided a urine containing a large
amount of hippuric acid. This was one of the earliest discoveries of the
influence of food on the composition of the urine.
65
The celebrated Pettenkofer reaction for bile salts was not determined
by accident. Liebig thought that fat arose from carbohydrate. To test
this, Pettenkofer treated a solution of cane-sugar with strong sulphuric
acid in order to dehydrate the sugar and obtain a rest rich in carbon
which might be convertible into fat. Since the liver or bile was believed
to further such a reaction, Pettenkofer added bile salts to the mixture and
obtained, nqt fat, but the well-known color reaction. Using this reaction,
he was able to show that normal feces contained no bile salts, though these
might be found in diarrhea.
In 1844 Pettenkofer found a compound in the urine which united
with zinc chlorid and he established its chemical composition. Its identity
remained hidden until it was one day shown to Liebig, who warmed it
over a flame on a porcelain cover, and from the odor evolved immediately
concluded that it must be related to the creatin of muscle. Such is genius !
Voit, who was acquainted with the work of Bidder and Schmidt, sug-
gested to Pettenkofer that he devise a respiration apparatus which would
measure the output of carbonic acid and water in a dog weighing 20 to
30 kilograms. Pettenkofer, who was interested to work with men as
well as with dogs, constructed the chamber of the apparatus so that it had
the size of a moderately large stateroom on a steamer, in which a man
could sleep, work and eat without discomfort. The ventilation of the
chamber was about 500,000 liters daily. Portions of the ingoing air and
portions of the outgoing air were diverted in their course and analyzed
for carbon dioxid and water. The increase in these materials in the
total air leaving the chamber represented the amounts given off by the
subject of the experiment. This was the first respiration apparatus
checked by burning a candle in it. Pettenkofer criticized Eegnault and
Reiset for not doing this, and thus establishing the limitations of the
accuracy of their work, a test which would have shown why nitrogen gas
was apparently at times absorbed and at other times excreted by their
animals.
Voit writes: "Pettenkofer's talents produced the respiration ap-
paratus and after that we together began experiments with it. Petten-
kofer and I had an equal share in the experiments."
Carl von Voit (1831-1908) was born in Amberg and was the son of
August Voit, architect of the Munich Glaspalast. In 1848 he went to
Munich to enter the university. He joined a students' corps but soon
left it in disgust, feeling it was no place for him and perhaps reflecting
upon the German witticism, "Er war so dumm dass selbst seine eigene
Corpsbriidern es bemerckt haben." He entered enthusiastically into the
republican ideas prevalent in that year in Germany. His revolutionary
activities earned him a black mark on the qualifications list of the uni-
versity, a fact which he discovered long afterward when he had risen in
position and fame.
66
GRAHAM LUSK
After passing his "physicum" examination, he went to Wiirzburg
in 1851, which was at that time a much more celebrated medical center
than Munich. After a year he returned to Munich, which had received
an academic stimulus by the arrival of Liebig. He graduated in medicine
in 1854 and, in order to prepare himself for a scientific career, he de-
voted the following year to attending lectures in physics, zoology, an-
atomy and chemistry. The last-named course was given by Liebig. He
entered the laboratory of prac-
tical chemistry then conducted
by Pettenkofer. With Petten-
kofer he studied an outbreak of
cholera, especially the accumu-
lation of urea within the organ-
ism during the infection and its
elimination subsequently. He
devoted a large part of his time
to the study of the works of the
great Liebig, whose reputation
filled the world. On Liebig's
advice he spent a year with
Wohler in Gottingen. He then
planned to pass a year with
Bidder and Schmidt in Dorpat,
but he was turned from this by
an offer of an assistantship to
Bischoff, professor of anatomy
and physiology in Munich. In
1859 he became professor extra-
ordinarius, and in 1863, at the
age of thirty-two, professor
ordinarius of physiology in
Munich, a position which he
held for forty-five years until
his death.
During his early student days he had a desk adjoining that of Brush,
for many years the dean of the Sheffield Scientific School. Of him
Voit said, "I can see him now, how accurately he worked !" And through-
out Voit's life it was "die Genauigkeit" upon which he placed the maxi-
mum of stress.
Perhaps it may be of interest to present some of the earliest of Voit's
work in this historical review. The ideas are largely expressed in the
light of the doctrines of Liebig. A young man is usually at first imbued
with the doctrines of his master. The master who has a knowledge of
accumulated facts can often most helpfully attempt to give the reasons
Fig. 7. Carl Voit. From a plate in the
"Jubelband" of the "Zeitschrift fur Biologic"
(Vol. XLII), published in honor of his seven-
tieth birthdav.
A HISTOKY OF METABOLISM 67
why things are; in other words, the doctrines and the theories. It is
only later, when the young man has accumulated new facts out of har-
mony with the old theories, that those theories are overthrown and left
as wrecks by the wayside. That is the history of science.
Voit (&) has put the matter thus:
I cannot agree with those \vho think that because they do not agree with
our conclusions «they can overthrow the whole piece of work (that of Bischoff
and Voit). For even though our theories should be as bad as represented, the
important part of the work, the experimental results, would still remain. Those
who know the history of science should have no idle illusions over the value of
their own opinions. Upon every page of history one can read that, the results
of a properly devised experiment are immortal, whereas the theories drawn from
the observation are frequently shown to be wrong, because it was not possible
at the time to take into consideration all the factors at work during the experi-
ment.
. . . From theories further scientific progress is evolved, they stimulate re-
newed activity. It often happens to the investigator that others with little
trouble to themselves present new conceptions of the work accomplished by him-
self, but the intelligent man, whose opinion and not that of the world in general
is worth while, will not forget to whom credit for the service belongs.
An early work by Yoit, "Beitrage zum Kreislauf des Stickstoffs" may
be thus abstracted: In recent times one has sought to obtain a more
intimate knowledge of the metabolism in the animal body by comparing
the intake of various constituents of food with the constituents of the
outgoing substances. In this category belong the experiments of Bidder
and Schmidt and of Bischoff (1853).
Bidder and Schmidt found in cats and dogs that almost all the nitro-
gen was eliminated in the form of urea. In one cat fed with meat 99.1
per cent of the ingested nitrogen was found in the urine, 0.2 per cent
in the feces, leaving only 0.7 per cent for the respiration.
Barral taught from experiments on himself that 8.33 per cent of
the ingested nitrogen was eliminated in the feces, 42.07 per cent in the
urine, leaving over 50 per cent for elimination by the lungs, an amount
certainly too large in the light of recent exact determinations of the
nitrogen elimination in the respiration, especially in those of Regnault
and Reiset, who never found more than 1/50 and usually less than 1/200
part of the ingested nitrogen thus eliminated. Voit calculates that Reg-
nault and Reiset's dogs, which absorbed between 121 and 212 gm. of
oxygen daily, could have eliminated only between 0.04 to 3.69 gm. of
nitrogen gas in twenty-four hours.
Both Lehmann and Boussingault, working with indirect methods,
found that much of the ingested protein nitrogen must have been elimi-
nated in the urine.
Bischoff was the first to use the titration method of Liebig for the
determination of nitrogen in the urine. This method is exceedingly accu-
68 GRAHAM LUSK
rate and rapid. Bischoff could not find all the ingested nitrogen in the
urine and feces. (The urines, however, were frequently alkaline.) When
500 gm. of meat were given to dogs a third of the nitrogen content, or
6 gin. must have been eliminated in the respiration. As this contra-
dicted Regnault and Reiset, Bischoff concluded that the nitrogen was
probably expired in the form of ammonia.
Perhaps Liebig's titration method might be wrong, so Voit devised a
method of distilling the ammonia derived from urine dropped upon soda-
lime. He made fifteen comparative tests, the first of which is thus
recorded :
N content of
5 c.c. urine
in grams
Liebig's method 0.2380170
Soda lime method 0.2277660
(The accuracy of this method of checking the results was subsequently
tested by Liebig himself and found to be correct.)
Neither Bidder and Schmidt, nor Bischoff, nor Voit, ever observed
undigested meat in the feces of a dog. But the dry feces contained 6.41
and 6.52 per cent of nitrogen.
Voit finds meat contains varying amounts of water and of nitrogen,
the latter between 3.41 and 3.69, with an average of 3.59 per cent.
Therefore, one cannot tell the exact composition of meat without some
degree of error.
Forty kilograms of meat, if estimated at 3.4 per cent of nitrogen
and then at 3.5 per cent of nitrogen content, would mean a variation
of 40 gin. of nitrogen.
Voit adopts the value 3.4 per cent, of nitrogen and he chooses well-
selected whole pieces of lean meat for his experiments in feeding animals.
He always collects the urine freshly voided from a trained dog and
the urine is always acid.
In this early work Voit gav$ to a dog weighing 27 kg. 1500 gm. of
meat for four days and collected the nitrogen eliminated in the urine,
feces and the bile. The dog lost 255 gm. in weight (this multiplied by
3.4 was believed to give the contribution of body protoplasm to the nitro-
gen excreted). The nitrogen balance read as follows:
Grams Grams
N in meat1 204.00 N in urine 197.48
N in lost body weight. . . 8.67 N" in feces 8.65
N in bile 2.09
212.67
208.22
A HISTORY OF METABOLISM 69
In another experiment, using a normal dog, the intake of nitrogen
contained in protein was 180.52 gm. and the outgo 180.96. In three of
the five experiments the whole of the ingested nitrogen in meat was re-
covered in the urine and feces. This did not support the idea that protein
nitrogen is eliminated in gaseous form through the lungs and the skin.
Bischoff stated that a part of the protein metabolism must be used
for the growth of the hair and the epidermis, and this would still further
lessen the possibility of its elimination as a gas in the experiments as
computed 'by Voit.
This work of Voit was carried further and published by Bischoff
(born 1807) and Yoit (/) in 1860 under the title, "Die Gesetze der Er-
nahrung des Fleischfressers," of which the following is an abstract :
"We propose to consider nutrition and the energy relations therein
involved as they concern the animal organism, much of which may seem
to be theoretical and therefore of little importance but which really
embodies the sum of the recently acquired knowledge concerning energy
and matter and which in part is concerned with our own observations."
All the experiments were done by Dr. Voit with the assistance of a
laboratory servant and it is Dr. Bischoff's opinion "that the numberless
analyses, the combustions and nitrogen, determinations of various foods,
of feces, etc., could not have been done with greater care or more tireless
zeal than they were done by Dr. Voit."
They do not believe that all the protein of the ingesta must first be
organized into the material of living cells before it can be metabolized,
but rather that the fluid protein of the blood penetrates living cells there
to be destroyed.
A dog was given 250, 500, 800, 1000 gm. of meat and still lost body
nitrogen. With 1800 gm. of meat the urea nitrogen was equal to that of
the food and when 2000 and 2500 gm. of meat were given the dog added
flesh to his body, but this had hardly begun before the quantity of urea
increased in the urine because the mass of metabolizing body tissue had
been increased. The dog would not eat more than 2500 gm. of meat.
The methods of calculation of the metabolism used by Bischoff and
Voit were much more crude than those of Bidder and Schmidt who pre-
ceded them. But the records of 'the protein metabolism, as measured in
the nitrogen in the meat ingested and in that of the urine and the feces,
are the classical observations on the subject.
In one experiment a dog weighing 35 kg. was given 31.6 kg. of rye
bread during a period of 41 days. The animal received 405.29 gm. of
nitrogen in the bread and eliminated 531.67 gm. in the urine and feces,
indicating a loss of body nitrogen of 126.38 gm., which corresponded to
a loss of "flesh" amounting to 3717 gm. Though the food was evidently
insufficient, the dog appeared well nourished and active at the end of the
experiment. His actual loss in body weight was only 690 gm. during
70 GRAHAM LUSK
the period. This was because of the saturation of the body tissues with
water when taking the bread diet, for when he was given 1800 gm. of
meat he passed a great stream of water, losing 300 gm. in body weight in
spite of a retention of the protein of meat which would have been the
equivalent of an addition to the body of 600 gm. of new "flesh" (vide
experiment of Stark, p. 14).
The authors found that, though gelatin could spare some body protein,
it could not entirely prevent its- loss. They state that it is an incomplete
(ungeniigendes) foodstuff.
Results — briefly abstracted.
We hold it for proved that the continued power to maintain movement on
the part of a fasting organism is derived from the metabolism of protein.
The three factors which induce metabolism are "blood, organ and oxygen,
and we believe that the metabolism of an organ is brought about by the united
action of all three influences.
The mass of non-nitrogenous and nitrogen-containing tissue, the quantity
of blood and blood plasma and the amount of available oxygen, these three fac-
tors determine the height of the metabolism.
If one gives to a fasting dog meat in such quantity that a loss from the
dog's body is not prevented, the metabolism rises. The increased quantity of
blood plasma increases the metabolism, although the mass of the organs remains
the same; the influence of oxygen, on account of the increased food and metab-
olism, is greatly reduced. ... As oxygen is present only in limited amount,
its action is reduced upon both body protein and body fat; the metabolism of
these is in consequence reduced.
If we increase the food protein and the blood plasma, the metabolism is
constantly increased until we reach a point when loss from the body is equal to
its repair. This is the moment when the metabolism of the protein parts of the
organism has so increased as to acquire all the oxygen available, and the metab-
olism of fat ceases.
If the amount of food be still further increased the metabolism scarcely in-
creases, for the available oxygen, through union with metabolic products,
has been reduced to a minimum. This is the moment when deposit, increase in
mass, excess for reparation, must and can ensue. . . .
But this process has a limit. As the intake of meat and the mass of the
nitrogen-containing tissue increases, the metabolic products also increase.
These require more oxygen. But the action of this is so reduced that, in spite
of the increased bulk of the plasma and of the organs, a limit to the metabolism
is set. As soon as the limit of metabolism is reached the limit of energy pro-
duction is also reached. If energy is no longer present and available, it is also
no longer possible to increase the metabolism. The animal can no longer eat and
refuses food. With a limitation of food intake the volume of blood and plasma
falls and the former condition returns.
This process constitutes an absolute proof that there is no such thing as
Luxus consumption of meat in the sense of the hypothesis of Frerichs' and of
Schmidt's ; i. e., that an oxidation of food protein in the blood takes place without
previous incorporation with the nitrogen-containing parts of the body tissue.
Sugar reduces the protein metabolism in the organs of the body and reduces
the quantity of protein in the food needed for replacement purposes, and pos-
sesses these influences even more than fat, probably because it has a greater
A HISTORY OF METABOLISM 71
affinity for oxygen than either ingested fat or body fat. . . . Starch behaves like
sugar.
It is established for all time and is and must be correct that the nitrogen-
containing materials are the sources of physical power, of the phenomena of
motion; also it is equally incontrovertible that fat and the so-called carbohy-
drates can yield only heat and never motion. From the foregoing results it
follows that the doctrine of Liebig regarding the division of the foodstuffs
into plastic and respiratory is correct.
The authors later suggest the names •"dynamogenetic" or "kinetoge-
neetic". for "plastic" food substances, and "thermogenetic" for "respira-
tory" foodstuffs.
The extension of the work to man is desirable. It should be known
to what extent ingested protein nitrogen appears in his urine as urea or
whether it is eliminated in other forms.
They expect people to say, "It is all self-evident and we have always
known these things," and still others to say, "This is not true, here are
facts which contradict you."
It is of great interest to note the affirmation of the doctrine of
Liebig in this early work, that though muscle effort was the cause of the
metabolism of protein, oxygen caused the destruction of fat and carbo-
hydrate up to the limit of the quantity of oxygen available. Both of
these doctrines were subsequently overturned by Voit. In the first place,
he found, the very same year as that in which he published his work with
Bischoff, that muscular work did not increase the protein metabolism of
a fasting dog or of one fed with meat. Later he showed the same to be
•true in the case of a fasting man and of a man fed with a mixed diet
containing a liberal amount of protein. He writes: "I maintain this
as an incontestable fact. It is of itself so important that I question
whether it is desirable to add a word of explanation. The results of a
properly conducted and properly appreciated experiment can never be
annuled, whereas a theory can change with the progress of science." How
quickly came the upsetting of the former assertion, "It is established
for all time and is and must be correct that the nitrogen-containing sub- t
stances are the sources of physical power, of the phenomena of motion!"
When I was in the Munich laboratory of Voit and happened to make
a positive assertion, the then second assistant, Max Cremer, said to me,
"Sagen Sie nicht, Herr Lusk, es ist so ; sagen Sie lieber moglicherweise
es kann so sein." Such are the cautious admonitions of those acquainted
with history.
The passing of the conception of oxygen being the cause of the
metabolism appears from the following words of Voit(&), written in 1865 :
"The conditions of protein metabolism lie in the elementary particles of
the organs of the body, which are the hearthstones for all variations and
activities. The life of the body is the sum of the action of all the
thousands of minute workshops. A combination with oxygen is not first
72 GRAHAM LFSK
necessary, but there is a breaking up into various constituents which,
under certain circumstances, may remain unoxidized.
"Through the peculiarities of cellular structure the conditions of oxi-.
dation are entirely different from those obtaining outside the cells. Under
ordinary circumstances nitrogen content means difficulty of decomposi-
tion, but in the body, protein is most readily destroyed. Hydrogen is
the most inflammable of the gases, but it can be respired up to quantities
of hundreds of liters daily without being oxidized.
"What the eye of the layman regards as rest is in reality an inter-
minable movement to and fro of the finest cellular particles, the most
complicated of all processes."
Volt's theory of "organized protein" and "circulating protein" served
its purpose in emphasizing the difference between the behavior of the
living protein of the tissue and the more readily metabolized protein of
the ingested food, even though the idea so troubled Liebig that, for the
thought of it, he could not tell his right hand from his left, and even
though it is now known that protein ingestion does not materially add
to the mass of blood protein.
Volt, in his necrology of Pettenkofer (d), thus describes a few of the
results obtained by their combined efforts with the celebrated respiration
apparatus: "Imagine our sensations as the picture of the remarkable
processes of the metabolism unrolled before our eyes, and a mass of new
facts became known to us ! We found that in starvation protein and fat
alone were burned, that during work more fat was burned, and that less
fat was consumed during rest, especially during sleep; that the car-
nivorous dog could maintain himself on an exclusive protein diet, and if
to such a protein diet fat were added, the fat was almost entirely de-
posited in the body; that carbohydrates, on the contrary, were burned,
no matter how much was given, and that they, like the fat of the food,
protected the body from fat loss, although more carbohydrates than
fat had to be given to effect this purpose; that the metabolism in the
body was not proportional to the combustibility of the substances outside
the body, but that protein, which burns with difficulty outside, metabolizes
with the greatest ease, then carbohydrates, while fat, which readily burns
outside, is the most difficultly combustible in the organism."
In Voit's great textbook, "Der Handbuch der Ernahrung und des
Stoffwechsels" (1881), one may read the words: "The methods deter-
mining the ingo and outgo of metabolic materials for animals and man
have very largely been devised by me." It was only Bidder and Schmidt,
with a crude respiration device, who had in any way approached the
methods of Voit.
It has already been shown how the scientific susceptibilities of nations
may be aroused and how two men of different nations may have their
disagreements. The polemics which Pfliiger, in Bonn, wrote against Voit,
A HISTORY OF METABOLISM 73
in Munich, have, however, historical interest. Voit (g), incensed by the
biting criticism of Pfliiger, adds a signed postscript to an article by Max
Gruber (1881) which concludes as follows: "It is to be regarded as
self-understood that I cannot enter into a method of dispute which is
so unworthy, a method which I can only despise. In science one should
seek to establish the truth by demonstrating the validity of one's opinions
after quiet and searching consideration and it is indeed an evil sign
when one goes as far as Pfliiger has gone in his polemic and uses lan-
guage which would not be tolerated in good society and would not be
regarded as permissible even in excited political debate. Such treatment
of scientific problems cannot possibly promote science but only hurt it,
and I am sure that many others think as I do, others who through honest
endeavor have shown that science was their primary interest, men who
have been able to open up new paths therein. It is fortunate that
Pfliiger, who has no sense of justice, is not the arbiter of the accom-
plishments of science but rather the future and those contemporaries who
can dispassionately estimate the work of others. I declare that I turn
away from this hateful discussion with loathing and cannot copy Pfliiger
in behavior."
To this Pfliiger (t) answers : "The unvarnished truth of my exactly
critical reply has seized Voit so that he was thrown into a paroxysm of
raving passion, and setting aside a real answer, he has poured upon me the
most insulting invective" (1881).
Answering this in the only purely polemical article he ever wrote,
•Voit(c) replies: "Gruber completely refuted the criticisms of Pfliiger
concerning our work and clearly explained Pfliiger's continual misrepre-
sentation of the same. It only remained for me to rebutt his groundless
accusations against the work put out from my laboratory. This could
only have been accomplished, not as Pfliiger says, in passion and raving,
which are foreign to me and hated by me, but rather by quietly explaining
in the postscript that I would not reply to remarks of mistrust and cal-
umny, which I can only despise" (1882).
Criticism is invaluable. Pfliiger later in life wrote, "Criticism is the
mainspring of every advance, therefore I practice it." But the quality of
it must not descend to billingsgate. Barker has aptly quoted from
"Truthful James,"
"I hold it is not decent for a scientific gent
To say another is an ass — at least to all intent ;
Nor should the individual who happens to be meant
Reply by heaving rocks at him, to any great extent."
Among the problems with which ^7oit concerned himself was the con-
version of starch into fat and of protein into fat and into sugar. His
earlier conception was that protein was largely convertible into fat, and
74 GRAHAM LUSK
this conception was in his mind to the end. In 1885 it was shown by
Rubner in Voit's laboratory that the relation between carbon and nitrogen
in meat protein, instead of being 3.68 C : 1 N, was really 3.28 C : 1 N.
Seven years after this Pfliiger's polemical arraignment cf Voit's older
work appeared, which was based upon a recalculation of the former experi-
ments of Pettenkofer and Voit (*). To this Voit made no reply, since
such a recalculation was merely in accord with Voit's later understanding*
At one time I had the good fortune to talk with Pfliiger for about half
an hour. He saw very few people and the introduction occurred under
especially favorable auspices. We discussed the production of sugar from
protein, which he freely admitted was possible, though at the time in his
writings he was inveighing against the idea. He was cordial, friendly
and appeared to me to resemble Voit more closely than any one I had ever
seen. His writings seemed to belie the character of the man.
Voit was the first to insist upon the value of flavor in the diet, A
food was a well-tasting mixture of foodstuffs, he insisted. A food without
flavor was rejected by both man and beast.
To give in detail the later historical development appears unnecessary.
A Munich review of the German translation of Lusk's " Science of Nu-
trition" (Stoffwechsel und Ernahrung) states that the development of the
school of Voit was nowhere else so thoroughly expounded.
Voit was always keenly interested in his lectures and his teaching.
He was precise in his statements, clear and interesting. He read his
lectures or presented the materials from notes, but no one in the audience
could tell whether he was reading from a text, as he often did, or extempo-
rizing. The lecture was in truth a "Vorlesung." He was conscientious
in every relation in life. A story is 'told that when the orders went forth
that the university would end on the fifteenth of the month, the professor
was greatly disturbed as to whether 'the order meant "including" or "ex-
cluding" the fifteenth. This was at a time when the average professor
stopped lecturing vvhen it suited his convenience, and many days before
the time set. His own standards which he set for himself were rigid.
He was an upright, honest, fearless, kindly man. At one time an assistant,
meaning to flatter him, said, "Your views are certainly the right ones,"
to which he replied in tones of sharp reproof, "It makes no difference
who is right so long as the truth is ultimately achieved."
Rubner, Erwin Voit (a brother), Friedrich M tiller, F. Moritz, Fritz
Voit (a son), Straub, Ellinger, Otto Frank, Prausnitz, Gruber, Cremer,
Weinland, Heilner, Atwater and I all owe allegience to the Munich school
of Voit.
Voit taught that one case carefully investigated was worth more than
many hundreds casually examined.
On the practical side, his investigations showed that an average labor-
ing man consumed food containing 118 gin. of protein and about 3,000
75
calories, or approximately the same diet as liad been estimated by Playfair
in 1865 (see p. 78). The unit of 3,000 calories was adopted as the
requirement of energy for the average adult male citizen when the Inter-
allied Scientific Food Commission met in Paris at the end of March, 1918,
to determine standards for the provisioning of a population of 225,000,000
people. The battleground around the 118 gm. of protein has been active
for forty years, with no greater result than the well-defined impression that
those who take that quantity of protein have a greater virility than those
to whom it 'is denied.
In the laboratory Voit was always enthusiastic. A new discovery was
the caiise of joy. The figures to be obtained excited his curiosity, he
would say, or the results were most interesting, most important. The
new method was extraordinarily accurate and the expectations therefrom
fascinating.
One day I burned my hand with ether in the laboratory. Some one
went for some cocain to relieve the pain, for which I offered to pay.
Money was refused. I had done so much for the State that the State
could well afford to pay. It was a new conception to me of a fundamental
relation of experimental laboratory work to the welfare of the State.
I look back upon my days in Munich with gratitude and to the
memory of Voit with respect and veneration.
Of those who were educated in the atmosphere of the Munich school
of Voit, Friedrich von Miiller is preeminent among physicians as the
leading internist of his time. And Rubner was the first to solve the
.problem initiated by Lavoisier, of demonstrating that the law of the
conservation of energy held true for the animal organism.
Max Rubner (1854-. . . .). — While still in Voit's laboratory as first
assistant Rubner (d) determined the calorific value of urine and feces un-
der different dietary conditions and laid the foundations for the computa-
tions involved in modern animal calorimetry (1885). Rubner applied the
knowledge he had won to the calculation of the heat production in man
and in many animals of different species. He (e) evolved the law of sur-
face area, that the heat value of the metabolism of the resting individual is
proportional to the area of the body surface. This law had been previously
indicated in the writings of Regnault and Reiset, as has been shown
(p. 43). His first publication regarding this was in 1883. A good
review of the literature on this subject is given by Benedict (z 1919).
Voit had constructed a calorimeter for measuring the heat production
of man and extensive and laborious experiments were carried out with it
during the years 1869, '70, '71, '74 and 1884. The mass of material
was never published on account of the imperfection of the apparatus.
Rubner (e), in 1891, working in his own laboratory at Marburg, vir-
tually with his own hands and with a very small allowance of money, made
a calorimeter which accurately measured the heat production of an animal.
70
GRAHAM U'SK
The interior of the apparatus was connected with a Pettenkofer-Voit
respiration apparatus. The heat measured by direct calorimetry agreed
within a fraction of one per cent with the heat calculated from the mot:il>-
olism products by indirect calorimetry. \7oit, when he heard of this
triumph of technic, remarked that it was the greatest discovery in its
way since the invention
of the thermometer.
Rubner's insistence
upon the importance of
the energy relations was
especially upheld in his
volume, "Die Gesetze
des Energieverbrauchs
bei der Ernaliruiig,"
published in 1902. On
account of the difficulty
of the style of presenta-
tion adopted in this
book it was some time
before its suggest iveness
was appreciated. En-
tirely different in style
and finely written in his
more popular "Kraft
und Stoff in Haushalt
der Natur," published
in 1909.
Rubner is a man
who finds his relaxation
among artists and can
himself paint a picture ;
a man of great talents
and fine personality. It
is interesting to note
that his advice on the food problems was largely disregarded by the
German authorities during the war (1914-18), and that his prophecies
regarding what would happen were fulfilled.
Nathan Zuntz (1847-1920). — No history of metabolism would be
complete without mention of Zuntz, in his early days a pupil and assistant
of Pfliiger, a practitioner of medicine for ten years, and long chief of the
agricultural college in Berlin. Zuntz studied the metabolism by means
of the gas analysis of the expired air obtained in short periods, and devised
a portable apparatus for the measurement of the metabolism of a man
walking at the sea level or on the snow fields of Monte Rosa. He made
Fig. 8. Max Rubner.
New York in 1912.
From a photograph taken in
A HISTORY OF METABOLISM 77
several balloon ascensions for scientific purposes. He also measured the
cost of energy at which horses and cattle performed work, and the loss of
energy through the bacterial putrefaction of the foods in such herbivora.
Magnus-Levy, a pupil, carried the Zuntz respiration apparatus to the
bedside of hospital patients and made pioneer investigations the validity
of which has been generally confirmed. Zuntz had a quiet, attractive
personality, without, however, possessing the breadth of view of Eubner,
who was the most frequent antagonist of his views.
Late French Work
If we turn back to France for a moment, which we left in the year
1849, we find an important paper by Berthelot (1827-1907) entitled "Sur
la chaleur animale," published in 1865, in which he argues concerning the
differences in the quantities of heat produced when equal weights of
carbohydrate and fat are oxidized in the body. He points out that it is
impossible to determine the heat production in the body by means of the
method of Lavoisier because 44 gin. of carbon dioxid produced from the
oxidation of carbon yield 94 calories, whereas the same amount produced
from methane yields 210,000 calories. He thus early concludes that 'the
quantity of heat liberated in the incomplete oxidation of a substance is
equal to the difference between the total caloric value of the substance and
that of the products formed."
Rubner's calorimetric observations were the realization of this theo-
retical conception.
The experiments of Charles Eichet (1850- . . ), published in 1885, con-
firmed Rubner's Law of Surface Area, and Richet affirms that in future
one should express all calorimetric observations in terms of surface
area and not. in weight, a principle now being largely followed in the
United States. Richet compared the heat production, as measured by his
calorimeter, of a cat, rabbit and goose of equal weights, as follows :
Calories
Weight per kilogram
in grams per hour
Cat . •• 3135 3.30
Rabbit 3100 3.32
Goose 3310 3.32
Writing about this work, in 1889, he says : "Let us consider a horse,
for example, which weighs 525 kg. and having a radius, one may assume,
of 50 centimeters, the surface area would then be 31.5 square meters.
This area is the same as that of 2250 sparrows, each weighing 20 grams.
Consequently, sparrows weighing 45 kilograms have the same surface as a
horse weighing 525 kilograms."
78 GRAHAM LUSK
In the summer of 1920, in Paris, Richet, in his opening address as
president of the Physiological Congress, said, "Seek to understand things;
their utility will appear later. First of all it is knowledge which matters."
And he illustrated this by citing the investigations of Claude Bernard on
the glycogenic function of the liver and the investigations of Portier and
himself, while they were sailing through tropical waters on the yacht
of Prince Albert of Monaco, upon the subject of anaphylaxis which they
carried on with poisons of sea anemones injected into birds.
Conclusion
The writer is conscious of the fact that this story is incomplete. For
example, he is not forgetful of the work of Lyon Playfair (1818-1898), a
pupil of Ludwig who in 1865 gave various dietary standards among which
that for a man working moderately was about the same standard fixed
later by Voit. Nor does he forget the recent work of Robert Tigerstedt of
Helsingfors, or of Tangl (1866-1916) of Budapest, of Johannson of
Stockholm. The complete story would be long, too crowded with details,
perhaps already a justifiable criticism, of the material here presented.
In a recent address given in Berlin, Friedrich Miiller stated that the
science of nutrition, which had been a German science, had partly passed to
America. But before it became German it was French, perhaps before
that English, and at its dawn Italian. In this country the early calori-
metric work of Wood and Reichert, both of Philadelphia, ought not to be
forgotten. Wood's work on fever is of importance. The work of Chitten-
den (a pupil of Kiilme of Heidelberg), continued by Mendel; of Atwater,
continued by Armsby, F. G. Benedict and H. C. Sherman; that of Mc-
Collum, a pupil of Mendel ; of Steenbock, a pupil of McCollum ; that of
Murlin, Du Bois, Ringer and me, has been work accomplished in the
earnest endeavor to unfold the truth as we have understood our mission.
We are not unmindful of the aid given by those of more purely chemical
tastes, like Osborne, Folin, Levene, Stanley Benedict, Jones, Van Slyke,
and Dakin; or of the mighty travail of Alonzo Taylor, chief scientific
adviser to Herbert Hoover in his work of providing nourishment for the
nations of the world.
Across the water in that wonderful island called Great Britain are
Hopkins, T. B. Wood, Halliburton, Cathcart, Leonard Hill, Hardy, E. H.
Starling and others through whose unrecognized efforts the food program
of their country was saved from disaster during the war. Strong scientific
personalities have developed in Britain, despite lack of national recog-
nition. These men and men in France, in Italy, as well as in Germany,
are carrying on to-day what will to-morrow be a part of the History of
Metabolism,
SECTION I
Dietary Constituents and Their
Derivatives
The Proteins and Their Metabolism A. I. Ringer
Introduction — Elementary Composition of Proteins — Classification of the Pro-
teins— The Structure of the Protein Molecule — Amino Acids or "Build-
ing Stones of Protein" — The Role of Amino Acids in the Structure of
the Protein Molecule — The Amino Acid Content of Different Proteins —
Reactions of Protein — Color Reaction — The Biuret Reaction — The
Xantho Proteic Reaction — The Million's Reaction — The Sulphur-lead
Reaction — The Moljsch Reaction — The Adamkiewicz-Hopkins-Cole Reac-
tion— The Triketohydrinden Hydrat Reaction — Precipitating Reactions
of Proteins — The "Salting Out" of Proteins by Means of Electrolytes —
Coagulation and Denaturalization of Proteins. — The Salt Formation of
Proteins — The Digestion of the Protein — The Absorption of Products
of Protein Digestion from the Gastro-intestinal Canal — The Fate of
Absorbed Amino Acids in the Blood — The Fate of Amino Acids in the
Tissues — Urea Formation — The Fate of the Xon-nitrogenous Fraction
of the Amino Acids — Protein Metabolism — The Question of Optimum
Versus Minimum Protein Diet — The Function of Protein in the Diet
— Incomplete Proteins — The Influence of Protein on Metabolism — The
Specific Dynamic Action of Protein.
The Proteins and Their Metabolism
A. I. RIXGER
NEW YORK
Introduction
The proteins are the most important constituents of the animal and
plant kingdoms. They are an ill-defined group, colloidal in character,
non-volatile and obtainable in a pure state with the greatest of difficulty.
Just as the molecules of the simple chemical compounds are built up of
atoms and radicals, the protein molecule is composed of the union of a
great many amino acids. In all, about twenty-one different amino acids
have been found, and there is every reason to believe that more will be
found in the course of time. When one realizes that the amino acids them-
selves are of rather large size and that all of them may be present in most
of the proteins, one can readily appreciate the enormous size and complex-
ity of the protein molecule. The exact determination of the molecular
weight of the protein seems at present to be a hopeless task, in spite of
many ingenious attempts. By means of the freezing point method, egg al-
bumin is found approximately to possess a molecular weight of about 14-
000, and calculating the molecular weight of hemoglobin on the basis of
one atom of iron, one gets the figure of 16000. The protamins, which
are the simplest proteins, have a molecular weight of approximately 4000.
Elementary Composition of Proteins
The proteins are composed of the following elementary constituents:
Carbon, Hydrogen, Nitrogen, Oxygen and Sulphur. The quantitative
relationship of these elementary constituents is found to fluctuate in
the different proteins within narrow limits. Carbon, 50 to 55 per cent ;
hydrogen, 6.5 to 7.5 per cent; nitrogen, 15 to 17.5 per cent; sulphur, 0.3
to 2 per cent; phosphorus, 0.4 to 0.8 per cent; oxygen, 21 to 23 per cent.
Classification of the Proteins
Up to the present we have not yet arrived at, any definite knowledge
concerning the structural formula of the protein molecule, and until that
81
82 A. I. RINGER
is achieved a satisfactory' chemical classification will not be possible. All
the known proteins possess certain chemical and physical properties in
common, and differ in others. The classification at present is based on
these differences. It is based upon differences in their solubilities, coagu-
lations, precipitations, etc. It is a crude, and more strictly physical than
chemical classification, but it answers the purpose to a certain extent by
bringing some order out of chaos.
The proteins are divided into three main groups :
I. The simple proteins which yield on hydrolysis a-amino acids.
II.- Conjugated proteins which are composed of simple proteins chem-
ically united with another organic compound.
III. Derived proteins which are proteins that are found in the in-
complete digestion or hydrolysis of either of the above naturally occurring
protein.
These three main groups may be further subdivided into the follow-
ing groups :
I. Simple Proteins.
a. Albumins
b. Globulins
c. Glutelins
d. Prolamiris (alcohol soluble proteins)
e. Albuminoids or Sclero proteins
f. Histones
g. Protamins
II. Conjugated Proteins.
a. Nucleoproteins
b. Glucoproteins
c. Phosphoproteins
d. Chromoproteins
e. Lentoproteins
III. Derived Proteins.
A. Primary B. Secondary
a. Proteins a. Proteoses
b. Metaproteins b. Peptones
c. Coagulated proteins c. Peptides
The albumins are present extensively in the animal and plant king-
doms. The most important ones of this group are serumalbumin (from
blood), ovalbumin (from the white of egg), lactalbumin (from milk).
As a class they are characterized by their solubility in distilled water,
dilute acid and alkali. In the presence of neutral salts they are coagulated
83
by heat, and are precipitated by alcohol, concentrated mineral acids and
the salts of heavy metals. They are quantitatively precipitated by satura-
tion with ammonium sulphate in neutral solution. Most of them may be
obtained in pure crystalline form.
The globulins are also present extensively in the animal and plant
kingdoms. They are found in the blood as serum globulin, fibrinogen
and its derivative fibrin ; in the muscles as myosinogen and myosin ; in the
egg as ovoglobulin ; in milk as lactoglobulin ; in the crystalline lens of the
eye as lentoglobulin ; in the thyroid gland in combination with iodin as
thyreoglobulin or iodothyreoglobulin ; in the urine as Bence Jones' pro-
tein.
As a class they are characterized by their insolubility in pure distilled
water and dilute acid solutions. They are, however, soluble in dilute neu-
tral salt solutions and in dilute alkaline solutions. They are coagulated
by heat and precipitated by alcohol. They are completely precipitated
by saturation with magnesium sulphate and by half saturation with am-
monium sulphate. They are strongly acid in reaction and possess the
power of turning blue litmus red.
The glutelins are a group of proteins which are present in the plant
kingdom only. We know the glutelin of wheat and the oxyzenin of rice.
They are soluble in dilute alkali, forming salts.
The prolamins or alcohol soluble proteins are a group of proteins found
in cereals. They are gliadin of wheat, hordenin of barley and zein of maize.
They are characterized by their solubility in 70 to 80 per cent alcohol,
and by their insolubility in water, neutral solvents and absolute alcohol.
The albuminoids or sclero proteins are a group of proteins found in the
framework of all connective tissues. In this group belong elastin, gelatin
and collagen, keratin from hair, bones, hoofs, nails, turtle shell, also silk
gelatin, reticulin, etc. They are characterized by their marked insolubility
in any of the neutral solvents and their resistance to chemical decom-
position.
The histones are a sharply defined group of proteins strongly alkaline
in reaction, and not found free in nature but in combination with acids or
other proteins. They contain a large amount of the dibasic amino acids
(see page 87), lysin, arginin and histidin. They are found in com-
bination with nucleic acid in the nucleoproteins and with hematin in hemo-
globin. They are soluble in water and precipitated by alkali. They are
coagulated by heat in the presence of small amounts of salts, and are pre-
cipitated by other proteins.
The protamins are the simplest of all the proteins. Similar to the
histones, they are strongly alkaline in reaction. They contain 25 to 30
per cent of nitrogen and are made up almost entirely of the dibasic amino
acids (ninety per cent). They are found in combination with nucleic
acid in the nuclei of the spennatozoa of numerous fish. They are soluble
84 A. I. RINGER .
in water, and are not coagulated by heat. They turn red litmus blue. Be-
cause of their basicity they have the power of absorbing carbon dioxid
from the air, forming carbonates. They form stable salts with mineral
acids and have the power of precipitating other proteins.
The conjugated proteins will be taken up in a separate chapter. The
derived proteins will be discussed in the chapter on digestion.
The Structure of the Protein Molecule
It has been known for a long time that if acids, alkalis or digestive
ferments like pepsin or trypsin be allowed to act on protein under suitable
conditions, there sets in a decomposition of the protein molecule, which,
if carried on for a long enough time, will cause an almost complete disap-
pearance of the protein. In the process of this decomposition a number
of cleavage products are produced which have been isolated, purified and
identified. They are all amino acids — i. e., organic acids which have an
ymino ( — NH2) radical attached to their o-carbons. These amino acids
are obtained from the splitting of all proteins, and because of that they are
known as the "building stones" of protein. To date, twenty-one different
amino acids have been obtained as cleavage products of the protein mole-
cule, and there is every reason to believe that the list is not yet complete,
though it may be said with certainty that the most important ones have
been accounted for.
Amino Acids or "Building Stones of Protein"
The known amino acids may be considered under the following head-
ings:
A. Monobasic Mono Amino Acids.
1. Glycocoll or glycin or a-amino acetic acid.
CH2NH2
COOH
2. Alanin or a-amino propionic acid.
CH3
I
a-CHNH2
I
COOH
Monoamino acids
reaction neutral
Dipeptids
Glycocoll
Glycyl-glycin
Alanin Alanyl-alanin
Two possible dipeptids between glycocoll and alanin
Glycyl-alanin
•Alanyl-glycirx
Leucin
Six possible tripeptids
between glycocoll, alanin.
and leucin
Alanyl- glycyl-leucin
L e ucyl- glycy 1- alanin
Tyro sin
Tryptophan
Histidin
Cy stein
Straight chain polypeptid (heptapeptid)
Glycyl-alanyl-leucyl-tyrosyl-tryptophyl-histidyl-cystein
PLATE I. SCHEMATIC REPRESENTATION OF THE AMINO ACIDS.
The neutral amino acids each contain a basic arriino group (blue) and ail acid
carboxyl group (red), which neutralize each other. These amino acids can link
themselves to one another in straight chains, in any combination and permutation,
the amino group uniting with the carboxyl group.
Aspartic Acid.
Dibasic acid,
reaction acid
Branched Polyp eptid.
Glycyl-alanyl-diaspartic-Acid
This tetrapeptidcan develop linkages along
two tranches, beside the main chain. Its
reaction is acid due to the preponderance
of carboxyl groups. Such polypeptids
linked would give an acid protein.
Serin
Prolin
Valin
Arginin
Diamino acid,
reaction basic
Schematic representation of a protein molecule
PLATE II. SCHEMATIC REPRESENTATION OF A PROTEIN MOLECULE.
This is the supposed composition of the protamin of the salmon (salmine). Six
tripeptids, each composed of two molecules of the diamino acid arginin and one
monoamino acid, are linked together. The protein is strongly basic because of the
preponderance of the amino groups.
THE PROTEINS AND THEIR METABOLISM 85
3. a-amino butyric acid.
CH3
CH
COOH
4. Valin or a-amino iso-valerianic acid or a-amino (3-methyl butyric
acid.
CH3CH3
\ /
P-CH
COOH
5. Leucin. or a-amino y-methyl valerianic acid.
CH3CH3
\/
Y-CH
a-CHNH2
I
COOH
6. Iso-leucin or a-amino |3-methyl valerianic acid.
CH3
Y-CH2
CH3-P-CH
COOH
86 A. I. RINGER
7. Normal Leucin or a-amino caproic acid.
CH3
6-CH2
Y-CH2
P-CH2
COOH
These amino acids are neutral in reaction, but have the property of
uniting with both acids and alkali. Glycocoll, for example, can combine
with NaOH forming sodium glycocollate:
CH2NH2 CH2NH2
" NaOH - * + H2O
COONa
Sodium So.dium Glycocollate
hydroxid
which is still capable of combining with an acid radical, because of the
free basic amino radical ( — NH2).
On the other hand, glycocoll can combine with an acid like hydrochloric,
forming a well defined salt, glycocoll hydrochlorid, which is acid in re-
action.
CH2NH2 CH2NH3C1
+ HC1 -»
COOH COOH
Glycocoll Hydrochloric Glycocoll hydrochlorid
acid
and is capable of uniting with alkali because of its free acid radical
( — COOH) known as carboxyl.
B. Dibasic Mono Amino Acids.
1. Aspartic acid or a-amino succinic acid.
COOH
P-CH2
a-CHNH2
COOH
THE PROTEINS AND THEIR METABOLISM
87
2. Glutamic acid or a-ammo glutaric acid.
COOH
Y-CH2
a-CHNH
COOH
These amino acids are strongly acid in reaction because of the fact
that they possess two acid radicals and only one base. In spite of the fact
that they are strongly acid, they possess the power of combining with other
acids, forming salts.
COOH
COOH
CH
COOH
Aspartic acid
COOII
Aspartic acid
hydrochlorid
They also have the power of combining with two alkali radicals be-
cause of the two carboxyl ( — COOH) radicals.
COOH
I
CH2
|
CHNH2
I
COOH
2NaOH
COONa
I
CH2
CHNH2
I
COONa
2HO
C. Hydroxy- and Thio-a-amino acids.
1. Serin or a-amino fi-hydroxypropionic acid.
P-CH2OH
COOH
88 A. I. RINGER
2. Cystein or o-amino j3-thio-propionic acid.
P-CH2SH
a-CHNH2
COOH
3. Cystin or dicystein.
CH2 — S — S — CH2
I I
CHNH2 CHNH2
COOH COOH
These three substances are neutral in reaction, and have properties sim-
ilar to those in group "A". The two latter are the only amino acids which
contain sulphur, and there is every indication to prove that only the latter
exists in protein and that the former is only a product of its hydrolysis.
4. p-Hydroxyglutamic acid, Dakin (1918, 1919).
COOH
CH2
P-CHOH
<x-CHNH2
COOH
This acid is similar to the dibasic acid glutamic acid, except that it
has an hydroxyl radical attached to the P-carbon. This is the youngest
member of the amino acid family, naving been discovered by H. D. Dakin
in 1918.
D. Diamino acids.
1. Lysin or a-E-diamino caproic acid.
e-CH2NH2
8-CH2
Y-CH2
P-CH2
I
a-CHNHj,
COOH
THE PROTEINS AND THEIR METABOLISM
89
2. Ornithin or a-arnino 6-amino valerianic acid.
5-CH2NH2
Y-CH2
a-CHNH2
COOH •
3. Arginin or a-amino 5-guanidin valerianic acid.
C —
Y-CH
I
P-CH
<x-CHNH
COOH
These substances are strongly alkaline in reaction. The last substance,
on hydrolysis with alkali or an enzyme known as arginase, splits into urea
and ornithin. This latter substance is not found as such among the pro-
tein cleavage products.
E. Aromatic amino acids.
1. Phenyl-alanin or a-amino /3-phenyl propionic acid.
CH
/ \
HC CH
|| {-Phenyl radical
HC CH
\ / -
C
CH2
CKNTH2 1
COOH
Alanin radical
90
A. I. RINGER
2. Tjrosin or a-amino para hydroxy phenyl propionic acid.
COH
/ \
HC CH
I II
HC CH
\ /
C
CH2
CHNH2
COOH
These amino acids are similar to those of the monobasic mono-amino
acid group, except that they are derivatives of the phenyl group.
F. Heterocyclic amino acids.
1. Prolin or a-pyrolidin carboxylic acid.
H2C — CH2
H2C CH — COOH
or
\
NH
Pyrolidin
radical
CH2
\
CH2
CH2
CH7
COOH
2. Oxyprolin or hydroxypyrolidin carboxylic acid.
HOHC - CH2 CH
CH — COOH or CHOH
\ /
Nil
COOH
THE PROTEINS AND THEIR METABOLISM
91
3. Histidin or a-amino fi-iminoazol propionic acid.
CH — Nil ~\
\rar [ Iminoazol radical
°
C —
CH2
CIINH2 Alanin radical
COOH
4. .Tryptophan or Indol a-amino propionic acid.
CH
/ \
HC C — C — CH2 — CHNH2 — COOH
HC C CH
\ /\V
CH NH
Indol
radical
Alanin
radical
The Role of Amino Acids in the Structure of the Protein
Molecule
From the above it is seen that all the amino acids, no matter how simple
or complex their structure, possess at least one amino ( — NH2) radical and
at least one acid ( — COOH) radical. These two radicals impart to each
amino acid the power of uniting with at least two. other amino acids of
similar or different structure, forming what are known as peptids.
H
CH —
N
\
H
COOH
Glycocoll
H
\
H
II
CH,—
III
H
— CH,
CO
H
N — CH,
COOH
Glycocoll
H COOH
Glycyl-glycin
H0
92
A. I. KINGER
In this reaction two glycocoll molecules are allowed to interact. The
basic amino radical of II unites with the acid carboxyl radical of I, giving
rise to the glycyl-glycin peptid III. This compound, while larger and more
complex than the original glycocoll, still possesses one free — NH2 and one
free — COOH at either end, which again makes it capable of uniting with
other amino acids at either end or with other peptids.
B
III
H
H
CH, — N
! \
H
CO N — CH2
/ I
H COOH
CH2 — N
I \
H
4- HOOC
Glycyl-glycin -\- Glycocoll
IV
H
CH — N — 00
CH2 —
CO
CH,
/ I
H COOH
Glycyl-glycyl-glycin
H
H
C
III
CH —
CO - - N — CH2
/ I
H COOH
Glycyl-glycin
III
HOOC — CH,
OC — CH2 —
Glycyl-glycin
H
H
H
CH, — N OC — CH,
H
CO - N — CH2 N<
OC — CH2 —
H COOH
Tetra-glycyl-glycin
H
H
THE PROTEINS AND THEIR METABOLISM 93
D
III I V
H H
X< H X<
H | H CH2 — X< / H
CH2 — X< -^ | OC — CH2
H -f HOOC — CH2
CO - - X — CH2
CO - - X — CH2 H /
/ + >X — CH2 H CO — X — CH2
H COOH- H /
COOH H COOH
Glycyl-glycin -f- 2 molecules of glycocoll — *• Tetra-glycyl-glycin
In these reactions we have illustrations of the various reactions that
glycocoll and its peptids may undergo. In B. we have a molecule of glycyl-
glycin unite with one molecule of glycocoll, giving rise to a tri-peptid
glycyl-glycyl-glycin.
In C. one molecule of glycyl-glycin unites with another molecule of
glycyl-glycin, giving rise to a tetra-peptid, while in D. one molecule of
glycyl-glycin unites with two molecules of glycocoll, giving rise to the
same tetra-peptid.
From these illustrations we also learn that no matter how many amino
acids are hooked on to one another, they will always have one — NH2 free
at one end, and one — COOH at the other, making the possibility of the
length of this chain indefinite.
We may therefore conceive of an amino acid as an individual with
an arm at either side, capable of clasping two other individuals. The
chain that may thus be formed is theoretically endless.
If a protein were made up by the union of a large number of molecules
of a single amino acid the problem would be comparatively simple. We
would be dealing with a straight chain of amino acids. The difference
between one protein and another would depend only upon the number of
amino acid molecules that go to make the protein molecule. But in the
natural proteins we have to deal with a union of about twenty-one amino
acids, which introduces an entirely new factor, namely that of isomerism
and stereo-isomerism.
Only one kind of union is possible between glycocoll and glycocoll.
Between glycocoll and alanin, however, two unions are possible, glycyl
alauin and alanyl-glycin.
94
A. I. RINGER
CH2NH2
I
H CH3
\ I
CO — N — CH
COOH
Glycyl-alanin
CH3
CHNH2
H
\
CO — N — CH2
COOH
Alanyl-glycin
That there is a difference between these two compounds we know from
the fact that they behave differently -in their physical property of rotating
the plane of polarized light. Glycyl-alanin rotates the plane of polarized
light 50° to the left, whereas alanyl-glycin rotates it 50° to the right
(Abderhalden and Fodor, 1912).
In the union of glycocoll, alanin and leucin, we have six different pos-
sible combinations, depending upon the position each amino acid occupies
in the molecule with reference to the 'other amino acids. That there is
a difference between these compounds we know from the fact that they all
have a different power of rotating the plane of polarized light : Thus :
I. Glycyl-alanyl-leucin
II. Glycyl-leucyl-alanin
III. Alanyl-glycyl-leucin
IV. Alanyl-leucyl-glycin
V. Leucyl-alanyl-glycin
VI. Leucyl-glycyl-alanin
20
D
— 90°
-60°
-11°
-30°
-17°
20°
With the increase in the number of amino acids the number of isomers
increases tremendously, as the following table taken from Abderhalden
shows :
Number of amino acids
2
3
4
5
6
7
8
9
Number of possible compounds
2
6
24
120
720
5,040
40,320
362,880
THE PROTEINS AND THEIR METABOLISM
95
Number of ammo acids
10
11
12
13
14
15
16
IT
18
19
20
Number of possible compounds
3,628,800
39,916,800
479,001,600
6,227,020,800
87,178,291,200
1,307.674,368,000
20,922^789,888,000
355,687,428,096,000
6,402,373,705,728,000
121,645,100,408,832,000
2,432,902,008,176,640,000
If it were possible to arrange twenty amino acids in one straight line
forming a protein molecule, 2,432,902,008,176,640,000 different kinds
of protein molecules could be formed. This figure, however, does not
yet by any means complete the list. While most of the amino acids are
able to form unions with other amino acids in a straight line, the dibasic
mono-amino acids and the diamino acids are able to form branched chain
compounds.
COOH
I
CH2
I
I
CHN
\H
COOH
Aspartic
acid
H\
N — CH
COOH
CH2
H\|
NCH
COOH
Glycocoll
Alanin
Aspartic acid
CO
HN — CH — COOH
CH3
CHNH2 CH2 CH3
HOOC ->
HCNH
nnnir f
^TTATTT r\f
1
CO,
COOH
CH2
HNCH
I
COOH
96 A. I. RINGER
In this reaction we see the possibility of a molecule of aspartic acid
uniting with one molecule of glycocoll, one of alanin, and one of aspartic
acid ; the resultant tetra-peptid has one free — NH2 and three — COOH
radicals, which means it can further form compounds along two branch
lines outside of the original line. The different possibilities can be best
illustrated graphically.
From the above consideration one can readily see the difficulties that
confront the investigator of the chemistry of the proteins, and when one
also realizes that one cannot claim to understand the nature of a chemical
compound until he has a knowledge of its structural formula, one can
readily appreciate how far from our goal we are. One can then also
realize how crude is our classification of proteins that has been given
above. Under the heading of what we call albumins we may have billions
of different proteins, resembling one another in some respects, and differ-
ing in others.
The Ami no Acid Content of Different Proteins
Until the technique of the quantitative determination of the amino
acids reaches the point where it will be possible to recover 100 per cent of
amino acids from a known mixture, ah exact answer to the problem of
the amino acid content cannot be given. The figures we can gather to-day
are therefore more of relative value than of absolute.
Not all proteins contain all the amino acids. We shall learn later
that from the nutritional point of view proteins are divided into "com-
plete" and "incomplete" and that under the latter we include those pro-
teins which lack some of the amino. acids which are essential for the
maintenance of proper nutritional .conditions of animals, like tryptophan,
tyrosin, lysin or cystin.
Reactions of Proteins
Color Reaction. — The proteins give a number of color and precipitating
reactions, which are characteristic of a group, though not specific.
The Millon's Reaction. — When a protein is boiled in Millon's reagent,
which consists of a mercury solution in nitric acid and to which a small
amount of nitrous acid is added, the solution will turn rose colored to
dark red. This reaction is given by all substances having an oxyphenyl
radical. In the proteins it is the tyrosin radical which gives this reaction.
Proteins, like gelatin, which do not contain tyrosin, do not give this re-
action.
THE PROTEINS AND THEIR METABOLISM
97
+
+
+
uuag
ut^s/Q
+
+
upna^
+ +
+
uiutSay
4-
S
H
La
C5
O
N
H
c
C
X
w
'di
G
98
A. I. RINGER
The Biuret Reaction. — When protein is treated with a strong sodium
hydroxid solution and then a few drops of a very dilute copper sulphate
solution is added, a beautiful violet blue color develops. This reaction
is due to the presence of the Biuret group.
CHNH
COOH
CH2 — NIL,
CO
\
NH
/
CH2
Biuret group.
COOH
2 Glycocoll Glycyl-glycin
All proteins and polypeptids give this reaction.
The Xanthoproteic Reaction. — When a protein is boiled with strong
nitric acid, a yellow solution is formed, which after making alkaline with
sodium hydroxid, turns red brown, and with ammonia, turns orange red.
This reaction is due to the presence of the benzene group.
The Sulphur-lead Reaction. — When protein is heated in a solution
of sodium hydroxid in the presence of lead acetate, a black color is pro-
duced, due to the presence of sulphur in the protein molecule. This re-
action in protein is produced by cyst in.
The Molisch Reaction. — When a few drops of an alcoholic solution of
a-napthol is added to a protein solution and this mixture stratified upon
concentrated sulphuric, acid, a beautiful violet mixture is formed at the
point of contact. This reaction is not given by the proteins themselves
but by the carbohydrate radical which is frequently bound to certain pro-
teins (glucoproteins).
The Adamkiewicz-Hopkins-Cole Reaction is obtained when to a solu-
tion of protein a small amount of glyoxylic acid is added, and the mix-
cure stratified upon concentrated sulphuric acid. A beautiful violet blue
color develops at the point of contact. This reaction is given by the amino
acid tryptophan, and proteins which do not contain this amino acid, like
gelatin, zein, protamins, etc., do not give it. The presence of sodium' or
potassium nitrate will interfere with this reaction.
The Triketohydrinden Hydrat Reaction (Ninhydrm). — When a small
amount of 0.1 per cent of triketohydrinden hydrate is added to a dilute
protein solution, and the mixture boiled for a minute or two and then
allowed to cool, a beautiful blue color will develop. This is characteristic
99
of all proteins and is given due to the presence of an a-amino radical next
to a free carboxyl (— COOH).
Precipitating Reactions of Proteins. — All proteins are precipitated by
absolute alcohol. With dilute alcohol the precipitating point of the differ-
ent proteins is different, and C. Tebb, 1904, has worked out a means of dif-
ferentiating between different proteins.
Various mineral acids, like nitric, metaphosphoric, and ferrocyanic
acid, as well as the alkaloidal reagents like phosphotungstic, phosphomo-
lybdic, tannic and picric acids, potassium mercuric iodids and potassium
bismuth iodids, have the power of precipitating the proteins.
Practically all the salts of the heavy metals have the power of precipi-
tating the proteins. Those that are employed for that purpose most fre-
quently are ferric chlorid, ferric acetate, copper sulphate, mercuric chlorid,
basic or neutral lead acetate, zinc acetate and uranyl acetate. The strongly
basic proteins, like histones and protamins, also possess the power of pre-
cipitating the proteins. Most of the above precipitations are irreversible,
i. e., by removing the precipitating agent the proteins cannot be dissolved
in water. On adding an excess of some of the salts of the heavy metals
to precipitated proteins, the proteins may go into solution again. This
is accounted for by the fact that the proteins undergo a certain degree of
hydrolysis and break up into molecules which are smaller and soluble.
The "Salting Out "of Proteins by Means of Electrolytes. — It was al-
ready recognized by Denis (1856 (a)) and worked out in great detail by
Kuhne (1886), Hofmeister (1887 (6)), and T. B. Osborne and his collab-
orators, that a great many salts have the power of throwing the proteins
out of their solutions by precipitating them. Those precipitated pro-
teins, after removal of the salts, can be redissolved in distilled water, which
makes the reaction a reversible one. It was further found that different
proteins will be precipitated out by the different salts at definite points of
salt concentration. This, therefore, enabled the above workers to frac-
tionate the proteins and to obtain them in fairly pure state.
Kauder, working in Hofmeister's laboratory (1886), found that when
small quantities of ammonium sulphate was added to blood serum, the
precipitation of globulins commenced when the salt concentration reached
13 per cent of complete saturation, and ended when it reached 24.11 per
cent. After the globulins were filtered off and fresh ammonium sulphate
was added, no precipitation took place until the concentration of the
ammonium sulphate reached 33.55 per cent, when the albumin fraction
began to be precipitated. The latter precipitation was completed when
the concentration reached 47.18 per cent.
Hofmeister further studied the relative influence of anions and the
cations on the power of precipitating proteins. His results are summarized
in the following table.
100
A. I. RINGER
TABLE II
RELATIVE INFLUENCE OF ANIONS AND CATIONS ON THE PRECIPITATION OF PROTEINS
Lithium
Sodium
Potassium
Ammonium
Magnesium
Sulphate
8.61
11.39
No pp.
13.39
15.93
Phosphate
Not inves-
11.69
13.99
16.57
Slightly soluble
tigated
Acetate
«
13.83
16.38
No pp.
No pp.
Citrate
(4
14.42
17.07
21.99
Xot investigated
Tartrate
«
15.11
17.08
25.05
«
Bicarbonate ....
«
No pp.
25.37
Not inves-
tigated
«
Chromate
«
21.22
25.59
No pp.
M
Chlorid
«
21.21
26.28
«
No pp.
Nitrate
Changes
46.10
No pp.
«
«
proteins
Chlorate
Not inves-
58.82
«
Not inves-
Not investigated
tigated
tigated
From this it is evident that both tne cation and the anions exert their
influence on the precipitation of the proteins, and that the relative order
of their efficiency is :
For Cations Mg<NH,<K<NA<L;
For Anions CLO3<NO3<Bicarbonate<Tartrate<Citrate<
Acetate <PO4<SO4
Coagulation and Denaturalization of Proteins
Because of the colloidal nature of the proteins, they are very susceptible
to even slight changes. Solutions of albumin will fall out of solution
merely on standing. A good many proteins will become coagulated even
on small rise in temperature, while most proteins coagulate on boiling.
This reaction in most instances is irreversible, i. e., the proteins become
denaturalized and cannot -be brought back into solution again.
Colloids that carry an opposite electrical charge may also coagulate
the proteins.
The Salt Formation of Proteins
Until recently the question of salt formation of proteins was one of
the most puzzling questions in biological chemistry. The proteins did
THE PROTEINS AND THEIR METABOLISM 101
not seem to unite with the different ions in the same stoichiometrical ra-
tios as they unite with crystalloids, and because of that, the proteins were
credited with special "absorption" properties. These were attributed to
all the colloids.
The recent researches of Jacques Loeb (1919-1921) seem to clarify the
whole problem. He proved that the proteins, and perhaps all other am-
photeric colloids, can exist in three states and that these states depend
entirely upon the hydrogen ion concentration of the medium in which
they are dissolved ; that each protein has a critical point in the hydrogen
ion concentration at which it does not dissociate and at which it is incapable
of staying united with either anion or cation. At this point a protein like
gelatin is almost completely insoluble, hence all the properties which are
dependent upon the solubility of gelatin, like its osmotic pressure, viscosity,
swelling and conductivity, are at a minimum. This point is known as
the "isoelectric" point. For gelatin this isoelectric point lies at a hydro-
gen ion concentration of CH = 2.10"5 or pH = 4.7, for casein 4.7, for
egg albumin 4.8, and for oxyhemoglobin at 6.8, and at these points we
find the proteins to be almost inert bodies.
On either side of this isoelectric point the protein molecule dissociates
in two different states. On the acid side, i. e., if the hydrogen ion con-
centration of a gelatin solution is raised and the pH falls below 4.7, the
protein dissociates into a cationic state, carrying a positive electrical charge
and capable of forming salts with anions forming protein chlorids, protein
sulphates, etc. In this state the amino radical becomes chemically active,
while the carboxyl, the other binding post of the protein molecule, is en-
tirely inert.
On the other hand, if the hydrogen ion concentration of the solution
is lowered and we have a rise in the pH above 4.7, the protein dissociates
into an anionic state carrying a negative electrical charge and capable
of forming salts with metals or cations, forming metal-proteinates, like
sodium gelatinate, calcium albuminate, potassium casemate, etc.
He further found that all proteins at their isoelectric points will aban-
don the chemical union they may have had with either anion or cation or
other protein, and may be obtained in a state of high purity. He also
found that for each given hydrogen ion concentration the proteins com-
bine with the various anions or cations in definite stoichiometrical ratios
similar to those of the crystalloids.
The Digestion of the Protein
During the process of mastication the proteins suffer only physical
alteration by being broken up into smaller particles. The saliva contains
102 A. I. RINGER
no enzyme which has any effect on the protein molecule by causing it to
split into smaller compounds.
In the stomach we find an enzyme, pepsin, which is secreted in an
inactive or zymogen state, and which is activated by the hydrochloric acid
of the gastric juice. The activation of this en^vme can be accomplished
also by organic acids, like oxalic, lactic and tartaric acids, or by inorganic
acids like nitric, phosphoric and sulphuric.
The pepsin in acid solution has the power of splitting the protein mole-
cule into simpler or "derived proteins." The longer digestion proceeds the
smaller will be the size of the molecules of the "derived proteins" and the
further these molecules will get away from the colloidal state and ap-
proach the crystalloidal. By means of fractional precipitation with am-
monium sulphate or zinc sulphate, various fractions can be recognized,
representing different stages in the digestion. These fractions are not
definite chemical entities, but mixtures of what are known as meta-pro-
teins, coagulated proteins, proteoses and peptones. Under no circumstances
and no matter for how long pepsin is allowed to act on protein does its
digestion lead to amino acid formation.
The hydrochloric acid plays an important part in the protein digestion.
It causes a swelling of the protein, and a breaking up of the larger
particles, converting it into a sort of gelatinous mass. The pepsin is thus
enabled to make its way into the interior of the particles with much greater
ease.
The products of protein digestion are passed on into the intestines,
where they meet the secretions from the pancreas, liver and intestines.
These render the mixture alkaline and thus prepare it for the action of
trypsin, which acts only in alkaline mediums, and which is secreted by
the pancreas in an inactive state, trypsinogen, and which is activated by
the enterokinase of the succus entericus.
The trypsin acts on the peptic digestive products and also on the native
proteins which have entered the intestines. The trypsin carries the di-
gestion of the proteins mostly to the peptid stage, i. e., small chain com-
pounds of amino acids, and to a considerable extent to the amino acid
stage. Ty rosin, leucin, tryptophan and cystin are the amino acids that
usually appear first in trypsin digestion.
When a. protein is completely digested the products fail to give the
biuret reaction, and when trypsin acts on protein long enough it carries
the digestion to the stage where no biuret reaction is obtainable. E. Fischer
and Abderhalden have shown that certain peptids exist which are composed
of phenylalanin and prolin, which resist the action of trypsin and can
only be broken up by another enzyme which is secreted by the intestinal
glands and is known as erepsin. This enzyme has the power of breaking
up all peptones into amino acids,
THE PROTEINS AND THEIR METABOLISM 103
Schematic Illustration of the Digestion of Proteins in the Gastro-
intestinal Canal
x;
1
\
Pepsin-HCl diges-
Metaprotein.
Proteose.
Peptone.
tion in the
|
stomach.
Proteose.
1
Proteose.
Polypeptids.
1
Proteose.
Peptones.
Dipeptids.
Peptones.
Polypeptids.
Amino-acids.
Trypsin diges-
J
|
Tyrosin.
tion in the in-
Polypeptids.
Dipeptids.
Tryptophan.
testines.
1
Cystin.
1
Leucin.
Dipeptids.
Amino-acids.
Amino-acids.
Prolin.
Phenylalanin, etc.
Erepsin. diges-
tion.
The above shows in a general way the scheme of protein digestion, and
is reproduced to show that the protein molecule does not break up in an
explosive manner, by which the whole molecule disintegrates, but that it
takes place in stages, and that a large number of intermediary bodies are
possible in the course of protein digestion.
The Absorption of Products of Protein Digestion
from the Gastro-Intestinal Canal
From what was said above it is evident that digestion in the stomach
does not proceed to the point where products are formed that are ab-
sorbable. Hence very little or no absorption of protein-digestion-products
takes place normally (London-Abderhalden). If amino acids or peptones
are introduced into the stomach they are absorbed with considerable rapid-
ity (Folin and Lyman, 1912 (a,)).
The greatest bulk of the absorption takes place from the intestines,
from which the lower peptids and amino acids are absorbed with great
lapidity, and carried by the blood stream to the various organs of the
body.
104 A. I. RINGER
Until about ten years ago it was believed that the amino acids were
resynthesized into serum albumin and serum globulin while passing through
the cells of the intestinal wall, and that these two products constituted
the sole source from which all the body proteins were built up. The rea-
son for that view was that while amino acids could be found in the in-
testines, none could be discovered in the blood stream. But since Van
Slyke's introduction of his micro method for amino acid determination,
this view had to be abandoned. Amino acids were then found to be pres-
ent in the blood of fasting animals to the extent of 3 to 5 mg. per 100 c.c.
of blood, and after a meal of meat the figures rose to 10 and 11 mgs.
(calculated as amino acid nitrogen; Van Slyke, G. M. Meyer, 1913).
Similar results were also obtained by Abderhalden and Lampe, 1912, and
Folin and Denis, 1912 (a).
The Fate of Absorbed Amino Acids in the Blood
The amino acids, after they enter the blood stream, disappear
from it fairly rapidly. This we know from various sources. First from
the fact that, there is. but a very moderate rise in the amino acid nitrogen
content of the blood during the height of digestion of a protein meal.
Second from the results of the Van Slyke and Meyer's experiments (1913)
which will be briefly summarized.
They found after injecting intravenously into a dog 1.90 grams of
amino acid nitrogen obtained from digested casein, that the blood amino
nitrogen rose from 4.05 mg. per 100 c.c. before the injection to 19.7 mg.
one-half hour after the injection and came down to 7.85 mg. three and
a half hours after the injection. At the same time they also found a
rise in the urea nitrogen of the blood, and on examining the tissues of
the body they found that their amino acid nitrogen content was increased
considerably. Thus in one experiment, after injecting intravenously
4.06 grams of amino acid nitrogen they found that the blood amino nitro-
gen, thirty minutes after the injection, rose from 3.9 mg. per 100 c.c.
to 45.2 mg. In the liver it rose from 31.5 to 93.5, in the muscles from 43
to 70 mg., while in the kidneys it rose from 45 to 106 mg.
From these experiments they concluded that there was a much larger
amount of amino nitrogen retained in the tissues than in the blood, and
that the tissues abstracted the amino nitrogen from the blood at a rapid
rate so as to keep its concentration in the blood at a comparatively low and
constant figure. They also concluded that the different tissues have differ-
ent powers of absorbing amino nitrogen and that the amino acids are kept
in the tissues, either by a process of mechanical absorption or in a loose
chemical union with its proteins.
THE PROTEINS AND THEIR METABOLISM 105
The Fate of Amino Acids in the Tissues
In the tissues the amino acids may undergo a number of changes, de-
pending upon the requirements of the cells. They may undergo de-
tfmination by a process of hydrolysis in which the NH2 is replaced by an
hydroxyl radical, giving rise to the corresponding alcohol, forming hy-
droxylacids.
CH3 CH3
I I
CHNH2 + HOH -» CHOH + NH,
I , I
COOH COOH
Alanin Water Lactic acid Ammonia
They may undergo deamination by a process of oxidation giving rise
to the corresponding keto or oxy-acids.
CH3 CH3
I I
CHNH2 + O ^ CO + NH3
COOH COOH
Alanin Oxygen Pyruvic acid Ammonia
They may be utilized by some cell in the synthesis of some organic
body like a ferment, product of internal secretion, serum albumin, serum
globulin, nucleoprotein, cell protein, etc.
Urea Formation
During the process of deamination ammonia is set free. This am-
monia is converted to its greatest extent into urea. We know that from
the fact that if an ammonia salt is fed to an animal most of it is excreted in
the form of urea (v. Schroeder, Salomon, Zaleski, Nencki and Pawlow),
and also from the fact that if a single amino acid is fed to an animal, all
of the nitrogen is excreted as urea (Levene and Kober; 1909). We also
know that the liver is the organ which has the greatest power of convert-
ing ammonium salts into urea, and if amino acids are perfused through
the surviving liver, urea is formed (Fiske and Karsner, 1913; Fiske and
Sumner, 1914).
106 A. I. RINGER
The reaction involved is no doubt the following: The ammonia as it
is set free, combines with the carbon dioxid and water of the blood and
tissue, forming ammonium carbonate.
/OH
-» CO
\OH
Carbon Carbonic
dioxid acid
/OH NH3 /ONH4
CO + -> CO
\OH NH3 . \ONH4
Carbonic Ammonia Ammonium carbonate
acid
The ammonium carbonate, on losing one molecule of water, is con-
verted into ammonium carbamate.
/ONH4 /ONH4
CO H2O -» CO
Ammonium carbonate Ammonium carbamate
which substance, on losing another molecule of water, is converted into
urea.
/ONH4 /NH2
CO - H2O -> CO
\NH2 \NH2
Ammonium carbamate Urea
In normal individuals, on normal diet, from 80 to 90 per cent of all
the nitrogen is excreted in the form of urea, while about 3 to 5 per cent
escapes in the form of ammonia.
Thus the nitrogenous element of the protein molecule plays a com-
paratively simple role in the physiological economy. As long as it is at-
tached as an amino radical it forms one of the binding posts of the amino
acid; it may enter into the formation of protoplasm, it may be built up
into complex protein bodies, ferments, etc. ; in other words it may play an
important role in the life of cells. The moment it becomes dissociated it
becomes dead matter, ready to be cast off and excreted in the urine.
There is no heat liberated in the transformation of proteins to the
amino acid stage, nor is there any heat liberated in the process of deamina-
tion or transformation of the ammonia into urea.
THE PROTEINS AND THEIR METABOLISM 107
The Fate of the Non-Nitrogenous Fraction of the
Amino Acids
The fate of the non-nitrogenous fraction- of the amino acid in the ani-
mal body has been the subject of careful study during the past fifteen
years, and the information obtained forms to-day one of the most interest-
ing chapters in physiological chemistry.
Various methods have been employed in attacking this complex prob-
lem. The amino acids were fed to normal animals, phlorhizinized and
depancreatized animals, and the results studied. They were perfused
through surviving organs like liver, kidneys and muscles, and products
of their metabolism sought for. They were incubated with different ex-
tracts of tissues, with ground up tissues, and their changes studied. Chem-
ical substances that are related to the amino acids were fed to animals
with the object of determining along which path the catabolism of the
amino acid could possibly proceed.
In summing up all the work, the following conclusions may be drawn :*
Glycocoll is completely converted into glucose (Ringer and Lusk, 1910).
After deamination either glycollic acid or glyoxylic acid may be formed.
COH
Glyoxylic acid
CH2NH
COOH
^CH2OH
Glycollic acid
COOH
Glycocoll
Neither one of these intermediary substances, however, has been found
to give rise to sugar when administered to diabetic animals (Greenwald,
1918 (#) ; Ringer and Dubin, unpublished).
Glycocoll also plays a role in the formation of one of the bile salts,
glycocholic acid, in which substance it exists combined with cholic acid.
This is the first instance where a product of protein catabolism may be
used by the cells in the synthesis of a definite compound that is essential
for the welfare of the animal body.
Alanin is also completely converted into glucose. On deamination it
may give rise to lactic or pyruvic acid.
'This subject is thoroughly reviewed in the Third Edition of Lusk's "Science of
Nutrition," pp. 184-207.
108
Lactic acid
Pyruvic acid
Alanin
Of the two substances lactic acid is always and completely converted into
glucose (Mandel and Lusk, 1906). Pyruvic acid, however, while it also
goes over into glucose, does not do it in a quantitative way (Ringer, 1913
(6)). Dakin and Dudley assumed the transformation of lactic acid into
glucose in the following way :
CH3
CH3
CH2OH
CH20
HOCH -»
CO -»
HCOH \
HCOH
COOH
COH
COH
N H(
]OH
CH3
CH3
CHoOH
/
/ HOC
;H
HCOH -»
CO -»
HCOH /
HCOH
COOH COH COH COH
2 Lactic acid Pyruvic 2 Glyceric Glucose
Aldehyd aldehyd
a-Amino butyric acid.has not been investigated properly. In one single
and uncorroborated experiment the giving of 10.3 grams of the substance
to a phlorhizinized animal was followed by the excretion of 3.0 grams of
extra glucose (Ringer, unpublished). On theoretical grounds this sub-
stance may be assumed to give rise to propionic acid, which was shown
to be converted into glucose.
CH3 CH3 CH3 CH3
CH2 -
CHNH,
CH2
CHOH
CH2
CO
CH2
COOH
Glucose
COOH
COOH
COOH
CO,
THE PROTEINS AND THEIR METABOLISM
109
The fate of valin in the body is not definite. Dakin (1913) has found
that it does not give rise to either glucose or acetone bodies. From a priori
reasoning, and from experiences that were obtained with substances chem-
ically related to it, one would have expected the transformation into glu-
cose of three of its carbons.
The fate of leucin is definitely known. It does not give rise to any
glucose, but gives rise to large amounts of |3-hydroxybutyric acid and
acetone. Baer and Blum, 1906 (a) ; Halsey, 1903; Dakin, 1913; Ringer,
Frankel and Jonas, 1913 (a) ; Embden Salomon and Schmidt, 1906). The
a-carbon is probably the first to suffer oxidation and the molecule becomes
converted into iosovalerianic acid, which on demethylation is converted
into butyric acid, and which on (3-oxidation is converted into P-hydroxy-
butyric acid, aceto-acetic acid and acetone.
CH3 CH3
\y
CH2
P-CH2 Deami- (3-CH2 Oxida-
nation tion
CH3 CH3
v
CII
CH3 CH3
\y
P-CH2
2 Oxida- a-CH2 Demethyl-
tion ation
o-CHNH2
COOH
. Leucin
O.CHOH
COOH
a-CO
COOH
COOH
C02
Isovalerianic
acid
CH,
CH,
OH,
CH
CH2 Oxidation CHOII Oxidation CO Decarboxylation CO
CH2
COOH
Butyric acid
CH,
COOH
(3-hydroxy
butyric acid
CH,
COOH
Aceto-acetic
acid
CH,
CO,
Isoleucin and normal leucin. — In Dakin's experiments (1913) we find
an increase of 3.8 and 2.9 grams of glucose after administering 15
grams of isoleucin. Dakin is not inclined to consider that as conclusive
proof that it is glucogenetic. From the structure of the normal leucin,
however, one may assume the possibility of sugar formation. Normal
valerianic acid may be formed after deamination and decarboxylation and
this has been shown to be glucogenetic to the extent of three of its carbons.
110
A. I. RINGER
That normal leucin does give rise to glucose was demonstrated by Green-
wald (1916 (e)).
Aspartic acid is definitely known to give rise to glucose to the extent
of three of its carbons. (Ringer and Lusk, 1910; Ringer, Frankel and
Jonas, 1913 (&) ). It does not give rise to acetone bodies. In all probability
the process of its conversion into glucose is the following:
COOH
COOH
GIL
CHNHj
I
COOH
CHOH
COOH
CH2
CO
COOH
COOH
-» CH2
COOH
C02
Aspartic acid Malic acid Oxalacetic acid Malonic acid
CO2 / \. COOH
CH2
CH3OH
CH3
CHOH
Glucose
COOH
Lactic acid
CO2
Hydracrylic acid
Glutamic acid is convertible into glucose to the extent of three of its
carbons. It does not give rise to acetone bodies. (Lusk, 1908 (a) ; Ringer,
Frankel and Jonas, 1913 (&)).
After deamination it probably passes through succinic and malic stages
and then proceeds as indicated under aspartic acid.
COOH
COOH
COOH
COOH
CH,
CH
Deamination | Oxidation
* CH.> *
Oxidation
Oxidation | — ^ Glucose
-CHOH
CHOH
CO
COOH
COOH
Glutamic
acid
COOH CO2
o-hydroxy- a-keto Succinic
glutaric acid glutaric acid acid
Malic
acid
$-hydroxyglutamic acid is convertible into glucose to the extent as is
glutamic acid. (Dakin, 1919),
THE PROTEINS AND THEIE METABOLISM 111
It does not give rise to acetone bodies. Its conversion into glucose in
all probability is also through a malic acid stage.
COOH COOH COo
CH2 CH2 CH3
I 1 I
CHOH — > CHOH — > CHOH -» Glucose
CHNH2 COOH COOH
COOH CO2
|3-hydroxyglutamic Malic Lactic
acid acid acid
Serin is converted into glucose, in all probability quantitatively. After
deamination it may give rise to glyceric acid, which is convertible into glu-
cose. (Dakin, Ringer and Lusk.)
CH2OH CH2OH
CHNH, Deamination CHOH > Glucose
COOH COOH
Serin Glyceric acid
Cystin in the body is broken up into two molecules of cystein.
CH2 — S - - S — CH, CH,SH
CHNH2 CHNH2 - -*2 CHNH2
COOH COOH COOH
Cystin Cystein
Cystein may undergo deamination and desulphurization yielding a
three carbon compound which is completely converted into glucose (Dakin).
The intermediary products are, in all probability, similar to those of serin.
Cystein to a small extent may also undergo decarboxylation, giving
rise to thioethylamin, which on oxidation gives rise to taurin.
CH2SH CH,SH CH2 — SO2 — OH
Decarboxylation | Oxidation
CHNH2 - —> CH2NH2 - -> CH2NH2
COOH CO2
Cystein Thioethylamin Taurin
This taurin is used by the liver cells to combine it with cholic acid, form-
ing taurocholic acid, which is one of the bile salts. This is therefore the
112
A. I. RINGER
second illustration of the body's ability to utilize split products of protein
for synthetic purposes. The hair and nails of animals are especially rich
in cystin and no doubt a certain proportion of the cystein goes into the
formation of these continually growing cells.
The greatest portion of the sulphur fraction of the cystein molecule
is oxidized to a sulphate state and excreted in the urine in the form of in-
organic salts. A small proportion of the oxidized sulphur combines with
ethereal substances like cresol, phenol and indoxyl, probably for detoxicat-
ing purposes, and is excreted in the urine, while a third portion of the
sulphur reaches the urine in an unoxidized form (neutral sulphur), prob-
ably in the form of taurin, small traces of cystein, sulphocyanid, etc.
Lysin is completely burned in the body without leaving any clue as
to the path of catabolism. It does not give rise to either glucose or acetone
bodies in the intermediary stages. After deamination it may pass through
a glutaric acid stage.
CH2NH2 COOH
CH,
CIL
Deamination
and Oxidation
CH2
CHNH2
As yet unknown
process of combustion.
COOH CO2
Lysin Glutaric acid
Arginin is first broken up into urea and ornithin. This is accom
plished by a ferment arginase which is found in the liver, kidneys, intes
tinal mucous membranes, thymus and muscles. (Kossel and Dakin, 1904
and 1905 ; Otto Riesser, 1906 (a) ; Charles Richet, 1894 (e)}.
NH
/
>-L-L«>
JLl :
}H2
Hydrolysis
)H2
H|OH
C
CHNH2
COOH
Arginin
CH2NH2
CH2 + CO
CH2
I
CHNH2
\NH.
COOH
Ornithin
Urea
113
Ornithin gives rise to glucose to the extent of three of its carbon atoms.
(Dakin, Ringer, Frankel and Jonas, 1913 (&)). After deamination it
probably passes through succinic acid stage.
COOH
Deamination
and oxidation
Glucose
CH2
|
CH2
CHNH2
I
COOH
Phenylalanin and tyrosin have the same fate in the animal body. The
former can be converted into the latter on perfusion through a surviving
liver. (Embden and Balder, 1913).
OH
CH2
CHNH2
COOH
Phenvlalanin
CHKEL
COOH
Tyrosin
They are burned in the body, giving rise to acetone bodies in the in-
termediary metabolism (Ringer and Lusk ; Dakin ; O. Neubauer and Gross,
1910; E. Schmitz, 1910), but not to glucose.
Phenylalanin and tyrosin, as will be seen later, are indispensable
amino acids (see page 000) i. e., an animal cannot maintain itself on
proteins which do not contain these acids. When one views that fact in
conjunction with the relationship that exists between the structure of the
adrenalin molecule and tyrosin, one is justified in the conclusion that these
two amino acids form the building material for adrenalin, even though
we have no direct proof that such is the case. (Stolz, 1904; E. Fried-
man, 1905 (a) ; Abel and Crawford, 1897).
OH
/\OH
V
CHOH
CH2NH — CH3
Adrenalin or Epinephrin
114 A. I. RINGER
Prolin is burned in the body, passing through a glucose stage. Three
of its carbons are convertible into glucose. (Dakin, 1913 ; Ringer, Frankcl
and Jonas.) In all probability, similar to glutaric acid, it passes through
a succinic acid stage. It does not give rise to aceton bodies.
COOH
CH2
> » Glucose
CH9
CH/ COOH
COOH CO2
Prolin Succinic Acid
The fate of oxyprolin has not been worked out definitely. Both prolin
and oxyprolin are intimately related to the pyrrol ring
CH
CH'
which forms the framework of hematin, one of the important derivatives
of hemoglobin. Prolin is also found in a number of other coloring sub-
stances of the body, like in hair, the skin of dark races, melanins, etc.
There can hardly be any question but that the body uses prolin and oxy-
prolin in the manufacture of the coloring materials.
The fate of liistidin in the body is not clear. • It does give rise to
small amounts of glucose when fed to diabetic dogs and it also causes a
slight rise in the acetone bodies formation when perfused through the
surviving liver. Neither reaction, however, is definite nor conclusive.
We must therefore wait for further research with this substance. Because
of its structural relationship to creatinin, the possibility of its being the
mother substance of creatinin has been suggested by Abderhalden.
CH — NH CH2 N — CH3
|J _^>CH
\
CH2 CO —
CHNH2
COOH
Histidin Creatinin
THE PROTEINS AND THEIR METABOLISM 115
Tryptophan does not give rise to glucose nor to acetone bodies. It is
one of the indispensable amino acids (see page 125). It may be con-
sidered the mother substance of thyroxin, the principal substance of the
hormone of the thyroid gland (Kendal, 1919 (c)).
H
H/\
-CH,-CHNH,-COOH
IH
IH/\.
-CH2-CH9-COOH
H\/\/H m\/\xo
H KB H NH
Tryptophan Thyroxin
The fate of the amino acids in the body may be summarized in the
following table :
TABLE III
FATE OF AMINO ACIDS IN THE ANIMAL BODY
Ammo-acid
Gives Rise to Glucose
Gives Rise to Acetone
Bodies
Glycocoll
Alanin ,
Valin
Leucin
Isoleucin
Normal Leucin
Aspartic Acid
Glutamic Acid
t-hydroxyglutamic Acid
erin
Cystin
Lysin
Arginin (Ornithin) ....
Phenylalanin
lyrosin
Prolin
Oxyprolin
Histidin
Tryptophan
+
+
+
+
+
Ten of the amino-acids are known definitely to give rise to glucose, and it
is very possible that the four marked with the query may also give rise to
glucose.
It was found by Lusk that dogs rendered diabetic by means of phlo-
rhizin excrete 3.6 grams of glucose for every 6.25 grams of protein that
they catabolize. Lusk and Mandel showed that severe human diabetics
may excrete sugar in the same proportion, which means that from every
one hundred grams of proteins catabolized, fifty-nine grams of sugar
can be formed.
This does not yet complete the tale for three of the amino-acids give
rise to not inconsiderable quantities of acetone bodies. Glucose and
P-hydroxy butyric acid seem therefore to be the two important stations along
116
A. I. RINGER
the highway of protein metabolism through which most of the amino acids
have to travel while on their catabolic path.
Protein Metabolism
The studies of the metabolism of proteins date back to the days of
•Bischoff and \roit, in the middle of the last century, when it was recog-
nized that the nitrogen excreted in the urine was derived from the catabol-
ized proteins. Twenty-four hours are usually considered the unit of time
for a protein metabolism experiment. Analysis is made of all the ingested
food and of all the excreta. By determining the amount of nitrogen
and multiplying that figure by 6.25, the protein factor is obtained. If
the amount of nitrogen in the excreta, urine and feces, is equal to the
amount of nitrogen in the food, we speak of the individual as being in
a state of nitrogenous equilibrium. If there is less nitrogen excreted in
the urine and feces than was ingested, the individual has stored some
of the ingested nitrogen in the body. We therefore speak of his being in
positive nitrogen balance. If, on the other hand, more nitrogen is ex-
creted in the urine and feces than was ingested in the food, the individual
must have lost nitrogen from his body, and we speak of that as his being
in a negative nitrogen balance.
If an animal or human individual is allowed to fast for a long period of
time, we find that nitrogen is excreted in the urine throughout the entire
period of the fast up to the moment of death. This shows that protein
destruction goes on in the body irrespective of any protein ingestion in
the food. The amount of nitrogen excreted in the urine gradually di-
minishes in amount, in all probability due to the gradual depletion in the
mass of the body proteins. Thus in the experiments by E. and O. Freund
(1901) on Succi they obtained the following results:
TABLE IV
Day of Fast
Nitrogen in Urine
Day of Fast
Nitrogen in Urine
1
17.0
12
6.84
2
11.2
13
5.14
3
10.55
14
4.66
4
10.8
15
5.05
5
11.19
16
4.32
6
11.01
17
5.40
7
8.79
18
3.60
8
9.74
19
5.70
9
10.05
20
3.30
10
7.12
21
2.82
11
6.23
THE PROTEINS AND THEIR METABOLISM 117
Ringer and Dubin in experimenting on a dog weighing 17.0 kg. which
fasted for forty-seven days, obtained the following results :
TABLE V
Day of Fast
Nitrogen in
Urine
Day of
Fast
Nitrogen in
Urine
Day of
Fast
Nitrogen in
Urine
1
3.09
14
2.23
30
1.98
2
3.51
15
1.95
31
2.09
3
2.97
16
1.93
32
2.04
4
2.99
17
2.05
33
1.96
5
2.87
18
2.20
37
1.74
6
2.91
19
2.04
39
1.63
7
2.81
20
2.08
42
1.55
8
2.96
21
1.93
44
1.44
9
2.89
22
2.04
45
1.39
10
2.60
23
2.07
46
1.57
11
2.48
24
2.05
47
1.59
12
2.49
26
2.11
13
2.27
28
2.04
During starvation the various processes of life require a certain
amount of fuel, which is derived from the body's own protein, carbohy-
drate (glycogen) and fat. If the necessary amount of carbohydrate and
fat is supplied in the food, but no protein, the individual is kept in a state
of "nitrogen hunger," and after five or six days the nitrogen excretion
reaches the lowest level that is compatible with life. Landergren calls
that the minimal nitrogen metabolism, whereas Rubner views that as
representing the "wear and tear" quota.
Table VI gives the results of a number of experiments by different
authors on the urinary nitrogen excretion in man when kept on carbohy-
drate and fat diet but free from protein.
From this table we see that 0.045 grams of nitrogen per kg. of body
weight per twenty-four hours is the minimal amount on which the body
can get along. It represents the "wear and tear" quota. This is an ir-
reducible minimum. It corresponds to that part of the protein which can-
not be replaced dynamically by any other foodstuff. It is that which is
used for the formation of blood corpuscles, hormones, for the growth of
bair, skin, nails, epithelial cells, etc.
If the carbohydrates are also removed from the diet and an isodynamic
quantity of fat added, i. e., if an individual is given a diet free from
both proteins and carbohydrates, with all the energy requirements supplied
118
A. I. RINGER
TABLE VI
Day of
Experiment
Nitrogen in
Urine in Grams
Body Weight
in Kg.
Nitrogen per Kg.
of Body Weight
Author
10
4
5
3.8
3.76
3.5
64.0
09.7
70.5
0.0594
0.0539
0.0497
Folin
Landergren
Folin
4
5
3.04
2.7
62.4
55,7
0.0487
0.0485
Landergren
Folin
8
7
7
3.12
3.34
2.42
63.5
71.3
57.5
0.0480
0.0468
0.0421
Klemperer
Landergren
Roche
12
2.6
64.0
0.0406
Folin
8
2.51
2.98
65.0
76.2
0.0395
0.0391
Klemperer
Thomas
6
2.01
88.0
0.0319
Afklerker
7
1.84
58.0
0.0317
Siven
Average
2.897
66.6
0.0446
in the form, of fat, we also have a condition of nitrogen hunger and should
expect the nitrogen excretion to be on as low a level as in the former case.
But this is not so. With fat alone the protein metabolism rises to about
double the "minimal" level. A typical experiment is that of Landergren's,
which is tabulated here:
TABLE VII
Day
Diet
Nitrogen in Urine in Grama
1
2
3
4
5
6
7
Carbohydrate
Carbohydrate
Carbohydrate
Carbohydrate
Fat alone
Fat alone
Fat alone
8.91
5.15
4.30
3.76
4.28
8.86
9.64
On the fourth day the nitrogen reached the "minimal" level which
would have continued thus had not the carbohydrates been replaced by
fat in the diet. The carbohydrates have the power of sparing body pro-
tein to an extent which is not possessed by any other foodstuff. A diet
made up so that half the calories are derived from carbohydrates and half
from fat will give the same results as a diet consisting entirely of carbohy-
drates.
Landergren assumes that the reason why protein metabolism is higher
when carbohydrate is absent from the diet is because a certain amount
of protein is destroyed in order to maintain the sugar concentration of the
blood, which is always kept at a definite level even during starvation,
lie designates that fraction of the protein metabolism as "glucose nitro-
gen." This fraction is equivalent approximately to 0.045 gram per kg.
of body weight. Rubner and Cathcart have corroborated Landergren's
findings, but do not agree with his interpretation.
THE PROTEINS AND THEIR METABOLISM 119
The Question of Optimum Versus Minimum Protein Diet
When protein, in amounts corresponding to the "wear and tear" quota
(0.045 grams per kg. of body weight), is added to a diet consisting of
carbohydrates and fats sufficient to cover all the caloric requirements of an
individual, he will not maintain nitrogenous equilibrium. For short
periods of time, Siven (1900) was able to maintain himself in nitro-
genous equilibrium on a level of 0.08 gram per kg. of body weight (almost
double the "wear and tear" quota).
When Voit studied the nitrogen excretion of a number of individuals,
who lived on general diets following the dictates of their appetites, he
found the average excretion for a man of 70 kg. in body weight was 19
grams of nitrogen per twenty-four hours. He therefore came to the con-
clusion that for a normal man to keep himself in a good condition of
nutrition a supply of 118 grams of protein per day was necessary. This
corresponds to 0.271 gram per kg. of body weight or six times as much
as the "wear and tear" quota.
These figures of Voit's were obtained after a statistical and not after
a physiological study, and therefore caused considerable discussion and
inquiry into their justification. The literature is filled with series of
experiments, of shorter or longer duration, tending to prove that physical
comfort and nitrogenous equilibrium can be maintained at much lower
levels of protein metabolism than Voit's figures.2 The most convincing of
these are the ones reported by Chittenden and Hindhede. In a series
of well-planned experiments on different individuals, representing different
classes of workers, and carried on for a period of eight months, Chitten-
den (1904) obtained results which led him to the conclusion that normal
adults can maintain themselves in nitrogenous equilibrium, and in good
health, on levels from 0.093 to 0.171 gram of nitrogen per kg. of body
weight,3 with the greatest number maintaining equilibrium with 0.120 to
0.140 gram per kg., which is approximately three times the "wear and
tear" quota. Taking the mean of the greatest number — 0.130 grams
per kg. of body weight — a man of 70 kg. would require 9.1 grams of
nitrogen per day, which is equivalent to 57 grains of protein or one-half of
Voit's figures.
Hindhede went a step further than Chittenden. His life for twenty-
one years has been practically one continuous experiment. He and his
family lived on an average of 50 grams of protein per person per day as
the maximum. The nitrogen output in his urine kept close to 7.0 grams.
2 For a complete review of the literature, see "Theorien des EiweissHtoffwechsels
nebst cinigen praktisehen Konseqiienx-en derselben." L. H. Mendel. Krgebnis.se der
Physiologic, 1911, Vol. XI, pp. 418-525.
•Of the twenty-six men studied one maintained equilibrium on a level of 0.003.
three between 0.100 and 0.109, three between 0.114 and 0.119, sixteen between 0.120
and 0.147, two at 0.150 and 0.151 and one at 0.171.
120 A. I. EINGER
His children, who were brought up on this low protein diet, measured and
weighed as much as others two years older, and possessed great endurance.
In another series of experiments his assistant lived for a period of
178 days on a diet consisting of 30.75 grams of protein (4.76 grams of
nitrogen) with a total food supply of 3500 calories per day. Throughout
the entire period he enjoyed excellent health and maintained his body
weight.
During the period of the World War opportunity was afforded to study
this problem on a large scale because of the forced reduction in protein in-
gestion by most of the people of the Central European empires.
Thus Lichtwitz (1917) reports the maintenance of nitrogenous equilib-
rium by citizens of Gb'ttingen, living on 2400 calories and 64.9 grams of
protein per day and weighing 70 kg.
Jansen (1917 (a)) carried on a series of experiments on thirteen indi-
viduals for periods of several months (March to May, 1917). They
were engaged in light work and received 60.5 grams of protein, with car-
bohydrates and fats to make up a total energy supply of 1600 calories per
day. On this diet they were unable to maintain either nitrogenous equilib-
rium or body weight.
The average loss per day was 0.28 kg. of body weight and 11.77 grams
cf protein (1.9 grams nitrogen). He then increased the carbohydrate
and fat in the diet to the extent of 500 calories, i. e., they received the
same amount of protein, but a total energy supply of 2100 calories. Doing
the same amount of work, they were able to maintain nitrogenous equilib-
rium and body weight. The average weight of his subjects was 62.1 kg.,
the nitrogen ingested was 9.68 grams; hence the amount of nitrogen per
kg. was 0.156 gram, or slightly above Chittenden's figures.
These experiments by Jansen prove definitely that it was not the low
protein in the diet that was responsible for the loss in body weight and
negative nitrogen balance, but the low caloric supply.
The question of optimum versus minimum protein supply in the diet
of man cannot be answered on the basis of physiological experiments alone.
In a great many instances, it is purely an economic question, and at the
same time psychological factors and the influence of habit play a tre-
mendous role.
Advocates of a low protein diet describe in glowing terms the psychic
state of well-being when on a low protein diet, whereas the man accustomed
to a full protein diet complains bitterly when forced to live on a restricted
protein diet.
The consensus of opinion of most workers in this field seems to be
that for a normal individual the ingestion of \roit's quota of 118 grams
of protein per day (19 grams of nitrogen or 0.271 gram per kg. of body
weight) is not objectionable, but offers no special advantage. Man can
THE PEOTEINS AND THEIR METABOLISM 121
get along perfectly well, grow to maturity, maintain his body weight and
nitrogenous equilibrium on protein levels exactly one-half that of Voit's
(that is, 0.130 gram per kg. of body weight) provided, of course, that he
has a plentiful supply of dynamogenetic substances in the form of carbohy-
drates and fats to cover all of the body requirements.
From the mere fact that the hardest possible physical work is not
associated with any increase in protein metabolism we may justly con-
clude that protein was not intended for dynamogenetic purposes. Its main
function is to supply the "wear and tear" quota, "growth" quota with a
reasonable surplus to allow for reserve and "factors of safety."
Sufficient data seem to have been gathered to date to show that 0.130
gram of nitrogen per kg. of body weight per twenty-four hours covers all
of these requirements.
The Function of Protein in the Diet
Incomplete Proteins
The object of all food is to supply fuel, which, in the process of its
catabolism, will yield energy to the cells. The use of protein serves a
double function. While it may be used for dynamogenetic purposes, of
far greater importance is its use in supplying the building stones of the
protein to the body, i. e., the amino acids.
Originally it was believed that the peptones in the digested protein
were the products that were resorbed and used for protein regeneration,
and that the protein derived from the same species were utilized to
greater advantage than proteins derived from foreign species (Michaud,
1909). It was further believed that, in those peptones were nuclei of
linked amino acids, which corresponded to those of the animals experi-
mented upon, which made it possible for that animal to maintain equilib-
rium with a smaller amount of nitrogen derived from protein that was
similar to its own protein. This conception, however, cannot stand, in
view of the results obtained by Loewi (1902 (a.) ). He was the first to keep
an animal on a diet consisting of carbohydrates and fats, with all the
nitrogen that it required, supplied in the form of digested protein, that
gave no biuret reaction, i. e., digested to the amino acid stage; proving
that the animal body is capable of synthesizing its own protein from
the elementary amino acids. These experiments have been repeated by
Abderhalden and corroborated in a very convincing way. He not only
cleared up the problem as to the possibility of synthesizing protein from
the simple amino acids, but also introduced a new method for studying
whether certain amino acids were dispensable or indispensable in the ani-
mal economy, and whether the body has the power of producing them
122 A. I. RINGER
de novo or not. Abderhalden prepared a mixture of amino acids con-
sisting of the following:
Amino Acid
Grams
Xitrogon Content in Grams
Glycocoll
5.0
0.9335
Alanin
10.0
1:5730
Serin
3.0
0.4002
Cystin
2.0
0.2330
Valin
5.0
0.5980
Leucin
10.0
1.0690
Isoleucin
5.0
0.5345
Aspartic Acid
5.0
0.5265
Glutamic Acid
15.0
1.4250
Phenvlalanin
5.0
0.4245
Tyrosin
5.0
0.3370
Lvsin (CO3)
5.0
0.9585
Arginin (C03)
5.0
1.6090
Prolin
10.0
1.2170
Histidin
5.0
1.2980
Trvptophan
5.0
0.6860
100.0 grams
amino acids
= 13.87 grams nitrogen
Of this mixture he gave 25 grams per day to dogs whose nitrogen, metabo-
lism had been studied for periods of over seventy days. In addition to the
amino acids, the dogs received daily 2.0 grams of predigested nucleic acids
from thymus and yeast, 50.0 grams of a mixture of glycerin, oleic, stearic
and palmitic acids, 20.0 grams of cholesterin, 50.0 grains of glucose, 5.0
grams of nitrogen-free bone ash and salts. This experiment lasted for
eight days, and throughout the entire period the animal was able to main-
tain nitrogenous equilibrium and to retain its*body weight.
The remarkable thing about this experiment is, that the animal received
all of its food in its elementary form, and it had to synthesize not only its
own protein, but also its fat.
This method of study is of great importance, because it enables us to
make any kind of desirable mixture of amino acids, and also enables
us to eliminate one or more amino acids and study their individual influ-
ences.
Thus he found that an amino acid mixture, containing no glycocoll or
prolin, will enable an animal to maintain nitrogenous equilibrium. He also
found that he can replace arginin by ornithin and obtain nitrogenous
equilibrium. This proves that the body is capable of forming its own
glycocoll and prolin and that the arginin union can be accomplished in
the body.
He also proved that animals can utilize, with equal completeness, the
amino acid mixtures obtained from the following digested proteins : casein,
ox beef, milk powder, egg albumin, horse meat and dog meat.
Incomplete Proteins. — In the early studies of protein metabolism it
was discovered that certain proteins could not maintain nitrogenous equilib-
123
rium. Gelatin was found to be one of these. No matter how much gela-
tin was administered to an animal, the animal would still continue to
burn some of its own protein in addition. Krummacher (1896 a) went so
far as to administer all of the animal's caloric requirements in the form of
gelatin, but was not able to obtain nitrogenous equilibrium.4 Various the-
ories were advanced which were supposed to explain the reasons for this.
Kauffman, in 1905, conceived the idea that the explanation may be found
in the fact that gelatin lacks certain amino acids which may be indispens-
able to the animal organism. These are tryptophan, tyrosin and cystin.
He therefore added small amounts of these to gelatin, carried out a series
of experiments on man and dog, and found that nitrogenous equilibrium
could be maintained under those circumstances. Abderhalden confirmed
the experiments and went a step further. He took casein, digested it to
the amino acid stage, and fed it to a dog for a period of seven days. Dur-
ing those seven days the dog gained 20.0 grams in weight and retained
0.12 gram of nitrogen per day. (See Table VIII, Section II.) During
the succeeding six days the animal was given a corresponding amount
of casein digest minus tryptophan. The animal lost 250.0 grams in body
weight and lost nitrogen to the extent of 0.83 gram per day or
5.0 grams for the period of six days. (See Table VIII, Section III.)
During the succeeding six days the animal was put back on its original
diet. It regained 100.0 grams in weight and on the fourth day established
nitrogenous equilibrium.
TABLE VIII
ABDERHALDEN'S EXPERIMENTS
DOG WAS FED 22 GRAMS OF PREDIGESTED DOG MEAT. EXPERIMENT SHOWS THAT NITROGEN-
OUS EQUILIBRIUM AND BODY WEIGHT CAN BE MAINTAINED ON IT
Day
Diet
Body
Weight
in Grams
Nitrogen
in Food
Total
Nitrogen
Excretion
Nitrogen
Balance
1
22 g r a m s of predi-
gested dog meat
8250
2.50
2.27
-f 0.23
2
2 grams predigested
nucleic acid
8245
2.50
2.32
+ 0.18
3
50 gr. gl y c e r in-fat
mixture
8240
2.50
2.32
+ 0.18
4
2 gr. cholesterin
5
50 gr. glucose
5 gr. bone ash salts
8245
8240
2.50
2.50
2.32
2.32
4-0.18
-4-0.18
6
8250
2.50
2.35
+ 0.15
7
8250
2.50
2.26
+ 0.24
Total
17.50
16.16
-4- 1.34
+ 0.19
4 For complete review of literature see Murlin, J. R., American Journal of Physi-
ology, 1907, vol. 19, p. 285 and 1907, vol. 20, p. 234.
124
A. I. RINGER
. II
DOG WAS FED 18 GRAMS OF PBEDIGESTED CASEIN. EXPERIMENT PROVES THAT NITROGENOUS
EQUILIBRIUM AND BODY WEIGHT CAN BE MAINTAINED ON IT
Day
Diet
Bodv
Weight
in Grams
Nitrogen
in Food
Total
Nitrogen
Excretion
Nitrogen
Balance
41
8300
2.51
2.32
+ 0.19
42
8315
2.51
2.37
-fO.14
43
18 grams of predi-
gested casein
8320
2.51
2.42
+ 0.09
44
8310
2.51
2.20
+ 0.11
45
The rest as above
8320
2.51
2.40
+ 0.11
46
8320
2.51
2.41
+ 0.10
47
8320
2.51
2.42
+ 0.09
Total
17.57
16.54
+ 0.83
Average
+ 0.12
III
DOG WAS FED 22 GRAMS OF PREDIGESTED CASEIN, MINUS TRYTOPHAN. EXPERIMENT PROVES
THAT ANIMAL LOSES ITS OWN NITROGEN BY BEING IN NEGATIVE NITROGEN BALANCE,
AND ALSO LOSES IN BODY WEIGHT
Day
Diet
Body
Weight
in Grams
Nitrogen
in Food
Total
Nitrogen
Excretion
Nitrogen
Balance
48
8290-
2.52
3.03
— 0.51
49
8300
2.52
3.07
— 0.55
50
51
22 g r a m s of predi-
gested casein mi-
nus tryptophan
8250
8210
2.52
2.52
3.67
3.65
— 1.15
— 1.13
52
The rest as above
8150
2.52
3.40
— 0.88
53
8070
2.52
3.30
— 0.78
Total .'
15.12
20.12
— 5.00
Average
— 0.83
IV
DOG WAS FED 20 GRAMS OF PREDIGESTED CASEIN PLUS TRYPTOPHAN. EXPERIMENT SHOWS
THAT NITROGENOUS EQUILIBRIUM WAS REACHED ON THE FOURTH DAY. ANIMAL GAINED
IN WEIGHT PROVING THAT TRYPTOPHAN IS AN ESSENTIAL AMINO ACID
Day
Diet
Body
Weight
in Grams
Nitrogen
in Food
Total
Nitrogen
Excretion
Nitrogen
Balance
54
8100
2.51
2.97
— 0.46
55
8125
2.51
2.87
— 0.36
56
22 g r a m s of predi-
gested casein plus
tryptophan
8150
2.51
2.62
— 0.11
57
8150
2.51
2.48
+ 0.03
58
The rest as above
8150
2.51
2.46
+ 0.05
59
8170
2.51
2.51
0.00
Total
1506
15.91
— 0.85
Average .
— 0.14
THE PROTEINS AND THEIR METABOLISM 125
DOG WAS FED 25 GRAMS OF THE AMINO ACID MIXTURES AS THE SOLE SOURCE OF NITROGEN
SUPPLY. EXPERIMENT PROVES THAT NITROGENOUS EQUILIBRIUM AND BODY WEIGHT
CAN BE MAINTAINED ON IT
Day
Diet
Body
Weight
in Grams
Nitrogen
in Food
Total
Nitrogen
Excretion
Nitrogen
Balance
60
8190
3.47
3.15
+ 0.32
61
25 grams of a m i n o
acids mixture'
8200
3.47
3.27
+ 0.20
62
8200
3.47
3.40
+ 0.07
63
8200
3.47
3.58
— 0.11
64
The rest as above
8200
3.47
3.48
— 0.01
65
8200
3.47
3.49
— 0.02
66
8200
3.47
3.34
+ 0.13
67
8200
3.47
3.65
— 0.18
Total
27 76
27 36
+ 040
Average
-|- 0.05
These experiments are of the utmost importance because they show
the value of tryptophan in the physiological economy. They prove defi-
nitely that if an animal is kept on a diet free from tryptophan, the body
has to burn its own protein to supply tryptophan to the cells that require
it. (See the relationship between tryptophan and thyroxin, the active
principle of the thyroid secretion, page 115.)
The proteins that do not contain all the indispensable amino acids are
designated incomplete proteins, and the above experiment shows that a
complete protein like casein can be made incomplete and cause it to be a,
non-sustainer of nitrogenous equilibrium by merely removing the trypto-
phan.
The study of the physiological values of the incomplete proteins and
the influence of the individual amino acids have been carried on in-
tensively for the past fifteen years.
In 1907 Hopkins and Willcock published a series of experiments on
mice. They fed mice on a diet in which all the protein was supplied in
the form of zein, a protein derived from maize, containing neither lysin
nor tryptophan. The zein was mixed with carbohydrates, fats, lecithin
and salts. In the first series of experiments five young mice were kept on
this diet for seven days. On the seventh day they all showed the follow-
ing losses in weight in per cent: 11.8, 17.6, 13.1, 23.2, 27.1.
As a control, four mice were kept on a similar diet, but the zein was
replaced by a similar quantity of casein. On the seventh day the following
increases in weight in per cent were recorded: 20.2, 21.8, 9.1, 21.0.
One of the mice of the first series was then given half of its protein
in the form of zein and the other half in the form of casein, and it promptly
began to gain in weight. After fifteen days it gained in weight to the
extent of 46 per cent.
126
A. I. RINGER
In another series of experiments, also on young mice, they studied the
length of time the animals were able to survive the zein diet, and com-
pared it with the controls that received two per cent of tryptophan in ad-
dition to zein. They found that of fifteen mice kept on the zein diet all
died between the
twelfth and twenty-sec-
ond day, whereas of the
fifteen on the zein plus
tryptophan diet onl]
three died before the
twentieth day and
the others lived froi
twenty-four to forty-five
days.
There is therefoi
no question whatsoever
but that the addition of
tryptophan prolonged
the time that the ani-
mals could live on zein.
In studying the weights
of the animals, however,
they could not find any
differences, i.e., the
animals lost about as
much in weight with
the tryptophan as with-
out it.
Osborne and Men-
del took up the study of
this subject on a very
large scale (1911).
They kept thousands
of rats for periods of
years, under absolutely
controllable conditions
of diet. They were thus
able to study the influ-
ence of isolated food
8 12 16 20 24 28 32 36 40 44 48
DIAGRAM I. Diagram constructed from the results
of Hopkins' and Willcock's experiments 5, 6, 7. The
heavy lines show the survival periods (in days) of
twenty -one individual mice upon the zein diet with
tyrosiu. The light lines show the same for nineteen
mice upon the zein diet with tryptophane.
substances. They found
the study of the changes in the body weight of the rat a most satisfactory
index of the rate of growth. They selected the white rat because it is
easily reared and cared for and because its food requirements are com-
paratively small. It also offers advantages because of the fact that it
THE PROTEINS AND THEIR METABOLISM
127
thrives well on unvaried diets and maintains its health even though con-
stantly confined to a cage. As the longevity of the white rat is about
three years, they were able to study the influence of certain diets practically
throughout the whole life time of the animal.
From hundreds of experiments published, four are selected here to
illustrate the physiological value of some of the amino acids.
210
190
170
150
130
110
90
70
50
NlT
N
s7
RIOJUANL
A
if
I
DAYS 30 40 60 80
Diagram II illustrates graphically
100 180 140 160 ISO 200
the result of Osborne and Mendel's experiments
Rat No. 710 was kept under observation from May 9, 1913, to Sep-
tember 5, 1913, a period of 120 days. During that period the animal lived
on the following food mixtures: zein, 18.0 grams; protein-free-milk, 28.0
grams ; starch, 27.0 grams ; butter fat and lard, 27.0 grams ; water, 15 c.c.
The influence of this diet on the animal's body weight is presented in
Table IX. Every one of the rats that was kept on this diet lost in weight.
Rat 710 lost 39 per cent of its body weight in 120 days.
The experiment on Rat 1519 started on May 9, 1913, and ended Nov.
7, 1913. Between May 9 and August 8 it was kept on a mixture of zein,
!<;.!>:.> grams, tryptophan, 0.54 gram, the rest as above. During this
period the animal lost weight steadily, reaching the lowest level of 100.0
grams on August 8 ; 0.54 gram of lysin was then added to the diet.
There followed an immediate gain in body weight, reaching the highest
128
A. I. RINGER
TABLE IX
OSBORNE AND MENDEL'S EXPERIMENTS
RAT 710
Date
Diet
Body
Weight
in Grama
Date
Body
Weight
in Grams
1913
May 9
18 grams zein
218
1913
July 11
168
13
28 grams protein-free milk
218
15
169
16
27 grams starch
212
18
170
20
27 grams butter fat and
205
22
159
23
lard
201
25
165
27
15 c.c. water
199
29
156
31
191
Aug. 1 . .
157
June 3 ....
194
5
147
6
186
8
154
10
184
12
148
13
187
15
150
17
183
19
143
20
180
22
144
24
175
26
137
27
180
29
138
July 1
177
Sept. 2
136
4
177
5
133
8
170
BAT 1519
Date
Diet
Body
Weight
in Grams
Date
Body
Weight
in Grams
1913
May 9
16.92 grams zein
128
1913
Aug. 15
109
13
0 54 gram tryptophan
122
19
109
16
The rest as above
123
22
113
20
117
26
118
23
115
29
118
27
114
Sept 1
119
30
113
5
118
June 3
111
9
116
6
109
12
116
10
106
16
118
13
107
19
121
17
105
23
122
20
106
26
120
24
106
30
123
27
105
Oct 3
129
July 1
106
7
135
4
107
10
142
8
102
14
150
11
102
17
150
15
104
21 ....
148
18
103
24
147
22
103
28
148
25
102
31
149
29
102
Nov 4
145
Aug. 1.
100
7
141
5
100
8
100
12
0.54 ^ram Ivsin added
104
THE PROTEINS AND THEIR METABOLISM 129
TABLE X
RAT 1773
Date
Diet
Body
Weight
in Grams
Date
Body
Weight
in Grams
Sept. 23, 1913
26.!
70
66
Dec. 5, 1913
9
78
79
30
zein
61
12
81
Oct. 3
58
16
86
7
*
57
19
88
10
56
23
93
14
53
26
99
17
53
30
101
21
49
Jan 2 1914
105
24
49
6
112
28
48
9
113
31
46
13
115
NTov. 4
46
16
118
7
45
20
120
11
43
23
121
14
41
27
125
18
zein + tryptophan -)- lysin
47
30
130
21
57
Feb 3
132
25
67
6 ....
133
28
71
10 ...
137
Dec 2
76
RAT 1900
Date
Diet
Body
Weight
in Grams
Date
Body
Weight
in Grams
Nov. 10, 1913.
13 .
zein -|- lysin
49
50
Jan. 1, 1914
5
55
65
17
45
8
69
20
45
12
80
24
43
15
83
27
44
19
87
Dec. 1
40
22
90
4
39
26
91
g
zein -4- tryptophan
39
29
98
11
39
Feb. 2
99
15
41
5
103
18
42
9
113
22
43
25
42
29
zein -}- tryptophan -j- lysin
49
point of 150 grams on October 14. It will be noticed in this experiment
that on zein plus tryptophan the loss in weight was not as marked as on
zein alone (rat 710). In many other experiments, Osborne and Mendel
found that on zein and tryptophan the animals were able to maintain their
body weight, but in no instance was an animal able to grow until after
lysin was added. This led them to differentiate between maintenance
and growth in nutrition. Without tryptophan, they showed, all animals
130 A. I. RINGER
will lose in body weight quite sharply; after adding tryptophan, the curve
of body weight becomes more horizontal. For an adult to just maintain
his body weight is perfectly normal. But merely maintaining body weight
for a child or growing animal is a decided abnormality. They have to
grow, and growth does not, occur until lysin is added to the diet.
The records of Rats 1773 and 1000 are corroborative of the first two.
From all the above data, the conclusion must be reached that the pr<>-
teins in the dietary of all animals fulfill a series of functions which are
not fulfilled by any of the other foodstuffs. They supply amino acids
which the body itself cannot manufacture. Tyrosin, tryptophan and lysin
are indispensable amino acids without which nutritional equilibrium can-
not be established. Only plant cells have the power of synthesizing these.
For a protein, therefore, to be physiologically adequate, it must con-
tain all of these amino acids and in sufficient quantities.
The study of the protein metabolism really resolves itself into a study
of the metabolism of the amino acids. When we speak of a minimum
protein requirement, we may in reality translate that into a minimum re-
quirement of indispensable amino acids and the "wear and tear" quota
may really represent that amount of protein which contains all the indis-
pensable amino acids that are necessary for our maintenance.
The Influence of Protein on Metabolism
The Specific Dynamic Action of Protein
The final stage of all the metabolic processes in the animal body is
one of oxidation, whereby energy is liberated in the form of heat. The
amount of heat produced depends entirely upon the amount of material
that is oxidized. When an animal is at rest and fasting, the oxidation
processes are at a low ebb, the heat production is at a correspondingly low
level. (We speak of its basal metabolism.) If the subject becomes more
active, the oxidative processes and heat production increase in definite
proportion, so that by doing fairly hard physical work the metabolism may
reach a point double and triple the basal level.
A most remarkable phenomenon was observed by Voit in his early
respiratory metabolism experiments. He found that even though at per-
fect physical rest, the heat metabolism of an individual increases after
the ingestion of food ; to a slight extent after carbohydrates, to a greater
extent after fat, and to a most marked extent after protein. In other
words, if we determine the starvation caloric requirements of an individual,
and put him on a protein diet sufficient to cover those requirements, the
individual's metabolism will increase as a result of ingesting the food and
produce more heat than before.
THE PROTEINS AND THEIR METABOLISM
131
In diagram III we have a graphic illustration of one of Lusk's experi-
ments on a dog showing the influence of the ingestion of 1200 grams of
lean meat on the metabolism of the dog. During the two hours before
the meat ingestion, the heat production was 22 to 23 calories per hour.
Within two hours after the meat ingestion the heat production went up to
over 35 calories per hour, reached 44 during the third hour and remained
85 R.Q.
75
40 CALORIES
35
30
25
2D6MS.
N.
1.5
1.0
.5
i
\.
22230 I 23456789 10 III? "is 14 15 16 17 18 19 20 21
HOURS AFTER 1200 6RAMS MEAT
DIAGRAM III. Showing the respiratory quotient, the total metabolism determined
by indirect (heavy black line) and direct (broken line) calorimetry as well as the
nitrogen elimination (dotted line) during hourly periods after the ingestion of 1200
grams of meat.
at that high level for about eight hours, gradually coming down and reach-
ing the basal level at the end of twenty-two hours. Ordinarily we notice
increased heat production as a result of increased oxidation processes going
on in the cells, as during periods of greater activity. The increase in
Lusk's experiments corresponds to an increase in metabolism caused by vio-
lent exercise, and yet the animal was lying perfectly quietly and at rest.
Voit assumed that this marked increase in oxidation and heat forma-
tion was due to the cells being stimulated by the presence of food in the
blood brought to them, and that the intensity of metabolism of a cell was
a function of the quality and quantity of food material surrounding the
132 A. I. RINGER
cell. The greater the amount of food brought to the cell, the more was it
stimulated to catabolize it.
Rubner, Zuntz and Lusk have performed a great many experiments
which may 'throw light on the cause of this increase in metabolism. Be-
cause of the specificity of each foodstuff to stimulate metabolism, Rubner
called it the ''specific dynamic action" of the foodstuffs. He believes that,
localise the carbohydrates and fats are directly available to the cells for
their nutrition there is therefore comparatively little increase in heat pro-
duction after their ingestion. In the case of protein, however, it can con-
tribute to the cell metabolism only in so far as it can give rise to glucose, and
all the intermediary products which cannot go over into glucose are burnt,
but their heat is given off as free heat and cannot be used by the cells.
Lusk proceeded to look for the cause of the specific dynamic action
of the proteins along new lines. He realized that in order to analyze
the action of protein on metabolism, one must take up the study of the
influence of the individual amino acids, for it is they which come in
intimate contact with the cells of the body. Then he reasoned thus: if
Rubner's hypothesis be correct — that the fraction of the protein molecule
which goes over into glucose is the one which contributes to the life of
the cell, and that the fraction which does not go over is burned, giving
rise to free heat — then amino acids like glycocoll and alanin, which are
completely converted into glucose, should exert no specific dynamic influ-
ence at all, whereas glutamic and aspartic acids, which contribute only
three of their carbons to glucose formation, should have a marked dynamic
effect. Also, substances like leucin and tyrosin, which do not give rise to
any sugar, should have a most pronounced dynamic effect.
Experiments not only failed to lend any support to Rubner's theory,
but revealed just the contrary of what was expected. Glycocoll and alanin
were found to possess a very pronounced power of stimulating metabolism
nnd heat production. Leucin and tyrosin possess that power to a lesser
extent, and aspartic and glutamic acids have none at all.
In another series of experiments Lusk found that the administra-
tion of 5.5 grams of glycocoll raised the heat production of a dog 7.3
per cent and 5.5 grams of alanin raised it 7 per cent. When he gave the
two amino acids together there was a summation of influences and the
heat production wa's raised 18 per cent. Ten grams of glycocoll caused
a rise of 15.0 and 17.5 per cent in two successive experiments, and the
giving of 20 grams of glycocoll caused a rise of 33.5 and 34.0 per cent in
two experiments. Similar results were obtained after administering 20
and 30 grams of alanin.
These experiments prove beyond any question that the stimulus these
ammo acids exert is directly proportional to the amount of material ad-
ministered.
Since glycocoll and alanin have been shown to be completely converted
THE PROTEINS AND THEIR METABOLISM 133
into glucose in the diabetic animal, the question naturally presented itself,
Will these amino acids exert a specific dynamic influence when given to a
phlorhizinized diabetic animal?
In a series of experiments Lusk proved that in spite of the fact that
all of glycocoll and alanin are converted into glucose and that none of it
is oxidized, it still possesses the power of raising the heat production. The
respiratory quotient in all cases remaining at the low diabetic level lends
additional confirmation to the belief that none of these amino acids are
oxidized in the diabetic animal.
From all this it becomes evident that the specific dynamic action of
protein is a stimulus to metabolism which is given to the body by certain
of the amino acids. It is not the result of these substances burning up
as a sort of a bonfire, giving rise to free heat. They act as catalytic agents,
spurring up the oxidative processes in the cells. The reaction is in reality
much more "specific" than Voit and Rubner realized. It seems to reside
in certain amino acids and not in others.
What the significance is of this spurring of metabolism by protein we
do not know. All physiologists are agreed that the extra heat is waste-
ful and physiologically uneconomical. Advocates of the high protein diet
seem to attach a great deal of importance to the sense of well-being a per-
son experiences after a meal rich in protein, but whether a psychic state
of well-being can be taken into consideration in determining physiological
requirements and laws seems highly questionable. The drinking of wine
and other alcoholic beverages certainly puts one in a psychic state of
well-being, but no one will claim that this is sufficient evidence for its physi-
ological requirement.
Nucleic Acids Walter Jones
Chemical Part — Plant Nucleic Acid — The Fundamental Groups of Yeast
Nucleic Acid — The Nucleotides of Yeast Nucleic Acid — The Nucleotide
Linkages of Yeast Nucleic Acid — Inosinic Acid and Guanylic Acid — The
Nucleosides of Yeast Nucleic Acid — Animal Nucleic Acid — The Partial
Decomposition Products of Thymus Nucleic Acid — Physiological Part —
The Physiological Decomposition of Nucleic Acid — The Formation of
Uric Acid from Nucleic Acid — The Formation of Uric Acid from the
Oxy-purines — The Formation of Oxy-purines from Amino-purines — The
Physiological Destruction of Uric Acid — The Distribution of the Purine
Ferments — The Enzymatic Decomposition of Combined Purines.
Nucleic Acids
WALTEE JONES
BALTIMORE
Chemical Part
By a tedious manipulation it is possible to isolate from animal and
plant tissues an organic acid, rich in both phosphorus and nitrogen, whose
decomposition products are so far characteristic that not one of them is
identical with any known decomposition product of a carbohydrate, a pro-
tein or a fat (Altman, 1889), (Osborne and Harris, 1902), (Kossel,
(a), (&), 1879, 1880). The substance has been prepared from meta-
morphosed cell nuclei (Miescher, 1897), and as the amount of it that is
obtainable from a tissue is proportional to the richness of the tissue in
cell nuclei, it is properly regarded as a nuclear constituent and called
nucleic acid.
. Nucleic acid cannot be prepared sufficiently pure for chemical analysis,
so that its chemical composition has not been directly found. This can be
inferred, however, from a summation of its unique decomposition products.
But chemical composition, physical properties and other considerations
pertaining to nucleic acid as such, are matters about which, in the present
state of our knowledge, physiology is little concerned. It is -the decom-
position products that are of importance, and these decomposition prod-
ucts are the same whether they are produced by chemical action outside
of the body or by physiological agents present in the tissues ; so that
a discussion of the chemical decomposition of nucleic acid will disclose its
metabolic possibilities.
Plant Nucleic Acid
It was formerly supposed that a multiplicity of nucleic acids exist,
and that each tissue contains its individual substance of this class. But
without entering into the obscure and contradictory older contributions,
it is safe to state that everything known is in accordance with the assump-
tion that there are two, and only two, nucleic acids in nature: one is
obtainable from plant tissues (yeast nucleic acid) (Kossel, 1893),
and the other is obtainable from animal tissues (thymus nucleic
135
130 WALTER JONES
acid). (Kossel and Neuman (a) (b) (c), 1893, 1894.) It will, therefore,
be necessary and sufficient to examine two nucleic acids in o^der to get a
knowledge of them all.
The Fundamental Groups of Yeast Nucleic Acid. — When yeast nu-
cleic acid is heated for a short time with very dilute sulphuric acid, part
of its molecule easily undergoes hydrolysis with the formation of pentose,
phosphoric acid and two purine derivatives (guanine and adenine). But
when the nucleic acid is submitted to severe hydrolysis by heating wit
stronger sulphuric acid in an autoclave at 160°, a second part of its molt
cule is decomposed with the formation of pentose and phosphoric acic
as before, but in addition, two pyrimidine derivatives (cystosine anc
uracil). So that by hydrolysis with mineral aeid in one way or another,
yeast nucleic acid produces six substances.
1. Phosphoric Acid
2. Pentose
3. Adenine
4. Guanine
5. Cytosine
6. Uracil
These six substances constitute the fundamental groups of which ^^
nucleic acid is composed, and as will 'be seen later, the same six substance^
are formed when yeast nucleic acid is decomposed by physiological agents.
One of them is so simple as to require no treatment ; the other five shoulc
be discussed.
Pentose.— There are theoretically possible, eight aldo-pentoses of the
formula C5H10O5. The substance which is obtained from yeast nucleic
acid is that one of the eight possibilities that has the geometrical config-
loinT Cdled dex{r°-ribose' (Levene and Jacobs (c) (g) (h), 1909, 1909,
CHO
HCOH
HCOH
HCOH
CH2OH
rat01! H^T? ^ foimd ^ rarel? in nature> ™* **
has ^eat physiological significance, but at present we can only
fer d-ribose to the general metabolism of the carbohydrates: in which
case , does not properly fall into a discussion of nucleic acids.
,Both cytosine
(Kossel and Stendel (a) (6), 1902, 1903) and uracil
NUCLEIC ACIDS
137
(Ascoli, 1900) are chemically referable to hypothetical pyrimidine. Cyto-
sine is 6-amino-2-oxypyrimidine and uracil is 2-6-dioxy-pyrimidine.
Cytosine
C4H5N30
Uracil
C«H4N202
Pyrimidine
The two substances are corresponding oxy- and ammo-compounds, so that
one may pass into the other by deaminization
,OH
H0 =
Cytosine
Uracil
in fact, cytosine can easily be converted into uracil, and will be so con-
verted in a laboratory manipulation of the material unless precautions are
taken against it. The relation of the two substances to each other sug-
gests the possible metabolic conversion of one of the compounds into the
other by the deaminizing ferments of the tiosues. This is, of course, pos-
sible, but the transformation has not been shown either by an organism
or by a tissue extract. In fact, very little is known about the metabolism
of the pyrimidine derivatives, so that of the six fundamental decomposi-
tion products of yeast nucleic acid, physiological interest is directed almost
exclusively to the purine derivatives.
The Purine Derivatives. — By hydrolysis of yeast nucleic acid with
dilute mineral acid, it is possible to obtain only the two amino-purines,
guanine and adenine; but. in studying the metabolism of these two, it is
necessary to consider three other purine derivatives, viz., hypoxanthine,
xanthine and uric acid. The chemical relation of these five substances to
one another is skown in the following arrangement, in which the purine
ring is represented by the letter P.
[In this article, purine formulas are used to which the physician may
not be accustomed and a word of explanation may not be superfluous.
There are two tautomeric formulas for purine derivatives (enol formulas
and ketol formulas) which are not chemically distinguishable from each
other. One of these formulas is almost universally (but arbitrarily) used
by chemists and physiologists. The other formula has been adopted in the
following pages for its exceeding convenience in dealing with the prob-
lems under consideration.]
138
WALTER JONES
Guanine
C5H5Nr>()
2-amino-6-oxy-purine
Trie Acid
CBII4N403
2-6-8-trioxy-purine
/OH
P— OH
\OH
P— OH
\BD
Xantliinc
C5H4N402
2-6-dioxy-pnrine
/OH
P— OH
\H
Adenine
C5H5N5
6-amino-purine
/H
P—
\H
Hypoxanthine
C5H4N40
6-oxy-purinc
/H
P— OH
\H
Guanine and adenine are referred to collectively as the amino-ptirines ;
xanthine and hypoxanthine as their corresponding oxy-purines. The
amino-purines may easily be converted into the oxy-purines by a deamin-
izing agent (nitrous acid).
C5H3N4(NH2)+H20
adenine
C5H3N4(OH)+NH3 (Kossel ($, 1886)
liypoxanthine
C5II,N4O(NH2)+H2O = C5H3N4O(OH)+NH3 (Strecker, 1858)
guanine xanthine
and it will be seen that these transformations are actually brought about
by deaminizing ferments present in the tissues. But guanine and adenine
cannot be directly converted into one another. The one has its ammo-
group in position two ; the other, in position six.
NH N
N N
By oxidation, liypoxanthine could conceivably be changed into xanthim
C5H4N40 + O = C5H4N402
NUCLEIC ACIDS 139
and this in turn could be oxidized to uric acid
C5H4N402 +0 = C5H4N403
but it would be necessary to introduce the first oxygen atom into position
two, and the second, into position eight. While no chemical oxidizing
agent has been found that can effect this selective oxidation, oxidizing
ferments are present in the tissues that can direct the oxygen atoms into
their proper positions, and bring about the conversion of hypoxanthine
successively into xanthine and uric acid.
The converse reactions which involve the withdrawal of oxygen can
be effected in the laboratory. Uric acid has been successively reduced to
xanthine and hypoxanthine. (Sundwick, 1911.)
The Nucleotides of Yeast Nucleic Acid. — The older investigators
knew that by mild acid hydrolysis, nucleic acid is partly split up, setting
free part of its phosphoric acid, part of its carbohydrate and all of its
purine bases; but that the remainder of its phosphoric acid and carbo-
hydrate, together with its pyrimidine compounds, are set free only after
most violent methods of hydrolysis. It was therefore natural to assume
that nucleic acid is composed of four "complexes," all of which produce
both phosphoric acid and carbohydrate, but each "complex" produces a
different one of the four nitrogenous compounds. The two purine "com-
plexes" evidently undergo hydrolysis with ease, while the two pyrimidine
"complexes" are very stable. If the term "nucleotide" be substituted for
the term "complex," this becomes essentially the modern nucleotide the-
ory of the constitution of nucleic acid. This theory was originally pro-
posed on the speculative grounds as outlined above, before any nucleoside
or nucleotide had been prepared from nucleic acid; but it has recently
received firm experimental support by the preparation from yeast nucleic
acid of the four assumed nucleotides
H0\
O=P— O.C5H8O3.C5H4N5O
HO/
Guanine Nucleotide (Jones and Richards, 1914) (Read, 1917)
HO\
0=P— O.C5H803.C4H4N30
HO/
Cytosine Nucleotide (Thannhauser and Dorfmiiller (a) (6), 1918, 1919)
HO\
0=P— O.C5H803.C5H4N5
HO/
Adenine Nucleotide (Jones and Kennedy, 1918)
140
WALTER JONES
H0\
0-P— O . CBH803 . C4H3N202
HO/
Uracil Nucleotide (Levene (d), 1919)
They are crystalline dibasic acids which closely resemble phosphoric acic
in their acidic conduct. They form crystalline dibrucine salts which diffe
from one another in their solubilities, thus making possible the purificatioi
of the nucleotides and their separation from one another.
The two purine nucleotides easily undergo acid hydrolysis, giving ris
to phosphoric acid pentose and purine base: but the pyrimidine nucleotide
are very stable, and must be treated severely before hydrolysis is effect*
This explains the conduct of nucleic acid toward hydrolytic agents.
It will be seen that a thermostable physiological agent (a ferment?'
is present in the pancreas, which at the body temperature causes a decor
position of yeast nucleic acid into its four component nucleotides.
The Nucleotide Linkages of Yeast Nucleic Acid. — It has been pointe
out that the work of the earliest investigators indicated the nucleotide
structure of yeast nucleic acid. But this work gave no suggestion of
points where the four nucleotides are united to one another in yeast nucle
acid, or in other words, the location of the nucleotide linkages. The loc
tion was later assumed, without any evidence, to be through the phosphoric
acid groups, but this assumption is not correct. The nucleotide linkag
involve neither the phosphoric acid groups, nor piurine groups, and prol
ably not the pyrimidine groups. This conclusion is based principally upoi
the following.
I. The conversion of yeast nucleic acid into simpler nucleotides
not attended by an increase in acidity. (Jones (e), 1920.) There woulc
be a marked increase in acidity if the nucleotide linkages involved
phosphoric acid groups.
II. The laws governing the liberation of phosphoric acid from thi
nucleotides are the same, whether the nucleotides are free or combined
nucleic acid. The same is true for the purines, and also for the pyrii
idines, so far as experiments with the latter are possible. (Jones (c
1920.)
If the nucleotide linkages involve neither the phosphoric acid gr
the purine groups nor the pyrimidine groups, they can only involve the
carbohydrate groups. Nucleic acid should therefore probably have the
following formula which represents the substances as a polysaccharide.
[ It should be noted that this formula is arrived at by exclusion and it
intended primarily to indicate the points at which the'nucleotide linka^
do not exist.
NUCLEIC ACIDS 141
HO\
0=P— O . C5H702 . C5H4N5
HO/ |
O
HO\ |
O=P— O . C5H6O . C4H4N3O
HO/ |
O
HO\ |
O=P— O . C5HCO.C4H3N2O2
HO/ |
O
H0\ |
0=P— O.C5H702.C5H4N50
HO/
Inosinic Acid and Guanylic Acid. — These two substances were known
to be constituents of animal tissues before the constitution of yeast nucleic
acid had been proposed, and one of them was the subject of considerable
discussion because it was looked upon as a peculiar nucleic acid ; but both
are purine nucleotides of the class that has been discussed.
Inosinic Acid. — This substance was discovered by Liebig (a) (1847)
in meat extract, and is now known to be a constant and characteristic con-
stituent of muscle tissue. By mild hydrolysis with mineral acid, it easily
decomposes into phosphoric acid pentose and hypoxanthine (Bauer, 1907)
( Xewberg and Brahn (a) (6) 1907, 1908).
C10H13N4P08 + 2H20 = H3P04 + C5H1005+ C5H4N40
The substance is marked by the pentose, which is identical with the pentose
of. yeast nucleic acid. The muscles of animals contain a nucleotide that
is unmistakably related to plant nucleic acid. (Levene and Jacobs (6)
1909.) The relation is not one of identity, for inosinic acid produces
hypoxanthine, where the nearest nucleotide of yeast nucleic acid produces
adenine. If the one nucleotide originates from the other (the plant food
of the animal), deaminization of the adenine group must occur somewhere.
Inosinic acid occupies a unique place in a discussion of yeast nucleic
acid, for, though it is not a nucleotide of yeast nucleic acid, it is the first
nucleotide whose constitution was solved, and the method of solution was
afterward applied to the purine nucleotides of yeast nucleic acid. Inosinic
acid is composed of three groups, and gives rise to three, and only three
substances by acid hydrolysis, viz., phosphoric acid, pentose and hypo-
xanthine. Theoretically, any one of the three groups may be the central
group connecting the other two.
U2 WALTER JONES
HO\
0=P— O.C5H803.C5H3N40 (1)
HO/
O
II
C6H904 . 0— P-0 . C5H3N4 (2)
OH
/OH
C5II904 . C5H2N4 . 0— P-0 (3)
\OH
Inosinic acid is a dibasic acid, so that formula (2) is excluded. It
sets free its hypoxantliine much more easily than its phosphoric acid.
This would not be possible if the hypoxanthine group were internal to the
phosphoric acid group; so that formula (3) is excluded. The correct
formula (1) remains. The order of the groups in adenine nucleotide and
guanine nucleotide has been proven in a similar way. (Jones (d) 1920)
(Jones and Read, 1917.)
Of the greatest interest is the hydrolytic action of ammonia on in-
osinic acid under pressure. When, so treated, the substance loses its
phosphoric acid completely, while the linkage between the pentose and
hypoxanthine groups is not disturbed, so that a phosphorus-free compound
is produced called inosine. (Levene and Jacobs (a) 1909.)
HO\ HO\
0=P-0 . C5H80:i . CBH8N40+H20= O=P-OH+C5H9O4 . O5H3N4
HO/ HO/
Inosine is typical of a class of compounds called nucleosides. As from in-
osinic acid, so also from any nucleotide a nucleoside may be prepared by
hydrolysis with ammonia.
Guanylic Acid. — This substance is a strict analogue of inosinic acid.
It is found in animal tissues (principally the pancreas) and doubtless
originates from the plant food, for it is identical with guanine nucleotide
prepared from yeast nucleic acid. By mild acid hydrolysis, it splits easily
into phosphoric acid pentose and guanine, setting free the guanine much
more rapidly than the phosphoric acid. As with inosinic acid, guanylic
acid loses its phosphoric acid and forms its nucleoside by hydrolysis with
ammonia.
Tlif chemical analogy between the two nucleotides is shown in the fol-
lowing equations:
NUCLEIC ACIDS 143
I. By acid hydrolysis
HO\
0=P-0 . C5H803 . C5H3N40+2H20=H3P04+05H1005 +C5H4N4O
HO/
inosinic acid pentose hypoxanthine
H0\
0-P-O.C5H803.C5H4N-50+2H20=H3P04+C5H1005+C5H5N50
HO/
guanylic acid pentose guanine
II. By hydrolysis with ammonia
H0\
0=P— O . C5H803 . C5H3N40-j-H20=H3P04+C5H904 . C5H3N4O
HO/
inosinic acid inosine
H0\
0=P— O . C5H803 . C5H4N50+H20=H3P04+C5H904 . C5H4N5O
HO/
guanylic acid guanosine
'Thus, inosinic acid (from muscle) is hypoxanthine nucleotide, or
deaminized adenine nucleotide, one of the purine nucleotides of plant
nucleic acid.
(juanylic acid (from pancreas) is guanine nucleotide, one of the nu-
cleotides of plant nucleic acid.
The plant origin of both nucleotides is shown by the identity of their
characteristic pentose (d-ribose).
The Nucleosides of Yeast Nucleic Acid. — When yeast nucleic acid is
submitted to mild alkaline hydrolysis (as with ammonia at 110°),
it easily decomposes into its four component nucleotides. But when al-
kaline hydrolysis of the nucleic acid is effected at higher temperatures
(as with ammonia at 150°), the four nucleotides first formed lose their
phosphoric acid, and are converted into the corresponding four nucleosides.
(Levene and Jacobs (e~) (/) (fc), 1909, 1910.)
[The logical order of treatment is from nucleotides to nucleosides but
this is not the order of discovery as the nucleosides were discovered first.
A long period of time elapsed between Kossel's discovery of the funda-
mental decomposition products of nucleic acid and Levene's discovery of
the first partial decomposition products (the nucleosides). The isolation
of the nucleotides by Jones and by Thannhauser came afterwards.]
144
WALTER JONES
The four nucleotides
The four nucleosides
H0\
0=P— O. CBH803.C6H4NB
HO/
adenine. nucleotide
C5H904.C6H4N5
adenine nucleoside
H0\
0=P— O. C5H803..C4H3N202
HO/
uracil nucleotide
C5H904.C4H3N202
uracil nucleoside
HO\
0=P— O. C5H803.G4H4N30
HO/
cytosine nucleotide
H0\
0=P— O. C5H803.C5H4N50
HO/
guanine nucleotide
H
OH
OH
OH
C5H904.C4H4N30
cytosine nucleoside
C5H904.C5H4N50
guanine nucleoside
Tlie four nucleosides were prepared from yeast nucleic acid before the
nucleotides were known, and thus gave experimental probability to the
tetra-nucleotide structure of yeast nucleic acid, which up to that time had
been simply speculative.
The chemistry of the nucleosides is just what one would suppose a
priori, and it follows closely that of the simple nitrogen derivatives. They
offer two possibilities, (1) hydrolysis, (2) deaminization. Thus by hy-
drolysis, adenosine and guanosine are decomposed into pentose and the
respective purine bases.
C8H,04.CBH4NB + H20 - C5H1005 + C5H5N5
adenosine pentose adenine
0BH,04.CBH4NB0 + H20 = C5H1005 + C5H5N5O
guanosine pentose guanine
NUCLEIC ACIDS 145
Just as the free amino-pnrines (guanine and adenine) are deaminized to
the corresponding oxy-purines (xanthine and hypoxanthine), so also the
amino-micleosides (guanosine and adenosine) form the corresponding oxy-
nucleosides (xanthosine and inosine).
These relations are shown in the following diagram. Horizontal ar-
rows indicate hydrolysis ; vertical arrows, deaminization.
CBH3N40(NH2) C5H904.C6H2N40(NH2) C5H804 . C5H2N4 ( NH2 ) C5H3N4(NH2)
guanine < guanosine adenosine » adenine
C5H3N46(OH) C6H904.C5H2N40(OH) C3H904 . C5H2N4 ( OH ) C5H3N4(OH)
xanthine < -- xanthosine inosine - > hypoxanthine
With the pyrimidine nucleosides the matter is a little different. Deamini-
zation converts the amino-nucleoside (cytidine) into its corresponding oxy-
nucleoside (uridine).
C5H9O3 . C4H2N2O(NH2) C4H3N2O(NH2)
cytidine cytosine
C6H903 . C4H2N2O(OH) C4H3N2O(OH)
uridine uracil
But the two pyrimidine nucleosides are very stable, and are not hydro-
lyzed by mineral acid into pentose and free pyrimidine as is the case
with the purine nucleosides. Of course it is possible that animal ferments
are capable of effecting hydrolysis of the pyrimidine nucleosides.
One might therefore suspect that the metabolism of yeast nucleic
acid is a play upon hydrolysis, deaminization and oxidation, which will
produce various nucleotides, nucleosides and free bases, and if continued
far enough must finally end in the formation of uric acid. In Part II
it will be shown that such is actually the case.
ANIMAL NUCLEIC ACID
The chemistry of thymus nucleic acid is best appreciated by a com-
parison of the substance with yeast nucleic acid. When thymus nucleic
acid is boiled with dilute sulphuric acid it easily sets free both of the
amino-purines (guanine and adenine), with part of its phosphoric acid and
part of its carbohydrate. But when thymus nucleic acid is submitted
to severe acid hydrolysis (as with 30 per cent sulphuric acid at 150°),
the two pyrimidine derivatives are set free with the remainder of the car-
bohydrate and phosphoric acid. All of these statements are equally true
for yeast nucleic acid; but it must be noted that thymus nucleic acid
yields thymine (Kossel and JSTeuman (a)(&), (1893, 1894)) where yeast
imcleic acid yields uracil.
146
WALTER JONES
thymine
Another point of difference between the two nucleic acids is in resj
to their carbohydrate group. The carbohydrate group of yeast nucleic
acid is a pentose group, and a pentose is formed by hydrolysis of the nu-
cleic acid ; but the carbohydrate group of thymus nucleic acid is a hexose
group, and the decomposition products of a hexose (formic acid and
levulinic acid) are formed by hydrolysis of the nucleic acid.
C0H1206 - CH3CO.CH2C02H
levulinic acid
HCOH
The fundamental groups of the two nucleic acids are therefore as follows
Of Thymus Nucleic Acid Of Yeast Nucleic Acid
Phosphoric acid Phosphoric Acid
1.
2.
3.
Guanine
Adenine
4. Cytosine
5. Thymine
6. Hexose
Purine Derivatives
Pyrimidine Derivatives
Carbohydrate
Guanine
Adenine
Cytosine
Uracil
Pentose
This fundamental identity or analogy of the two nucleic acids is very
striking, especially in connection wi+h their curious and parallel hydro-
lytic conduct; and it strongly suggests that the two nucleic acids have a
similar chemical constitution. Such a question, however, can only be
decided by a study of the partial decomposition products of thymus nucleic
acid, and in such a study one must be careful lest he fall into the "argu-
ment in a circle." Thus, the constitution of thymus nucleic acid may
be assumed in the beginning? and from this assumed constitution, that of
its decomposition products may be inferred. The latter may then be used
to prove the constitution of the nucleic acid. The matter is mentioned
here, not, in disparagement of the work that has been done with the prod-
ucts of the partial hydrolysis of thymus nucleic acid, but because the
writer believes that the logical fallacy indicated has occurred in the orig-
inal discussion of the subject.
NUCLEIC ACIDS 147
THE PARTIAL DECOMPOSITION PRODUCTS OF THYMUS
NUCLEIC ACID
Levene and Mandel (a) (1908) prepared an indefinite substance from
thymus nucleic acid which produced phosphoric acid, levulinic acid and
thymine. They conclude that the substance is thymine-hexa-nucleotide.
Levene and Jacobs (i) (1913) prepared a substance from thymus
nucleic acid that forms guanine and levulinic acid. It is possibly guanine-
hexa-nucleoside.
If these two substances, one a nucleoside and the other a nucleotide,
indicate that thymus nucleic acid is constructed throughout upon nucleo-
sides and nucleotides, then the later work of Levene and Jacobs (j) (1912)
suggests the structure of thymus nucleic acid. Their argument is based
upon the assumed structures of three compounds which they obtained by
the mild hydrolysis of thymus nucleic acid with sulphuric acid.
1. Hexa-thymidine di-phosphoric acid
2. Hexa-cytidine di-phosphoric acid
3. Hexa-cytosine-thymine-di-nucleotide 1
HO\
O=P— OH
O/
HO\
O=P— O . C0H9O5 . C5HC>T,O2
HO/
Thymidine Di-phosphoric Acid
HO\
0=P— O . CCH903 . C5HCN202
HO/ |
O
H0\ |
O^P— O . C6H9O3 . C4H4N3O
HO/
Thymine-Cytosine Di-nueleoti.de
H0\
O=P— O . C0H9O3 . C4H4N3O
HO/ |
0\
O=P— OH
HO/
Cytidine Di-phosphoric Acid
1 In the nomenclature of the decomposition products of nucleic acids the prefixes
"'penta" and "hexa" have reference to the carbohydrate groups. "Hexa" means "from
thymus nucleic acid"; "penta" means "from yeast nucleic acid."
U8 WALTER JONES
If the structures of these compounds be admitted, then the constitu-
tion of thymus nucleic acid is indicated.
HO\
0=P— O . C6H1004 . C5H4N50
O/
H0\ |
0=P— O . CCH80, . C6HCN202
HO/
O
HO\ |
0=P— O . C0H802 . C4H4N3O
HO/
0\
0=P— O.C«H1004.CBH4N8
HO/
Reduced to its simplest terms, this complicated formula means the fol-
lowing :
1. Thymus nucleic acid, like yeast nucleic acid, is a tetra-nucleo-
tide composed of the groups of four mono-nucleotides.
2. The linkages that join the four mono-nucleotide groups to one an-
other are differently located in the two nucleic acids.
With the latter statement physiology is at present little concerned.
With the former statement physiology is very much concerned; for the
decomposition of the two nucleic acids under the influence of animal fer-
ments follows parallel lines. With reference to animal metabolism the
two nucleic acids have an "equivalent" structure.2
Physiological Part
THE PHYSIOLOGICAL DECOMPOSITION OF NUCLEIC ACID
The discovery of nucleic acid in the tissues naturally prompted a host
of investigations to find a physiological agent capable of decomposing the
substance. It was assumed, without justification, that such a decomposi-
tion would involve the simultaneous disruption of all of its linkages with
the simultaneous production of all of its fundamental decomposition prod-
ucts. Of these substances, only phosphoric acid and the purine bases can
1 While this article was in press Levene abandoned the above formula for thymus
ic acid (J. Biol. Chem., 48, 1921. 122) and Thannhauaer Iras added an important
contribution to the subject. (Thannhauser and Ottenstein, Zeits. f. physiol. Chem.,
114. 1 .'"_ 1 . .v.l. )
NUCLEIC ACIDS 149
be easily detected, and as free phosphoric acid is constantly present in
tissue extracts, the decomposition of nucleic acid was generally consid-
ered proven, when a free purine base appeared during the digestion of
material at the body temperature.
All of the earlier work upon this subject was confused by unavoid-
able sources of error. The physiological decomposition of nucleic acid
could not be clearly followed until after the chemistry of the substance
had reached a comprehensive stage. Methods of isolating and separating
the decomposition products were not known; in fact, the identity of
the purine bases themselves was not established until very late. Chemists
were limited to one decomposition product, and to one reagent for its de-
tection. Putrefaction played an important part that was not taken into
account.
These are a few of the many circumstances that not only put the ear-
lier investigators at a great disadvantage, but made their work difficult to
understand and in some cases impossible to interpret. It is, therefore,
not in derogation of many of these obscure investigations, but in the
interest of clearness that we pass immediately to the work of Iwanoff
(1903).
He cultivated various molds (Penicillium glaucum and Aspergillus
niger) on thymus nucleic acid, and found that both phosphoric acid and
purine bases were produced as the molds grew, although there was not
present any ferment that could hydrolyze a protein. Iwanoff naturally
concluded that he was dealing with a specific ferment, adapted to the
decomposition of nucleic acid, and called it "nuclease." Shortly, follow-
ing this work, many researches were reported to show the existence of a
similar ferment in animal and plant tissues, so that the wide distribution
of nuclease was soon conceded.
But it was shown later that the physiological decomposition of nucleic
acid is a rather complicated matter involving a number of active agents,
and that various gland extracts differ markedly from one another in the
extent to which they can carry this decomposition. It is certain that the
first stage consists in the disruption of the nucleotide linkages with the
consequent production of simpler nucleotides, but without setting free
either phosphoric acid or purine bases. (Jones (e), 1920.) It would be
proper to apply the term nuclease to this ferment, or to abandon the term
altogether, since it can have no such meaning as was originally ascribed
to it.
Leaving out of consideration the two pyrimidine nucleotides (of
which little is known), the purine nucleotides may undergo enzymatic
decomposition in either of two ways, depending on the particular physio-
logical agent that they encounter. The purine base may be set free, or the
phosphoric acid may be liberated with the production of a nucleoside.
WALTER JONES
Finally, the nucleosides under proper enzymatic conditions decompose into
free purine and carbohydrate.
HO'H
H0\
L o=P-0 . C5H803 ! C6H4N
HO/
adenine nucleotide
H0\ |
= 0=P— O . C5H9O4+
HO/
adenine
HOH
H0\ H0\
II. 0=P— O : C6H803 . C6H4N5 = 0=P— OH+C5H904 . C5H4NB
HO/ HO/
adenine nucleotide adenine nucleoside
III. CBH904 . C5H4N5
adenine nucleoside
H0 = CH0
105
adenine
Purine bases are, therefore, produced in the nuclein metabolism along
different lines, and their subsequent conversion into uric also occurs
along different lines. The intention of the following pages is a dis-
cussion of these various paths from nucleic acid to uric acid, and it would
be logical to proceed from nucleic acid, but it is more convenient to be-
gin at the end, and end at the beginning.
The Formation of Uric Acid from Nucleic Acid. — Uric acid was for-
merly supposed to be an intermediate product in protein metabolism, but
its specific origin was clearly indicated when the purine groups of nucleic
acid were discovered; and endeavors were naturally 'made to place this
indication on an experimental basis. Horbaczewski (6)(c) (1889, 1891)
was the first to do this. His results are fundamental and quickly told.
Calf s spleen was ground to a pulp with water, and kept at the \>ody tem-
perature until putrefaction was well advanced. The putrid product was
then sterilized by the addition of lead acetate, arterial blood was added,
and the material was allowed to digest at 40° as a slow stream of air was
passed. In the end-, uric acid could be found, while similar experiments in
which no air was passed produced xanthine and hypoxanthine instead of
uric acid.
Horbaczewski did not clearly understand what he was doing and took
a great deal of useless trouble. The preliminary putrefaction and the
use of arterial blood were superfluous procedures while the sterilization
with lead acetate might have vitiated his results. Nevertheless, he started
with nucleic acid of spleen pulp and ended with uric acid.
Horbaczewski also found that in man the ingestion of nucleic acid pro-
NUCLEIC ACIDS 151
duced an increase of uric acid in the urine, whereupon he formulated the
well known leucocytosis theory.
It is frequently stated that the entire work of Horbaczewski was "un-
intelligent" ; yet he showed the physiological origin of uric acid from
nucleic acid, and thus solved one of the most important physiological prob-
lems of his day.
The Formation of Uric Acid from the Oxy-purins. — Of Horbaczewski's
many vagaries, perhaps the most serious was his misconception of the
path along which uric acid is formed from nucleic acid. He stated posi-
tively, that as no one had been able to oxidize either xanthine or hypo-
xanthine to uric acid outside of the body, these substances could not be
intermediate products in the passage from nucleic acid to uric acid, and
therefore, the purine groups of nucleic acid must have been deaminized and
oxidized before they were set free. However this may be, Spitzer (1899)
found that an aqueous extract of spleen can bring about the required oxida-
tion. To the extract he added a weighed amount of oxy-purine and digested
the mixture at 40°, as a slow current of air was passed. The oxy-purine
disappeared and in its place was found a reasonable equivalent of uric acid.
The active agent that brings about the transformation is called xanthine-
oxidase. Its presence can be shown in tissue extracts that are devoid of
power to bring about other purine transformations ; hence xanthine-oxidase
is specific.
The Formation of Oxy-purines from Amino-purines. — In order to pass
from nucleic acid to uric acid three transformations are required (though
not necessarily in the order given).
1. Liberation of the purines
2. Deaminization
3. Oxidation
Of these three, deaminization remains to be considered.
All gland extracts contain nucleic acid ; so that the purine ferments
may be studied by examining the purine products of autodigestion. When
an aqueous extract of pig's pancreas is allowed to digest at 40°, free purine
bases soon make their appearance. They are not, however, the amino-
purines (guanine and adenine) that one would expect to be formed from
nucleic acid, but the two corresponding oxy-purines (xanthine and hypo-
xanthine). The .same results are obtained with thymus. These experi-
ments lead to the assumption that in the digestion, the amino-purines are
first formed but are subsequently converted into the oxy-purines by a deam-
i nix ing agent present in the tissue extract.
A most unexpected result was obtained with pig's spleen. The end
products of the self-digestion of an aqueous extract of this tissue are
guanine and hypoxanthine, i.e., one amino-purine, and one oxy-purine. It
is reasonable to suppose that initially both amino-purines are liberated from
152
WALTER JONES
the nucleic acid of the gland extract, but only one of them is subsequently
deaminized. This necessitates the conclusion that both thymus and pan-
creas contain two independent deaminizing ferments (guanase and ade
nase), only one of which (adenase) is present in the spleen.
An equally curious result was obtained with pig's liver. The ei
products of self-digestion are guaninc and xanthine. This is easily ac-
counted for by assuming that the guanine set free from the nucleic acic
remains unchanged, but that the adenine is deaminized to hypoxanthine
which in turn is oxidized to xanthine.
Representing the purine ring with its three replaceable hydrogen atoi
/H
by the symbol P— H, the results of autodigestion may be expressed as fol-
\H
lows :
/KH2
P— OH
\H
guanine
P—
\H
adenine
/NH2
P— OH
\H
guanine
P—
\H
adenine
/H /H
P— OH P— OH P— OH
\H \H \H
xanthine hypoxanthine hypoxanthine
Pig'8 Thymus and Pancreas Pig's Spleen
(Jones and Austrian (a), 1906) (Jones and Winternitz, 1905).
/OH
P— OH
Uric Ac-id
P— OH
\H
guanine
/OH
P— OH <
\H
xanthine
Pig's Liver
(Jones and Wintemitz, 1905)
P— NH
\H
adenine
P— OH
\H
hypoxanthine
XUCLEIC ACIDS 153
But these considerations are somewhat speculative. There is but
one way to prove the presence of a ferment. The substance supposed to
bo decomposed must be introduced; as digestion proceeds it must disap-
pear, and in its place must be found a reasonable equivalent, of the sub-
stance supposed to be formed. Accordingly, dilute aqueous extracts of
the various tissues were prepared and portions taken so small that the
purine bases formed from the extract itself could be ignored. The purine
base in question was then added to the tissue extract, the material was
allowed to digest at 40° under antiseptic conditions, and the product
was finally examined for purine bases. In this way each of the glands
was found to possess the ferments that had been indicated by the results
of autodigestion. Thymus converted guanine into xanthine, and adenine
into hypoxanthine. Pancreas did the same. Spleen converted adenine
into hypoxanthine, but left guanine unchanged. Liver converted adenine
into hypoxanthine, and hypoxanthine into xanthine, but left guanine un-
changed. Three independent factors of purine fermentation are thus
disclosed (Jones (a), 1905).
1. guanase, 2. adenase, 3. xanthine oxidase
Dog's liver contains guanase but not adenase ; pig's spleen contains adenase
but not guanase ; neither tissue contains xanthine-oxidase. The three fer-
ments are therefore independent of one another.
THE PHYSIOLOGICAL DESTRUCTION OF URIC ACID
Many experimenters have observed that uric acid may be made to dis-
appear by digestion at 40° with aqueous extracts of certain glands in the
presence of a sufficient supply of oxygen. But the disappearance of uric
acid and its physiological destruction are two different things. While
undoubtedly an element of truth permeated all of the earlier work, this
work is so full of error and confusion that we must look upon much of it as
a fortunate accident. Uric acid was destroyed by laboratory methods used
in examining the products of digestion, or was lost in coagula. Its de-
struction product was incorrectly stated to be glycocoll, oxalic acid or
nothing at all. So that even now a considerable amount of ingenuity is
required to value the results of the early workers. A great deal of time
can be saved and annoyance avoided by proceeding directly to the mod-
ern well-established conclusion that certain tissue extracts are capable of
bringing about the conversion of uric acid into the more soluble allantoine
provided that a sufficient amount of air be supplied. (Wiechowski (a)
(6)(c)(d).) The gradual emergence of this truth from a mass of ob-
structing error is most interesting. While the principal credit is given to
Wiechowski, it is difficult to say who really made the discovery.
154
WALTER JONES
o (
NH— C=O
l'-XH\ + H20 + O
\ c=o
NH— C— NH/
L'ric Ac-id
NH— 0=
\
H2N\
NH— CH— NH/
allantoine
c=o
co.
Thus tho pnrino fermentation is effected by four independent physio-
logical agents.
1. guamse, 2. adenase, 3. xanthine-oxidase, 4. uricase.
Three of these lead up to the formation of uric acid and the fourth brings
about its destruction.
Nucleic Acid
guanme
adenine
; i
allantoine uric acid xanthine hypoxanthine
A study of the localization of these ferments discloses interesting and
important matter.
THE DISTRIBUTION OF THE PURINE FERMENTS
1. With very rare exceptions, the four ferments of the purine fer-
mentation are not present in any one tissue. The distribution character-
izes the tissue and the species. This variation of the distribution with
species, as well as the independent existence of guanase, adenase and xan-
thine-oxidase is shown by an examination of the livers of four different
species. (Jones and Austrian (a) (1906).) Ox liver forms uric acid from
both amino-purines, pig's liver from only one (adenine), rabbit's liver only
NUCLEIC ACIDS 155
from the other (guanme),» and dog's liver from neither. The results are
shown in the following diagrams which are abbreviations of the one on
page 138. The absence of a ferment. is indicated by a dotted line.
ox liver pi^s liver raDoiVs liver clod's liver
II II II I !
. I I . — i — 1 . 1 i .—4—4
2. The purine ferments do not appear in an organ simultaneously,
but are formed successively as embryonic development proceeds; so that
the distribution depends not only upon the particular tissue and the species,
but to a considerable extent upon the age of the animal. None of the
purine ferments can be demonstrated in the aqueous liver extract of a
pig embryo less than 90 mm. in length. As the embryo increases in length
from 90 mm. to 200 mm., adenase makes its appearance, but xanthine
oxidase appears only after the birth of the animal. (Jones and Austrian
1907.)
3. The distribution of the purine ferments in the organs of man is
very characteristic. Adenase is not present in any human tissue. Guanase
is irregularly distributed, being present in the kidney, liver and lung but
absent from the spleen and pancreas. (Jones and Austrian (6). ) It is
significant that human urine contains adenine, but not guanine. Xanthine
oxidase is profusely present in the human liver but is confined to the one
organ. (Miller and Jones; Winternitz and Jones.)
TJricase is not present in the liver, nor in any other organ either of
children or adults, nor is allantoine present in human urine, except a trace
of the substance that is ingested with the food. It seems curious that
man should have lost so useful a function as ability to destroy uric acid.
4. Uricase may be regarded as a liver ferment since it is probably
present in the livers of all the lower animals except the ape (ox, dog, pig,
sheep, rabbit, guinea pig, horse, rat, opossum, monkey), and except for
an occasional occurrence in the spleen (ox), the ferment is found only
in the liver. Its location makes it very effective, so that allantoine is
far more abundant than uric acid in the urine of the lower animals. This
appears in the analyses of the urine of seventeen animals, twelve of which
were made by Hunter and his associates. They calculate a factor for
each animal species called the "uricolytic index," which is directly pro-
portional to the allantoine, and inversely proportional to the uric acid.
The following table, adapted from that of Hunter and Givens (c) (1914),
shows the great preponderance of the allantoine over the uric acid in the
urine of the lower animals, in contrast to the urine of man and the ape.
15« WALTEK JONES
Animal Species. Uricolytic Index.
Opposum T9
Sheep 80
Horse 88
Monkey . . . . : 89
Goat 92
Cow 93
Guinea pig 94
Rabbit 95
Raccoon 95
Rat 96
Coyote 97
Cat 97
Dog 98
Badger 98
Pig 98
Ape 0
Man 0
5. Xanthine oxidase, like uricase, is generally confined to the liver
(ox, pig, rabbit, guinea pig, opossum, man), but is not so widely dis-
tributed as uricase. Thus certain livers (rat and dog) are provided with
a ferment to destroy uric acid but with none to form it This is not an
uncommon circumstance. Rabbit's liver it able to oxidize hypoxanthine to
uric acid, but cannot form hypoxanthine from adenine.
Perhaps the most active occurrence of xanthine oxidase is in human
liver, which accords with man's low" output of purine bases, the ratio of
purine bases to uric acid being thirty-five times greater in monkey's urine
than in human urine.
The deficiency of xanthine oxidase in the organism of the monkey (cer-
copithecus) was noted by Hunter. In a haphazard quantity of urine
he found
Uric acid 320
Xanthine 950
Hypoxanthine 360
Guanine 000
Adenine . . ; 000
•
Even subcutaneously injected xanthine was recovered unchanged. (Hun-
ter and Givens (6).)
Xanthine oxidase is not present in yeast where such a multitude of fer-
ments occur, nor is uric acid to be found in plants.
6. Guanase is the most widely distributed of all the purine ferments.
With many animal species it is uniformly present in all of the principal
organs (rat, ox, guinea pig, rabbit). But pig's organs are peculiarly de-
ficient in the ferment, and the muscles of the animal frequently contain
deposits of guanine, due perhaps to "guanine gout." (Virchow (a) (6),
866, 1866.) Pig's urine contains guanine and the purine bases are
always in excess of the uric acid. (Pecile ; Mendel and Lyman.)
7. Adenase, on the contrary, is very rare, having a distribution that
is somewhat complementary to that of guanase. Its presence cannot be
shown in any of the principal organs of the rat, man or rabbit. As the two
NUCLEIC ACIDS 157
ferments are seldom associated with one another, it seems queer that they
should ever have been thought identical.
Muscular hypoxanthine, which forms a considerable part of what
Burian and Schur call "endogenous" uric acid, is not the result of the
action of adenase on adenine. Leonard and Jones were not able to observe
a transformation of adenine into hypoxanthine by aqueous extracts of
muscle, while Voegtlin and Jones found that perfused adenine is not
altered by surviving muscle.
But the path of adenine metabolism does not always pass through hypo-
xanthine. None of the organs of the rat exhibit adenase (Rohde and
Jones), and Nicolaier found that in rats subcutaneously injected adenine
is oxidized but reaches the kidney without deaminization where it forms
concretions of 6-amino-2-8-dioxypurine.
/H . /OH
P— ]STH2 + 20 = P— NH2
\H \OH
adenine 6-amino-2-8-dioxy-purine
Ebstein and Bendix found a similar transformation of adenine in
the organism of the rabbit. But these two are the only authentic cases
in the literature where oxidation of a free amino-purine was found to oc-
cur without deaminization.
8. The distribution of the purine ferments is often obscure, because
a given tissue extract may be able to bring about the decomposition of a
combined, purine but unable to effect a similar decomposition of the free
base. Thus, dog's liver cannot convert free adenine into hypoxanthine,
but it can form hypoxanthine from nucleic acid with the greatest ease.
Human tissues do not contain adenase, yet the subcutaneous injection
of adenosine causes a marked increase of uric acid. (Thannhauser and
Bommes. )
A purine base may even undergo both deaminization and oxidation
while still combined. Benedict (a) (1915) has shown that about 90 per
cent of the uric acid of ox blood is in combined form. It is present only in
the corpuscle and is set free by a ferment present when the blood is allowed
to stand. This contrasts sharply with the uric acid of chickens' blood,
which does not have a purine precursor. Here the uric acid is all free
and in the plasma.
Bass found that the purine bases of human blood are combined, and
can only be detected after acid hydrolysis. He was able to isolate adenine
but at most only traces of guanine.
9. The purine metabolism does not always suggest evolutionary rela-
tions, but it often does. The proof that uricase is not present in the
tissue extracts of either the ape or man, and that allantoine is not present
in the urine of either species (Wiechowski (e)), surely justifies all the
158 WALTER JONES
labor that has been expended upon the purine metabolism. Both species
also fail to exhibit ademise, and exhibit guanase irregularly in the various
organs. (Wells and CaldwelL)
" The gradation from man to ape to monkey in relation to adenase
is interesting. Hunter and Givens (fe) found that injected adenine was
largely excreted unchanged in the urine of the rtonkey Oercopithecus, and
Hunter and Givens (a) were able to show adenase in slight activity in organ
extracts of a second monkey Cebus apella. With organ extracts of a third
monkey Macacus rhesus, Wells was able to obtain a striking demonstra-
tion of adenase.
The distributions of the purine ferments in the organs of the rabbit
and guinea pig are coincident throughout, (Mitchell.)
10. The purine metabolism of the rat is curious. Rohde and Jones
found that neither the individual organs nor the combined organs of the
rat exhibit xanthine oxidase in spite of the fact that they could show the
plentiful presence of uric acid in rat's urine. They also found that the
combined organs of the rat could not change hypoxanthine. This ap-
parent contradiction is not different from many similar cases, and could
be accounted for by assuming that in rats, uric acid is formed along a
path that does not involve xanthine-qxidase. But Ackroyd (6) found that
the injection of hypoxanthine causes an increase in the allantoine of rat's
urine. This was a most puzzling matter until the work of Benedict (6)
appeared.
11. Benedict found that the Dalmatian coach hound excretes both
allantoine and uric acid, and that when the urine of the animal is acidi-
fied with hydrochloric acid, a crystalline deposit of uric acid is formed.
Careful analyses of the dog's urine were made for both allantoine and
uric acid, over a long period of time, and then uric acid was injected sub-
cutaneously. This caused the expected rise in the allantoine but the in-
jected uric acid also appeared, and quantitatively. From these results
Benedict concludes that "uric acid and allantoine are interrelated in metab-
olism in other ways than have heretofore been assumed."
THE ENZYMATIC DECOMPOSITION OF COMBINED PURINS
Many observations indicate that the organism treats combined purines
differently from free purines. The following two experiments go to the
root of the matter.
1. When adenine is digested for several days with an aqueous extract
of dog's liver, the substance remains unaltered and can be recovered.
Dog's liver does not contain adenase. But when nucleic acid (yeast or
thynius) is digested with an aqueous extract of dog's liver, hypoxanthine
is formed in an amount corresponding to the adenine group of the nucleic
acid used. This is very clear. Dog's liver can deaminize combine adenine,
NUCLEIC ACIDS
159
but not free adenine. The tissue contains both adenosine deaminase and
inosine hydrola.se but neither adenosine hydrolase nor adenase (Amberg
and Jones), as indicated in the diagram:
C5H904 . C5H2N4(NH2)
adenosine
C5H3N4 (NHa)
adenine
C6H904.C5H2N4(OH)
C5H,N4(OH)
hypoxantliine
In the nuclein metabolism there are two paths to hypoxantliine, one of
which cannot be used by dog's liver.
II. When an aqueous extract of pig's pancreas is allowed to digest
at 40° C., xanthine and hypoxanthine are formed. This was to be expected
because the gland contains both guanase and adenase. But when the di-
gested extract is boiled with dilute mineral acid the free purines are greatly
increased. Guanine and additional hypoxanthine appear.
These results can be explained in only one way. The nucleic acid
is first decomposed into its simple nucleotides, as was to be expected. Each
of the purine nucleotides is then decomposed in two ways by the action of
two ferments present in the gland extract. In one way, the purine base
is set free (action of purine nuclease), and in the other way, phosphoric
acid is split off leaving the nucleoside (phospho-nuclease). Thus in the
self-digestion of the pancreas four purine compounds are initially pro-
duced; guanine, adenine, guanine nucleoside, adenine nucleoside.
The two free purines are deaminized and we therefore find the oxy-
purines among the products. The adenine nucleoside is also deaminized
to hypoxanthine nucleoside but the guanine nucleoside is not similarly
deaminized. Hence subsequent acid hydrolysis produces guanine and hypo-
xanthine.
Using the terminology of yeast nucleic acid, the autolysis of pig's pan-
creas is expressed in the following diagram
Nucleic Acid
guanine
xanthine
guanosine
adenosine
adenine
hypoxanthine
160
WALTER JONES
The gland evidently contains adenase, guanase and adenosine deaminase,
but not guanosine deaminase (Jones (b) 1911.)
By similar experiments and similar reasoning the localization of the
nucleic ferments of many glands has been shown but much space would
be required to consider the individual cases. The general scheme of nu-
clein metabolism so far as it concerns purine derivatives, is indicated in
the following diagram which shows the theoretical possibilities, nucleic
acid being represented as a di-purine di-nucleotide. The independent ex-
istence of each ferment indicated by an arrow has been fairly well si
H0\ /NH,
O=P— O.C5HTO,.C6N4— OH
HO/ I \H
/NH,
C.N4H— OH
\H
guanine
C.N.H— OH
\OH \H
uric acid xantbine
H0\ /H
0=P— O.C6HA.C,N4— NH,
HO/
CBH,O4.C5N4— OH
\H
guanosine
5N4— NH,
\H
adenosine
/OH
C5H804.C5N4— OH
\H
xanthoaine
C.H,04.C5N4— OH
\H
inosine
/H
C,N4H-XI
\H
adenlne
c5x4H— o;
\H
hypoxanthi
Urobilin and Urobilinojjen Louis Bauman
Chemistry — Occurrence — Mechanism of Urobilin Formation — Determination
—Clinical Significance — Resume.
Urobilin and Urobilinogen
LOUIS BAUMAN
NEW YORK
Chemistry
In 1868 Jaffe first described a reddish substance which he found in
human and canine bile and which resembled one of the urinary pigments.
Both absorbed certain rays between the B and F lines of the spectrum and
both fluoresced in the presence of zinc salts. Jaffe named the compound
urobilin. It is interesting to note that even at that time he was aware
that the pigment was not, preformed, but resulted from the oxidation of a
chromogen, which is now known as urobilinogen (LeNobel).
Urobilinogen has the empirical formula, C:53II42O6N"4. Fischer and
Boese showed that it contained 4 pyrole nuclei and that its structural
formula closely resembled that of bilirubin.
Bilirubin.
H2C=HC— C C— CH3 CH3-C C— CH=CH]2
II II I! II
CO C C— OH
/\ /\ /\ /
/ NH \ / NH
O C=C
\ NH / \ KE
\X \/ \/ \
HO— C C C C— CH3
COOH-CH2-CH2-C C-CH, CH3-C G-CII2CH2COOH.
Urobilinogen.
CH3-CH2-C C-CH3 CH3-C C-CH2CH3
HC C C C-OH
\ /\ /\ /
Nil \ / NH
r\_ _r\
NH / \ NH
/ \X \/ \
HO-C C C C-CH3
I! II II II
COOH-CH2-CH,-C C-CH3 CH3-0 C-CH2CH2COOH.
163
164 LOUIS BAUMAN
Urobilinogen is a colorless compound which forms monoclinic crystals
melting at 192° C. Its molecular weight is 600. It is soluble in chloro-
form and other organic solvents and is readily oxidized to urobilin by the
oxygen of the air and by oxidizing substances.
II. Fischer synthesized urobilinogen by reducing bilirubin with sodium
amalgam ; he also described some of its physical and chemical properties.
Ho obtained it to the extent of about 46 per cent of the bilirubin which
he employed, and assuming that it was derived from one-half of the
bilirubin molecule he named it hemibilirubin. Later Fischer and Meyer-
Betz (a) (1911) proved that urobilinogen and hemibilirubin were identi-
cal. Fromholdt obtained the same substance by a somewhat similar method.
When urobilinogen is treated with para-dimethylamino-benzaldehyd,
dissolved in hydrochloric acid, the so-called Ehrlich reagent, it forms a
red compound which absorbs certain rays in the orange and green regions
of the spectrum between the D and E lines. The red compound results
from the oxidation of a colorless chromogen. A solution containing one
part of urobilinogen in 640,000 parts of water still gives the Ehrlich
reaction (Fischer and Meyer-Betz (a), 1911). This reaction is not specific,
for it is obtained with any pyrole derivative that contains a free hydrogen
atom attached to one of the carbon atoms of the ring. Urine containing
indol derivatives also gives the color test but does not exhibit the char-
acteristic absorption bands (Fischer).
Urobilin is easily obtained from urobilinogen by oxidation. It is a
reddish yellow or brown substance of uncertain composition, and probably
contains a number of urobilinogen molecules that have been oxidized and
polymerized. It is soluble in aqueous alkali and in most organic solvents
such as alcohol, ether and chloroform. Urobilin absorbs certain rays in the
region of the B and F lines of the spectrum. It forms a colored salt with
mercuric chlorid, the so-called Schmidt test. When an alkaline solution
of urobilin is neutralized with copper sulphate solution a red compound,
soluble in chloroform, is formed. This copper compound exhibits the
characteristic urobilin absorption bands (Bogomolow). Urobilin is pre-
cipitated from watery solution by ammonium sulphate. It can be reduced
to urobilinogen by bacteria (Charnas). Fischer isolated 160 grams of
urobilin from a large amount of human feces. His analysis, carbon 63.46
per cent, hydrogen -7.67 per cent, and nitrogen 4.09 per cent, agreed with
that reported by Garrod and Hopkins about 14 years previously. When
urobilin was subjected to dry distillation or reduction by glacial acetic
acid and zinc dust two substances were obtained. The one contained
nitrogen while the other resembled cholesterol or one of the bile acids,
and did not contain nitrogen.
Occurrence. — Because urobilin and urobilinogen have the same clinical
and physiological significance, and for the sake of brevity, the term uro-
bilin will be used to include both substances.
UROBILIN AND UROBILINOGEN 165
Urobilin occurs in normal bile and in normal stool except in that of
the new-born. It is present in the urine in negligible quantities. Con-
cerning its presence in the blood there is little definite information. If it
occurs therein it is not demonstrable by our present methods. The writer
has frequently attempted to determine its presence in the serum of patients
that were excreting considerable quantities in the urine and stool, but
without avail. When normal serum is heated with strong hydrochloric
acid a positive Ehrlich reaction is obtained, but this is probably due to
decomposition of one of the heterocyclic amino acids, such as tryptophan.
Gerhardt and others have obtained the reaction with serous fluids other
than blood. Conner and Eoper claim to have found it in the serum of
pneumonia patients shortly before death. When urobilin is added to
blood it rapidly disappears probably as a result of oxidation by oxyhemo-
globin (Roth and Herzfeld).
An increased amount of urobilin is found in the. stool, in the bile,
and occasionally in the urine, in pernicious anemia and other conditions
associated with a destruction of red blood cells, and also in diffuse lesions
of the liver. Urobilin is absent from the stool in jaundice due to complete
closure of the common bile duct and in severe diarrhea.
Mechanism of Urobilin Formation. — The voluminous literature per-
taining to this subject abounds in theoretic discussion and hypotheses.
The enterogenous theory had its chief exponent in Friederich Mueller (6)
(1892). It appears to be least open to criticism, and is supported by
numerous clinical and experimental observations. It postulates that uro-
bilin results from the reduction of bilirubin by the bacteria of the large
intestine. The following evidence is submitted in support of the enterog-
enous theory: 1. The transformation of bilirubin into urobilin in vitro
by bacteria (Mueller, 1892 (a) ; Fischler (a), 1906). 2. Urobilin is ab-
sent from the stool and urine of severely jaundiced patients but. appears
when urobilin-free bile is administered by stomach tube (F. Mueller (&),
1892). 3. Bilirubin alone is found in the intestine of the new-born until the
third day, when urobilin appears coincident with the development of the
bacterial flora. 4. Diarrheal stools often contain bilirubin but no urobilin.
This is apparently due to the rapid propulsion of the intestinal contents
—that is, the stool is expelled before the bacteria have had an opportunity
to reduce bilirubin. 5. Urobilin is not present in the small intestine where
bacteria are absent, but appears distally to the ileocecal valve (Schmidt).
Normally some urobilin is absorbed from the large intestine and
brought to the liver where it is partly excreted into the bile and partly
converted into another substance, probably bilirubin. The liver does not
permit urobilin to escape into the general circulation. The traces that are
normally found in the urine may be due to absorption from the lower
bowel by the blood of the inferior hemorrhoidal plexus.
When extensively diseased the liver may permit urobilin to escape into
166 LOUIS BAUMAN
the general circulation and then it is excreted by the kidneys. In con-
ditions causing a rapid disintegration of red blood cells, as in pernicious
anemia, hemolytic jaundice, internal hemorrhage, etc., a large amount of
hematin is converted into bilirubin, and this permits an increased ab-
sorption of urobilin from the intestine. Under these circumstances some
urobilin may escape into the general circulation* even though the liver be
functionally intact. In recent years hematin. and bilirubin have been
demonstrated in the blood serum in pernicious anemia (Schumm).
While the enterogenous theory explains most of the known facts it
does not satisfactorily account for all of the experimental results recorded
in the literature. Fischler (a) (b) (1906, 1908) has submitted evidence
favoring the liver itself as a site of urobilin formation. The following ex-
periments may be (fited in this connection : When the common bile duct of
dogs is tied and a biliary fistula is established it is found that in spite of
the deviation of the bile to the exterior urobilin persists in the stool but
disappears from the tyle. If, to such animals, poisons that exert a par-
ticularly destructive effect on the liver parenchyma such as ethyl alcohol,
amyl alcohol and phosphorus, be administered there results a large in-
crease in the urobilin content of the bile and a lesser increase in the feces.
Fischler maintains that under these conditions the liver itself produces
urobilin some of which is absorbed by the blood and excreted into the
intestine. The disturbing features in Fischler's experiments were the
lack of uniform results, the licking up of bile from the fistula by some
of the dogs and the presence of jaundice in others. While Fischler believes
that the liver may form urobilin he concedes that the intestines are the
usual site of its synthesis. Meyer-Betz criticizes Fischler's conclusions
and seeks to explain all of his results by assuming that some bilirubin
reached the intestine by way of the blood because of the common occurrence
of jaundice in bile fistula dogs. Wilbur and Addis have, in a measure,
substantiated the work of Fischler. They observed an increased excretion
of urobilin in the stool (and occasionally in the urine) of a dog that had
cirrhosis of the liver. Further, they found that when the common bile
duct was ligated the urobilin at first disappeared from the stool only to
return later in diminished quantities, and that when a biliary fistula was
produced in these animals the urobilin of the stool decreased but did not
wholly disappear.
The arguments in favor of the so-called histogenic theory, which
ascribes the formation of urobilin to the tissues, appear to be weak and
inconclusive. The occurrence of urobilinuria after internal hemorrhage,
for instance, is better explained by the enterogenous theory.
Determination. — The method of Wilbur and Addis is now commonly
employed in this country for the determination of urobilin in the stool,
bile and urine. The principal steps involved are as follows (the reader
is referred to the original for all details) : 10 c.c. of the 24-hour volume
UROBILIN AND UROBILINOGEN 16Y
of urine are added to 10 c.c. of saturated alcoholic zinc acetate solution and
filtered. One c.c. of Ehrlich's solution is added to 10 c.c. of the filtrate.
The reaction is allowed to progress in the dark for one-half hour. The
solution is then diluted until the respective spectral absorption bands of
urobilin and urobilinogen just disappear. The dilutions required give the
value for 5 c.c. of urine. If this figure is multiplied by the factor,
volume of urine c.c.
— the number 01 dilutions lor the 24 hours is obtained.
5
The feces are ground with water and made to a definite volume. An
aliquot portion is extracted with 3 volumes of acid alcohol and then
treated with zinc acetate and Ehrlich's reagent. The steps that follow and
the computation are similar to those described for the urine. The average
normal excretion in the stool per day is about 6,500 dilutions (Wilbur
and Addis). Schneider (a) (1916) determines the urobilin in the duo-
denal contents by mixing 10 c.c. with 10 c.c. of the zinc acetate solution, and
then filtering. (One drop of ammonia is added to the filtrate if it is not
already alkaline.) One c.c. of Ehrlich's reagent is added to 10 c.c. of
the filtrate. The dilutions are expressed in terms of 1,000 c.c. of bile.
Clinical Significance
An increased amount of urobilin in the urine is frequently observed
in diffuse involvement of the liver as a result of fatty or paren-
chymatous degeneration, cirrhosis, new growth, abscess or even in the
congestion due to heart disease. Wilbur and Addis record a daily
excretion of from 1,100 to 3,000 dilutions of urobilin in the urine of
patients suffering from cirrhosis, hemochromatosis or liver abscess. Owing
to the variability of urobilin excretion in the urine it is desirable to con-
tinue the determinations over several days. Urobilinuria is quite common
in the infectious diseases that produce degeneration of the liver as scarlet
fever, lobar pneumonia, rheumatic fever, malaria, tuberculosis, etc. In
biliary obstruction the amount of urobilin in the stool is proportional to
the degree of patency of the common bile duct. Fischer and Meyer-Betz (&)
(1912) studied the effect of administering fresh animal bile on the uro-
bilin excretion in the urine. Under these conditions the urine of normal
subjects contained little urobilin while patients suffering from liver disease
excreted considerable amounts. Similar results were obtained when uro-
bilinogen itself was administered. In the writer's limited experience the
excretion of urobilin in liver disease has been quite irregular. At times no
increase was observed; at times an increase occurred in the urine alone
or in the feces alone while in some instances an increase in both urine and
feces occurred (Bauman). It is conceivable that in hepatic conditions
an increase in the urobilin of the stool may precede urobilinuria. The
168
LOUIS BAUMAN
increased excretion of urobilin in the stool of some cirrhosis patients was
pointed out by Mueller (a) (1892).
A disease or condition causing an increased destruction of red cells
is usually if not always accompanied by an increased elimination of
urobilin in the bile, in the stool and sometimes in the urine as well. In
secondary anemia the excretion of urobilin remains normal or subnormal
while in pernicious anemia it may rise to 15 times the normal amount,
hence urobilin estimations may serve to differentiate the two conditions.
Schneider (a) (1916) studied the urobilin in the duodenal contents of
pernicious anemia patients. He found over 2,000 dilutions in pernicious
anemia while in secondary anemia little or no increase could be detected.
Aftef splenectomy a decrease of the urobilin occurred. These results have
been confirmed by Giffin, Sandford and Szlapka. Robertson (b) (1915)
and McCrudden emphasize the diagnostic value of urobilin estimations of
the stool, thus confirming the work of Wilbur and Addis. Most recently
Howard and Hansmann, working in the writer's laboratory, studied the
excretion of urobilin in the feces, urine and bile of a number of pernicious
anemia patients. They conclude that the estimation of the stool is more
reliable than that of the bile. Attempts to demarcate the 24-hour quantity
of feces were unsuccessful. In pernicious anemia a marked increase of
urobilin in the stool occurred even when the blood examination showed no
abnormality. The urobilin was occasionally diminished during the re-
missions so frequently encountered in this disease.
Although obviously inaccurate the "quantitative" estimation of uro-
bilin in the stool yields information which possesses considerable clinical
value. On a priori grounds it would appear preferable to approximately
determine the total daily excretion than that contained in a casual sample
of bile; furthermore, it obviates the passage of the duodenal tube, a pro-
cedure which is sometimes disagreeable to the patient.
The diagnostic value of urobilin estimations is illustrated by the fol-
lowing case report:
An Italian, J. G. (history number 44,031), entered the Presbyterian
Hospital in November, 1919, complaining of gastric distress and constipa-
tion which had lasted for 2 years but which was never accompanied by
real pain, vomiting or diarrhea. During the 2 weeks prior to admission
he had experienced a sudden attack of weakness and dizziness followed
by the appearance of tarry stools and shortness of breath. During the
period of illness he had lost approximately 25 pounds.
Physical examination showed evidences of neuroretinitis in both eyes
occurring in an anemic man measuring about 5y2 feet and weighing 143
pounds. The remainder of the examination was irrelevant. Eadiographic
examination and sigmoidoscopy were also negative.
The red cells numbered 2,000,000; hemoglobin was 40 per cent; white
blo<xl cells 6,800, of which 58 per cent were polymorphonuclear. The
UROBILIN AND UROBILINOGEN 169
blood smear showed irregularity in size and shape of the red cells, with
central pallor and polychromatophilia on one occasion. The Wassermann
test was negative. The gastric meal contained no free hydrochloric acid
and a total acidity of 32. Lactic acid and occult blood were absent. The
stool was repeatedly examined; occult blood was found on one occasion
only. The urobilin content of the stool was persistently subnormal; there
was none in the urine.
The patient was given two blood transfusions and was discharged
after one month with the diagnosis of pernicious anemia. This diagnosis
was made largely because of the negative radiographic examination.
During the following 6 months the patient's weight gradually in-
creased by 15 pounds; and his blood recovered to the extent of about
5,000,000 red cells and 70 per cent of hemoglobin. He was readmitted
in June, 1920, largely because of the uncertainty of the diagnosis and
because his gastric symptoms had increased in severity. The red cells
now numbered 5,200,000, and the hemoglobin 80 per cent. The 24-hour
stool contained 1,760 dilutions of urobilin; the urine contained 400 dilu-
tions on one occasion and 1,088 on another.
Fluoroscopy now showed a mass in the region of the cardiac end of
the stomach, and this was confirmed by an exploratory laparotomy, which
further revealed metastatic involvement of the liver and retroperitoneal
lymph nodes. .
In this case the severe anemia during the earlier period of the disease
was probably caused, by a profuse hemorrhage from the tumor. The low
urobilin content of the stool militated against pernicious anemia and
favored a new growth. The late occurrence of urobilinuria was due to
the involvement of the liver.
Our ignorance of the fate of urobilin in the blood and tissues and its
irregular excretion in the urine in cases of liver disease detract from its
value as a functional test of liver efficiency. The interest aroused by
the work of Wilbur and Addis in this country, and by that of Fischer
abroad will stimulate investigation so that information relating to this
phase of the urobilin problem will probably be furnished in the near
future.
Resume
Urobilinogen and urobilin are almost exclusively derived from bili-
rubin by reduction by the bacteria of the large intestine. Urobilin is an
oxidized and polymerized urobilinogen.
The determination of urobilin in the feces, urine and bile may be a
valuable means of estimating the rate of blood destruction, thus aiding
in the differential diagnosis of primary from secondary anemia; it may
also serve to determine the functional state of the liver.
Creatin and Great inin . Louis Bauman
Chemistry — The Creatin Content of Muscle and Other Tissues — The Origin
of Creatin — Creatin Metabolism — Muscle — Blood — Urine — Creatinin
Metabolism — Muscle — Blood — Urine — The Fate of Administered Creatin
or Creatinin — Resume.
Creatin and Creatinin
LOUIS BAUMAN
NEW YORK
Chemistry
Creatin, methylguanidoacetic acid (CH3N — CH2COOH), was first
isolated from meat extract and named by Chevreul in 1835. Twelve
years later Liebig isolated it from the muscle of various animals, analyzed
it and converted it into its anhydride which he named creatinin. Creatin
was synthesized from sarcosin and cyanamid by Volhard (1868), and
from sarcosin and guanidin carbonate by Horbaczewski (a) (1885).
Creatin forms transparent prismatic crystals which contain one mole-
cule of water. At room temperature it is soluble in water to the extent
of 1.35 per cent. When heated with water or dilute mineral acids it is
converted into creatinin. Conversely creatinin is converted into creatin
when heated with calcium hydroxid solution.
CO
Creatinin ( | ) also occurs in the form of prismatic
/"ITT -\y C\TT
U±l3lN ^ti2
crystals which dissolve in water to the extent of 10 per cent; it is also
more soluble in alcohol than creatin. Owing to its basic nature it is
readily precipitated by the so-called alkaloidal reagents.
In watery solution creatin is slowly transformed into creatinin, the
rate of transformation is slightly less than 0.5 per cent per day at 36° C.
Under similar conditions creatinin is changed into creatin so that at the
end of 11 months an equilibrium is established in either case. When
these substances are dissolved in the urine a similar change takes place
(Myers and Fine (fc), 1915).
Both creatin and creatinin reduce alkaline copper solutions. When
boiled with mercuric oxid they are oxidized to methylguanidin and oxalic
171
acid (Dessaignes). When creatin is oxidized with hydrogen peroxid in
the presence of ferrous sulphate, glyoxylic acid is formed (Dakin (c) ). Ee-
cently a new substance, methylguanidoglyoxylic acid, was obtained upon
oxidizing creatin with mercuric acetate in watery solution (Bauman and
Ingvaldsen). The successive steps in the oxidation of creatin may be
formulated as follows:
1. NH2C(:NH)N(CH3)CH2COOH1 + O = NH2C(:NH)N
(CII3)CHOHCOOH.
2. NH2C(:NH)N(CH3)CHOHCOOH + O = NH2C(:NH)N
(CH3)COCOOH.
3. NH2C(:NH)N(CH3)COCOOH + H2O = NH2C(:NH3)N
(CH3)H + COOHCOOH.
The ease with which creatin is oxidized by metallic salts is noteworthy.
The alleged occurrence of methylguanidin in the blood, muscle and urine
may in reality be the result of oxidation of creatin by the mercuric or
argentic salts which are ordinarily used for the purpose of isolation.
When picric acid is added to urine a characteristic potassium creatinin
picrate is precipitated (Jaffe (e), 1886) ; this compound may be readily
converted into the time-honored zinc chlorid salt according to the method of
Benedict (a) (1914). In this manner relatively large quantities of
creatinin (and creatin) may be prepared so that it has become readily
accessible to most laboratories and is now used to prepare standard solu-
tions for its quantitative colorimetric determination.
Jaffe (e) (1886) first noted that an alkaline solution of creatinin re-
duces picric acid to a reddish compound (probably picramic acid). Folin
(a) (1904) proved that the intensity of the color was directly proportional
to the amount of creatinin and therefore that this reaction was well adapted
for its quantitative colorimetric determination. The publication of this
method proved to be an incentive for numerous investigations of the
physiological behavior of creatin and creatinin, since the former may
readily be converted into the latter by relatively simple means.
The Creatin Content of Muscle and other Tissues
Creatin is a characteristic constituent of the muscle tissue of all
vertebrates. In the skeletal muscle of the horse, for example, it forms
approximately one-third of the total extractive nitrogen, the remainder
being formed by carnosin and other compounds (Von Fuerth and
Schwartz). Creatin is most abundant in voluntary muscle; there is less
in heart muscle, and least in involuntary muscle. The following table
gives the average percentage of creatin in the moist tissues of various
animals:
CREATIN AND CREATININ
Tissue
Animal
Creatin
mg. %
Author
Voluntary muscle . . .
Liver
Rabbit
Dog
Cat
Kitten1
Human
Horse
Pig
Sheep
Beef
Rat
Fish2
Doe
518
367
449
224
393
380
450
410
440
458
500 to 700
18
Myers and Fine (1913 (1))
i u u (
i n (( (
Van Hoogenhuyze and Verploegh ( 1905 )
' •' S H it
' " t .1 a
' « < <( «
Myers and Fine (1915 (4) )
Okuda
Beker
Heart muscle
Doe
216
Uterine "
Dog
30
Testes
Beef
Beef
38
87
Brain
Beef
56
Kidney
Dog
Beef
56
16
Brain
Dog
Pig
Doe
14
15
110-124
Jannev and Blatherwick
Testes
Doe
181
Pancreas
Doe
18
« u «
1 The creatin content of kitten muscle varies with the age of the animal.
2 Various species of fish muscle were analyzed. The figures represent minimal and
maximal values.
Denis (e) (1916) determined the creatin content of a relatively large
number of samples of human muscle and found it to vary from 360 to 421
milligrams per cent. The muscle of children and that of persons dying
of a wasting disease was usually found to be low in creatin.
As the creatin content of muscle is determined by the Folin method
it was important to know if the color reaction was entirely due to this
substance. By first transforming the creatin in muscle extract into cre-
atinin and then quantitatively removing the latter by precipitation, Bau-
man and Ingvaldsen (a.) (1916) were able to show that creatin alone was
responsible for the Jaffe reaction.
The Origin of Creatin
A vast amount of experimental work has been done on this problem.
The only other guanidin derivative which has been found in the animal
body is the amino acid, arginiii (alpha amino, delta guanido valerianic
acid, (NH2C(:NH)NH— CH2CH2CH2CHNH2COOH). Arginin has
been perfused and administered in various ways in order to see if it was
converted into creatin. On the whole the results have not been uniform
or conclusive. By analogy one might assume that arginin would first be
oxidized to guanidoacetic acid or glycocyamin (NH2C( :NH)NH-CH2
!74 LOUIS BAUMAN
COOH). This compound is converted into creatin when fed or injected
into animals (Czemicki ; Jaffe, 1906; Dorner; Bauman and Hines).
Van Hoogenhuyzo and Verploegh (a) (1905) failed to observe an
crease in creatinin excretion after the ingestion of proteins relatively rk
in arginin. Myers and Fine (1905) report that the concentration
muscle creatin does not appear to be markedly influenced by the feedii
of proteins having a high or low content of arginin. Jaffe (/) (1906) di<
not observe an increase in creatinin excretion after the injection of arginii
into rabbits. Bauman and Marker also failed to note an increase
muscle creatin when arginin was circulated through dog muscle.
Thompson (a) (1917) administered arginin to ducks, dogs and rabbit
and observed an increase in the elimination of creatin or creatinin and oi
the creatin content of the muscle. Inouye observed that arginin was coi
verted into creatin when perfused through the liver of cats. In grown
pigs the nature of the protein in the diet determines whether or not
creatin appears in the urine (McCollum and Steenbock). Denis (/)
(1917) has shown that the creatin excretion in hyperthyroidism may
much increased by the addition of protein to the diet. In children thf
creatin of the urine varies with the amount of protein in. the diet (Denis
and Kramer). Creatinuria in women follows the ingestion of lar£
amounts of protein (Denis and Minot (a)).
Kiesser observed an increase in. muscle creatin and in the creatinin
excretion of rabbits after the injection of cholin and betain.
Harding and Young found that arginin was without effect on the
creatin excretion of growing dogs but that a variation in the cystin con-
tent of the diet was followed by a similar variation in the creatin
elimination.
Most recently Wishart observed an increase in muscle creatin follow-
ing the injection of guanidin salts into cats, dogs and frogs. The as-
sumption is that guanidin is detoxicated by conversion into creatin.
In the foregoing experiments the factor of creatin destruction by the
tissues must not be overlooked. Creatin . may be synthesized from a
precursor but subsequently destroyed.
Creatin Metabolism
Muscle. — Before discussing this subject it may be well to remind the
reader that the experimental results obtained by different investigators are
often conflicting and therefore hard to reconcile with one another.
Considerable evidence seems to show that creatin is a product of muscle
metabolism. Its preponderance in muscle suggests that it results from
metabolic processes peculiar to this tissue (Pekelharing). Muscle creatin
increases with an increase in muscle tonus and conversely paralyzed muscle
175
is low in creatin (Pekelharing and Van Iloogenhuyze (a), 1909; Jansen
(b ) ). Voluntary muscle lias an affinity for creatin, for when it is injected
into rabbits the creatin content of their muscles is increased by 5 per cent
(Myers and Fine (e), 1913).
The constancy of the creatin content of muscle of a given species of
animal under uniform conditions of diet was first pointed out by Myers
and Fine (c) (1913). During starvation or carbohydrate abstinence the
creatin 'content of muscle at first increases and then progressively de-
creases with the length of the fast (Mendel and Rose (&), 1911). The
muscle of rabbits that had fasted for 6 days contained 0.55 per cent
of creatin, while that obtained from rabbits that had been starved for 24
days contained 0.36 per cent (Myers and Fine (d) 1913). The decrease
in creatin is explained by the loss of this substance through the urine.
Benedict and Osterberg maintained phlorhizinized dogs in approximate
nitrogen equilibrium by feeding creatin free protein. Under these con-
ditions the excretion of creatin continued unchanged, and in spite of the
relatively large quantity lost in the urine the muscle of these animals
actually contained more than that of normal dogs. The authors conclude
that the creatin excreted in the urine is not dependent on the amount of
body tissue destroyed, that it is not derived from muscle creatin, and
further that creatin is probably formed in large amounts and is normally
utilized or destroyed for the greater part. The creatinin of the urine
can only account for a small part of the creatin that is normally katabol-
ized. Folin and Denis (7t) (1914) found that when creatin was injected
into cats it was absorbed by the muscles to an extraordinary degree. They
believe that living muscle does not contain free creatin and that that found
on analysis is a post-mortem product, The vital combination must be a
very loose one to be sure.
According to several authors creatin is not destroyed during aseptic
or antiseptic autolysis of muscle (Denis (e*), 1916 ; Mellanby (a) ). Myers
and Fine (fc) (1915) find that no destruction of creatin or creatinin occurs
when rabbit muscle is permitted to autolyze (under aseptic conditions) at
body temperature. On the other hand the work of Hoagland and McBryde
seems to show that during aseptic autolysis of beef muscle creatin at first
increases and then decreases.
Blood. — Normal blood contains between 3.5 and 6 milligrams of
creatin per 100 c.c. (Folin and Wu). In nephritis as much as 31.7 mgs.
have been'observed (Myers and Fine(</), 1915). Though the concentration
of creatin in the blood is higher than that of creatinin the former is usually
not excreted by the kidney while the latter is a normal constituent of the
urine. In other words the renal threshold for creatinin is lower than for
creatin. The concentration of .creatin in the plasma is lower than in
whole blood (Hunter and Campbell
Urine. — Under normal conditions ereatin is absent from the urine of
men when living on a ereatin free diet; it is constantly present in th<
urine of children and frequently occurs in the urine of women. Powi
and Kaper have shown that children eliminate more ereatin during th
day than at night. In the young the supply of carbohydrate and fa
appears to be unable to meet the demands of growth and maintenance,
and as a consequence muscle tissue disintegrates, ereatin is liberated ah"
appears in the urine. The frequent occurrence of acetonuria in childre
and the rapidity with which the glucose content of their blood is lowered
during starvation are further indications of a limited supply of glyco,
(Sawyer, Stevens and Bauman). The occurrence of ereatin in the urin
of children may also be due to a diminished ability to destroy it (Krau
(&), 1913; Gamble and Goldschmidt (a), 1919). In infants the in-
creased excretion of ereatin when they are on a pure milk diet may be dui
to the ereatin present in the milk and not to the protein therein (GambL
and Goldschmidt (6), 1919). .
Sawyer, Stevens and Bauman observed that the increased excretion o
ereatin which occurs in children when deprived of carbohydrates is usually
followed by a period of ereatin retention upon resumption of the normal
diet. It appears as if the body retained ereatin with great regularity
under these circumstances.
The alleged occurrence of creatinuria after menstruation (Krause (a)
1911) has not been confirmed by M. S. Rose, who found no definite rela-
tion between the ereatin output and the sexual cycle, nor was creatin
excretion affected by protein feeding. In normal pregnancy the excretion
of creatin is usually less than 20 per cent of the creatinin excretion (Van
Hoogenhuyze). A pregnant woman excretes about 170 mgs. of creatin
and the same woman during the lying-in period eliminates about 470 mgs.
(Van Hoogenhuyze and ten Doesehate). After cesarean section an in-
creased elimination of creatin occurs even when the uterus has been re-
moved at the time of operation (Mellanby (6), 1913 ; Morse). F. G. Bene-
dict (c), and F. G. Benedict and Diefendorf first noted the occurrence of
creatin in the urine of starving men and women. Mendel and Rose (a)
(1911) found creatin in the urine of adult animals when they were de-
prived of carbohydrates and began to break down their body proteins.
Certain animals having small reserves of glycogen and fat, as the rabbit,
will excrete creatin after a short, fast, while others with large stores of fat,
as the pig, can be fasted for from 14 to 16 days without excreting creatin
(McCollum and Steenbock). In this respect the human being and dog
occupy intermediate positions. Mendel and Rose (a) (1911) found that
rabbits began to excrete creatin on the second day of starvation and that
the amount excreted gradually rose until death. Depriving the tissues of
carbohydrates by means of phlorhizin poisoning also leads to creatinuria
(Mendel and Rose (a), 1911 ; Cathcart and Taylor).
CKEATIN AND CEEATININ 177
From the foregoing one might conclude that creatinuria regularly
accompanies undernutrition, whatever the cause. This is actually the case.
Diabetes, carcinomatosis, hyperthyroidism, fevers, incessant vomiting and
other wasting conditions are usually accompanied by the appearance of
creatin in the urine. Feeding thyroid substance increases the metabolic
rate and leads to the elimination of creatin (Krause and Cramer) . Shaffer
(a) (1908) found that of 10 cases of hyperthyroidism 8 exhibited creatin
in the urine. Denis (/) (1917) has shown that the creatin excretion in this
condition is increased by feeding a high protein diet. As hydroxbutyric and
acetoacetic acids often accompany creatin in the urine it has been supposed
that a causal relationship exists between acidosis and creatin excretion.
Underhill (fc) (1916) noted that rabbits began to excrete creatin when they
were fed on acid producing diets or when hydrochloric acid itself was
administered. In both series of experiments the supply of carbohydrates
was sufficient and the protein per se was without influence. Underhill (I)
(1916) also found that the administration of alkalies diminished the
creatin output during the early days of starvation. In phlorhizin glyco-
suria, however, alkali administration was without effect (Underhill and
Baumann). McCollum and Hoagland (a) (1913) observed that pigs elim-
inated creatin when fed on fats, water and neutral salts, but failed to do
so when the salts were alkaline. Considering all the known facts per-
taining to this phase of the subject it appears unwise at present to assume
a causal relationship between acidosis and creatinuria.
Creatinin Metabolism
Muscle. — Skeletal muscle contains from 5 to 15 mgs. of creatinin per
100 grams of moist tissue (Myers and Fine (i), 1915 ; Folin and Denis (</),
1914), that is, from 5 to 10 times the amount which is present in the
blood which circulates through it. Shaffer (6) (1914) holds that this is an
argument in favor of the view that creatinin is formed in muscle tissue.
The rate of conversion of creatin into creatinin in autolyzing muscle is
proportional to the temperature and is 3 times more rapid than in watery
solution.
Blood. — The blood of normal individuals contains from 1 to 2 mgs.
of creatinin per 100 c.c. (Folin and Denis (#), 1914). In nephritis rela-
tively large quantities, as much as 33 mgs. have been reported. In patho-
logic conditions of the kidney uric acid and urea are retained before crea-
tinin and elevations of the last above 5 mgs. indicate a grave prognosis
except in acute renal inflammations (Myers and Lough).
Urine. — In a classical article published in 1905, Folin showed that the
excretion of creatinin on a meat free diet was constant for each individual
178
LOUIS BAUMAX
and independent of the exogenous metabolism and the total nitrogen
cretion. Shaffer (a) (1908) confirmed these observations and found tlu
the hourly excretion of creatinin was also uniform. This constancy of ci
atinin elimination has been used to control the accuracy of the 24-hoi
urine collection. The daily creatinin excretion for an adult man l
lx>tween 1 and 2 grams. From the viewpoint* of quantity it is second
importance to urea. A normal man excretes between 7 and 11 mgs.
creatinin nitrogen per kilo of body weight; this has been named tl
croatinin coefficient by Shaffer (a) (1908). It is apparently a function
the mass of active muscle tissue for stout and elderly people, and worm
often have values below 7. The coefficient of the dog averages 8.4. M yoi
and Fine (c) (1913) have studied the relation of the creatinin coefficient
the total creatin content of the body. In the case of the rabbit this is
quite constant, averaging 44.7 mgs. of body creatin to 1 of creatinin ii
the urine. The daily output of creatinin represents a conversion of aboi
2 per cent of the total creatin present in the body. The creatin conter
of the rabbit per kilogram is about one-third higher than that of man, anc
its creatinin coefficient is proportionately higher, that is, 14.
The creatinin excretion of women is lower than that of men. Trac
and Clark found the average creati-nin coefficient of 26 women to be 5.(
According to these authors the low coefficient of women is due t
their relatively inferior muscular development. Hull found the avera
creatinin excretion to range between 670 and 880 mgs. Muscular activity
has no effect on creatinin excretion (Van Hoogenhuyze and Verploegh (&)3
1908; Shaffer (a), 1908).
During starvation there is a gradual decrease in creatinin in the
urine along with an increase in creatin (Cathcart (a), 1907; Howe, Mat
till and Hawk (6) ; Hunter, 1914), Pigs that were fed on a liberal amount
of carbohydrate, salts and water reached a stage when the creatinin a<
counted for 18 per cent of the total nitrogen in the urine (McCollum am
Hoagland (a), 1913). Fevers cause an increase in urinary creatini
(Van Hoogenhuyze and Verploegh (&), 1908 ; Klercker (c), 1909 ; Leatheg
(a)). Myers and Volovic observed that the increase was proportional
the height of the temperature.
Creatin is often present in the urine in conditions associated witl
dissolution of muscle tissue, and then the creatinin is usually founc
to be decreased (Levene and Kristeller). Spriggs reported a very lo\
creatinin excretion in 2 cases of muscular dystrophy and also in a case
of amyotonia congenita. In progressive muscular dystrophy, McCrudden
and Sargent observed large quantities of creatin in the urine with a con-
stant creatinin elimination.
In wasting or atrophy of muscle the creatin eliminated in the uriiu
is probably derived from the disintegrated muscle fibres.
CREATIN AND CREATININ 179
The Fate of Administered Creatin or Creatinin
A number of investigators have attacked this problem. The experi-
ments of Myers and Fine (e) (1913) are fairly representative. These ob-
servers found that when creatin was injected into rabbits a small portion
was deposited in the muscles, and from 25 to 80 per cent, depending on
the amount injected, could be recovered from the urine. When creatinin
was administered an average amount representing 80 per cent of that
injected was found in the urine and the remainder was deposited in the
muscles. When creatin was fed to man a slight increase in creatinin
elimination occurred which accounted for from 3 to 4 per cent of the in-
gested substance ; from 0 to 39 per cent, again depending upon the amount
administered, appeared in the urine unchanged (Myers and Fine (/t),
1915). Many of the other investigators obtained similar results. See
Folin (e) (1906), Klercker (a) (&) (1906, 1907), Wolf and Shaffer, Van
Hoogenhuyze and Verploegh (&) (1908), Pekelharing and Van Hoogen-
huyze (&) (1910.), Foster and Fisher, Towles and Voegtlin, Folin and
Denis (a) (1912) and Krause.
Summarizing, it may be said that when creatinin is administered it is
excreted almost quantitatively, whereas creatin is only partly excreted,
the major portion being probably destroyed in the body. Only a small
percentage of the administered creatin is excreted as creatinin. There
is no evidence that creatin is converted into urea. On a high protein
diet a smaller amount of administered creatin is retained than on a low
diet. According to Krause (&) (1913) children are less able to destroy
creatin than adults.
Gibson and Martin observed that creatin was promptly excreted when
administered to patients suffering from progressive muscular atrophy.
Resume
The creatin content of muscle is fairly constant for a given species of
animal under uniform conditions of diet.
Muscle creatin is diminished during carbohydrate privation. This
change is ascribed to the loss of creatin in the urine.
The normal excretion of creatin by children and young animals in
general is probably due to their relatively high planes of metabolism and
their small reserves of glycogen. In the absence of carbohydrate, fat,
and protein to a lesser extent are called upon to supply the body require-
ments; under these circumstances muscle tissue is disintegrated, creatin
is liberated and excreted in the urine.
The precursor of creatin has not been definitely established. Creatinin
180
LOUIS BAUMAN
is probably derived from creatin, that is, a definite percentage of the
body creatin is daily converted into creatinin. The creatinin excretion is
proportional to the bulk of active muscle tissue. The daily amount of
creatinin excreted by a given individual is constant under widely varying,
conditions. It is increased during fever and diminished during starvation
and during periods of muscle disintegration.
Creatinin is eliminated by the kidneys with great facility and is on!
retained in the blood in advanced disease of the kidneys. When creatinii
is fed or injected it is almost quantitatively eliminated, whereas creath
under similar circumstances is largely destroyed in the body.
Normal Fat Metabolism w. R. Blot
Introductory — The Lipoids — Simple Lipoids — Compound Lipoids — Derive
Lipoids — Simple Lipoids — Compound Lipoids — Derived Lipoids — Fa
Digestion and Absorption — The' Stomach — The Intestines — Factors
Fat Digestion and Absorption — Summary — Fat in the Blood — Alimen-
tary Lipemia — Lipoids of the Blood — Fat in the Tissues — Storing of Fat
— Changes in Fat in the Tissues — The Liver in Fat Metabolism — Later
Stages — ^-oxidation — Fat Excretion.
Normal Fat Metabolism
W. R. BLOCK
BERKELEY
Introductory
In the course of the great development which has taken place in bio-
chemistry during the last few years our knowledge of metabolism has been
greatly extended, especially in the fields of the proteins and the carbo-
hydrates. Comparatively little has been added to that of the fats, for
which the main reason is the difficulty of chemical examination and de-
termination. The fats are relatively inert substances which do not lend
themselves readily to reactions which may be used as a basis for their
study, and as a result there is not the same background of exact chemical
«/ / o
knowledge as in the case of the proteins and carbohydrates. Another rea-
son is that in their function as stored material, the part which they and
their derivatives play in the life processes of the cells has been obscured,
and all the more so since the comparative inertness of the fats would seem
to render them unfit to take part in the delicately balanced reactions of
living protoplasm. Just the opposite may, however, be said of certain
of their derivatives such as the phospholipoids, members of which group
are among the most reactive substances found in living beings. In fact,
so great is their tendency to break up, to oxidize, to combine with a great
variety of substances that it is with extreme difficulty that they can be
prepared pure enough for analysis. In recent years methods have been
devised for the study not only of the fats but of the more important
related substances in living organisms, and the result has been an aroused
interest in the whole field. With the accumulation of data has come the
realization that the study of the metabolism of the fats, meaning essentially
that of the fatty acids, involves many if not all of the compounds of the
fatty acids, and that only by a consideration of the whole group of com-
pounds can a true picture of the metabolism of fat be obtained. For this
reason it has appeared necessary to reclassify the fats and related sub-
stances on the basis of their relationship to the fatty acids in metabolism,
and a brief outline of such a classification with a short description of
some of the more important members is given below. For a more detailed
183
184
W. K. BLOOR
discussion of the classification and of the members the reader is referrec
to other sources (Bloor (i), 1»20; Leathes (c), 1910).
The Lipoids
Naturally occurring compounds of the fatty acids, together witl
certain substances found naturally in chemical association with them.
The group is characterized in general by insolubility in water anc
solubility in "fat solvents," chloroform, benzol, etc.
Simple Lipoids. — Esters of the fatty acids with various alcohols.
Fats. — Esters of the fatty acids with glycerol. (Fats which are liquit
at ordinary temperatures are called oils.)
}]'a.res. — Esters of the fatty acids with alcohols other than glycerol
Beeswax, lanolin, cholesterol oleate.
Compound Lipoids. — Compounds of the fatty acids with alcohols but
containing other groups in addition to the alcohol.
Phospholipoids. — Substituted fats containing phosphoric acid anc
nitrogen. Lecithin, cephalin, etc.
Glycolipoids. — Compounds of the fatty acids with a carbohydrate anc
nitrogen but containing no phosphoric acid. Cerebron.
{Amino lipoids, Sulpho lipoids, etc. — Various groups which may
added as soon as they are sufficiently well characterized.)
Derived Lipoids. — Substances, derived from the above groups
splitting, which have the general properties of the lipoids.
Fatty acids of various series.
Sterols. — Alcohols, mostly large molecular solids, found naturally n
combination with the fatty acids and which are soluble in "fat solvents."
Cetyl alcohol (C16H33OH), myricyl alcohol (C30H61OH), cholestei
(C27H43OH).
Simple Lipoids. — The Fats. — Esters of the triatomic alcohol glycerol
They are commonly called fats when they are solid at ordinary tempera-
tures and oils when liquid. Of the lipoids these are the most widely
distributed in nature, the most important from the point of view of nu-
trition and the best understood chemically. As ordinarily occurring, thej
are triatomic esters, i. e., all three of the hydroxyl groups of the alcohc
are replaced by fatty acids. Diatomic and monatomic esters are occa-
sionally found but usually only where metabolic processes are in active
progress as in germinating seeds and during fat digestion. The fattj
acids in combination with a single glycerin molecule may be either all the
same — producing simple glycerides — or may be different, producing mixec
glyeerides. As the knowledge of the chemistry of the fats increases
becomes evident that mixed glycerides are of much more frequent
currenco than was previously supposed — a fact which is of considerable
NORMAL FAT METABOLISM 185
interest from a biochemical point of view because of the potential optical
activity of many of these mixed esters, since optical activity is recognized
as a property closely connected with life processes. Thus
H H
O-R! HO— O-Ro (Rl Ra R:< ^S Afferent
fatty acid radicals)
HC— O— R2 HC— O— R3
H H
should from the structure be optically active. Up to the present time no
optically active fats have been found in nature or been prepared syn-
thetically, which may mean merely that present day methods of prepara-
tion and separation of isomers are not adequate for the purpose. On the
other hand many of the phospholipoids are optically active and contain
different fatty acids in combination, and since there is good reason to
believe that the phospholipoids are stages in the metabolism of the fats
and are known to be constituents of living tissues, the inference is that
while the fats themselves may not take part in life processes they are
readily changed into substances which do.
Waxes. — Distinguished from the fats by the fact that the alcohol in •
combination is not glycerol. These are substances widely distributed in
nature but in amounts much smaller than the fats. They are characterized
in general by great chemical inertness; they are much more difficult to
oxidize or to hydrolyze either by enzymes or other agents. The con-
stituents of the waxes have been completely worked out in but few cases,
so that our knowledge of the chemistry of these substances is very frag-
mentary. The alcohols found in combination in the waxes are mostly of
largo molecule (see under Sterols), and the fatty acids are also generally
large molecular and either saturated or containing hydroxyl groups. Com-
mon examples of the waxes are :
Beeswax. — A mixture of many substances of which the best-known
ones are esters of myricyl (C3oHG1OH) and ceryl (C2CH53OH) alcohols
wirh palmitic (C1GH32O2), cerotic (C2GH52O2) and melissic (C30HCOO2)
acids and much free cerotic acid.
Cetin. — The ester of cetyl alcohol (C1GH33OH) and palmitic acid.
Wool Wax (Lanolin). — Contains esters of cholesterol derivatives with
various fatty acids.
Cholesterol esters of palmitic and oleic acids are present in blood.
Compound Lipoids. — Phospholipoids. — Compounds of the fatty acids
and glycerol containing phosphoric acid and nitrogen. They are widely
distributed in nature, being constant constituents of living cells. They
180
W. R. BLOOR
may bo regarded as phosphorized fats — glycerides in which one fatty aci<
lias been replaced by a substituted phosphoric acid. On hydrolysis thej
yield fatty acids, glycercphosphoric acid and a basic substance, which ii
the case of lecithin is mainly cholin and in cephalin probably aminoethyl
alcohol.
In Cuorin, a phospholipoid from heart muscle, the proportion of phos
phoric acid to fatty acid is greater than in lecithin.
Since satisfactory chemical characterization and identification of mos
members of this group has not yet been made reference will be made t<
only a very few.
In general they are very active chemically, undergoing rapid chan^
in air and light, becoming colored and rancid. They are not soluble ii
water in the ordinary sense, but mix with it, forming opalescent colloidal
suspensions. They are readily hydrolized by many reagents as well as
the lipases and esterases and even by boiling with alcohol (Erlandsen).
They form combinations readily with many substances, as, for example
with proteins and carbohydrates, but these combinations are unstable
and of inconstant composition, so that it is doubtful whether they are true
chemical compounds. The similarity in chemical composition indicates
close relationship to the fats ; the constant occurrence in quantity in livii
active cells, the ready reactivity to oxidation, hydrolysis and combinatior
with other tissue constituents and, above all, the miscibility with the uni-
versal solvent, water, indicate that the phospholipoids are the intermediate
step through which the fats pass before being finally utilized. The fattj
acids obtained from the phospholipoids were thought by the earlier investi-
gators (Hoppe Seyler, etc.) to be the same as those in ordinary animal
fats, i. e., stearic, palmitic and oleic, but recent work, particularly that of
Loathes (c), 1910, Hartley (a), 1907-08, Erlandsen and MacLean have
shown that the earlier supposition is not correct and that, if care be taken
to avoid oxidation, mainly unsaturated fatty acids are obtained.
The Lecithins. — The best known of the phospholipoids. They are chai
acterized by their insolubility in acetone — a property which is made us
of in their separation. They are readily soluble in other fat solvents ane
form a colloidal solution with water. Most members of this group are verj
sensitive to chemical change, so that it is almost impossible to prepare
them in pure form. In addition to their chemical sensitiveness they pos-
sess, in a higher degree than most other organic compounds, the power of
uniting with other substances such as salts (NaCl), compounds of the
heavy metals as Pt and Cd, and with many organic substances such as
alkaloids, toxins (snake venoms), carbohydrates and proteins. The
combinations are not of constant composition and are broken up by rel-
atively gentle treatment, e. g., boiling with neutral solvents, and it is
therefore a question whether they are true chemical compounds or merely
physical (adsorption) mixtures. This power of combination is of great
187
significance in the consideration of these lipoids as constituents of livin«r
matter.
The chemical formula of a typical lecithin which embodies our
knowledge of its composition at the present time is :
CH2— O— K! As indicated by the formula
I the fatty acid groups (Rx and E2)
are generally different and the com-
pounds are optically active. The
CH — O — K2 fatty acids are often unsaturated,
particularly in the lecithins from
O the active organs as heart, liver,
// etc.
CH2— O— P— OH
I
O
CH
O
H
Ceplialins. — These differ from lecithins in being difficultly soluble in
alcohol and in containing a different basic group, the exact nature of
which is unknown, but which is believed to be amino-ethyl alcohol. They
are widely distributed in the body and, according to Thudicum, are the
main phospholipoids of the brain. They have recently received a good
deal of attention because of their connection with blood coagulation
(Howell). MacLean has shown that they are formed rather easily from
lecithin and that one of the difficulties in preparing pure lecithin is its
tendency to lose its methyl groups and pass over into cephalin.
Glycolipoids. — These substances, characterized by their content of car-
bohydrate, are less understood than the phospholipoids. The only one
which has been well studied is the cerebrone of Thierfelder, a constituent
of brain tissue. The carbohydrate is galactose, the fatty acid a higher
isomer of stearic acid, and there is also a basic substance known as
sphingosine.
Derived Lipoids. — Fatty Acids. — The fatty acids found combined in
the fats include practically all the known fatty acids of the various series
which contain even numbers of carbon atoms arranged in straight chains.
Fatty acids of odd numbers of carbon atoms are so rare that their natural
origin is questionable, while branched chains are unknown. A few acids
188
\V. E. BLOOR
of the benzene series should perhaps be included since they are found in
certain natural oils (chalmougra oil, etc.)- The fatty acids most fr
quently found in animals are palmitic, oleic and stearic acids. In activi-
tissues fatty acids of the linoleic and possibly of still more unsaturated
series are to be found, while in the brain hydroxy acids are present, to-
gether with a great variety of unsaturated fatty acids.
In milk are to be found all known even numbered members of the
acetic acid series, beginning with butyric and ending with arachidic.
Sterols. — This group includes the alcohols found naturally in com-
bination with the fatty acids in the waxes. They are generally inert
substances of large molecule, mainly of the straight chain monatomic group
of alcohols. The notable exceptions to this rule are cholesterol and related
substances, — secondary alcohols belonging to the terpene series; most
sterols occur in the free as well as in the combined form. The more im-
portant members of this group are cetyl (C1GH34O) and octodecyl
(Cj8H38O) alcohols in spermaceti, ceryl alcohol (C2(iH54O) in Chinese
wax, myricyl alcohol (C30HG2O) in beeswax, cocceryl (C30H62O2) in
cochineal wax and the cholesterol group containing cholesterol (C27H44O)
in most animal tissues and fluids, the isomeric phytosterol similarly dis-
tributed in plants, isocholesterol (C2r,H4GO) and a number of others more
or less well characterized. Of these, the only one which calls for extended
discussion is cholesterol. According, to our present information it is a
monatomic secondary alcohol with a terminal vinyl group. The nucleus
probably contains four to six carbon rings and belongs in the general
group of terpenes. The details of structure are illustrated in tne formula :
CH3
\
CH.CHo.CIL,.— C17H,nCH : CII2
/ / \
CH3 H,C CH2
\ /
CH(OH)
In the free form or as esters with the fatty acids it is widely distributed
in animal tissues and fluids and either as such or as various derivatives
(the bile acids have been so regarded) it is probably of great importance
in animal metabolism.
Of the fatty acids those most frequently found in combination with
cholesterol are oleic and palmitic acids.
Cholesterol is a colorless, odorless substance crystallizing in thin
plates^ insoluble in water, soluble in fats and fat solvents, melting at
3.5° C., and is optically active. Specific rotation [a] ft = . - 29.92.
The corresponding alcohol in plants is phytosterol which, according to
Gardner, changes to cholesterol during intestinal absorption in animals.
NORMAL FAT METABOLISM 189
Closely related substances found in animals and probably derived from
cholesterol are coprosterol in feces and isocholesterol in skin and hair
waxes.
Fat Digestion and Absorption
The Stomach. — Digestion. — Fat splitting enzymes (lipases) may ap-
pear in the stomach from either of two sources — as part of the gastric
secretion or by regurgitation from the intestine. The presence in the
stomach of secretions from the small intestine, especially bile, has been
known clinically for many years, and while the tendency has been to
minimize the influence of these secretions on fat digestion it is realized
that under suitable conditions splitting of fats in the stomach may assume
considerable proportions. Cannon has shown that fats slow the emptying
of the stomach by inhibiting the production of acid, also that the pylorus
is kept closed by the presence of acid on the intestinal side of the sphincter.
In the absence of acidity the pylorus may relax or open and allow regurgi-
tation of intestinal contents including lipases by reverse peristalsis, and
under the conditions of low gastric acidity considerable lipolysis would
take place. Boldyreff found that after a meal rich in fat there is a reflux
of pancreatic secretion into the stomach.
Quite aside from the regurgitated intestinal material the stomach has a
lipase of its own, a fact which was claimed many years ago by Ogata and
other observers. Their work received little attention until it was confirmed
by Volhard and his pupils. Volhard's work stimulated investigation and
discussion and the existence of a gastric lipase has been a much debated
topic since that time. One difficulty has been to rule out the possibility of
intestinal lipase, and when this has been successfully accomplished the low
values obtained for lipolysis by pure gastric juice have thrown doubt on
its existence in amounts worthy of consideration. Volhard found un-
doubted digestion of the emulsified fat of milk and egg-yolk both by gastric
juice obtained by siphon and by glycerin extract of the mucous membrane
of the fundus, and his findings have been confirmed by several workers
since (Davidsohn, 1912), while London and others were unable to dem-
onstrate lipase in gastric juice from a Pawlow stomach. Davidsohn has
compared the properties of gastric and of pancreatic lipase and found
differences in their optimum reaction. For pancreatic lipase the optimum
+
reaction was H = 1 X 10~8, while for stomach lipase it was 2 X 10"6 —
also that pancreatic lipase was much more sensitive to sodium fluoride.
The probable reason for the conflicting results regarding gastric lipase
has recently been found by Hull and Keeton, who studied the lipase in
gastric juice obtained from Pawlow stomachs and in normal stomachs,
of which the pylorus had been ligated and the flow of secretion stimulated
by gastrin and by food. They found that the gastric lipase was sensitive
190 W. R. BLOOR
to acid, being destroyed by a fifteen minutes' exposure to 0.2 per cent
hydrochloric acid, and that if the acidity was reduced either by ordinal
neutralization with alkali or by protein a fairly good lipase action coult
bo demonstrated (about five times as great as that of the succus entericus).
The practical bearing of their work was to indicate that after a meal anc
before the stomach acidity had reached a vakie high enough to destroy
the lipase (being kept down by the proteins of the food) considerable
fat splitting might take place, at least of emulsified fats.
The sum of the work to date leaves little doubt that a lipase is secretec
by the stomach. Whether there is much fat splitting will depend on
number of factors among which are the following: (a) The acidity of
stomach contents — high acidity destroying and lower acidity down to
certain point inhibiting the activity of the gastric lipase. The degree of
acidity is dependent on the amount of acid secreted and on the amoi
of neutralizing substance (mainly protein) present. The presence of fat
inhibits acid secretion, (b) The state of division of the fat. Since the
lipase and the fat have no mutual solvent, the splitting can take plac
only at the surface of the fat particles, and unless these are very small an(
the surface correspondingly great (as in an emulsion) not much splittii
is likely. The acidity of the stomach is probably rarely weak enoi
to permit the formation of soap emulsions so that the lipolytic activity of
the gastric juice would be confined to natural emulsions as milk, etc. The
splitting of the fat in these emulsions may be very considerable (Volhard).
(c) The length of time the fat remains in the stomach. The presence
of much fat slows the passage of food from the stomach (Cannon), giving
more time for the gastric lipase (and also the regurgitated pancreatic
lipase) to act.
Absorption. — Klemperer and Scheuerlen, by ligating the intestine oi
dogs below the pylorus and weighing fat before and after 3 to 6 hours ii
the stomach, found that none had been absorbed. The objection might
be raised in this case, as in many similar ones, that the operative pro-
cedures were responsible for the failure. Histological observations from
von Kiilliker onwards have demonstrated fat droplets in the gastric epi-
thelium although none were seen in the lymphatics. Weiss believed that
absorption into the epithelia was confined to young animals, in which
belief he is opposed by Greene and Skaer, who found absorption (into
the epithelium) in both young and old animals and also that the amount
of absorbed material (observed by staining) and the depth of penetration
depended on the length of stay of the fat in the stomach. The histological
picture was found by these observers to resemble strongly the appearanc
of the intestinal mucosa during fat absorption. After the fat left the
stomach the cycle reversed and the fat disappeared (back into the
stomach?).
Mendel and Baumann studied the absorption of fat by the stomach
NORMAL FAT METABOLISM 191
historically and chemically, and confirmed in general the work of Greene
and Skaer, although in some animals they found no penetration. They
found no change in the fat content of the blood as a result of the presence
of fat in the stomach, but they point out that the absorption would be
necessarily slow and that the fat may have been removed from the blood
as fast as absorbed. That absorption of other substances went on normally
in these same animals was shown by tests with iodids. On feeding fat
stained with Sudan III no color could be observed in the lymph or in
the blood.
The Intestines. — Passage from the Stomach. — When the amount
of fat in the food is small it probably does not affect appreciably the rate
r>f emptying of the stomach, which proceeds normally as described by
Cannon — the pylorus opening under the stimulus of a sufficient acidity
of the food on the gastric side and closing when the acid food
reaches the intestinal side of the opening valve. When the amount of fat
in the food is large the gastric secretion is inhibited, the amount of acid
produced is lessened, and it therefore takes longer for the food to reach the
degree of acidity necessary to bring about the opening of the pylorus.
The rate of emptying of the stomach is thus slowed and the rate at which
the fat reaches the intestine is lowered. When, however, the fat is taken
in liquid form (as oil) or suspended in a liquid, as in milk, it may pass
immediately through the stomach like other liquids.
Thus in all cases except where the fat is taken in quantity in the form
of oil (an unusual condition) it is passed into the intestine in small por-
tions. When it reaches the intestine in large quantities diarrhea may be
produced either through action of the fat itself or more probably as the
result of irritation produced by the abnormally large amounts of soaps
formed. One result of the normal functioning of the gastric mechanism
is therefore the delivery of the fats to the intestine in small amounts, which
has a direct bearing on the question as to the form in which it is absorbed
from the intestine, since under these circumstances the chances are that
the fat will be completely hydrolyzed in the presence of the relatively
large amounts of pancreatic and intestinal lipases which it encounters.
When the amount of fat in the food is so large that there is great in-
hibition of gastric secretion the pylorus appears to lose its tone after some
hours and allows the passage of intestinal contents — bile and pancreatic
secretion with its lipase — to pass into the stomach, where considerable
hydrolysis of the fats may take place. Boldireff has shown that this re-
gurgitation may be made to take place readily in humans by feeding
fat containing fatty acid.
Natural food fat always contains some free fatty acid and the amount
is increased during the processes of cooking and by whatever lipolytic
action occurs in the stomach, so that by the time the fat reaches the
intestine there is probably always a considerable quantity of free fatty
192 W. R. BLOCK
acid present which, uniting with the alkali of the intestinal secretions, pro
daces soap enough to emulsify the whole amount and thus prepare it fc
the action of the intestinal lipases.
The Lipases of the Intestinal Tract and Digestion. — Lipases are
creted into the intestine mainly by the pancjeas, although Boldireff hi
found that the intestinal secretions contain a lipase acting on emulsified fa
which is different from pancreatic lipase in that its action is not accelerate
by bile. Boldireff tested lipolytic action with monobutyrin, milk
olive oij (Jansen objects to the use of monobutyrin because it is sj
by water alone and because in all probability a different ferment, monc
butvrinase [an esterase] is involved). The lipolytic activity of intcstii
juice is ordinarily slight, and in the presence of normal pancreatic seci
tion is probably not an important factor in fat digestion. Bile increas
its activity. The flow of secretion in fasting is small and is increased
the presence of food, secretin, acids and soaps. In general, the amc
of secretion is less the farther away from the duodenum it is collected.
The excitants for the secretion of pancreatic juice are normally acic
+
(H), fats and water; alkalies have a retarding action. Acids act prol
ably by the formation of secretin, rather than by reflex action on
intestine, as Pawlow believed, although stimulation of the nerve supply
will cause secretion. Fats are found. to act as excitants only when partially
saponified, and soap is probably therefore the active substance — which
rendered the more likely since soap has been found by Fleig to produce
secretion. By the time it reaches the intestine fcod fat normally coiitaii
enough free fatty acid to form a considerable amount of soap with
alkali of the intestinal secretions. Water acts mainly indirectly by stii
ulating acid gastric secretion. The nervous system undoubtedly als
plays an important part in pancreatic secretion not only as a regulat
but also in the production of the secretion (Bylina, 1911).
The amount of pancreatic juice secreted in a 24-hour period has
found to vary greatly, the average from normal dogs (Pawlow and
workers) obtained by pancreatic fistula being about 22 c.c. per kilo per
24 hours. For human beings the amount is reported to be about 600 c.c.
per day.
The pancreatic lipase (steapsin) hydrolyzes the fats to fatty acids and
glycerol, an action which is reversible, as was first reported by Pottevin,
later confirmed by Taylor and Hamsik (a) (1909), and finally more con-
clusively by Foa (a), who determined the exact conditions by which an ex-
cellent synthesis may be accomplished. By using oleic acid homogenized
with glycerol and mixed with glycerol extract of pancreas (therefore with
excess of glycerol) he was able to get a synthesis of about 62 per cent of the
oleic acid used in 50 hours at 38° C. The compound formed was mainb
the triglycerid. Armstrong and Gosnev have made an exact stuc
NORMAL FAT METABOLISM 193
of the reaction, using castor bean lipase. They found that, proceeding in
cither direction with the glycerid or with glycerol and oleic acid in the
proportions found in the natural glycerid the equilibrium point was
reached when about 40 per cent of the acid was combined. During the
synthesis the compounds formed were apparently mainly diglycerids.
During the hydrolysis with excess of water and near the beginning a
small amount of a lower glycerid was present, but as the action continued
the molecule was completely hydrolyzed. When only a small proportion
of water was present a greater proportion of mono- and diglycerids was
produced. Conversely when the synthesis is effected in the presence of
water more of the triglycerid is formed. Synthesis in the presence of
extra glycerol results as would be expected in a proportionately greater
combination of fatty acids with the formation cf more of the lower types
of glycerid although the diglycerid is probably still the main product.
The pancreatic lipase, although secreted with the pancreatic juice in
water-soluble form, is with difficulty extracted from the gland by water.
Glycerol is generally used for the purpose and the result is a suspension
which may become inactive on filtration, indicating that the lipase is
probably not in true solution.
Pancreatic lipase is secreted mainly in the active form, and its activity
is increased by the presence of bile (bile salts) and by many other sub-
stances as, for example, blood serum, soaps, saponins, alcohol, etc.
Its action is inhibited by cholesterol. Rosenheim has succeeded in sepa-
rating from the lipase of pancreatic extracts (glycerol) a co-enzyme with-
out which the enzyme is inactive. As is generally the case with co-enzymes
this one is heat-stable. Since the inactive enzyme is activated by blood
serum the assumption is made that the activating substance is a hormone
produced by the pancreas and secreted into the blood.
Normally the provisions for the digestion of the fats in the intestine
are such as to insure practically complete splitting. Fat is delivered
to the intestine in small amounts — when there is little fat in the food this
follows as a matter of course; when fat is present in large proportion
emptying of the stomach is slowed, whereby the same result is effected.
Lipase is abundant, being found both in the gastric secretion and in the
pancreatic and intestinal secretions. The amount in the pancreatic
secretion alone is sufficient to digest quickly several times the amount
of fat supplied in the ordinary diet. The gastric lipase, under
fayorable conditions, can digest considerable quantities, and even the
intestinal lipase can probably affect splitting of the daily quota of fat,
since in cases where the pancreatic secretion is lacking very little unsplit
fat is found in the feces. Emulsification by soap is an important factor in
the hydrolysis, and there is normally abundant provision for the forma-
tion of soap. There is always some free fatty acid in natural fats, and
the amount is increased by cooking and by the action of the gastric lipase,
194
W. K. BLOOR
so that by the time the fat reaches the intestine a considerable amount oi
free fatty acid is present. The free fatty acid is neutralized by the alkal
carbonates of the various secretions that find their way into the intestine
forming soaps which quickly and completely emulsify the remaining
fat, thus preparing it for rapid digestion by the lipases. Added to the
other factors is the continuous absorption which removes the products of
hydrolysis from the field of action, thereby in a balanced reaction like
the hydrolysis of a fat, providing the best conditions for rapid and cor
plete action. Under these conditions it is probable that the amount oi
fat which escapes digestion is negligibly small.
The Absorption of Fat from the Intestine. — The manner in whic
the fat leaves the intestine has received its share of experimentation anc
speculation. The earlier belief was that the fat was absorbed as such
emulsified form, based largely on the observation that emulsions are oftei
found in the intestine during fat absorption and that the fat in the chyle
is also in the emulsified form. While it was known that the chyle fa
was in general much more finely divided than the intestinal fat, that
objection might be explained away by the assumption that the particle
were absorbed only as they reached a fine state of division. Further evi-
dence believed to point in the same direction is that large amounts oi
characteristic food fat may be laid down in the fat depots of animals witl
slight change. Another argument, later shown to be faulty, was that if
stained fat were fed similarly stained fat appeared in the chyle,
additional bit of evidence in favor of absorption of unchanged fat vrs
the observation of Ravenel that bacteria may be carried through the
intestinal wall if fat is fed along with them when they do not pass througl
otherwise. The fact that other foodstuffs such as the carbohydrates ane
proteins were known to be absorbed in water soluble form and that much
free fatty acid and soap were to be found in the intestine during fat diges-
tion led Kiihne to put forward the hypothesis that fats also were absorbed
in water soluble form, being first split in the intestine and then re
synthesized in passing through the intestinal wall. This hypothesis
brought forth a large amount of experimental work which finally resulted
in practical adoption as the most satisfactory explanation of the method
of transference of fat from the intestine to the blood.
The earliest conclusive work on the subject was that presented bj
Munk (a) (1891), who, making use of a human patient with a chyle fis-
tula, was able to show that fatty acids and esters of the fatty acids with
alcohols other than glycerol were absorbed, appearing in the chyle not as
these substances but as neutral triglycerids. He was followed by v. Wal-
ther, who confirmed his results with fatty acids or soaps, and more recentb
by Frank (c) (1898), with ethyl esters of the fatty acids and Bloor (al
(1913) with an optically active mannite ester of a fatty acid. In all these
cases the evidence indicated that no trace of the substance fed appeared ii
NORMAL FAT METABOLISM 195.
the chyle but always the glycerol triesters of the fatty acids involved. The
presence of the glycerids in the chyle presupposed a splitting of the esters
fed and a synthesis of the fatty acids with glycerol which if not supplied
with the fatty acids by the experimenter must have been furnished by the
organism. Further details on this interesting point have been furnished in
recent work by Bang (a) (1918), who found that fatty acids alone pro-
duced but little lipemia while when these are fed with glycerol there is
marked lipemia, indicating that the ability of the organism to supply gly-
cerol is limited. One experiment which he reported in which he fed 59
grams of fatty acid to a dog and recovered only 2 grams in the chyle would
indicate that absorption in this case was directly into the blood.
Direct evidence against the absorption of fat in emulsified form has
also been forthcoming. Connstein, experimenting with lanolin, a wax
which emulsifies well with water and has a melting point (40°-42° C.)
only slightly above body temperature, showed that when this substance
was fed about 98 per cent of it could be recovered in the feces, showing
that neither emulsifying power nor melting point was the criterion for
absorption. The same fact was more strikingly shown by Henriques and
Hansen, who dissolved vaselin in lard and fed the well emulsified
mixture to rats and were able to recover practically all (98 per cent) of
the vaselin fed while the lard was completely absorbed. The com-
panion test to this one — the attempt to recover the substance from the
chyle — was carried out by Bloor (a) (1913) with negative results. In this
experiment a liquid paraffin was dissolved in olive oil, the whole well emul-
sified and fed, to dogs. A suitable time after the feeding chyle was collected
from the thoracic duct, the contained fat extracted and examined for the
paraffin oil. None was found. Thus though all conditions were favorable
for the absorption of unchanged emulsion which would have included the
mineral oil, no trace of it could be demonstrated while the food fat was
completely absorbed. Summing up all the evidence then, the hypothesis
of Kiihne appears to be very well supported. Facilities are provided
for complete splitting of the fats in the intestine, fatty acids and soaps
are absorbed and appear in the chyle as triglycerids, esters of the fatty
acids which are hydrolyzable by the intestinal Upases are absorbed but
always as triglycerids, while non-hydrolyzable esters of the fatty acids
and other fat-like substances which cannot be made water soluble are
rejected. Altogether it seems likely that fats are no exception to the rule
that substances pass from the intestine only in water solution, and since
solubility in water appears to be a necessary prerequisite for use in living
cells the intestine acts as a barrier against the admission of substances
that cannot be made soluble. The fact that fats appear in the blood
stream largely in the insoluble suspended form is probably only an
apparent exception since they are readily and quickly transformed in the
blood into soluble phospholipoid.
196 W. K BLOOR
Synthesis of the Fats During Absorption. — It is a necessary corollary
of the foregoing that the splitting of the fats which takes place in the
intestine is followed by a resynthesis before the fat reaches the thoracic
duct. Direct proof of the synthesis has, however, not been satisfactory
furnished. Ewald thought that he had demonstrated a synthesis by th<
surviving intestinal mucous membrane, as did also Hamburger, but Fr
and Hitter, on repetition of their experiments, were unable to get posi
tivo results, and pointed .out that their results were irregular and tha
such positive findings as were obtained were due to faulty technique. Sim
ilarly Moore failed to demonstrate synthesis in vitro using mixtures o:
sodium oleate and glycerol with hashed intestinal mucous membrane.
On the other hand, Moore showed that during fat absorption the fatty
acid in the mucous membrane of the intestine amounted to 15-35 per
cent of the total fat, while in the mesenterial glands and lymph vessel
it amounted to only about 4 per cent, which facts they believed to show
that the synthesis took place in the mucous membrane and not in th
lymph glands.
Paths of Absorption of Fat. — The thoracic duct is probably not th
only channel by which fat reaches the blood stream. Munk and Eosenstein
in chyle fistula experiments with a human being were able to recover noi
more than 60 per cent of the total fat fed. In experiments with d
Munk and Friedenthal. were able to .show an absorption of 32 to 48
cent of the fat fed after tying off all the neck and arm veins of
sides. The blood fat increased from 0.5 per cent to 2.92 per cent, with
notable increases of fat in the corpuscles. Others have found, on the
contrary, that tying off the thoracic duct prevented any increase in blood
fat. Munk also noted the accumulation of fat droplets in the liver duri
normal fat absorption ("physiological fat infiltration"), which he be-
lieved to originate from fat directly absorbed into the portal vein
although it could equally well be ascribed to fat which had reached the
blood stream by the thoracic duct. v. Walther found in the chyle not
more than 1/10 of the fat which had disappeared from the intestine of
dogs. A similar observation is reported by Frank (1898). Attention should
be directed to the fact that in these thoracic duct experiments the operative
procedure is severe and the results found may not represent what happens
normally. Aside from the thoracic duct there is left the path of absorption
taken by other foodstuffs, i. e., directly into the circulation by the intestinal
capillaries and the portal vein, but there is very little direct evidence of
absorption by this channel. D'Errico showed that during fat absorptio:
the fat content of the portal vein was always higher than of the jugular an
concluded that fat was normally absorbed directly into the circulation lik
other food substances. Very recently Zucker has reported negatively a
repetition of this work.
Changes in Fats During Absorption. — In spite of the faot that lar;
NORMAL FAT METABOLISM 197
amounts of food fat may by certain treatment be transported without con-
siderable change directly to the fat depots, evidence is available to show
that under normal conditions where the animal has free choice of food
and where the amount of fat ingested is not too large, the fat in the chyle
may be noticeably different from the fat in the intestine. Two factors
appear to be at work in the production of the differences: (a) selection
from the food fat of the more desirable or useful portions (generally the
lower melting), and (b) other changes either of the nature of additions
or of chemical changes — saturation or desaturation — which may alter
the composition considerably. With regard to the first factor — selection —
Munk has found that in dogs fed with lard the feces fat had a considerably
higher melting point than the fat fed. With regard to the second factor —
admixture or alteration — during the passage from the intestine, Munk
and Rosenstein after feeding cetyl palmitate found the chyle fat to
consist of one part of triolein and six parts tripalmitin, with a melting
point of 36° C. Frank (1898), after feeding ethyl palmitate, found 36
per cent of olein in the chyle fat, and after feeding mutton tallow (m.p.
51.7° C.) obtained a chyle fat melting at 38° C. In these cases there was
an alteration in the direction of obtaining a lower melting fat. Bloor
(1913-14) obtained evidence of an alteration in the other direction, i. e.,
the chyle fat having a higher melting point than the fat fed. After feed-
ing olive oil of which the constituent fatty acids had a melting point of
16° C. and an iodin number of 86, chyle fat was obtained with a melting
point of 30° C. and iodin numbers down to 72. Other evidence corroborat-
ing the above findings was furnished by Raper (1912-13). In most of
these cases the influence of lipoids present in the fasting chyle was excluded
so that we may conclude that the fat may be considerably modified during
the process of absorption. The modifications as found appear to be pur-
posive in that in all cases the tendency appears to be toward the production
in the chyle of a fat approximating the properties of the body fat of the
animal. As to the significance of these changes Frank was of the opinion
that there is an addition of body fat either by way of secretion into the
intestine or after the fat leaves the intestine. It has been shown by Leathes
(1909) that the liver has probably the power of desaturating the fatty
acids — a power which all living cells may possess to some degree, and
there is a possibility that the intestinal cells can desaturate or saturate the
fatty acids during their passage through. The mechanism would allow
adaptive changes in the fats during absorption.
Factors in Fat Digestion and Absorption. — Pancreatic Secretion.—
The pancreas is the main source of lipase in the intestine. The amount
of secretion, generally given at 500 to 600 c.c., is sufficient for the rapid
hydrolysis of at least its own weight of emulsified fat, and since the
amount of fat in the daily human diet does not often exceed 100 grams,
is greatly in excess of the needs. In the absence of pancreatic secretion.
198 W. R. BLOOR
the amount of fat absorbed falls off, but not to the extent that would
expected from the loss of such an important secretion. Also, as hi
been noted many times, the fat which is found in the feces in these cas
is almost entirely present as fatty acids, indicating that the other hyc
Ivtic agents present (see previous discussion, pages 189-192) and also prol
ably bacteria very effectively take on the work of the pancreatic lipas<
Complete extirpation of the gland produces much more marked effect
than exclusion of the secretion. Emulsified fats are better utilized th*
non-emulsified and feeding of pancreas improves the utilization of bot
With regard to complete extirpation various factors complicate the situa-
tion, such as shock of operation, deprivation of the internal secretior
both of which are severe in their effects on the animals, the inability
digest and utilize other foodstuffs, which results secondarily in a failui
to utilize fat, the efficiency of the pancreatic secretion in forming emulsion
which are stable in the faint acidity found in the intestine, the disturbanc
in the intermediary metabolism of fat which results in an accumulatior
of fat in the liver and other tissues and the slowing of the emptying of the
stomach in the absence of pancreatic secretion.
Taking all the evidence together there can be no question that the
intestinal secretion of the pancreas is an indispensable factor in the proj
digestion and absorption of fat. Whether its internal secretion is
equal importance cannot be stated at the present time. Lombroso founc
that fat absorption was not much affected by stopping the pancreatic
secretion or on extirpation, if a small portion of the gland were left
place, from which he reasons that it is the internal secretion which is oi
importance. On the other hand, it is well known that in severe diabetes
where the carbohydrate tolerance is very low, that fats are readily digestec
and absorbed, and indeed in such amounts that they cannot be taken cai
of in 'the blood, resulting in the extreme and lasting lipemia which
occasionally reported. The lipemia may be the direct result of the absence
of internal secretion, resulting in failure of the intermediary fat metab-
olism or a secondary effect of the failure to utilize carbohydrate.
The Bile. — The importance of the bile in the digestion of the fats
has been extensively studied. Early experiments by Claude Bernard and
Dastre demonstrated the probable necessity of both bile and paneroati
secretion for effective fat absorption. Work by Bidder and Schmidt,
Rohmann and others have shown that exclusion of the bile from the in-
testine may result in fat losses up to 85 per cent of the fat fed.
icterus with complete exclusion of bile there is considerable loss of fa
but not to the extent observed in operative exclusion. The importance o
bile in fat absorption seems thus to be well established. As to its functioi
in this relation evidence has been brought forward by Moore and Rock
wood to show that one very important part which it plays is in increasi
the solubility of the fatty acids and soaps produced by hydrolysis of th
NORMAL FAT METABOLISM 199
fats. It also increases the formation of soaps from the fatty acids as
shown by Pfliiger, and later by Kingsbury. These effects are partly due
to the bile salts but to a considerable extent to other substances, e. g., mucin
and lecithin.
The accelerating or activating effect of bile on the pancreatic lipase
has been shown by Eachford and by von Fiirth and Schiitz, who found
that the fat splitting power of pancreatic juice was increased several fold
by the presence of bile. The active substance in the bile which produces
the acceleration has been, shown by both investigators to be the bile
salts. Aside from any positive action of the bile the mere exclusion from
the intestine of a pint or more of alkaline colloidal secretion must have a
profound effect on intestinal processes. As regards further and unknown
functions of the bile mention should be made of the important findings of
Hooper and Whipple that dogs cannot long survive complete exclusion
of bile from the intestine unless liver is included in their diet.
In the absence of both bile and pancreatic secretion very little fat is
absorbed, probably not over 20 per cent of emulsified fat, is in milk,
and much less of non-emulsified fat, although splitting is generally good —
80 to 90 per cent of the rejected fat consisting of free fatty acids. Traces
only of soaps are present, which would point to the lack of alkali ordi-
narily furnished by the pancreatic secretion and the bile as the significant
factor in absorption.
The Nature of the Food Fat. — Lipase can act only on the surface of
the fat, hence the necessity as a preliminary step, of breaking up the
fat masses to as fine a state of division as possible as in emulsions,
so as to increase the available surface. For ready emulsification the fat
must be liquid or at least semi-solid at body temperature, and we find
that the utilization of a food fat depends largely on its fluidity at body
temperature. Thus v. Walther, in feeding experiments, found that various
fats which were liquid at body temperatures were absorbed to the extent
of 97 to 98 per cent, while tristearin (m.p. 60° C.) was absorbed to the
extent of only 14 per cent. Dissolving tristearin in almond oil so as to
bring the melting point down to 55° increased its absorption to 89 per
cent, indicating the importance of the liquid fats and especially of triolein
as a solvent for the harder fats, making it possible to deal with them in the
organism both in hydrolysis and in transport. On the other hand, experi-
ments with ethyl stearate (m.p. 30° C.) have shown that melting point in
the intestine is not the only factor in absorption, since this substance is
very little better absorbed than tristearin, although it is liquid at body
temperature. Also when it reaches the thoracic duct (as tristearin) it
was found mixed with enough softer fat to bring its melting point down
to near body temperature. It seems from these experiments that the
organism is able to protect itself against the absorption of high melting
fat which it would have difficulty in dealing with, first by limiting the
200
W. K. BLOOR
amount absorbed and second by mixing it with enough low melting fat
bring the melting point of the mixture to somewhere near body temper
tu re. (Kecent work by Lymau indicates that available glycerol may he
limiting factor in absorption of the simple esters, just as it is with the
fatty acids.)
Aside from the high melting fats and excepting certain ones lil
castor oil which are either irritating to the intestine or which form irritat
ing soaps, there appears to be little difference in the extent of utilizatioi
of fats of whatever origin, animal or vegetable, a result which might ha\
been foretold since the fatty acids in combination in fats from varioi
sources are largely the same, the main difference being in the relative
amounts of each constituent of the mixture.
Emulsification in Fat Digestion and Absorption. — It is generally
assumed that fats must be emulsified in the intestine before they can
digested and absorbed, for the reason that while the Upases found in the
intestinal secretions are always in water solution the fats are insoluble
in water and lipolysis can take place only at the surface, which emulsifica-
tion greatly increases. The assumption has the support of a large number
of observations on fat in the intestine during digestion. That emulsioi
are not always present in the intestine under these conditions is, however,
attested by observations of Moore arid Rockwood, who found in many case
no emulsion but a brownish liquid with an acid reaction. No examinatk
was made as to whether this liquid contained fat and it is possible that it
consisted of a bile solution of the fatty acids. Where conditions for
tion are exceptionally good the emulsion may be only transitory. The
conditions for the emulsification of the food fat on its entry into the ii
testine are ordinarily very favorable. There are present free fatty acic
in the fat, alkali in the secretions, and other substances such as proteins
lecithin, etc., which are either emulsifiers themselves or which act t(
stabilize emulsions. The acidity of the intestine which many observers
have found need not be a hindrance since it is due mainly to carbonic acid
and emulsions formed with the aid of pancreatic secretion and bile
known to be stable in solutions of carbonic acid.
Summary. — It will be seen that no definite answer can yet be giver
as to the way in which fat passes through the intestinal wall.
Emulsification is probably at least an early if temporary step. Hydrolysis
undoubtedly takes place in large measure and would therefore seei
to be a necessary preliminary to absorption. Soap formation under th«
conditions of reactions of the intestinal contents (faint acidity) inc
the presence of bile probably takes place to a considerable extent. Soar
being water-soluble is assumed by many to be the form in which the fat
are finally absorbed, but it should be borne in mind first that soa]
3 a difficultly diffusible substance and second that in water solution
it hydrolyzes, forming aggregates of free fatty acid which would be still
NORMAL FAT METABOLISM 201
less diffusible. On the other hand, the earlier theory of absorp-
tion of fat as such has secured some additional support from the observa-
tions of Green and Skaer that fats can penetrate for considerable distances
into the stomach walls of animals, confirming on animals the much earlier
observation of Schmidt that fat penetrates readily into olant cells,
especially if it contain a little free fatty acid. The ability of certain types
of animal tissue cells to engulf foreign particles, including fats, has been
shown by Evans, just as the phagocytic white blood cells are known to do.
(The part which these same white blood cells take in fat absorption, while
known to be large for the individual cell, is net believed to be important
in the aggregate.) However, even in plants a preliminary hydrolysis
would seem to be necessary since in fat seeds, such as the castor bean,
hydrolysis is known to take place before the fat is utilized. Even so,
hydrolysis produces another kind of insoluble substance — the fatty acid —
which, however, is different and probably essentially so in that in the
presence of alkali it becomes water soluble. To what extent fat passes
the intestinal walls as fatty acid — bile being the ferry, as has been sug-
gested by Mathews — cannot be determined. Neither can it be said what
factors determine whether the digested fat shall pass directly into the blood
by way of the portal system or indirectly by way of the thoracic duct. In
the former case it passes directly to the liver, and in the latter it avoids it.
It seems quite certain that esters of the fatty acids which cannot be
hydrolyzed in the intestine and so rendered water-soluble and also oily
substances of other kinds which cannot be made water-soluble are rejected
no matter what their other properties may be nor how intimately they may
be mixed with the fats. Water solubility of the absorbed products seems
to be as essential for the fats as for other food substances. The mechanism
for excluding substances which are not water-soluble is perfect, presumably
because such substances could not possibly be handled in the organism.
Fat in the Blood
Alimentary Lipemia. — The study of the blood brings us one step
nearer to the actual seats of metabolism than that of the urine and other
waste products. It is the great distributing system of the body. The
recognition of these facts has turned the attention of most investigators
to the blood, with the result that thereby much has been added to our
knowledge of metabolism. Because of the greater difficulty of their study
the discoveries regarding the fats haye as usual rather lagged behind those
of the other foodstuffs, although a good deal has been accomplished.
Methods for fat determination in foods and tissues have been adapted for
use with blood, and new methods have been devised especially suited to
use with small amounts of blood, so that processes can be followed in
202 W. R. BLOOR
tlio living animal with considerable exactness. The result has been a
accumulation of data from which we can now begin to get an insight int
the history of the fats after they leave the intestine. After absorptio:
that part of the food fat which has passed into the lacteals finds its wa;
into the blood stream by way of the thoracic duct in the form* of a si
pension of very fine particles (generally less than 1 H in diameter),
which the Brownian movement is marked and which give the chyle an
the blood plasma their milky appearance. The milkiness persists for so:
time but has generally disappeared in from eight to fourteen hours aft
the fat is eaten. According to present observations milkiness persisti
fourteen hours after a meal indicates an abnormality in fat metaboli
Emulsified fat (particles 2 to 5 JA in diameter) injected directly into th
veins disappears within a few minutes, the difference from alimentar;
lipemia being due probably to the larger size of the fat particles, althou
there is a possibility that the relatively small amount injected would
quickly removed and stored while a larger amount would not Rabben
found that homogenized fat (particles up to 2 JA in size) injected
quantity disappeared rather slowly (7 hours). The extent and duratio:
of the increase of the blood fat following a meal depends on the amoun
of fat fed and also apparently on. the level of the blood lipoids at th
time of feeding. When the blood lipoid level is high the maximum i
the blood is reached sooner and the fall from the maximum is slower th
is the case when the lipoid level in the blood is low. The amount of ext
fat in the blood does not, however, at any time represent the amou
which has disappeared from the intestine so that absorption by the tissu
from the blood must normally be rapid. The extent of alimentary lipemi
varies greatly in different animals. In rabbits it is very difficult if n
impossible to produce. In geese stuffed with rye values as high as 6 pe:
cent have been recorded. This is probably a cumulative value, since und
these conditions fat absorption must be continuous. In dogs the bl
fat values rarely exceed three per cent, and in humans two per cent. I
human beings with diabetes, lipemia, which is probably primarily of al
mentary origin, with values of over 20 per cent, has been recorded, an
while this is an extreme instance, high values are not uncommon in un
treated cases. The passage of fat from the blood is probably inhibited
in these cases, since on a low calorie low fat diet it may take a month fo:
values to get down to normal.
The mechanism of the disappearance of fat from the blood is uncertai
Stained or otherwise distinguishable fat injected into the circulation dis-
appears promptly as indicated, and is found to have accumulated in the
liver, bone marrow, spleen and muscles in the order named — which is true
also of other finely suspended material of other kinds. During fat diges-
tion the fine fat particles are found to have accumulated in various place
along the endothelial lining of the blood vessels. Various theories havi
eu
:
NORMAL FAT METABOLISM 203
been advanced to explain the way in which the material passes across the
vessel walls into the tissues. One of the earliest was that there is the
same process of hydrolysis and resynthesis as takes place in the passage of
the intestinal wall, which postulates the presence of lipases in the neighbor-
hood of where the transfer takes place. In this connection much confusion
has resulted from the failure to distinguish between "esterases" — enzymes
which can hydrolyze simple esters such as ethyl butyrate and also, though
more slowly, glycerids of the lower fatty acids, as for example tributyrin,
but cannot hydrolyze ordinary fats (or, at least, only very slowly), and
true lipases such as are found in the pancreatic secretion, which split fats
readily; and still further uncertainty has been caused by the failure to
exclude cells or portions of cells from the extracts used for testing. Es-
terases appear to be quite widespread in the blood and tissues, although
generally in small amounts and of slight activity, while lipases in sig-
nificant amounts appear to be confined to the pancreas. Even in the
mammary gland and the fat depots where the exchange of fat would
presumably be most active no significant amount of lipase can be demon-
strated. So that the primary requisite for hydrolysis and resynthesis, an
adequate supply of lipase at the tissue cell wall is missing. On the other
hand, esterases which are capable of splitting lecithin are found to be
quite widely distributed (Thiele, 1912-13) and, for reasons which will
appear later in the discussion, are believed to be of importance in fat
metabolism.
Coincident with or immediately following the rise of fat in the blood
during fat absorption certain changes have been noted in the other blood
lipoids which appear to be of importance in fat metabolism. A consid-
erable increase of lecithin is noted by all workers. A similar increase of
cholesterol is found by some but not by others, which may be explained by
the fact that it apparently comes later. It is becoming more and more
evident that these three substances — fat, cholesterol and lecithin — are
closely connected in fat metabolism, and when one is increased the others
are very generally also found to be similarly high. The period during
which fat is abnormally high in the blood during fat absorption (about
eight hours) is apparently long enough to produce increases of lecithin,
which follow quickly the increases in fat, but may not be long enough to
bring about increases of cholesterol which take place later and more slowly.
The close relation of lecithin and cholesterol to fat would indicate that
these are stages in metabolism through which the fats may or must pass
before they are utilized, a supposition which is supported in the case of
lecithin by the close similarity in composition and in the case of cholesterol
by the constant relation in the blood serum between cholesterol and its
fatty acid esters.
The blood corpuscles appear to take a considerable part in the changes
in the blood lipoids during alimentary lipemia. The old observation of
204 W. R. BLOOR
Munk and Friedenthal that the fat content of the corpuscles increase
during fat. ahsorption has been recently confirmed and it was also show
that the increase of fat was accompanied by increases of lecithin, fro:
which the inference was drawn that the corpuscles take up the suspend
fat from the plasma and transform it into lecithin. Some support i
given to this inference by the observations of Thiele and of Foa (11)15)
who found that the blood esterase decomposes lecithin only when corpuscl
are present, indicating that this esterase, which presumably also syntliesi
lecithin, is present only in the corpuscles. On the other hand, later wor
in this laboratory has shown that in certain dogs lecithin does not marked!
increase in the corpuscles but does in the plasma. As has been recent!
pointed out by Bang (1918), animals show great individuality in thei
blood reaction to ingested fat. Some can dispose of large amounts withou
showing much effect on the blood lipoids; others react strongly. Hi
makes some suggestions to explain the differences — habituation to fat
and the presence of carbohydrate in the food or of much stored glycoge
being in his opinion important factors. As regards lecithin formation i
the blood it is not likely that it is confined to the corpuscles but probable
that other cells with which the suspended fat comes in contact have the
same function. Furthermore, the failure to find increased lecithin valu
in the corpuscles of certain animals does not necessarily mean that it i
not formed there. It may be formed and pass at once into the plasma.
Lipoids of the Blood. — A great deal of investigative work has bee
done on the lipoids of the blood both in the normal and in various path
ological conditions, the results of which in general bear out the rule jus
enunciated, that when one of the constituents (fat, cholesterol, lecithin)
is found abnormal the other two will also be abnormal and in the sam<
direction. It has been shown how feeding fat increases the blood lecithin
and while there is some question as to whether blood cholesterol is i
creased in the lipemia produced by a single fat feeding there is none at
where the lipemia persists. Feeding cholesterol produces not only increase
of blood cholesterol but also of blood lecithin. Whether feeding lecithin
would produce increases in the other two constituents has not been reported
and probably cannot be determined since lecithin is largely hydrolyzed
in the alimentary tract and probably absorbed as fat although some may
appear as such in -the chyle. While there are not enough data available
to justify the statement that there is a constant relation between the
three constituents in normal and in most pathological conditions, the
tendency seems to be in that direction and, at any rate, it appears reason-
ably certain that the three substances are interdependent, and also that all
are concerned in the metabolism of the fatty acids.
The concentration of fat, cholesterol and lecithin in the blood is fairly
constant for the same species but varies greatly in different species, the
variation being noticeable mainly in the plasma. The coneentration in
NOKMAL FAT METABOLISM 205
the plasma and the corpuscles of the same animal is different. In general,
the lipoid level in the plasma is higher in the carnivora than in the
herbivora, being undoubtedly influenced by the amount of fat habitually
present in the diet. There is no such difference between the concentration
of the lipoid constituents in the corpuscles of the various species, the
tendency being rather to a similarity of composition in all.
The level of the blood lipoids may be affected by various conditions,
the most frequent being alimentary lipemia as discussed above. Other
foods than fat apparently do not affect the level, at least not unless the
diet is continued for some time. Fasting for short periods may or may
not raise the level of the blood lipoids (dogs), depending probably on the
nutritional condition of the animal. After the first two weeks of fasting
there is generally a slow fall, although here again the nutritional condition
of the animal at the beginning of the fast is probably important. Nar-
cotics— chloroform, ether and alcohol (especially the two latter) — if long
continued generally cause an increase of the blood lipoids. Chloroform
may not produce any effect during or immediately after the narcosis, but
the effects may appear two or three days later. As reasons for the effects
may be given the increase in the lipoid solvent power of the blood due to
the dissolved narcotics and also their poisonous effects on the tissues,
especially the fatty tissues — which absorb these substances selectively —
producing more or less disintegration of the cells. Poisoning with phos-
phorus or phlorizin will sometimes produce an increase of the blood lipoids,
but the reaction is not constant. In late pregnancy in mammals there is
often a rise in blood lipoids, due probably to preparation for lactation.
It has been found that there is a relation between the level of blood lipoids
and the amount of fat secreted in the milk of lactating animals, also that
the lipoid phosphorus is higher in lactating animals than in dry ones.
Fat in the Tissues
Storing of Fat. — Lipoid material exists in the tissues in two states or
conditions: (a) stored, or inactive, consisting of almost pure fat with not
more than traces of other lipoids ; and (b) cell lipoid, "built in" or active,
forming part of the living tissue and taking an active part in life processes.
Of this latter, phospholipoid is the one present in largest amount and
widest distribution, then cholesterol and its compounds followed by the
series of more or less well characterized substances which include most
of the known lipoids. The cell lipoids are relatively constant in com-
position and appear to be characteristic of the tissue.
Stored fat is found in various parts of the animal body, mainly in
more or less well defined fat depots such as the abdominal, subcutaneous
and intermuscular, and around the organs. It is not normally found
206 W, R. BLOOR
in more than small amounts in active tissues such as the heart, kidney an
muscles, although considerable lipoid material of other kinds is prese:
there. The stored fat has its origin in part directly from the fat of tl
food and in part indirectly by synthesis from other food substances, main
carbohydrate. Synthesis from protein probably does not ordinarily ta"
place to any considerable extent. Under certain circumstances — stuffing
of an animal with fat, especially after starvation — food fat may be laid
down in the fat depots. with but little if any change, but under ordinary
conditions where the animal has a normal choice of food there is a marked
tendency to produce a fat characteristic of the animal ; for example, b
fat has certain definite characteristics which distinguish it from hog fat a
both from human fat. The laying down of a characteristic body fat
an animal from its food must involve several factors such as choice fro:
the food, fat as to which portion is to be immediately consumed and whii
stored, the nature of the fat synthesized from carbohydrate, also, in ca
the stored fat is used, choice as to whether the harder or softer constituen
are to be used first, since there is some evidence to show that the fat of
starved animal has a higher melting point than the normal body fat of
the animal. Although the laying up of a characteristic fat is partly the
resultant of these factors, their activity is limited and in the end the fat
stored is greatly influenced by the food fat especially if it forms a large
proportion of the diet. The question has a considerable economic interest
in connection with the fattening of animals, e. g., hogs for market, since
it has been found that if too much liquid fat is included in the diet t
result is a soft meat from which the fat oozes out on standing.
Changes in Fat in the Tissues. — If the stored fat is thus marked!
influenced by the food fat, the built in fat or cell lipoid is just as notably
characteristic of the tissue and uninfluenced by the food fat, and since the
fatty acids found in combination in the cell lipoids are often different
from those ordinarily found in the food, the question arises as to the power
of the tissues to alter for various purposes the fat presented to them.
The differences between the fatty acids of the active tissues and those of
the food consist mainly in (a) their degree of saturation, (b) the groups
with which they are combined. They are in general much more un-
saturated, the iodin absorption value of the fatty acids of the tissues is
found to be in the neighborhood of 130, while that of the stored fat is
from 35 to 70. The iodin value of the blood lipoids in normal human
beings is about 66 (calculated). The fatty acids in the tissue cells are
largely combined as phospholipoids, although there are also a number of
other combinations of the fatty acids to be found in the organs and in the
brain and nervous tissue. These, with few exceptions, are not well
understood chemically, and since they apparently take but a small part in
ordinary fat metabolism they will not be considered here. The presence
of compounds of the unsaturated fatty acids, especially phospholipoids, in
NOEMAL FAT METABOLISM 207
largo amount (up to 15 per cent) in the cells of continuously active organs
like the heart and kidney as well as in lesser percentages in the muscles
furnish a basis for the theory that they constitute the form in which the
fats are utilized, and that food fat must undergo these changes — desatura-
tion and phcsphorization — before it can be utilized. The theory is given
support from the fact already discussed that whenever there occurs i\
large accumulation of fat in the blood, most frequently in alimentary
lipemia, there is accompanying it a marked increase in the amount of
lipoid phosphorus present.
The Liver in Fat Metabolism. — That the liver plays an important
part in fat metabolism is indicated by the work of many investigators.
Munk (1902) found that the liver was loaded with fat during fat absorp-
tion. Leathes and Meyer- Wedell, by the use of a fat with high iodin num-
ber, found not only that the accumulated fat of the liver after feeding was
food fat but that the liver was the only organ in which such marked accu-
mulation occurred. In various abnormal conditions, such as poisoning with
phosphorus, chloroform or phloridzin, in diabetes, in starvation, etc., great
increases of the fat in the liver may occur which are believed to be the
result of mobilization of stored fat since the fat found in the liver at these
times has the properties of stored fat rather than of normal liver fat.
The accumulations of fat in the liver whenever fat is being extensively
moved by the blood stream indicate that the liver must have an important
function in fat metabolism. Is it a temporary storehouse by means of
which the fat in the blood is kept within limits as is the case with the
carbohydrate, or does the fat undergo some essential change there?
Leathes' theory of the function of the liver in fat metabolism is that
mobilization of fat to' the liver is a normal process, that the fat is brought
there for two purposes: (a) introduction of double bonds (desaturation)
which paves the way for breaking the long fatty acid chains into shorter
ones, and (b) phosphorization of the fat, changing it into phospholipoids
which increasing evidence seems to show is the initial stage in the inter-
mediary metabolism of fat. The desaturation he believes to be specific for
the liver, but phosphorization may be accomplished in other places. His
theory is based on the following evidence: The fatty acids ordinarily
found in the liver differ from those of the stored fat in being much more
unsaturated. The liver is the only point of mobilization of fat from the
intestine or the fat stores. The inference is that the liver desaturates
the fatty acids which are brought to it. Since, however, similar un-
saturated fatty acids are found in other organs like the heart and kidney
it might with equal correctness be inferred that desaturation occurs in
these also. Some work by Mcttram with the plaice in which he found
that the fatty acids of the liver had a lower iodin number than those of
either the food or the muscles, would indicate that the liver may not always
have the function of desaturation. But as it is the only place where
208 W. R. BLOOR
temporary accumulations of fat occur and is the most important gland i
the organism the probable correctness of Leathes' hypothesis as regards
desaturation must be admitted. That phosphorization takes place in othi
locations than the liver is indicated by work on changes in fat in th
blood in which it is shown that the blood cells may have this functioi
Allowing the correctness of the assumption that phospholipoid ("lecithin"
is the essential intermediate step in fat metabolism, the questions of f;
transport in the blood and in and out across cell walls after it enters tb
blood stream as well as its further utilization are greatly simplified, sin
lecithin is soluble in the blood plasma and since there are present in a
organs and tissues esterases which hydrolyze lecithin readily but whii
have little effect on the fats. That blood lecithin may be a source of fa
in the living organism is well shown by the work of Meigs and coworke:
who found that milk fat could be satisfactorily accounted for by decreas
in lecithin in the blood passing through the mammary gland.
Later Stages — (3-oxidation. — As regards later stages in the inte:
mediary metabolism of the fats little is definitely known. The fatty aci
ordinarily disappear in metabolism without leaving any traces in the wa
of intermediate stages by which the process of breakdown may be f ollowi
In certain cases, however, as in severe diabetes and even in short peri
of fasting, acids appear in the urine which are now believed to be late
stages of fatty acid combustion. These unburned residues are P-ox
butyric and diacetic acids which with their derivative acetone constitu
the "acetone bodies." That these substances are actually stages in th
breakdown of the fatty acids is strongly indicated by the work of Knoo
whose hypothesis of (3-oxidation seems to account satisfactorily for tb
final stages in the process of oxidation and breakdown of the fatty acids.
For the stages between, we can only surmise. As pointed out by Leathes
the introduction of double bonds produces points of weakness in the long
chains where oxidation with subsequent breaking readily takes place, pro-
ducing shorter chain mono- and dicarboxy acids. (In this connection it
is interesting to note that in such a process of oxidation and breaking
down, only one monocarboxy acid would be produced from a long chain
fatty acid, the other fragments being dicarboxy acids. Thus from an un-
saturated fatty acid of the linoleic series such as Hartley finds in the liver,
H H H H
CH3 . (CH2)4 . C = C . CH2 . C = C . (CH2)7 . COOH
there would be formed,
CH3 . (CH2)4 . COOH CH2 . (COOH)2 (CH2)7 . (COOH)2
caproic acid malonic acid and azelaic acid
of which the dicarboxy acids would presumably have a different type of
metabolism from the monocarboxy acids.)
NORMAL FAT METABOLISM 209
Knoop's hypothesis that the fatty acid chains are broken down two
carbon atoms at a time is supported by the following evidence (Knoop, F.
(a) 1904-05. Making use of benzol derivatives of the fatty acids which are
utilized with much more difficulty in the organism than the fatty acids
themselves, he found that the fatty acid side chains on the benzol nucleus
are broken down two carbon atoms at a time and that the breaking is pre-
ceded by oxidation at the (3-carbon atom. Oxidation of the fatty acids in
vitro usually takes place at the a-carbon atom, and Knoop's theory was re-
ceived skeptically by chemists until further work by Dakin confirmed his
results both on animals and in vitro, and indicated that (3-oxidation is prob-
al>ly the common type of oxidation of the fatty acids in the animal organ-
ism. The theory adequately explains the appearance, in diabetes and other
conditions, of (3-oxybutyric and its derivatives, which are regarded mainly
as residues of the fatty acids which have escaped complete combustion
because of an abnormality in metabolism. Later work has shown that
certain groups in the protein molecule may also form "acetone bodies,"
but it is believed that this source is relatively unimportant.
The fact that the fatty acids are broken down two atoms at a time
and the fact that naturally occurring fatty acids contain even numbers
of carbon atoms would render it probable that they were built up two
carbon atoms at a time, affording a basis for a theory of fatty acid syn-
thesis from carbohydrates in support of which there is considerable experi-
mental evidence. That fat is formed from carbohydrate has long been
known empirically since farm animals are ordinarily fattened on a diet
which consists mainly of starch; and scientifically acceptable proof was
furnished by Lawes and Gilbert many years ago. The probable mechanism
of the synthesis has been indicated by changes which take place readily
in carbohydrates. Thus sugars readily yield lactic acid by various treat-
ment— action of bacteria, of weak alkalies, etc., and lactic acid in turn
breaks down readily to acetaldehyd. The acetic aldehyd by aldol con-
densation may be made to form (3-hydroxybutyric aldehyd, which by
shifting of the oxygen atom — simultaneous oxidation and reduction —
yields butyric acid. The butyric acid fermentation of dextrose or lactic
acid observed by Pasteur may probably be explained in this way. The
likelihood of this procedure being the true method of synthesis of the
fatty acids is rendered probable by the work of Kaper (1906-07), who
showed that in addition to butyric acid, caproic and caprylic acids are
formed, and that the synthesis of higher fatty acids may be brought about
in vitro from aldol and therefore from acetaldehyd. Smedley has raised
objections to the assumption that the higher fatty acids are formed from
acetaldehyd by aldol condensation, basing her objection on the fact that
the aldol condensation when applied to the higher aldehyds in vitro pro-
duces branched chains instead of straight chains, also that no free aldehyds
(except sugars) are found in the living organism. She suggests as the
210 W. K. BLOOR
probable intermediate stage between carbohydrate and fatty acid, pyruvic
acid CH3 . CO . COOH, which she has shown to produce straight chain
higher fatty acids in vitro by condensation with fatty aldehyds. To get
around her own objection that aldehyds are not found in living organisms
she postulates that combination is affected with aldehyds in the "nascent"
condition. The earlier suggestion of Emil Fischer that the higher fat
acids are formed by direct condensation of sugar molecules with reductic
and oxidation has neither chemical nor biological evidence to support it
but is nevertheless interesting since the most widely distributed fa
acids, stearic, oleic, linoleic, etc., are those containing eighteen cart
atoms in the chain, while the sugar most commonly present is a hexc
It seems likely that the higher fatty acids may be synthesized in moi
than one way and that the intermediate ones may be formed either
synthesis from the lower ones and the elementary substances or by dc
gradation from the higher members.
Fat Excretion
Probably no one of the foodstuffs is completely burned in the ani
organism. The occurrence in the urine of residues of the protein molecu
which still have some caloric value — urea, uric acid, traces of amin
acids, etc. — is well known. The much debated question of the presence
of sugar in normal urine has recently been convincingly answered in the
affirmative by Benedict. Traces of fatty acids are present in normal
urine but except in rare conditions the amounts found are not impor-
tant. Fatty material, mainly in the form of fatty acids, is always
present in the feces in considerable amounts. This fat may come from
at least three sources: (a) undigested material from the food, (b) from
the cellular material of the gastro-intestinal tract — epithelial cells, bodies
of bacteria, etc., and (c) -a, true excretion of unused or unusable fat. To
what extent food fat passes the tract unabsorbed under normal conditions
cannot be stated, but it seems likely from considerations discussed earlier
in the chapter that fats suitable as regards consistency and composition
are completely digested and absorbed. Some of the feces fat undoubtedly
arises from cellular material, but there is also considerable evidence to
show that there is a true excretion of fat into the intestine. In fasting,
fat is present in the feces to the extent of about % of the total dry matter.
Isolated rings of intestine with their blood supply intact fill up with
material similar to feces containing about 35 per cent of their content of
fat, an amount, when calculated for the whole intestine, agreeing with
the figure for fat in fasting feces (Hermann, 1889-90). Loops of intestine
with one or both ends opening outside the abdominal wall secrete a fluid
which contains fatty material. In some animals the excretion flows free!
NORMAL FAT METABOLISM 211
and may be collected from the fistula ; in others it is viscous and must be
washed out. In one dog used by the writer in which the fistula (about 14
inches of jejunum) had been established for about a year, a total of 0.72
gm. of fatty material, mainly soaps, was collected from the fistula in five
days. At least two kinds of soap were present, one in the form of soft
lumps, being probably palmitate, and the other in solution yielding a liquid
fatty acid and being probably oleate. Experimenters from time to time
have reported cases in which more fat appeared in the feces than was
present in the food.
The Carbohydrates and Their Metabolism
A. I. Ringer and Emit J. Baumani
Introduction — Chemistry of the Carbohydrates — Classification and Nomen-
clature— Constitution — Isomerism and Asymmetry — Mutarotation — Isoi
erism of the Aldohexoses — Chemical Eeactions of the Carbohydrates
— Synthesis and Degradation of Carbohydrates — Glucosides — Specie
Properties of Monosaccharides — Hexoses — Methyl Glucosides — Pentos
— Disaccharides — Polysaccharides — Digestion of Carbohydrates — Salivary
Digestion — Action of Ptyalin — Gastric Digestion of Carbohydrates — In-
testinal Digestion of Carbohydrates — Absorption of Carbohydrates — The
Sugar of the Blood — Carbohydrate Tolerance — Carbohydrate Tolerance
Standard — Glycogenesis and Carbohydrate Tolerance — Glucolysis and
Carbohydrate Tolerance — Endocrine and Nerve Control of Glycogenesis,
Glycogenolysis and Glucolysis — Influence of the Thyroid Glands — Influ-
ence of the Pituitary Gland — The Intermediary Metabolism of Carbo-
hydrates— The Formation from Carbohydrate — The Function of Carbo-
hydrate in the Diet — Influence of Carbohydrate on Intermediary Metab-
olism of Fat— Antiketogenesis.
The Carbohydrates and Their
Metabolism
A. I. EIISTGER
AND
EMIL J. BAUMANN
NEW YORK
1. Introduction
The carbohydrates, or sugars as they are called, are found in all cells.
The name sugar is commonly applied to anything having a sweet taste, as
sugar of lead for lead acetate. It is now used non-technically for some
of the simpler members of this group — milk sugar (lactose), cane sugar
(sucrose), etc. The generic name carbohydrate is derived from the fact
that these substances are composed of the elements carbon, hydrogen and
oxygen, the latter two being in the proportion in which they exist in
water — two atoms of hydrogen to one of oxygen — in most, though not all
cases ; in other words, they are hydrates of carbon or carbohydrates.
In the plant world the carbohydrates are found serving two main
functions : first, they act as the main constituent of supporting tissues or
framework of the cell — cellulose ; second, reserve food is stored up in this
form as starches. In the animal world, carbohydrates no longer act as
supporting structures of cells. Nitrogenous substances, belonging mainly
to the class called proteins, take the place of them, but they are found
as a form of reserve food — glycogen or animal starch. It is interesting
to note that in some of the lower animal forms (in some molluscs), the
supporting tissue, chitin, is a substance that may be considered as an
intermediate of the proteins and carbohydrates. It is a nitrogenous carbo-
hydrate from which glucosamine can readily be obtained. Carbohydrates
are also found in the nuclei of all cells, in nucleic acids, and one of
the simplest sugars, glucose, is almost always present in tissue fluids.
They are the simplest organic substances found in living matter and the
most abundant. All the more complex constituents of cells are derived
from them ultimately.
213
214 A. I. RINGER AND EMIL J. BAUMANN
2. Chemistry of the Carbohydrates
Classification and Nomenclature. — The „ carbohydrates, as has already
been indicated, are composed of carbon, hydrogen and oxygen, usually
having the formula C*H2nOn. There are many substances having this
generic formula that are not carbohydrates, e. g., CH3-CHOH-COOH
(lactic acid), but a more comprehensive definition will develop as the
subject is presented.
Carbohydrates may be divided into three great groups, according
to the number of saccharide groups (simple sugars) they contain:
monosaccharides, disaccharides, polysaccharides. Important monosac-
charides are d-glucose or grape sugar, d-fructose or levulose, d-mannose,
d-arabinose and d-ribose. Common disaccharides are sucrose or cane
sugar (also known as saccharose), lactose or milk sugar, and maltose 01
malt sugar. These comparatively simple carbohydrates are often called
sugars. Common polysaccharides are cellulose, starches, dextrins, glyc
gen and gums.
The monosaccharides are further divided according to the number
of carbon atoms they contain — trioses, pentoses, hexoses, octoses, nonoses,
etc. Those found occurring in nature are chiefly the tetroses, pentoses,
hexoses and a few heptoses. Some of the carbohydrates have the proper-
ties of an alcohol and aldehyde, others of 'an alcohol and a ketone, and
these are known respectively as aldoses and ketoses. So an aldehyde sugar
having six carbon atoms would be called an aldo-hexose, and a ketone
sugar having six carbon atoms would be called a keto-hexose.
Constitution. — In the discussion of the structure of the carbohydrates,
d-glucose will be used as a typical example of the aldoses. The manner
in which the elements carbon, hydrogen and oxygen are combined in
these compounds has been a problem which has gradually been elucidated
during the last century, although the last word on the subject has not yet
been written. The first step in the solution of the problem may be said
to have been devised by Liebig, when he gave forth his method for deter-
mining the percentages of carbon and hydrogen in organic matter. With
the development of definite concepts of valency by Kekule and others,
and of the asymmetric carbon atom by Le Bel and Van't Hoff in 1875, a
fairly definite idea of the structure of these substances became known.
As shown by elementary analysis, glucose has the empirical formula
CH2O, and the molecular formula, C6H12O6, as shown by molecular
weight determinations, by the cryoscopic and ebullioscopic methods. When
treated with acids, acid anhydrids and acid chlorides, glucose forms ethe-
real salts or esters,1 e.g., acetyl chloride will form a glucose pentacetate,
C6H70(O.CO.CH3)5.
1 Alcohols are compounds of carbon containing one or more hydrojcyl groups, as
CH8OH, methyl alcohol. An organic acid is a compound containing a carboxyl group
THE CAKBOHYDKATES AND THEIR METABOLISM 215
O
/
C — H
HCO.OC — CH3
I
HCO.OC — CH3
HCO.OC — CH3
HCO.OC — CH3
I
HCO.OC — CH3
H
That is, glucose behaves like a compound having five alcohol (OH) groups
here, and Berthelot, who first prepared the acetates of glucose, called the
sugar a pentatomic aldehyde alcohol. When acted upon by metallic
hydroxides, glucose forms compounds resembling alcoholates, further dem-
onstrating the presence of alcohol groupings.
Glucose is reduced by sodium amalgam to form a hexahydric alcohol,
which in turn may be reduced by hydriodic acid to iodohexane, a derivative
of normal hexane, which indicates that glucose is a normal chain com-
(COOH). Acids and alcohols react forming ethereal salts or esters, much as acids
and bases react to form salts, thus:
CH3OH + CH3COOH ^± CH3COOCH3
methyl alcohol acetic acid methyl acetate (ester)
O
Substances having the group — C are called aldehydes, and those that contain
J. H
CO
the carbonyl group CO are known as ketones. A fundamental distinction between alde-
hydes and ketones, is that when they are oxydized, aldehydes yield acids containing the
same number of carbon atoms as the original substance while ketones break up on oxi-
dation, yielding products which do not contain as many carbon atoms as the original
substances. Thus:
O
CHSCH,C + O _> CH3CH2COOH
\H
propyl aldehyde propionic acid
CH,
CO + 3 O _^ CH3COOH + HCOOH
CH3
methyl ketone acetic and formic acids
(acetone)
210
A. I. IUi\GEK AND EMIL J. BAUMAOT
TABLE I. — CLASSIFICATION OF CARBOHYDRATES
Carbo
hy- .
drates
1. Monosaccharides-
2. Disaccharides
3. Polysaccharides
1. Bioses
Trioses
2.
3. Tetroses
4. Pentoses
5. Hexoses
6. Heptoses
Type 1.
Type 2.
aldose (glycolicaldehyde)
aldose (glycerose)
ketose (dioxy acetone)
aldose (erythrose)
ketose (erythmlose)
aldoses (arabinose, xylose, ri-
ketose (arabinulose.) bose)
aldoses (glucose, galactose, man-
nose)
ketoses (fructose, sorbose)
aldoses (mannobeptose, gluco-
beptose)
Aldehyde group functional
Maltose (glucose and glucose)
. Isomaltoso (glucose and glucose)
• Lactose (glucose and galactose)
Turanose (glucose and fructose)
Aldehyde not functional
Sucrose (glucose and fructose)
Trebalose (glucose and glucose)
Type 1. Mannotriose (glucose and gali
tose and galactos
1. Trisaccbar-J fRaffinose (galactose and glu-
ides Im « cose and fructose)
•** ' 1 Melicitose (glucose and glu-
cose and fructose)
{Stachyose (fructose and glucose and
galactose and galactose)
Dextrins
Glycogen
Starches
Celluloses
Gums
2. Tetrasac-
cbarides
3. Colloidal
Polysaccbarides
THE CARBOHYDRATES AND THEIR METABOLISM 217
pound.- By oxidizing glucose with bromine, gluconic acid is obtained.
This has the same number of carbon atoms as glucose, and in this way the
presence of an aldehyde is indicated, a fact which is confirmed by oxidizing
glucose with nitric acid to saccharic acid, a dicarboxylic acid, also con-
taining six carbon atoms.
C6tf1200 + O »C6H1207
Glucose Gluconic Acid
C6H1207 + 0 >CGH1008
Gluconic Acid Saccharic Acid
Owing to the stability of glucose it may be assumed that each hydroxyl
group is attached to a different carbon atom, and as glucose is a derivative
of normal hexane, as shown above, its formula may be written
CHO
CH— OH
CH— OH
CH— OH
CH— OH
1
CH2 — OH
This formula was originally proposed by Baeyer (1) and Fittig (2)2
But glucose is far less active than might be expected of a compound that
is an hydroxyaldehyde. Thus it does not react easily with sodium sulphite,
pyrotartaric acid, nor with phenylhydrazineparasulphonic acid as might
be expected of a substance having the formula shown. It does not
undergo Perkins' reaction for aldehydes with acetic anhydride and so-
dium acetate. Aldehydes are generally more volatile than the corre-
sponding alcohols. This is not true of glucose. Moreover, glucose and
many of its derivatives, as shall be seen presently, occur in two isomeric
forms which exhibit no aldehyde properties at all. This difficulty was
overcome by Tollens' (1883) suggestion of a ring (the y-oxide or y-lactone)
formula for glucose. This formula has now been generally adopted. On
* The presence of a ketone group (CO) in carbohydrates was first demonstrated
by Kiliani in 1885 when he showed that, unlike glucose, which owing to its aldehydic
nature yields compounds with the same number of carbon atoms when oxidized, fructose,
under similar conditions, yeilds a number of products having less than the same
number of carbon atoms than the original substance, as, for instance, trihydroxy-
butyric acid.
218
A. I. RTXGER AND EMIL ,T. BAUMANN
the basis of this configuration it is assumed that glucose may readily
behave like an aldehyde by breaking the Y-oxide ring, thus :
O
H /
HOCH HO— C— OH C
\ I\H
a carbon HCOHX HCOH HCOH
N^ -f- water — water
P carbon HOCH O " > HOCH , -» HOCH
— water -j- water
Y carbon HC^ HCOH HCOH
S carbon
HCOH
CH2OH
Closed ring or
Y-oxide form
HCOH
CH2OH
Aldehydrol
HCOH
CH2OH
Aldehyde
An intermediate aldehyde-hydrate or aldehydrol form is believed to
result by hydrolysis, and from this in turn the aldehyde form originates.
The action is a reversible one, and it is assumed that when an agent that
will act upon the aldehyde group is added to an aqueous solution of glucose,
the small amount of aldehyde-hydrate present is acted upon, thereby dis-
turbing the equilibrium. A fresh quantity of the hydrate is formed and
so the process is kept up.
Isomerism and Asymmetry .-^-Bodies having the same elementary com-
position, but possessing different properties, are called isomers or isome-
CH3\
rides. Thus ethyl alcohol CH3 and methyl ether O are isomers.
| CH3/
CH2OH
Both have the empirical formula of C2HCO. When, however, in addition
to having the same number of atoms of the same kind, these atoms are ar-
ranged in the same general -way, so that each compound has the same chemi-
cal groups, and consequently similar chemical properties, but the "space
relationships" of these groups within the molecule are different, such sub-
stances are said to be stereoisomeric.
Sugars illustrate this form of isomerism especially well. For example,
glucose and galactose are both aldohexoses. They have the same empirical
formulae and the same chemical groups, but the space relationships or
configuration of these groups differ.
These differences are illustrated in the following structural formulas :
THE CARBOHYDRATES AND THEIR METABOLISM 219
° O
H
H
HCOH HCOH
HOCH HOCH
HCOH HOCH
HCOH HCOH
CH2OH CH2OH
d-Glucose d-Galactose
Pasteur was the first to clearly demonstrate the importance of the
relationship of the atoms to one another in the molecule, and added one
of the most fundamental facts concerning the structure of the molecule to
the chapter of chemistry. To biochemistry, or for that matter to all medi-
cal sciences, Pasteur's contribution on this fascinating subject is of supreme
importance, and to-day we are really only beginning to appreciate how
important molecular structure is in metabolism.
While Pasteur was studying crystalline structure (in 1848) he investi-
gated the tartaric acids. Two forms of tartaric acid were known then — •
that obtained from wine, which rotated the plane of polarized light to the
right, and that, called racemic acid, having the same composition, and no
action on polarized light. He expected that these two forms of tartaric
acid would have different crystalline forms. He worked with the sodium
ammonium salts of these acids and found that the ordinary tartaric acid
from grapes had pretty much the same form as racemic acid. However,
closer examination of the crystals of racemic acid showed that there were
really two types present, one having a pair of diagonally opposite facets
so arranged that if superimposed upon the other, these facets would not
correspond. In the one type, one of these facets was on the right side,
and in the other type of crystal, the corresponding facet was on the left
side. And one of the forms of racemic acid proved to be the same as the
optically active tartaric acid obtained from wine.
Pasteur then separated the two types of crystals found in racemic
acid, studied their behavior toward polarized light, and discovered that
in one case the plane of polarized light was rotated to the right, and in
the other the plane of polarized light was rotated to the left. The differ-
ence between the two forms of tartaric acid thus became apparent. The
natural tartaric acid rotates the plane of polarized light to the right;
220
A. I. KINGEK AND EMIL J. BAUMAOT
the form isolated by Pasteur from racemic acid rotates the plane of
polarized light to the left ; racemic acid, optically inactive, is in reality a
mixture of both — the dextrorotatory and the levorotatory.
Here are two substances having the same empirical formula and the
same chemical groups similarly arranged, but their physical properties —
their crystalline form and behavior toward polarized light — are markedly
different. It will likewise be found that their chemical properties are
different. These are not due to differences in chemical composition, but
to differences in molecular form. More than a quarter of a century
later, Le Bel and Van't Hoff independently formulated the hypothesis of
the asymmetric carbon atom, on the basis of Pasteur's fundamental dis-
covery. Only such compounds of carbon as have so-called asymmetric
Fig. 1. Illustrating two carbon atoms with their four valences taken up by
four different radicles arranged in such a way that the space relationship of the
two is like that of a mirror image.
carbon atoms can exist in stereoisomeric forms. An asymmetric carbon
atom is one that has four different atoms or atomic groups attached
to it.
If the carbon atom is pictured as lying at the center of a tetrahedron
with the four atoms attached to it at the apices, it is possible to arrange
these in two ways, one of which is the mirror image or antipode of the
other (Fig. 1).
Molecular asymmetry of this type is most readily recognized by means
of the action of such substances on polarized light. Compounds having one
or more asymmetric carbon atoms usually have the power of rotating the
plane of polarized light except when one asymmetric carbon atom is
neutralized by one or more other asymmetric atoms. However, one does
not meet such substances very often. One of the first cases known in
which one asymmetric carbon atom neutralizes another is mesotartaric
acid, discovered by Pasteur. The various tartaric acids may be repre-
sented thus:
THE CARBOHYDRATES AND THEIR METABOLISM 221
COOH COOH COOH
H — C — OH HO — C — H H— C — OH
HO — C — H H — C — OH H — C — OH
COOH
d-Tartaric acid
COOH COOH
1-Tartaric acid Mesotartaric acid
It is found that optical antipodes rotate the plane of polarized light in
equal amounts but in opposite directions, so that, if one has a mixture of.
equal parts of the dextro- and levorotatory forms of a compound, the result-
ing mixture would of course exert no influence upon the plane of polarized
light.
The degree of rotation varies directly as the concentration of the sub-
stance and inversely as the length of the column of solution through which
the observation is made. It depends also upon the temperature (there
being less rotation in general as the temperature increases) and on the
wave length of the light used in making observations. The degree of
rotation for many substances is greater with light of short than of long
wave lengths. . Hence the necessity of using a standard temperature and a
monochromatic source of light for making observations. The unit of
measurement of rotation of the plane of polarized light is called the specific
rotatory power and is defined as the rotation of one gram of substance
dissolved in one cubic centimeter of solute and for a tube one decimeter
in length, usually at 20 degrees centigrade and for sodium light. It is
calculated from the observed angle of rotation, produced by a solution of
known concentration, in a tube of known length, by the following formula :
20
in which [«] ?? is the symbol for specific rotation at 20° for sodium light
(the D line of the spectrum), a the observed angle of rotation, P the
concentration of the substance, a"nd 1 the length of the tube in decimeters.
The solvent is usually given, as the angle of rotation varies somewhat
with different solvents.
Mutarotation. — Isomerism of Glucose .—When pure d-glucose, derived
from natural sources, is dissolved in water, and its specific rotation de-
termined at once, it will be found to be +109°. On standing, the specific
rotatory power changes slowly, until after 24 hours or more, at 20°, it
becomes +52.5°. If a small quantity of alkali is added to the newly
222
A. I. RINGER AND EMIL J. BAUMANN
prepared solution, this change will take place in a few minutes. This
phenomenon was first observed by Dubnmfaut in 1846. By crystallizing
ordinary commercial glucose from different solvents and by other methods,
two different glucoses have been obtained, having specific rotatory powers
of -|- 109 and + 19 respectively. If either of these is dissolved in water,
it will slowly change its specific rotation to -|- 52.5. This phenomenon
is termed mutarotation or birotation.
Tanret, in 1895 and 1896, was the first to demonstrate that we were
here dealing with more than one form of glucose. He called the glucose
with the high initial specific rotation a glucose, and the glucose of the
specific rotatory power 52.5 he designated (3-glucose. However it has
been found that Tanret's ^-glucose was really a mixture obtained by
allowing the glucose of high or low rotatory power to reach equilibrium.
This happens when there are present 37 per cent of ct-glucose and 63 per
cent of the glucose having the initial specific rotatory power of +19,
which is now called P-glucose. The equilibrated mixture of a-and P-glu-
cose is known as y-glucose.
The difference in structure of « and-p-glucose is due to the difference
in the positions of the hydrogen atom and hydroxyl group of the carbon
atom that is potentially aldehydic. It may be represented as follows :
CH2OH
ct-Glucose
CH2OH
(3-Glucose
The conversion of one form to the ojther is assumed to take place by
the formation of an intermediary compound, the exact nature of which is
still a matter of dispute.
Isomerism of the Aldohexoses. — The number of possible stereoiso-
meric forms of a substance can be calculated by the formula of Le Bel
and ^Tan't Hoff. Number = 2n, where n is the number of asymmetric
carbon atoms in the molecule. If the open chain formula of glucose is
examined it will be found that it has four asvmmetric carbon atoms:
THE CARBOHYDRATES AND THEIR METABOLISM 223
O
//
a
*HCOH
*HCOH
*HCOH
I
CII2OH
Accordingly there may be 2 4 or 16 possible aldohexoses. Largely through
the researches of Emil Fischer, 14 of these are now known, although only
three — glucose, mannose, galactose — occur naturally. These isomers are
represented in Table II.
TABLE II. — ALDOHEXOSES
1. Mannitol Series
COH
COH
COH
COH
He
-\
>OH
HO-C
^ TT
j-tt.
HO-C
•\ TT
y'Xl
H-C-OH
H-C
HO-C
*\ TT
y-JTL
TT f
>OH HO-C-H
HO-C
^ TT
y--tl
.
TT f
>OH
HO-C
y""-H-
Hi
-i
^-OH
HO-C
^ TT
y--Tl
Hf
-\
>OH
HO-C-H
Hi
-'
>OH
(
^-^^ OTT
y±l2U±l
CH2OH
CH2OH
CH2OH
1-Mannose
d-Mannose
1-Glucose
d-Glucose 3
• All sugars known as rt-sugare are not necessarily dextrorotatory, nor are all
1-sugars neciarilv levorotatory." All com,x,«nd« «leriv«l from ^uco^ by r^ctiona
that leave the stereochemical structure unchanged an- designated d-compounda, r
gardless of their rotation, and similarly for 1-forms.
224
A. I. KINGEK AND EMIL J. BAOIAXX
COH
COH
COH
1
COH
HO-C-H
H-C-OH
1
H-C-OH
HO-C-H
H-C-OH
HO-C-H
H-C-OH
HO-C-H
HO-C-H
H-C-OH
HO-C-H
H-C-OH
H-C-OH
HO-C-H
H-C-OH
i
HO-C-H
CH2OH
1-Idose
CH2OH
d-Idose
1
CH2OH
1-Glucose
CH2OH
d-Glucose
2. Dulcitol
Series
COH
COH
COH
COH
HO-C-H
H-C-OH
H-C-OH
HO-C-H
H-C-OH
HO-C-H
H-C-OH
HO-C-H
H-C-OH
HO-C-H
H-C-OH
HO-C-H
HO-C-H
H-C-OH
HO-C-H
H-C-OH
CH2OH
1-Galactose
CH2OH
d-Galactose
CH2OH
1-Talose
CH2OH
d-Talose
COH
COH
COH
COH
HO-C-H
H-C-OH
H-C-OH
HO-C-H
HO-C-H
H-C-OH
HO-C-H
H-C-OH
r
HO-C-H
H-C-OH
HO-C-H
1
H-C-OH
HO-C-H
H-C-OH
HO-C-H
H-C-OH
CH2OH
1-Allose
unknown
CH2OH
d-Allose
CILOH
1-Altrose
unknown
CH2OH
d-Altrose
THE CARBOHYDRATES AND THEIR METABOLISM 225
Since there are two closed ring forms for each aldohexose, the a and
(3 forms, there should be 32 closed chain aldehexoses,4 with which the 16
already discussed make a total of 48 isomeric aldohexoses theoretically
possible. Most of the carbohydrates exist in more than one form and
possess the power of mutarotation.
TABLE III
SPECIFIC ROTATIONS OF SUGABS
Sugars
a-form
/3-form
Equilibrated
Mixture
d-Glucos6
+ 110°
+ 20°
+ 52 5°
d-Mannose
+ 76°
14°
4- 14°
d-Galactose
4- 140°
+ 53°
4- 81°
d-Fructose
+ 17°
— 140°
— 93°
1-Arabinose
+ 76°
+ 184°
4- 104°
d-Xylose
4- 100°
— 8°
+ 19°
1-Rhamnose
7°
4- 32°
+ 9°
d-Maltose
4- 166°
+ 119°
+ 137°
d-Lactose hydrate
+ 86°
4- 35°
4- 55°
d-Melibiose .-
+ 171°
+ 124°
4- 143°
d-Ribose
4- 18.8°
Sucrose
4- 66.5°
a Methyl glucoside 4-157°. /3 Methyl -glucoside — 33°.
Chemical Reactions of the Carbohydrates
In most cases glucose will be used as a typical carbohydrate in dis-
cussing the reactions which the carbohydrates undergo. (Only those that
have a direct interest to the biochemist will be presented.)
Synthesis and Degradation of Carbohydrates. — Most of the methods
of synthesizing the carbohydrates we owe to the masterly researches of
Emil Fischer, who devised most of the methods and synthesized a vast
number of them.
1. Polymerization (aldol condensation) of simple sugars by action
of dilute alkali, e.g.,
2 C3HC03
Glycerose
CCH1200
Fructose
This reaction is somewhat similar to one by which it is believed carbo-
hydrates may be formed in plants from formaldehyde. Baeyer, in 1870,
first advanced the theory that the plant tissues formed formaldehyde from
CO2 and H2O. Loew, in 1886, discovered that formaldehyde (H(
and lime water at room temperature produced a sweet substance which was
unfermentable. Fischer later showed that what is formed here is a acrose,
«In the closed chain formula there is an additional asymmetric carbon atom, so
that the number of isomers is 25 or 32.
226
A. I. RINGER AND EMIL J. BAUMANN
which is the inactive form of fructose, so that chemically at least this is a
possible mechanism by which plants synthesize carbohydrates.
2. Synthesis of higher forms from a lower monosaccharose. — Here, a
method of wide application in chemistry has been successfully used to
synthesize a large number of carbohydrates. It consists in forming a
cyanhydrin of a lower aldose with hydrocyanic acid, hydrolyzing the
nitrile to form the corresponding acid and reducing this substance to the
next higher sugar, e. g., glucose may be converted to glucoheptose in this
way.
ON
CH2OH
o-Glucose -f- Hydrocyanic
acid
COOH
HOCH
HO— C— H
HCOH
HOCH
HCOH
HCOH
CH2OH
— > a-Glucose
nitrile
Hydrolysis
2 HO
/O
HCOH
HOCH
HCOH
HCOH
I
CH2OH
a-Glucoheptoiiic
Acid
Reduction
with
[ N
sodium
amalgam
C
I
HOCH
I
HCOH
HOCH
HCOH
I
HCOH
CH2OH
a-Glucoheptose
Aldehyde Formula
The ability of hydrocyanic acid to unite with aldoses is of considerable
interest physiologically. This acid is found in small amounts in a number
of plant tissues. It greatly accelerates the action of a proteolytic enzyme
(papain) which it may do by means of a reaction somewhat similar to the
first stage indicated above.
3. Conversion of a higher to a, lower monosaccharose. — By the action
of hydroxylamine upon glucose, glucose-oxime is produced. This product
is converted to gluconic nitrile by the action of acetic anhydrid and sodium
acetate, removing one molecule of water and acetylating the hydroxyl
groups, forming penta-acetyl gluconic acid. Ammoniacal silver solution re-
moves hydrocyanic acid from this substance, leaving the acetyl derivative
of the pentose arabinose. Ammonia will form an acetamid arabinose,
which in turn yields arabinose by the action of dilute sulphuric acid.
CII:NOH
HCOH
HOCH
HCOH
HCOH
c
|\H
HCOH
HOCH
HCOH
HCOH
CH2OH
Glucose
plus
Hydroxyl-
amin
Acetic
Anhydrid
CH2OH
Glucose
Oxime
H
HCO.OC — CH3
riL,CO — OCH
HCO.OC — CH3
I
HCO.OC — CH3
CH2O.OC — CH3
plus
H — CO.OC — CHa
ammoniacal
silver CH3 — CO.OCH
solution
HCO.OC — CH3
HCO.OC — CH3
CH2O.OC — CH3
arabinose pentacetate
By this reaction glucose has been converted successively into arabinose,
erythrose, glycerose and gly collie aldehyde.
OxidltoL Action of alMies.-Mosi of the S1mpler carbohydrate
are unstable in alkaline solution and undergo a great variety of changes,
228 A. I. RINGER AND EMIL J. BAUMANN
the exact nature of them, all not being known yet. If the sugars are treated
with a weak alkali at room temperature, a molecular rearrangement takes
place slowly which is known as a tautomeric rearrangement. The mechan-
ism of these interesting changes will be presented later. If an aldose or
ketose is treated with strong alkali, it becomes yellow or brownish and
acquires the odor of caramel. This is the basis of Moore's test for the
detection of carbohydrates. The character of the products formed varies
with the strength of alkali used and the amount of oxygen available, for
the products are largely oxidation products, the sugar being' a reducing
agent. Over one hundred degradation substances have been identified
as the products of the interaction of sodium hydroxid and glucose.
Among others, a large series of acids may be formed^ varying in com-
plexity from carbonic acid, formic acid, oxalic and lactic acids, to saccharic
and gluconic acids. In the absence of much oxygen, products like glycolic-
aldehyde CH2OH, glycericaldehyde CH2OH, glyoxal CHO, oxyace-
CHO CHOH CHO
CHO
tone CH2OH, etc., are formed.
CH3
The first stages in the oxidation of glucose results in the formation of
gluconic and glucuronic acids — both monocarboxylic acids, and then sac-
charic acid — a dicarboxylic acid.
CHO CHO COOH COOH
CHOH CHOH CHOH CHOH
I I
CHOH CHOH CHOH CHOH
CHOH CHOH CHOH CHOH
CHOH CHOH CHOH CHOH
CH2OH COOH CH2OH COOH
Glucose Glucuronic Gluconic Saccharic
Acid Acid Acid
(Glucuronic acid is the most interesting of these derivatives physiologically.
Many substances that are not readily oxidized in the body, such as camphor,
THE CARBOHYDRATES AND THEIR METABOLISM 229
chloral, thymol or phenol, are excreted in the urine of the carnivora and
herbivora as conjugated glucuronat.es. These glucoside 5 compounds serve
as a means of removing injurious substances from the body. In the
plant kingdom, glucuronates have also been found frequently, e. g., in
the sugar beet.)
As one would expect of ketones, the ketohexoses do not yield acids
containing the same number of carbon atoms on oxidation. The molecule
divides at the ketone group.
Monosaccharides, and many disaccharides and trisaccharides, are oxi-
dized in acid solution, forming products similar to those formed by the
action of alkali, but the oxidation occurs much less readily.
These reducing powers of the simpler carbohydrates are utilized in
detecting and estimating them quantitatively. In alkaline solution they
will reduce many metallic hydroxides, such as those of copper,, mercury,
bismuth, silver, gold, etc. Methylene blue, permanganates, bromin,
chlorin, etc., are also reduced by sugars, the last three in acid solution as
well as in alkaline solution.
The carbohydrates are usually estimated quantitatively or detected
qualitatively by an alkaline cupric tartrate solution, known as Fehling
eolution or some modification of it. If glucose be heated with cupric hy-
droxid [Cu(OH)2] and sodium hydroxid, it will reduce some cupric hy-
droxid to cuprous oxid [Cu2O]. When much cupric hydroxid is present
it will remain partly dissolved and some of it may be dehydrated to form
black cupric oxid [CuO].
Many substances, usually those having several hydroxyl groups, such
as tartrates, citrates, glycerol and sugars, possess the property of dissolving
metallic hydroxids, as in the case of sodium tartrate and Cu(OII)2 form-
ing cupric tartrate. If enough sodium tartrate be added to cupric hy-
droxid and sodium hydroxid, all the cupric hydroxid will dissolve. When
glucose is heated with such a solution reduction of the cupric hydroxid
will occur with no danger of formation of cupric oxid, which might obscure
the result. Fehling's solution is an alkaline cupric tartrate solution made
from copper sulphate, sodium potassium tartrate (Rochelle salt) and sodi-
um or potassium hydroxid. When kept for any length of time, the tartrate
will reduce the cupric salt. To avoid this the copper sulphate is kept sepa-
rate and is known as Fehling's solution "A" and the alkaline tartrate solu-
tion as Fehling's solution "B".
The stages in the reduction of copper by reducing sugars are roughly
as follows : the alkali decomposes the sugar into a number of fragments
which reduce the cupric salt to insoluble yellow cuprous hydroxid, first.
If heating is continued, the cuprous hydroxid loses a molecule of water
and is converted into red cuprous oxid, which is also insoluble.
6 A glucoside is an ether of glucose (or other sugars) and an alcohol. On hydrol-
ysis with acid, the sugar is liberated.
230 A. I. RINGER AND EMIL J. BAUMANN
/OH CuOH Cu\
2 Cu minus minus O
\OH - > CuOH -* Cu/
water and oxygen water
blue yellow red
It should be noted that in Fehling's solution both cupric hydroxid
and cupric tartrate exist in equilibrium. As reduction occurs, more cupric
hydroxid is formed from the tartrate.
This reaction is not completed in a definite time, since many of the
degradation products, as giuconic acid, are slowly oxidized. So that when
quantitative estimations are made, very definite conditions of concentration
and time of heating must be observed. The cuprous oxid formed may be
weighed directly or oxidized to cupric oxid and this weighed. Or it may
be dissolved in acid and estimated electrolytically or by a number of
volumetric methods.
To avoid the inconvenience of keeping two solutions, Benedict has
substituted sodium citrate for Rochelle salts in Fehling's solution and
sodium carbonate for sodium hydroxid. This solution keeps indefinitely
and serves very well for the qualitative detection of reducing substances.
Reduction of Carbohydrates. — While most of the reactions which carbo-
hydrates undergo in living matter are oxidation reactions, not an incon-
siderable number are reductions, such as the processes whereby micro-
organisms, of the group known as anaerobes, metabolize sugars and give
off carbon dioxid in the absence of air.
Sugars are reduced by sodium amalgam, forming, in the case of hexoses,
hexahydric alcohols.
/O
C CH2OH
HCOH HCOH
I I
HOCH HOCH
I +2 H |
HCOH HCOH
I I
HCOH HCOH
CH2OH CH2OH
Glucose Sorbitol
A number of these alcohols are found in plants, such as sorbitol, which
is derived from glucose ; mannitol from mannose ; dulcitol from galactose.
Mannitol is especially widely distributed. In some fungi there is more
mannitol present than glucose. Like the sugars, they are sweet,
THE CARBOHYDRATES AND THEIR METABOLISM 231
Conversion of Glucose into Fructose and Mannose. — In the presence
of alkalis, aqueous solutions of glucose, mannose and fructose are con-
verted into one another; slowly at room temperature, more quickly and
with some decomposition at higher temperatures. These most interesting
and important reactions were first observed by Lobry de Bruyn and A.
Van Ekenstein, 1902-1903. They noticed that if glucose were treated
with weak alkali at room temperature, the specific rotation changed from
+ 52.5° to abou-t 0°. After standing several days or weeks, mannose and
fructose, as well as glucose, could be isolated from the solution. The
mechanism of the process was explained by Wohl. It will be remembered
that except for the terminal and a-carbon atoms, the space configuration
of glucose, fructose and mannose is the same. The hydrogen atom at-
tached to the a-carbon in glucose and mannose "swings" from its position
to give rise to the common enol form. In the case of fructose the swing-
ing H atom is attached to the terminal C atom. The enol form is then
converted into all three of the possible hexoses.
CHO
HCOH
HOCH
HCOH
HCOH
CHOH
COH
HOCH
HCOH
HCOH
CH2OH
Enol Form
I
CH2OH
CO
i
HOCH
HCOH
HCOH
CH2OH
Fructose
CHO
I
HOCH
I
HOCH
I
HCOH
HCOH
I
CH2OH
Mannose
232
A. I. RINGER AND EMIL J. BATJMANN
Lobry de Bruyn isolated another hexose, glutose, as a product of the
action of alkali on glucose. Glutose is formed through the intermediate
stage of a second enolic form derived from fructose, thus :
CH2OH CH2OH
CO
I
HOCH
HCOH
HCOH
CH2OH
Fructose
COH
II '
COH
HCOH
I
HCOH
CH2OH
Enol Form
CH2OH
CHOH
CO
HCOH
I
HCOH
I
CH2OH
Glutose
d-Galactose behaves similarly to d-glucose when treated with dilute alkalis.
An equilibrium ensues between it and d-talose, d-tagatose and 1-sorbose.
Reactions of sugars with Substituted Hydrazines. — One of the most
important reactions in sugar chemistry for identification of sugars is
that which takes place when aldoses or ketoses are heated with an excess
of phenylhydrazine in dilute acetic acid. Quite insoluble definite crystal-
line compounds are formed, called hydrazones and osazones, which are
readily identified by their crystalline structure, melting point, etc. These
osazones (and hydrazones) were the compounds that enabled E. Fischer to
elucidate the chemistry of the sugars.
The reaction takes place in two stages. In the first, which goes on at
20° C., a hydrazone is formed. •
/o
C CHiN.NH — C6H5
\H
HCOH HCOH
HOCH + CCH5NH.NH2 HOCH
HCOH
HCOH
HCOH
HCOH
CH2OH
Phenylhydrazone
CH2OH
Aldose Phenylhydrazine
(Glucose)
An excess of phenylhydrazine (which should be present) then acts as an
oxidizing agent, forming a carbonyl group (CO) from a CHOH group,
THE CARBOHYDRATES AND THEIR METABOLISM 233
while the phenylhydrazine is converted to anilin and ammonia The car
bonyl group then reacts with another molecule of phenylhydrazine to
form the osazone, thus :
CH :N . NH - C6H5 CH -N . NH - C6H,
l> 5
HCOH
HOCH
HCOH
HCOH
CO
I .
HOCH
-> HCOH
HCOH
CH2OH CH,OH
Phenylhydrazone + phenylhydra- intermediary + anilin + ammonia
zine oxidation
product
— C6H5
CO
I
HOCH
HCOH
HCOH
— C6H5
— C6H5
HOCH
HCOH
HCOH
CH2OH
phenylosazone -f- water
CH2OH
Intermediary oxida- -j- phenylhydra-
tion product zine
Because the second stage of the reaction is a' process of oxidation, it
follows that those sugars that are most easily oxidized (as d-fructose) most
readily form osazones.
Aldoses and ketoses may be differentiated by means of their reaction
with methyl phenylhydrazine. According to Newberg, ketoses form osa-
zones, while aldoses reach only the hydrazone stage. The asymmetrically
substituted hydrazines do not act as oxidizing agents. Since the conversion
of hydrazone to osazone involves oxidation, the reason for this behavior
is evident.
Most of the hydrazones are very soluble in water and therefore not
adapted for identification. Mannose, however, is a notable exception.
It forms a crystalline precipitate easily identifiable. The osazones are,
as a rule, quite insoluble in water. In order to form more specific com-
234 A. I. RINGER AND EMIL J. BAUMANN
pounds for identification, disubstituted hydrazines have been used with
excellent results in many cases. Thus, galactose forms a very characteristic
methyl phenylhydrazone with rnethylphenylhydrazine. Other characteris-
tic sugar compounds with the hydrazines are the diphenylhydrazone of
arabinose, benzoylphenylhydrazones, etc.
Glucose, fructose and mannose form the same phenylosazone — glucos-
azone — as would of course be expected from their configuration, as previ-
ously noted (see page 231).
As stated above, the asymmetrically substituted hydrazines do not
form osazones with glucose because they cannot act as oxidizing agents.
Fructose, however, already having a CO group present, is readily attacked
by them.
The osazones and hydrazones, then, form an admirable means of isolat-
ing carbohydrates from a solution containing inorganic and organic sub-
stances, i. e., biological fluids, like blood, urine, etc. To recover the free
sugar from the hydrazone, Fischer , decomposed them with hydrochloric
acid into phenylhydrazine and sugar.. It was later discovered that boiling
them with benzaldehyde and water, in the case of the monosubstituted
hydrazones, or with formaldehyde, in the case of the disubstituted hydra-
zones, was advantageous (Heizfeld, Ruff and Ollendorf), for then, in-
soluble benzaldehyde phenylhydrazone or formylphenylhydrazone were
formed, and the phenylhydrazones could be removed by filtering off these
insoluble derivatives.
C6H1205 :N . NH— C6H5+C6H5CHO->C6H12O6+C6H5CH -N . NH— C6H5
Phenylhydrazone -f- benzaldehyde — *• sugar -(- benzaldehyde
phenylhydrazone
Sugars cannot, however, be so readily recovered from their osazones.
When the latter are treated with concentrated hydrochloric acid it will
remove both hydrazine groups, forming an osone:
/o
CH:N.KE— C6H5 C
I |\H
C:N.H — C6H5 C=0
HOCH +2 HC1 + 2 H2O^HOCH + 2 C6H5NH.NH2.HC1
HCOH HCOH
HCOH HCOH
! I
CH2OH CH2OH
Phenylosazone -J- hydrochloric acid — » osone -}- phenylhydrazine. hydro-
and water chlorid
THE CARBOHYDRATES AND THEIR METABOLISM 235
The osones are colorless liquids which act as strong reducing agents.
By reducing them the sugars may be obtained. Glucose, fructose and
mannose form the same osazone, and so, of course, the same osone. When
glucosone is reduced, d-fructose is obtained. These reactions may there-
fore be used for converting an aldose into a ketose.
TABLE IV
MELTING POINTS
OF HYDRAZONES
Arabi-
nose
Glucose
Mannose
Galactose
Maltose
Lactose
Phenylhydrazone
151-3°
144-6°
186-8°
158°
p-bromophenylhydrazone . .
o -methylphenylhydrazone
150°
161°
164-6°
130°
208-10°
178°
168°
180°
....
a-ethylphenylhydrazone . . .
153°
159°
169°
a-amylphenylhydrazone . . .
120°
128°
134°
116°
123°
a-allylphenylhydrazone . . .
145°
155°
142°
157°
132°
o-benzoylphenylhydrazonc .
170°
165°
165°
154°
128°
di-phenylhydrazone
218°
161°
155°
157°
/3-naphthylhydrazone
141°
157°
167°
176°
203°
OF OSAZONES
Arabi-
nose
Glucose
Mannose
Galactose
Maltose
Lactose
Phenylosazone • .
160°
208°
208°
193°
206°
200°
p-bromophenylosazone
196-200°
222°
198°
D-nitroohenvlosazone .
257°
261°
258°
Ghicosides
A glucoside is a compound which, upon hydrolysis with acids, yields
glucose (or another sugar) and one or more other substances. A great va-
riety of substances occur in plants, and to a lesser extent in animals, com-
bined with a sugar (usually d-glucose). The general formula is
/H
C — 0 — R
HOCH
CH.OH
in which R may represent an alcohol, acid, aldehyde, phenol or a large num-
ber of other substances.
236
A. I. RIXGER AND EMIL J. BAUMAKtf
They are usually prepared by extraction with water or alcohol, and
are mostly colorless, levorotatory, crystalline substances, with a bitter
taste.
Most glucosides may be hydrolyzed by enzymes contained in the same
tissue, but in other cells of the same plant from which the glucoside is
obtained. These enzymes have the generic name of glucosidases. The
best known glucosidase is emulsin of almonds. It hydrolyzes only ^-glu-
cosides, i. e., derivatives of ^-glucose. Maltase hydrolyzes o-glucosides.
These specific reactions have proven very useful in the elucidation of the
structure of many glucosides and polysaccharides. Myrosin, obtained
from black mustard seeds, is another enzyme of wide application. It
acts upon many glucosides, all of which contain sulphur, such as glucotro-
paolin, sinalbin and sinigrin.
While d-glucose is found as a constituent of glucosides more often
than all other sugars, many other sugars may be found in glucoside com-
bination. Galactose is a constituent of a number of plant glucosides (solan-
in, digitonin, etc. ) and of a group 'of substances found in nerve tissue,
called galactosides or cerebrosides. d:Ribose also forms important gluco-
sides, among which are the four nucleotides, which make up plant nucleic
acids. Glucosides of d-arabinose and 1-arabinose, 1-xylose and a number
of methyl pentoses are also known.
TABLE V
SOME OF THE NATURAL GLUCOSIDES *
Glucoside
M.P.
Products of Hydrolysis
Arbutin
CijHjgOj
187°
Phenols
Glucose + hvdroquinone
Phlorhizin
170°
Glucose + phloretin
Amvgdalin
CjoHjAjN
200°
A Idehydes
2 Glucose + d-mandelonitrile
Jalapin
C t4H6aOw
131°
Acids
Glucose + jalapinolic acid
Strophantin
Rhamnose -f- mannose + strophantidin
Glucotropaolin . . .
Sinalbin
C14H18O8NS2K
C^H.AvNA
138°
Mustard Oils
Glucose + benzyl isothiocyanate + KHSO,
Glucose + sinapin acid sulphate + acrinyl-
Sinigrin
CuHjoC^NSjK
1266
isothiocyanate
Glucose -f- allyl isothiocyanate + KHSO«
Digitalin
217°
Various
Glucose + digitalose + digitaligenin
Dioitonin
C^H^OK
225°
Glucose + galactose + digitogenin
Digitoxin
145°
2 Digitoxose -+- digitoxigenin
Indican
c,4H]7o0N
100°
Glucose + indoxyl
Saponarin
Glucose + saponaretin
Saponins
Glucose + galactose + sapogenins
Vernin
C10H1305N5
d-Ribose + guanine
* Arranged after R. F. Armstrong, The Simple Carbohydrates and Glucosides,
Longmans, Green & Co., N. Y., 1912.
THE CARBOHYDRATES AND THEIK METABOLISM 237
Special Properties of Monosaccharides. — The general properties and
reactions of the monosaccharides have just been presented and it remains
to point out properties of the individual carbohydrates that are of special
interest biologically.
Hexoses. — Only two hexoses are found naturally as such, d-glucose and
d-fructose; d-glucose, the most common monosaccharide occurring in na-
ture, is found in most plant and animal tissues. Commercially it is ob-
tained by hydrolyzing starch with dilute acid. This glucose is a mixture of
a- and ^-glucose and is called y-glucose. It is readily purified by one
crystallization from glacial acetic acid and washing with alcohol. From
aqueous solution it crystallizes with one molecule of water. This form
melts at 86° C. The anhydrous form, obtained by crystallization from
aqueous solution at high temperature, melts at 146° C. One hundred
parts of water dissolve 81.7 parts of anhydrous glucose at 15° C., while in
alcohol it is. rather insoluble. It is insoluble in ether and almost insoluble
in acetone. Its aqueous solutions are neutral and are not. electrolytes.
When heated to 170° it darkens and gives off much water, leaving
in the residue a deliquescent substance, glucosan, which can be converted
to glucose by boiling with water or acids. It is not sweet nor does it
undergo fermentation. It is dextrorotatory.
Methyl Glucosides. — a-Methyl glucoside was first obtained by E.
Fischer, by dissolving glucose in acetone-free anhydrous methyl alcohol,
containing 0.25 per cent hydrogen chlorid, heating it under pressure, dis-
tilling off the alcohol and obtaining the crystals from the residual solution.
Both the a- and (3-methyl glucosides are found in this reaction, the equilib-
rated mixture containing 77 per cent of the o-form.
a-Methyl glucoside forms rhombic crystals melting at 165° C., easily
soluble in water, difficultly soluble in cold alcohol, practically insoluble in
ether. Its specific rotation is -f- 157° and does not show mutarotation.
It does not reduce, does not form hydrazones, nor exhibit any aldehydic
properties and is therefore believed to exist in the y-lactone form only.
GEL — O — CH
HC — 0 — OIL
CH2OH
a-Methyl Glucoside
(3-Methyl Glucoside
238 A. I. RINGER AND EMIL J. BAUMANN
If the mother liquid from the methyl glucoside be concentrated to a
syrup and allowed to stand for several weeks, (3-methyl glucoside will crys-
tallize out. It can be more readily obtained from this mother liquid by
treating it with yeast, which hydrolyzes the a, but not the (3-form, to
glucose, and this in turn is converted to ethyl alcohol and carbon dioxid.
P-methyl glucoside crystallizes with one half molecule of water of crystal-
lization, and melts at 108° C. Its specific rotation is — 32°.
By boiling with acids both methyl glucosides are converted into glucose
and methyl alcohol. <x-Methyl glucoside is also hydrolyzed by maltase, an
enzyme of yeast, but P-methyl glucoside is not. Emulsin, an enzyme found
in bitter almonds, decomposes the (3-methyl glucoside, but not the a-form.
This is a splendid illustration of the specificity of biochemical reactions.
Mannose. — d-Mannose occurs free in some plants, but usually it is
found as an anhydride condensation product called Mannan.6 It is
most readily prepared from the vegetable ivory nut by hydrolysis with
dilute hydrochloric acid, neutralizing the acid and converting the man-
nose to the very insoluble, characteristic mannose hydrazone, from which
mannose is obtained in the usual way. A not uncommon form in which
mannose also occurs in nature is as the alcohol mannitol. Mannose can
be obtained from mannitol by oxidation. This was the. method by which
it was first prepared (Fischer and Hirschberger) and only later was it
identified with the natural product. On the other hand, d-mannitol may
be prepared by reduction of d-mannose with sodium amalgam.
In general behavior, mannose is quite similar to d-glucose. It forms
the same phenyl osazone, exhibits mutarotation and has similar solubilities.
It forms rhombic crystals, melting at 132° C.
Galactose. — d-Galactose is rarely found free in nature. When found,
it is often the result of special conditions. For example, Lippmann dis-
covered galactose as a crystalline efflorescense in ivy berries after a sharp
frost — the first of the autumn. Usually galactose occurs combined with
sugars and with other substances as galactosides. It is most commonly
found combined with glucose, as lactose in milk, and with sucrose in the
trisaccharide raffinose, in beets.
Ci2H22Ou + H2O > C0H12O6 -f- C6H12O6
lactose d-glucose d-galactose
018H8201B + 2H20 > CeH1200 + C6H1206 + C6H12O6
Raifinose d-Fructose d-Galactose d-Glucose
It is interesting to observe that the amount of raffinose found in the beet
is increased when the plant is subjected to a sudden frost.
From algse, lichens and mosses, mucilages can be obtained that yield
6 Polymers of, the sugars are given the name of the sugar with the ending — an.
Thus common starch is a glucosan.
THE CARBOHYDRATES AND THEIR METABOLISM 239
galactose on hydrolysis. Galactose is present here m a polymeric form
called galactans. Galactans are also found in certain gums and pectins.
The pectins are found in apples, pears, beets, carrots, flax, etc., and these^
on mild hydrolysis, are converted to pectic acids, the calcium salts of which
cause fruit juices to jell. On hydrolysis with acids they yield d-galactose
and 1-arabinose.
It is usually prepared from lactose by heating with two per cent
sulphuric acid, precipitating the sulphuric acid with barium carbonate
and concentrating the nitrate to a syrup from which d-galactose slowly
crystallizes in large prisms with one molecule of water of crystallization.
The hydrated form melts at 118-120° C. From alcoholic solution it
crystallizes in leaflets which melt at about 165° C. It is sweet, easily
soluble in water, but practically insoluble in absolute alcohol and in ether.
It behaves somewhat like d-glucose ; it exhibits mutarotation, both a- and
P-forms having been prepared and when treated with sodium amalgam,
it is reduced to the alcohol dulcitol, which occurs naturally in Madagascar
manna.
On oxidation with nitric acid mucic acid is formed. Mucic acid is
a very characteristic oxidation product of galactose (and lactose), with a
melting point "of 212-215° C., 'quite insoluble in water (about 0.3 per
cent at 15° C.), and therefore is used frequently as a means of identify-
ing galactose. It is optically inactive.
Fructose. — d-Fructose (levulose) was discovered by Dubrunfaut in
1847 in the hydrolysis products of cane sugar. It occurs in the juices of
many plants and fruits with glucose, especially in tomatoes, certain man-
na and mangoes. In young sugar cane it occurs in equal amount with
glucose and sucrose. As the cane grows older, the proportion of fructose
to the two other sugars decreases to about 15 per cent and in the mature
plant to about 1.5 per cent of the total amount of the three sugars present.
In honey, glucose and fructose are found in nearly equal proportions, to-
gether with a little sucrose and dextrine.
d-Fructose also occurs combined with other sugars, as in sucrose (glu-
cose and fructose) ; raffinose (glucose, galactose and fructose) ; etc. It
is a constituent of certain glucosides and saponins. The polysaccharide
inulin, which is obtained in quantity from the tubers of the dahlia, sun-
flower and other members of the same family, is a fructosan, and hence
yields only fructose on hydrolysis. This is, in fact, the simplest way to
obtain fructose, as from 7 to 17 per cent of inulin is found in the roots
of the dahlia. It is purified by recrystallization from water at 60-70° G.
Fructose forms anhydrous rhombic crystals, tastes almost as sweet as
cane sugar and melts between 95 to 105° C. It is very soluble in water
and hot alcohol, but only slightly soluble in cold alcohol. Its aqueous solu-
tions exhibit the property of mutarotation and exist in solution, presum-
ably as an equilibrated mixture of stereoisomeric forms, but the two forms
240 A. I. RIXGER AND EMIL J. BAUMANX
have not yet been separated, as have the two forms of glucose and other
sugars.
Fructose is reduced by sodium amalgam to two alcohols, d-mannitol
and d-sorbitol being formed in equal quantities.
CH2OH CH2OH CH2OH
HCOH CO HOCH
HOCH HOCH HOCH
HCOH HCOH HCOH
HCOH HCOH HCOH
CH2OH CH2OH CH2OH
d-Sorbitol d-Fructose d-Mannitol
By oxidation with mercuric oxid,, for example, fructose is converted
to acids having less than six carbon atoms,, such as carbonic, formic, glycol-
lic, oxalic, tartarie and d-erythronic acids. When boiled with dilute mineral
acids, it forms levulinic acid (CH3 — CO — CH2 — CH2 — COOH),
formic acid and other substances. Levulinic acid is a characteristic degra-
dation product of hexoses and hexosans, and is used as a means of differ-
entiating between hexoses and pentoses.
Levulinic acid is a colorless oil that boils at 146° C. at 18 mm. pres-
sure. It crystallizes in rhombic leaflets when placed over sulphuric acid in
a cool place. The crystals are deliquescent, easily soluble in water, al-
cohol and ether, and melt at 33° C.
Pentoses. — Eight aldopentoses are theoretically possible, and of these
seven are known. Pentoses exhibit mutarotation, and therefore, like the
hexoses, indicating that they exist in ah a and P and Y lactone fcrm. Two
of them, arabinose and xylose, are widely distributed in the vegetable
world as polysaccharides, called pentosans. They are very resistant to
the action of alkali and are hydrolyzed by dilute acids to form the simple
sugars :
(C5H804)n + (H20)n » (C5H1005)n
Pentosan Pentose
Pentoses are distinguished from hexoses by their behavior when boiled
for a long time with hydrochloric acid. Hexoses are converted to levulinic
acid by this treatment, while pentoses form furfuraldehyde. Pentoses may
be estimated by the use of this reaction. The furfuraldehyde is distilled
off and then coupled with phloroglucinol and the condensation product
is weighed.
THE CARBOHYDRATES AND THEIR METABOLISM 241
COH
HOCH
HOCH
HOCH
CH2OH
1-Ribose
CQH
HCOH
HOCH
! •-•./
HOCH
CH2OH
1-Arabinose
TABLE VI — ALDOPENTOSES
COH
COH
HCOH
HCOH
HCOH
CH2OH
d-Ribose
COH
HOCH
HCOH
HCOH
CH2OH
d-Arabinose
HCOH
HOCH
HCOH
CH2OH
1-Xylose
COH
HCOH
HCOH
HOCH
CH2OH
1-Lyxose
COH
HOCH
HCOH
HOCH
CH2OH
d-Xylose
COH
HOCH
HOCH
HCOH
I 4
CH2OH
d-Lyxose
The same reaction is used for the qualitative detection of pentoses.
Color reactions are obtained by heating pentose with hydrochloric acid
in the presence of phloroglucinol or orcinol.
Xylose. — 1-Xylose (wood sugar) is. formed from the xylans called
wood gums, found in vegetable cell walls, and next to cellulose the most
important carbohydrate found in plants. It forms monoclinic prisms
or needles; has a sweet taste, is readily soluble in water and hot alcohol,
but not in ether. It melts at 185° according to some, as high as 154°,
according to others. Its specific rotation is -f 85.7°. The equilibrated
mixture has a specific rotation of + 18.5°.
It gives the usual aldose reactions. It is best identified by oxidizing
to 1-xylonic acid and converting the latter to the characteristic double
cadmium bromid salt.
(C5H9Oc)2.Cd.CdBr2.2H2O
l-Arabinose. — This pentose was first isolated by Scheibler (1873). The
gums of cherry, plum, gum arabic, etc., are composed chiefly of arabans,
and from them 1-arabinose is obtained on hydrolysis with acids.
It crystallizes in needles, melting at 160° C. It is readily soluble in
water, difficultly soluble in 05 per cent alcohol and almost insoluble in
242 A. I. RINGER AND EMIL J. BAUMANN
absolute alcohol. It exhibits strong mutarotation in aqueous solution.
The specific rotations for a-1-arabinose, (3-1-arabinqse and the equilibrated
mixture are -f 76°, +184° and -f 104° respectively.
The most characteristic compounds of arabinose are parabromophenyl
hydrazone, diphenyl hydrazone and phenyl-osazone. The diphenyl hydra-
zone, melting at 218° C., is a colorless crystalline substance and is usually
used for identifying arabinose.
d-Ribose. — Unlike the other two pentoses which have been considered,
d-ribose does not appear as a pentosan, but is an important constituent
of plant nucleic acid, as proven by Leveue and Jacobs (1912). It seems
probable that the known plant nucleic acids are quite similar, and it has
been established that there are four molecules of d-ribose in those plant
nucleic acids that are known.
Methyl Pentoses. — Several of these have recently been isolated from
plants. They differ from pentoses in having a methyl radical replace one
of the hydrogens of the primary alcohol, — CH2OH, forming the group
CHOH.CH3, as in
COH
HCOH
HCOH
HOCH
I
HOCH
CH3
Rhamnose. — 1-Rhamnose is a constituent of many glucosides and is
perhaps the most common of the methyl pentoses. It crystallizes with one
molecule of water and exists in a and (3 forms.
Digitoxose is probably a reduced methyl pentose obtained from digi-
talis :
CH3 . CHOH . CHOH . CHOH . CH2 . COH
The methyl pentoses behave like the pentoses on the whole, but yield
methylfurfuraldehyde on distillation with acids.
Dioses, Trioses, Tetroses, etc. — The simplest sugar is the diose, glycol-
ic-aldehyde, COH but it has not been found in nature. It is of inter-
CH2OH
est, however, as a possible product of the intermediary metabolism of carbo-
hydrates. There are three trioses of interest, two aldoses, d-and 1-glyceroses
or glycericaldehydes, and one ketose, dihydroxyacetone.
THE CARBOHYDRATES AND THEIR METABOLISM 243
COH
HCOH
I
CH2OH
d-Glycericaldehyde
or
d-Glycerose
COH
HOCH
CH2OH
1-Glycericaldehyde
or
1-Glvcerose
CH2OH
CO
I
CH2OH
Dihydroxy acetone
All of these substances are intermediary products in the metabolism of
carbohydrates, and are of interest on that account.
There are four possible aldotetroses of which three are known, but they
have not been found to occur in nature in the free states.
COH
HOCH
HOCH
CH2OH
1-Erythrose
COH
HCOH
HCOH
CH2OH
d-Erythrose
COH
HCOH
HOCH
CH2OH
1-Threose
COH
HOCH
HCOH
I
CH2OH
d-Threose
The alcohol of erythrose, erythritol, has been obtained from various alga?
and mosses.
Disaccharides
These sugars contain twelve carbon atoms and are made up of two
hexoses united by an oxygen atom. When acted upon by hydrolytic agents,
they take up one molecule of water and are converted into the hexoses of
which they are composed.
The hexoses in these carbohydrates are bound together in much the
same way as they are in the glucosides; hence the aldehyde or ketone
radical of one of the hexoses is the point of union, while the ketone or
aldehyde radical of the other hexose may or may not remain free.
Those disaccharides that have a potentially free aldehyde or ketonic
group give the typical reactions of the hexoses, such as reduction of alkaline
copper and other metallic hydroxides and combination with hydrocyanic
acid. They exhibit mutarotation and exist in two forms which are in
equilibrium in aqueous solution. The union of the two hexoses is similar
to that found in the case of the glucosides. In fact, many of them are
hydrolyzed by certain glucosidases.
When an aldehyde or ketone group is free, as in maltose, phenyl osa-
zones, that are only slightly soluble but difficult to purify, are obtained.
The hydrazones are almost all easily soluble in water. The disaccharides
244
A. I. RINGER AND EMIL J. BATJMANN
CH2OH
Glucose Radical
CHjGE
Fructose Radical
Sucrose or Cane Sugar
(Neither aldehyde nor ketone functional)
CH2OH
Glucose Radical
CH2
Glucose Radical
Maltose
(One aldehyde radical free and functional)
CH2OH
Galactose Radical
CH2
Glucose Radical
Lactose
(One aldehyde radical free and functional)
THE CAKBOHYDRATES AND THEIR METABOLISM 245
that have no free aldehyde or ketone do not form osazones. Other than
the phenyl osazones, the disaccharides form no compounds that are char-
acteristic.
In the determination of the configuration of the disaccharides, the
chief points to be elucidated were (1) the nature of the component hexoses,
(2) whether the disaccharide was an a- or P-glucoside, (3) the place of
union of the two monosaccharides.
The nature of the component hexoses was determined by hydrolyzing
the disaccharide with acid and identifying the hexoses. The nature of the
glueosidic union was established by the behavior of the disaccharide toward
maltose and emulsin. If the disaccharide is hydrolyzed by maltase, it is an
cc-glucoside; if by emulsin, it is a P-glucoside. This point has also been de-
termined by studying the optical behavior of the hexoses as soon as formed
by the action of an enzyme, toward a drop of alkali. If the rotation is
increased, it indicates the presence of a p-glucose ; if the mutarotation is
in the other direction, an a-glucose has been formed.
Points of special interest of the individual disaccharides will now
be presented.
Sucrose. — Sucrose, known also as saccharose or cane sugar, is indus-
trially the most important of the disaccharides. It is very widely dis-
tributed in the plant world, where it serves chiefly as a reserve material.
It crystallizes readily, is very soluble in water and very sweet. It
does not exhibit mutarotation in aqueous solution. It is dextrarotary and
has a specific rotation of + 66.5°. When heated, it melts at 160° C.,
and at 200° C. it darkens, forming caramel, in which process water is
given off.
Chemically, sucrose behaves neither as an aldehyde nor as a ketone;
it does not form hydrazones or osazones, nor does it reduce Fehl ing's
solution. Sucrose is readily hydrolyzed by boiling with acids, one mole-
cule of glucose and one of fructose being formed. The same hydrolysis
may be brought about by an enzyme, invertase or sucrase, present in yeasts
and other fungi, as well as in many other plants and in the digestive tracts
of many animals.
The products of hydrolysis of sucrose have a resultant levorotation,
since fructose is more levorotatory than glucose is dextrorotatory. This
process is therefore called inversion and the product invert sugar. Because
sucrose exhibits neither aldehyde nor ketone properties, it is believed that
the glucose and fructose molecules, that compose the sucrose molecule, are
united in such a way that both aldehyde and ketone groups are destroyed.
The formula usually ascribed to sucrose is Fischer's modification of the
Tollens formula, in which it is both a glucoside and a fructoside.
Lactose. — Lactose or milk sugar was first obtained about 1615 by
Fabricio Bartoletti. It is always found in the mammary secretion, but
has not been found in the vegetable kingdom. It is often found in the
246 A. I. RIXGER AND EMIL J. BATJMAXX
urine of pregnant and lactating women. Human milk contains 5 to 7
per cent lactose, occasionally more, while the milk of other animals con-
tains somewhat less.
Lactose is readily prepared from milk by coagulation of the casein
with the enzyme rennet, and the clear liquid or whey which separates from
the precipitated protein is concentrated under diminished pressure to a
syrup, from which crude lactose-crystallizes. It is purified by recrystalliza-
tion from water.
Erdmann (1855) obtained lactose in two crystalline forms, one of
which had a specific rotation of 4- 90° and the other of -j- 35°, each show-
ing a motarotation and the specific rotation of the equilibrated solution
being -(- 55.3°. This was the first of the disaccharides in which the ex-
istence of more than one form was demonstrated.
Sodium amalgam reduces lactose, forming mannitol, dulcitol, lactic
acid, hexyl-alcohol and other products. Lactose is a glucose-galactoside
and not a galactose-glucoside, as shown. by its behavior on gentle oxidation,
so that only the free aldehyde group will be oxidized. Under such con-
ditions lactobionic acid is formed, which on hydrolysis yields galactose and
gluconic acid, showing that the free aldehyde group is that of glucose,
while, if the free aldehyde group were that, of galactose, galactonic acid and
glucose would result from the hydrolysis of the oxidation product.
Lactose is much more difficultly hydrolyzed by acids than sucrose. It
is also hydrolyzed by the enzyme lactase, found in the intestinal mucose of
animals, as well as by aqueous extracts of kefir and some yeasts and al-
monds (crude emulsin). It is not hydrolyzed by maltase, invertase or
any enzymes in brewers' yeast. This serves as a simple means of distin-
guishing between lactose and glucose, a problem often met with by the path-
ological chemist, since glucose is readily fermented by yeast. Lactose also
forms a fairly characteristic osazone, which may be readily distinguished
from glucosazone. A good way to prepare the osazones from biological
material is to precipitate most of the interfering substances by adding
mercuric nitrate in dilute nitric acid solution and then solid sodium car-
bonate. Then filter, cover the filtrate and prepare the osazone in the usual
way with phenylhydrazine hydrochlorid and sodium nitrate.
Maltose. — Maltose or malt sugar is formed by the action of diastase
upon starch. The sugar was first isolated by De Saussure in 1819, but its
identity was determined by Debnmfaut in 1847 and he gave it the name
maltose. It occurs in plants and animal tissues to some extent, and re-
sults from the action of diastase of the pancreatic secretion, or ptyalin of
saliva on starch or glycogen.
Maltose crystallizes in small needles with one molecule of water of
crystallization. It is easily soluble in water and in alcohol its solubility
is 5 per cent. Its solutions show mutarotation. Its specific rotation in-
itially is + 119° and that of the equilibrated mixture is + 137°.
THE CARBOHYDRATES AND THEIR METABOLISM 247
Maltose reduces Fehling's solution and forms a phenyl osazona It
is hydrolyzed by acids forming two molecules of glucose, but is more
resistant to hydrolysis than sucrose. Maltose is also hydrolyzed by mal-
tase in the same way, but is not hydrolyzed by emulsin. Because of this
behavior, maltose is assumed to be a glucose-a-glucoside.
Polysaccharides
Those considered under this heading form colloidal solutions or are
insoluble in water. The more important ones are starch, glycogen, cellu-
lose, dextrins, inulin and gums. They are usually named from the sugar
they yield on hydrolysis, with the suffix "an." Thus starch is a glucosan;
inulin is a levulan.
Starch is one of the polysaccharides found in plants in the form of
a granule with a characteristic structure, so that it is possible to identify
the plant from which the starch came by microscopic examination. It
forms the reserve food of the plant cell. It is insoluble in the ordinary
solvents, but if poured into boiling water the granule is disrupted and a
colloidal solution results.
Upon hydrolysis with acids or enzymes, a series of simple polysaccha-
rides are formed, namely, soluble starch, erythrodextrin, achroodextrin,
and finally, maltose and glucose. It has been quite difficult to obtain any
knowledge of the number of hexose groups in starch and the dextrins.
Inulin is a levulan, found in the tubers of the dahlia and Jerusalem
artichokes. It forms the best source of obtaining d-levulose. It is not
unlike starch in its chemical behavior.
Cellulose is the main constituent of the wall of plant cells. It has a
more complex structure than starch. It is insoluble in all the usual sol-
vents, but will dissolve in ammoniacal copper salt solutions. On hydrolysis
with acids it yields glucose and other monosaccharides. Nitric acid with
cellulose forms nitrocellulose or gun cotton. Concentrated sulphuric acid
dissolves cellulose. Upgn diluting with water, it is again precipitated, but
in a different form. The resulting compound gives a blue color witli
iodin and is called amyloid.
A number of cellulose-like substances, called herni-celluloses, are
found in seeds and young plant tissues. They probably act both as sup-
porting structures and as a source of reserve food. Upon acid hydrolysis
they yield galactose, arabinose, mannose, rhamnose and occasionally fruc-
tose.
Gums are usually pentosans. They are white substances which dis-
solve in water, giving a thick, viscid, mucillaginous solution. Examples
are gum acacia (or arable) and gum tragacanth. l>>n hydrolysis they
yield pentoses or their derivatives, such as arabjnosc and rhamnose. Oc-
casionally hexoses also result from hydrolysis of some gums, such as man-
248 A. I. RINGEE AND EMIT, J. BAUMAKN"
nose and glucose. Phosphoric acid is usually associated with the gums,
as with many other polysaccharides, and it is most difficult if not impos-
sible to separate them. This suggests that sugar phophate may be pres-
ent in the polysaccharide molecule. Phosphoric acid sugar compounds
play a great role in biochemical phenomena.
Digestion of Carbohydrates
The carbohydrates that play a role in human metabolism are the poly-
saccharides, starches, glycogen and cellulose, and the clisaccharides, suc-
rose, lactose and maltose. During the process of digestion, the higher
carbohydrates are converted into monosaccharides, by processes of hydro-
lysis.
Salivary Digestion. — The first enzyme that acts upon carbohydrates
is encountered in the salivary secretion and is known under the names of
amylolytic ferment, diastase and ptyalin. It is a ferment that is suscep-
tible to changes in temperature. At 0° C. its activity is entirely suspended,
whereas at body temperature it shows its optimum activity. If the tem-
perature is raised above that, its activity diminishes until it reaches 65° to
70° C., when it is completely destroyed.
It is also highly sensitive to the hydrogen ion concentration, showing
1ST
greatest activity in an acid concentration of . An acid solution of
N
— — - inhibits the action of the diastase completely, as will also a strongly
alkaline reaction.
Salts, especially phosphates, seem necessary for ptyalin digestion for,
when saliva is dialyzed, it loses much of its amylolytic powers. These
may be restored by the addition of a little phosphate. It is quite pos-
sible that a carbohydrate-phosphate intermediary product of digestion is
formed similar to the hexose-phosphate that Harden and Young found
to be essential in fermentation. Salts of the heavy metals — such as
uranium, silver and mercury — will severely inhibit the action of ptyalin.
During the process of mastication the food is brought into intimate
contact with the saliva, but does not have sufficient time to bring about
considerable digestion. The greatest activity of ptyalin takes place in
the fundus of the stomach, before the acidity of the stomach reaches the
level of concentration at which it inhibits the action of ptyalin.
Action of Ptyalin. — The ptyalin does not affect cellulose. It acts on
boiled starch much more readily than on native starch. It acts by bringing
about a process of hydrolysis whereby the large starch molecule, which
belongs to the suspension colloidal group, is broken up into smaller and
smaller molecules, passing through various stages of "colloidality," be-
coming a soluble starch, then going through various stages of dextrins,
until it finally reaches the stage of the perfectly soluble disaccharide,
maltose.
It is impossible at present to sharply separate the different inter-
mediary products in starch digestion. The different stages, however, can
be recognized by means of the iodin reaction. The native starches give
a blue coloration with iodin, and as digestion progresses dextrins are
formed which give at first a violet red, then brown red, and finally no
color reaction at all with iodin. These dextrins are known respectively as-
erythrodextrins and achroodextrins.
In the salivary secretion we find another enzyme which acts on maltose
and is known as maltase. It acts on the maltose molecule, making it un-
dergo hydrolysis, and converting1 it into two molecules of glucose.
Gastric Digestion of Carbohydrates. — In the gastric secretion there
are no enzymes which attack carbohydrates. As long as the acidity of the
gastric contents is low the ptyalin and maltase, which are swallowed with
the saliva, may continue their activity. When the gastric acidity in-
creases in concentration it may help in hydrolyzing the disaccharides, but
this takes place o'nly to an insignificant extent.
Intestinal Digestion of Carbohydrates. — In the pancreatic secretions
we find an amylolytic enzyme which has all the properties of ptyalin, but
which has the power of acting at a much greater velocity. The intestinal
juices also contain three enzymes: sucrase, which has the power of split-
ting sucrose into glucose and levulose ; maltase, which splits maltose into
two molecules of glucose, and lactase, which splits lactose into glucose
and galactose. All the carbohydrates, therefore, are brought down in the
intestinal canal to the stage of monosaccharides. Separate enzymes are
present there for all types of carbohydrates that the human individual
ingests, except cellulose, which is left entirely untouched, and is eliminated
as such.
Absorption of Carbohydrates
The products of carbohydrate digestion are very soluble and easily dif-
fusible. The amount that is absorbed by the stomach is very small and
of no practical consequence. Practically all of the digested carbohydrates
are absorbed in the small intestines and very little is left in the material
that reaches the ileocecal valve.
All the absorbed carbohydrates are carried away by the blood stream
into the portal vein, thence to the liver. It is remarkable that in spite
of the easy solubility of sucrose and lactose, none of it is absorbed under
ordinary circumstances. The intestinal wall is almost impermeable to
them, whereas maltose may be absorbed to a slight extent. The body
cells have the power of utilizing maltose, probably because of the pres-
ence of a maltase in the blood stream, but cannot utilize sucrose or lactose ;
250 A. I. RINGER AND EMIL J. BAUMAOT
and if these enter the blood stream pareiiterally, they are quantitatively
excreted in the urine.
The carbohydrates that are absorbable, therefore, are the three mono-
saccharides — glucose, levulose, galactose — and the one disaccharide — mal-
tose.
The Sugar of the Blood. — That glucose is the most important sugar
of the blood we know definitely. Whether levulose and galactose exist
in the blood as such is at present not known. From the ease with which
these two sugars are converted into glucose when fed to a diabetic indi-
vidual, we have every reason to believe that they are converted into glucose
either1 in the process of absorption or soon thereafter.
Glucose exists in the blood in a state of free solution and not in any
chemical union. (Michaelis and Rona (1908).)
When one examines the blood of an individual for its glucose concen-
tration at frequent intervals of time, one finds that under normal conditions
it fluctuates within surprisingly narrow limits. In the morning before
breakfast, it usually is at its lowest -level, between 0.07 to 0.10 per cent.
Between one and one and a half hours after a meal rich in carbohydrates,
it rises to a level of 0.10 to 0.15 per cent. After that it gradually comes
down, to reach the fasting level about two to three hours after the meal.
This cycle of events repeats itself with each meal.
If a normal individual is allowed to fast for some time, the blood
sugar remains about 0.07 per cent and very seldom sinks below that fig-
ure. In such cases there is hardly any fluctuation in the blood sugar con-
centration from hour to hour.
There are a number of forces which are operative in keeping the blood
sugar concentration at such a constant level, and these are: I. Those
that prevent it from rising above normal levels; II. Those that prevent
it from falling below normal levels.
The factors that prevent the blood sugar from rising above normal levels
are: 1. Polymerization of glucose into glycogen by the cells of the liver
and muscles; 2. Utilization of glucose (oxidation) by the cells of the body
for dynamogenetic purposes ; 3. Conversion of glucose into fat.
The factors that prevent the blood sugar concentration from falling
below normal levels are : 1. Mobilization of glycogen from its storehouses
— liver and muscle — and its hydrolysis, which results in glucose formation ;
2. Increase in protein metabolism with the result that a large number of
ammo acids are converted into glucose.
The moment sugar enters the intestinal canal its absorption begins.
This causes an increase in the glucose concentration of the blood in the por-
tal vein. Synchronous with the increase in the portal concentration, there
takes place a withdrawal of glucose from the blood by the liver cells and
their polymerization of the glucose into glycogen. On the other hand, when
absorption of carbohydrates from the intestinal canal has stopped, the
THE CARBOHYDRATES AND THEIR METABOLISM 251
venous blood becomes poorer in glucose. The process then reverses. The
glycogen in the liver cells becomes hydrolyzed and a stream of glucose starts
into the blood. Apparently there must exist a very delicately adjusted
physicochemical relationship between the glucose concentration of the
portal blood, the glycogen content of the liver, and the glucose concentra-
tion of the hepatic vessels.
The capacity of the liver to store glycogen is enormous. Schoendorf
(1903 (&)) showed that the liver of dogs may contain as much as 18.7 per
cent of glycogen, and Otto (1891) showed that rabbit's liver may contain
as much as 16.8 per cent of glycogen after ingestion of large amounts of
carbohydrates. The liver of a man weighing about 70 kilos weighs ap-
proximately 2000 grams. On the basis of the above figures, we can readily
see that it can hold as much as 300 grams of glycogen, which is considerably
more carbohydrate than the average man consumes in any one meal.
The liver, therefore, through its glycogenetic function acts as a won-
derful regulator of the sugar in the blood. It prevents any marked fluctua-
tions in the concentration, and above all, any sudden increases in the sugar
content, which would be followed by loss of sugar through glucosuria.
The utilization of glucose by the muscle cells occurs as soon as its
absorption from the intestinal canal begins (Lusk, 1912-1915). Ap-
parently the body cells burn glucose with greater ease than any other food-
stuff, for, when glucose is present in abundance, the combustion of fat is
stopped almost completely, and that of protein is reduced to an absolute
minimum. Glucose in the body burns to CO2 and H2O, according to the
following reaction:
C6H12OG -f 6 O2 — » 6 CO2 -f 6 H2O
From this we see that when glucose is oxidized a certain volume of oxy-
gen is required, and for every volume of oxygen used, a corresponding vol-
ume of carbon dioxid is given off. The ratio between the volumes of
CO
CO2 and O2 is known as the Respiratory Quotient. The value of -p—
^2
in this case equals 1. In the combustion of no other foodstuff does the
CO.>
Respiratory Quotient equal 1. When fat burns the -^p quotient is 0.707,
and when protein burns, the quotient is 0.801.
In Lusk's experiments on dogs, forty-five minutes after glucose in-
gestion, the respiratory quotient was 0.99, showing that glucose burnt
almost exclusively.
If the absorption of glucose from the intestinal canal still continues,
we have a third factor brought into play, namely its conversion into fat.
In normal individuals, during the process of glucose absorption from
the intestinal canal, we have a series of three outlets which are operating
to prevent its accumulation in the blood. Schematically we may repre-
252
A. I. KINGER AND EMIL J. BAUMANN
sent the arrangement by an inclined tube that has a series of outlets at
different levels, with openings at the bottom through which sugar may be
pumped in. The level of sugar in this inclined tube will depend upon
the speed with which it is pumped in and with which it pours out at the
various outlets. If the inflow is so rapid that the first outlet cannot take
care of it all, it will mount until it reaches the second. If that is not
sufficient, it will reach the third, and if that is not sufficient, it will mount
still higher.
Glucose
r*
Intestine
Glycogen
•reservoir
Bypergl
iucaemia
Torm&Uon *f Glyeog
from Blood Sugar
Glucoauri
Fat Formation
Blood
Level .
i
Glucose Oxidation
©and -@ under Control at Pancreatk Hormone.
®o»»ier Control of Sym-palKeiic Nervous System. AnlAirenaLn
©Regulated by Renal Threshold.
Fig. 2. Schematic illustration of the factors which regulate the sugar concentra-
tion of the blood.
The level of sugar in this tube at any given time will depend upon the
relationship between the velocity and volume of the sugar inflow at the
bottom, and the volume and velocity of its outflow through the three
normal channels.
In the body, the glucose concentration of the blood at any given time
also depends upon the speed and amount of its absorption from the in-
testinal canal, and upon the speed of its removal by utilization, glycogen
and fat formations. Normally it seldom goes above 0.12 or 0.13 per
cent, because the glycogen formation proceeds at such a rapid pace that
it does not permit its accumulation in the blood. When we ingest carbo-
hydrates in the form of starch, we can take absolutely unlimited quantities.
Because the digestion of it is rather slow, the absorption follows suit, and
THE CARBOHYDRATES AND THEIR METABOLISM 253
at no time do we find an accumulation above those levels. If, however
we ingest a large amount of carbohydrates in the form of glucose which
requires no digestion at all, and which is absorbed with great rapidity,
we find that glucose enters the blood stream at such a rapid pace that
the three outlets — utilization, glycogen formation, fat formation — are not
sufficient to remove it all. Its concentration in the blood stream rises
and we develop what is known as a condition of hyperglucemia.
Another process may be brought into play at this stage, namely that
of glucosuria,.
It is a well-known fact that the kidneys exercise a selective action on the
substances that circulate through it in the blood stream. At the present
state of our physicochemical knowledge it is difficult to say what the
mechanism of kidney secretion is. But we do know that for a number
of crystalloids the rate and amount of their excretion bears a definite re-
lationship to their concentration in the blood. (Amhard and Weil, 1914;
McClean, F. C., 1915.)
The behavior of glucose in the blood is like that of a pure crystalloid
(Michaelis and Rona, 1908), and one would expect the kidneys to per-
mit its free secretion in the urine. This, however, is not the case. With
the ordinary reduction tests (Fehling's solution, Benedict's solution, etc.)
we cannot detect the presence of glucose in the urine of normal indi-
viduals 7 if the blood sugar concentration fluctuates within the normal
limits. When, however, the concentration of glucose in the blood rises,
there comes a point at which the kidneys begin to excrete it in easily de-
tectible quantities.
The height of blood sugar concentration at which the kidneys begin
to secrete sugar differs with different individuals and is known as the
kidney threshold for sugar. With a very few it lies as low as 0.08 per
cent, which means that these people excrete glucose in detectible quanti-
ties all the time, and they suffer from a condition that is recognized as
renal glucosuria. Others will not excrete it even when the concentration is
as high as 0.26 per cent, as in cases of chronic nephritis. These two ex-
tremes are comparatively rare. The great majority of normal individuals,
however, excrete glucose in the urine in detectible quantities when the
glucose concentration of the blood rises above 0.15 to 0.16 per cent. There
is at present no explanation for this individual variation, except for the
statement that there must exist a difference in sensitiveness for glucose in
'Stanley R. Benedict has recently reported (1918) that the urine of a normal dog
and of two normal men can be shown to contain substances which are fermentible by
yeast and which reduce picric acid. He assumes that it is glucose. The dog weighing
18 kilos excreted in the neighborhood of 390 mgs. per 24 hours when kept on an ordi-
nary carbohydrate diet; 281 mgs. when kept on a low carbohydrate diet; 1!>4 mgs. when
fasting. His human subject, E. 0., weighing 86 kilos, excreted 996 mgs. per 2
when on an ordinary carbohydrate diet; 777 mgs. when on a low carbohydrate diet;
1479 mgs. when on a carbohydrate-rich diet. The second subject, weighing 5
excreted 640 mgs. when on an ordinary diet; 543 mgs. when on a low carbohydrate diet;
847/1156 and 1528 mgs. on each of three days of carbohydrate diet.
254 A. I. RINGER AXD EMIL J. BAUMAOT
the kidney cells of different, individuals. Because this glucosuria is caused
by too rapid absorption of glucose from the alimentary canal, it is known as
alimentary glucosuria.
Carbohydrate Tolerance. — In the preceding chapters it was shown that
the body is capable of taking care of large quantities of carbohydrates
(glucose) 1, by storing it in the cells of the liver and muscles in the form
of a colloidal state — glycogen; 2, by utilizing, i. e., oxidizing it in prefer-
ence to other foodstuffs ; 3, by converting it into fat. It was further shown
that these three factors tended to prevent the glucose from accumulating
in the blood above certain concentrations, at which it surpasses the kid-
ney threshold and forces the kidney cells to excrete the glucose in the
urine.
The appearance of glucose in the urine in detectible quantities by
means of the ordinary reagents (Benedict's or Fehling's solutions) has
always been considered a sign that the individual has overtaxed the "car-
bohydrate tolerating" mechanism, and the amount of carbohydrate that
it takes to bring about this condition has been known as the limit of his
toleranca (
We shall see. later that there are 'a number of pathological conditions
which affect the carbohydrate tolerance of individuals and that the carbo-
hydrate tolerance is therefore utilized as a means of detecting these patho-
logical conditions. It is therefore of the utmost importance to have a clear
concept of all the factors that determine and that may influence the carbo-
hydrate tolerance of perfectly normal people.
In the light of our present knowledge that glucosuria is the result of
hyperglucemia and that there exists a difference in the sensitiveness of the
kidneys of different individuals to glucose concentration in the blood, it
is advisable to eliminate this variable factor, and to determine the toler-
ance for carbohydrate on the basis of the blood sugar concentration. We
would therefore define the carbohydrate tolerance of an individual as
that amount .of carbohydrates (glucose)8 which the individual can ingest
without developing hyperglucemia, and is in reality a test for the prompt-
ness with which the individual can convert glucose into glycogen and fat
and also oxidize it.
Of course, one should not imply from the above that urinary examina-
tion for sugar is not necessary. It frequently does give valuable informa-
tion.
Soon after the introduction of reliable methods for blood sugar de-
termination (Lewis-Benedict, Bang) a whote series of studies were pub-
lished on the blood sugar curves after the ingestion of variable amounts
of glucose (Hamman and Hirschman, 1917. Hopkins, 1915. Jacobson,
1913. Bailey, 1919). The most satisfactory results are obtained after
'Glucose is used because this requires no time for digestion and thus another
possibly variable factor is eliminated.
THE CARBOHYDRATES AND THEIR METABOLISM 255
administering 100 grams of glucose dissolved in 400 c.c. of water to
which has been added the extract 1 or iy2 lemons. This is to be taken
in the morning before breakfast. The blood is examined for sugar im-
mediately before the test meal, and at intervals of half hours after the
meal, until the blood sugar comes back to normal.
With this procedure it* is found that most subjects have an initial fast-
ing blood sugar of 0.07 to 0.10 per cent; that about one hour after the
ingestion of the glucose the blood sugar reaches the highest point, which
is usually about 0.15 per cent or below; by the end of the second hour, it
is well on the way to normal again.
If the individual's blood sugar rises above the level of 0.15 at any time
after the ingestion of 100 grams of glucose, we are justified in concluding
that he has interference, with his carbohydrate tolerance. A number of
records have been published on individuals classed as normal who show a
much higher blood sugar concentration one hour after glucose ingestion.
Future observations on the same individuals will reveal whether or not
they were normal.
Carbohydrate Tolerance Standard. — It is of no practical value to know
the maximum glucose tolerance of a person. But it is of great practical
importance to know that by far the great majority of hundreds of cases
of normal individuals who have received 100 grams of glucose have been
able to tolerate it, i. e., have shown no hyperglucemia and no glucosuria
when tested with the ordinary reagents.
The setting of any physiological standard is difficult. We have, for
example, standard tables of weights. Are they in reality tables of what
we do weigh or of what we should weigh ? How many perfectly normal
human individuals actually bear the exact height to weight ratio? Still
we have accepted them as definite standards, realizing, of course, that
we may have plus or minus variations from the theoretical without being
classed as abnormal.
The study of the carbohydrate tolerance of human individuals is of
comparatively recent development. And it will advance our science ma-
terially if those workers who reported hyperglucemias in what appeared
to be normal individuals will repeat their tests on the same individuals
at intervals of several years to see whether tRose people do not ultimately
develop glucosuria and diabetes.
For persons weighing 60 kilos or more 100 grams of glucose should
be given. For those weighing less, the amount should be reduced pro-
portionately. But under no circumstances should more than 100 grams
be given to people weighing more than 60 kilos, because the increase in
weight is not so much due to muscle and liver (the glycogenetic organs)
as to fat and skeleton which play no role in carbohydrate tolerance.
Glycogenesis and Carbohydrate Tolerance.— While we have three out-
lets for the stabilization of the blood sugar concentrations, the most im-
256
A. I. KINGEK AND EMIL J. BAUMANN
portant one, because of its enormous elasticity, is the glycogenetic function.
It may truly be classed as a sort of "shock absorber" in the carbohydrate
metabolism. The capacity of the liver for glycogen may reach 300 grams,
while the muscles may hold as much as four per cent of their weight.
Glucolysis and Carbohydrate Tolerance. — The amount of glucose oxi-
dation that can go on during a period of glucose plethora (as after in-
gestion of large amounts of glucose) is comparatively fixed and limited
by the body's requirement for energy. Under those conditions no fat is
burned and the utilization of protein is reduced to the "wear and tear"
quota, which, from the dynamogenetic point of view, is insignificant.
A man weighing 70 kilos will, when at rest, require approximately 35
calories per kilo per 24 hours. That means TO X 35 = 2450 calories
per 24 hours or 102 calories per hour. If all that were to come from
glucose the maximum amount of glucose that he could utilize, i. e., oxidize,
102
would be — — = 27 grams per hour (each gram of glucose yields 3.7 cal-
3.7
ories), or for the two hours in which the carbohydrate tolerance test is
made a maximum of 54 grams of glucose can be burnt. Fully half of
the quantity given with a 100 gram test can be taken care of by oxidation.
The amount that can be taken care of by fat formation we do not
know. It can be determined by studying the respiratory quotient (Lusk,
1912), but has not been worked out for man after a 100 gram glucose in-
gestion.
TABLE VII
TYPICAL BLOOD SUGAE CURVES . OF NOEMAL INDIVIDUALS *
M. McN. Healthy medical student, aged 24. Original Lewis-Benedict method
Hour
Blood Sugar Per Cent
Urine Volume
Urine Sugar
8.25 A.M.
0.096
8.30
100 grams of glucose in 300 c.c. of water
8.42
0.095
44
0
9.07
0.095
374
0
9.23
0.104
572
0
9.40
0.114
60
0
10.15
0.124
157
0
10.45
0.108
364
0
12.00
0.086
251
0
H. G. Weight 53 kg. Folin method for sugar determination f
Hour
Blood Sugar Per Cent
Urine Sugar
9.35
9.40
10.40
11.40
12.30
0.096
93 grams of glucose ingested
0.130
0.142
0.101
0
0
0
0
* Hamman and Hirschman.
t Montefiore Hospital Records.
THE CARBOHYDRATES AND THEIR METABOLISM 257
Endocrine and Nerve Control of Glycogenesis, Glycogenolysis and
Glucolysis
Influence of the sympathetic nervous system and of the adrenals.
We now come to one of the most fascinating chapters in modern physi-
ology. Claude Bernard, in the middle of last century, found that by
puncturing the medulla, between the levels of origin of the vagus and
auditory nerves of animals, he was able to bring about glucosuria, which
was proven later to be the result of hyperglucemia. The intensity of
the reaction was found to be directly related to the nutritional condition
of the animal. Those that were well fed and contained a large amount
of glycogen in the liver reacted very strongly, showing hyperglucemia and
marked glucosuria ; those that were starved and contained little glycogen
in the liver reacted only feebly.
In 1901 Blum made the very important discovery that the injection
of adrenalin was also followed by glucosuria, which was later proven to
be the result of hyperglucemia. The adrenalin glucosuria resembled the
puncture or piqtfre glucosuria, as it is called, in many respects. Its in-
tensity is also dependent upon the amount of glycogen in the liver, and
it also fails to produce hyperglucemia and glucosuria if the liver and
muscles are free from glycogen.
It was further shown that repeated injections of adrenalin into animals
with large amounts of glycogen will ultimately result in a complete dis-
charge of all the glycogen from the liver.
A more intimate view of the relationship of the above two funda-
mental discoveries, one may gather from an analysis of the work carried
out in Macleod's laboratory. First it was shown that by giving a sufficient
amount of nicotine to cause a complete blocking of the sympathetic ganglia,
the subsequent performance of the piqure experiment is followed by no
glucosuria, indicating that the sympathetic nerve fibers may be the car-
riers of the impulses to the liver.
Secondly it was shown that by electrical stimulation of the great
splanchnic nerve on the left side a very marked hyperglucemia may be pro-
duced.
It was further shown by G. N. Stewart that stimulation of the great
splanchnic nerve is followed by the appearance of marked and easily
detectable quantities of adrenalin in the blood of the suprarenal
veins.
Lastly, it was shown by Mayer that after adrenalectomy in rabbits,
piqure produced no hyperglucemia nor glucosuria.
From all the above, a chain of evidence seems to be established that,
piqure and adrenalin glucosuria are in reality one and the same kind of
stimulation to the liver, and as we shall see later, every gland of internal
secretion that possesses the power of sympathetic stimulation possesses
258 A. I. RINGHBK A^TD EMIL J. BAUMANN
TABLE VIII
INFLUENCE OF ADRENALIN ox BLOOD SUGAK *
Rabbit I
Rabbit II
Before Injection
Blood Sugar
Per Cent
Urinary Sugar
Per Cent
Blood Sugar
Per Cent
Urinary Sugar
Per Cent
0.11
0
0.12
0
After injection of 1.0 mg. of adrenalin subcutaneously
15 minutes
0.18
0.16
30
0.25
0.19
0.09
60 "
0.35
0.28
0.21
I1/) hours
0.37
0.38
1.21
2
0.33
0.43
0.39
2% "
0.35
0.34
1.69
3
4 "
0.24
1.55
4V> "
0.27
3.55
5 "
5V> "
0.16
6
.
6V2 "
0.13
3.9
7
7% "
0.12
3.11
* Bang's experiment.
the power, through its hyperactivity, to cause a discharge of the glycogen
in the liver which is followed by hyperglucemia and glucosuria.
There is no interference with the animal's power to utilize carbo-
hydrates, i. e., to oxidize it, after adrenalin administration.
Influence of the Pancreas. — In 1889 von Mering and Minkowski made
the pathfinding discovery that the complete removal of the pancreas of an
animal is followed by the appearance of marked glucosuria, with all the
other symptoms of human diabetes. It was later, found that with this
glucosuria there runs parallel a very marked hyperglucemia. The glu-
cosuria persists even if no carbohydrate is given in the food, and it was
found that the sugar in the urine bears a definite relationship to the nitro-
gen that is excreted. For every gram of nitrogen that was found in the
urine 2.8 grams of glucose were present. Since one gram of nitrogen is
contained in 6.25 grams of protein, it is evident that the depancreatized
dog has the power of converting 6.25 grams of protein into 2.8 grams
of glucose.
The glycogen completely disappeared from the liver in spite of the
high blood sugar concentration, and if carbohydrate was administered to
the animal, it was quantitatively eliminated in the urine.
Experiments in which only portions of the pancreas were removed re-
vealed that animals have a large "factor of safety" in their pancreas and
THE CARBOHYDRATES AND THEIR METABOLISM 259
that by far the greatest portion can be removed with impunity. Of course
there is a certain degree of variation in different animals, but in the great
majority as much as four-fifths of the organ may be removed without pro-
ducing any diabetes. When only very small portions of the pancreas are
left intact, the animals develop a tendency towards alimentary glucosuria,
but no true diabetes. The transition from this stage to that of true dia-
betes is entirely dependent upon the amount of pancreatic tissue left intact.
The most convincing proof that the absence of the pancreas was re-
sponsible for the glucosuria was presented by Minkowski in experiments
in which he showed that animals that had their pancreas entirely removed
did not develop diabetes if a portion of the pancreas was transplanted sub-
cutaneously.
Since this was established attempts have been repeatedly made to ex-
tract a hormone from the pancreas and supply that to the depancreatized
animals with the hope that the pancreatic function would be replaced.
All attempts have failed, and the reason for it may be found in the fact
that the digestive ferments of the pancreas destroy that hormone.
Two very interesting series of experiments were performed by Forsch-
bach (1908 and 1913) and by A. J. Carlson and F. M. Drennan (1911).
Forschbach performed an operation on two dogs in such a way that
the blood of dog A was made to circulate in dog B. He then completely
removed the pancreas of dog B. As long as dog B received the blood
from dog A, dog B did not develop any glucosuria, proving conclusively
.that the blood of dog A carries a substance (hormone) which takes the
place of the pancreatic function. This was later corroborated by Hedon
(1909), who found that the glucosuria of depancreatized dogs disap-
peared soon after he transfused it with the blood of a normal dog.
Carlson's experiments were based upon principles similar to the above,
namely, that the blood carries a substance that is supplied to it by the
pancreas. He therefore performed complete pancreatectomy in animals
that were in the latter stages of pregnancy. Either very slight or no glu-
cosuria set in. After the birth of the puppies, however, the mother be-
came diabetic, proving that the fetus was able to supply the mother with
its pancreatic hormone ; true diabetes setting in after the fetal supply was
removed.
There is therefore no more question to-day but that the pancreas is
directly concerned with carbohydrate metabolism. It enables the body
to oxidize glucose and it enables the body to convert glucose into glyco-
gen. In its absence, or in case of its failure to functionate properly, the
two functions disappear and the body loses the power to oxidize glucose
and it also loses the power to convert glucose into glycogen, both of which
result in hyperglucemia and glucosuria.
We are now confronted by the problem of how the pancreas exerts its
influence on the carbohydrate metabolism. It will be a conservative esti-
260 A. I. EINGEE AND EMIL J. BAUMAM
mate to state that at least 200 publications have appeared on this sub-
ject.9 Every conceivable theoretical possibility finds its defense and ex-
perimental support in one place and is met by just as convincing objection
in another place.
That we are dealing with an internal secretion there is absolutely no
question. That it is the pancreas that is supplying that internal secre-
tion seems proved beyond doubt but its modus operandi and locus nascendi
is as problematical to-day as heretofore. To the Islands of Langerhans
we are now inclined to attribute the production of the "antidiabetic"
hormones, but there is still room for direct and crucial experiments to
prove this hypothesis.
Influence of the Thyroid Gands. — The thyroid influences the carbo-
hydrate metabolism to a very considerable extent. Because it seems to
have a stimulating effect on the entire plane of metabolism it undoubtedly
affects the velocity of carbohydrate oxidation at the same time. Speci-
fically it affects the carbohydrate metabolism in such a way that whenever
there is a hyperfunction there is a tendency to lowered carbohydrate toler-
ance, i. e., hyperglucemia and glucosuria after the ingestion of 100 grams
of glucose, and when theVe is a hypof unction, as in the case of cretinism and
myxedema, we usually find a normal or increased tolerance for carbo-
hydrates. (Janney and Isaacson, 1918.)
A great deal of confusion exists in the literature on the subject, prob-
ably because of the studies published on clinical cases that are not clearly
defined. Because of the present tendency to. attribute a great many cases
of nervous disturbances to hyperthyroidism, one will naturally get a good
many negative results. But when one examines the records of authentic
cases of hyperthyroidism, one seldom fails to find evidences of a very
marked lowering of the carbohydrate tolerance. Of interest in this con-
nection is the observation of Jones (1893) and of Fr. Miiller (1906(c)),
both of whom reported the development of glucosuria in patients who were
taking thyroid gland in excessive amounts. Von Notthaft (1898) also
reports a case of true exophthalmic goiter complicated by glucosuria de-
veloping in an obese individual who had taken 1000 thyroid tablets in the
course of five weeks.
There is no interference with carbohydrate oxidation in case of hyper-
thyroidism. The respiratory quotient after the ingestion of 100 grams of
glucose, in the observations of DuBois (1916(&) ), was 0.94 and 0.98, in the
latter case showing that 89 per cent of the calories was derived from the
glucose oxidation. On the other hand, the basal metabolism of the pa-
tient 17 hours after the last meal shows a respiratory quotient of 0.77,
'Excellent reviews of the literature up to 1908 are given by S. Rosenberg: "Innere
Sekretion, Pankreas und Glykolyse," in Oppenheimer's Handbuch der Biochemie des
Menschen und der Tiere. Vol. Ill, part I, pp. 245-270. And up to 1913 by F. M. Allen
in Studies concerning Glycosuria and Diabetes, chapter XXI, pp. 898-985.
THE CARBOHYDRATES AND THEIR METABOLISM 261
which indicates a low carbohydrate combustion which can only be ex-
plained on the basis of low glycogen reservoir. This is in conformity with
the findings of Cramer and Kraus (1913) who found that after thyroid
ingestion the liver does not retain glycogen as well as before.
The effect of the thyroid on carbohydrate metabolism, therefore, is
purely through its interference with glycogen formation and mobilization.
Its effect is similar to that of adrenalin and sympathetic stimulation, and
the probabilities are, that they all act through the same channel.
Influence of the Pituitary Gland. — The pituitary gland, similar to
the thyroid, has a tendency to affect the carbohydrate metabolism when
in a state of hyperactivity. Gushing (1913) found that the administra-
tion of extract of the posterior lobe of pituitary was followed by a reduc-
tion in the carbohydrate tolerance and by a mobilization of glycogen. On
the other hand, patients with acromegaly, who are supposed to suffer from
an hyperfunctioning of the anterior lobe of the pituitary, very frequently
show evidences of lowered carbohydrate tolerance and of glucosuria.
Borchhardt (1908) found glucosuria in 40 per cent of his cases of
acromegaly, but in no case of tumor of the pituitary that was not acro-
megalic.
There is at present no reason to believe that the pituitary extracts
affect the carbohydrate metabolism in any other way than do the extracts
of the adrenals and thyroid. All three seem to have the power of stimulat-
ing the sympathetic nervous system, and the reaction they produce differs
only in degree. The effect of adrenalin is most powerful; those of the
thyroid and pituitary will only be determined after their respective ef-
lects have been studied with their active principles.
Just as the patellar reflex may be used clinically for roughly de-
termining the state of nervous tension of an individual, so the carbo-
hydrate tolerance test may be used clinically for determining roughly
the state of an individual's tonus of the sympathetic nervous system. But
we cannot employ that at present to differentiate between affections of the
thyroid, pituitary or adrenal.
The Intermediary Metabolism of Carbohydrates
All the processes of metabolism aim at two objects, first to build up
and maintain the body structure, second to produce the material that can
be used for dynamogenetic purposes. It is most surprising that in spito
of the large number of chemical compounds that play a n.le in metabolism,
only very few are "fit to burn." In the chapter on protein metabolism n
was brought out that fully fifty-eight per cent of the protein molecule
passes through a glucose stage. Over ten per cent of the fat molecu
(the glycerol fraction) passes through a glucose stage, and all of the
262 A. I. RINGER AND EMIL J.
carbohydrates are converted into glucose. We can therefore see that glu-
cose is the main channel of chemical action in the animal body, for from
all sides the reaction swings in its direction.
But the cells of the body cannot oxidize glucose directly. The glucose
molecule must first undergo a series of reactions during which it is broken
up into much smaller and simpler compounds, and' only those can be oxi-
dized by the cells to yield energy. We may liken the process to the grind-
ing down of grain to a flour in a mill, which is at the same time forcing
the product through a series of sieves, each consecutive sieve having smaller
and smaller meshes. Only those particles that can go through the finest
mesh will be fit for consumption. All the others must be reground. One
difference between the mill and the animal body is that in the mill the
process is irreversible, that is to say, a particle that is once ground down
remains so, whereas in the animal body the process is a reversible one,
the particles possessing the power of again polymerizing and flying back
into an upper sieve. The result is a continuous and endless grinding pres-
sure from above and a continuous flying back to the upper sieves.
The grinding down process may be illustrated thus (the double arrow
showing where the process is reversible).
GLUCOSE
Glyceric Aldehyde v N Glycerol * To fat formation.
Jf
Pvruvic Aldehyde
.Jf.\\
Lactic Acid ^ZTll Alanin^nl To protein formation.
Pyruvic Acid
J
Acetaldehyde » Aldol Condensation > Fatty acid formation
Acetic Acid Alcohol
II
/\
CO2 H2O CO2 H2O
The study of the intermediary metabolism of carbohydrates is fraught
with great difficulty. In the first place we deal with substances that are
THE CARBOHYDRATES AND THEIR METABOLISM 263
exceedingly soluble and therefore offer great technical difficulties in their
isolation, purification and identification. Secondly, most of the sub-
stances are oxidized with great ease so that at no time can one find more
than traces of them, even though throughout the twenty-four hours large
quantities may have been produced. Our information therefore must be
pieced together from various and indirect sources.
It has long been known that in the presence of alkali, glucose undergoes
decomposition, giving rise to lactic acid. In the animal body lactic acid ap-
pears in the blood and urine in cases of asphyxiation, severe anemias, and
after great muscular exertion. The following experimental proof shows
that this lactic acid can have its origin in glucose. Mandel and Lusk
(1906) found that after giving phosphorus to a dog lactic acid appeared
in the urine in large quantities. When they administered phlorhizin to
the same dog the animal of course became diabetic, and the lactic acid
disappeared from the urine, indicating that the lactic acid could have been
derived only from the catabolized glucose. This work is corroborated by
von Fiirth (1914, b) who found that the amount of lactic acid excreted in
phosphorus poisoning is increased after administering glucose to the ani-
mal. Final and most convincing evidence was brought forward by Levene
and Meyer (1913, b) when they showed that leucocytes and kidney tissues
possess the power of converting glucose into lactic acid, and by Embden
and Krauss (1912) who found that the addition of glucose to blood that is
perfused through a surviving liver causes the appearance of considerable
amounts of lactic acid.
Embden, Baldes and Schmitz (1912) also demonstrated that washed
blood corpuscles have the power of converting glyceric aldehyde into lactic
acid to the same extent that they do glucose, indicating the possibility of
glyceric aldehyde being an intermediary stage. They also showed that
glyceric aldehyde when perfused through the liver is reduced to glycerol,
and S. Oppenheimer (1912) added the information that, glycerol when
perfused through the liver gives rise to lactic acid.
Then follow experiments by Mayer (1912) in which he showed that
after administering pyruvic acid to animals lactic acid appeared in the
urine, and by Embden and Oppenheimer who obtained large amounts of
lactic acid after perfusing the liver with pyruvic acid.
Finally, there is a whole array of experimental proof, showing with
what ease various substances which are believed to be products of inter-
mediary metabolism are converted back into glucose when fed to diabetic
animals ; for glyceric aldehyde, Woodyatt ( 1915) ; for dioxyacetone, Ringer
and Frankel (1914(c) ) ; for pyruvic aldehyde, Dakin and Dudley (1913) ;
for pyruvic acid, Ringer (1913), Dakin and Janney (1913), Cremer
(1913) ; for lactic acid, Mandel and Lusk (190G).
In the following chart the various reactions that may take place :
the intermediary metabolism of glucose are indicated.
264
A. I. EINGEK AND EMIL J. BAUMANN
THE CARBOHYDRATES AND THEIR METABOLISM 265
OCX
So
c
W
O
o
o
w"
W
W
<M
CO
+
o
c?
^o
o
O
w ^
w" w a 8 §•
Q — O — O — O "S
aw wo
o — o =o — o — o
266 A. I. RINGER AND EMIL J. BAUMANN
We must picture these changes more from the dynamic point of view
than from the static. We must realize that in every cell of the body the
protoplasm is in constant motion. It is a system where hundreds of chem-
ical reactions are going on continuously and almost simultaneously, where
molecules are flying hither and thither, some undergoing oxidation, others
undergoing reduction, and the whole struggling to reach an equilibrium.
This struggle fcr chemical equilibrium constitutes the life of the cell.
It is important also to bear in mind that the substances formulated in
the chart do not normally represent products of intermediary metabolism,
but rather stages or stations along a certain route of decomposition. The
reaction does not stop at any of these points for any length of time to allow
an accumulation of the products, except under abnormal conditions. For
example, when the supply of oxygen is insufficient the process may halt at
the lactic acid stage, then lactic acid can be detected in quantity. Just
as an express train operating between New York and Chicago cannot
arrive at its destination suddenly, but must go through certain stations
along the route, so glucose must pass certain intermediary stages before
reaching carbon dioxid and water. If the power does not hold out, natur-
ally there will be a forced stop at one of the stations.
When we view the reactions on the chart we must also realize that there
are two forces operative, one which drives the reaction downward and an-
other which drives it backward to glucose. We are inclined to attribute
them to the action of ferments. But ferments are blind forces that do not
determine the direction of the reaction. Whether it goes to one side or
another is controlled by physical chemical factors such as the mass action
or relative concentration of the components. When the glucose concentra-
tion is high, the reaction swings in two directions with relatively great
force and speed. Glucose is rapidly converted to glycogen on the one
hand and to glyceric aldehyde on the other.
Glycogen±^GLUCOSE;z±Glyceric aldehyde
But the reactions from glycogen to glucose and from glyceric aldehyde to
glucose cannot be considered stopped. They probably go on at the same
time, but the former reactions overshadow the latter. Similarly if gly-
ceric aldehyde is fed to an animal we may picture the reaction in both di-
rections, but going primarily in the line of least resistance.
^,-^.Dioxyacetone
Glucose jn;GLYCERIC ALDEHYDE^
**^Pyruvic aldehyde
And so on with the other reactions.
On the basis of these last considerations one may find an explanation
for the formation of glucose from practically all the intermediary metabo-
lites of glucose when administered to diabetic animals. When one gives
anv of these substances to a normal animal the reaction of that substance
THE CARBOHYDRATES AND THEIR METABOLISM 267
swings to left and right, that is, to glucose and downward. The particles
that go over to glucose are ultimately broken down again, so that in the
course of time the whole amount given is completely oxidized to carbon
dioxid and water. Because of the relatively high concentration in the
blood of the substance under discussion, the kidney may excrete some of it
and also those products which stand nearest to it (excretion of lactic acid
in the urine after pyruvic acid administration). But if the same metabo-
lite is fed to a diabetic animal, the moment a particle is converted to
glucose it becomes trapped, because these animals have lost the power of
splitting the glucose molecule. The reaction becomes one-sided and ir-
reversible, and if the oxidative processes are not very great the substance
may be completely converted to glucose.
Glucose < METABOLITE —^ Lower product
It will now be readily seen that a number of three carbon compounds,
namely glyceric aldehyde, dioxyacetone, pyruvic aldehyde, lactic acid and
pyruvic acid, may "be safely considered stages of glucose catabolism, and
that these substances in the animal body may undergo reactions whereby
one is converted into the others either by processes of oxidation, reduction,
hydrat.ion, dehydration or by rearrangement of the position of hydrogen in
the molecule. All of these steps are reversible.
One of the later stages in the reaction is a process of decarboxilation
during which a three carbon compound is converted into a two carbon com-
pound with the loss of carbon dioxid. This is the first irreversible reaction
in the entire chain.
CH,
CO CHO + C02
COOH
Pyruvic Acid > Acetaldehyde
That pyruvic acid can be converted into acetaldehyde was demonstrated
in a series of experiments by Neuberg and Karczaz (1011, 1912). They
found that all yeast cells possess that power and that the decarboxilation
is brought about by an enzyme, "carboxylase."
Acetaldehyde is a very important intermediary stage of carbohydrate
catabolism. Just as lactic and pyruvic adds link the carbohydrate metab-
olism with that of protein, so acetaldehyde links carbohydrate with fat me-
tabolism. As will be shown later acetaldehyde is in all probability the start-
ing point from which fat is built up in the body. Acetaldehyde in the
organism may undergo oxidation to acetic acid which on further oxidation
is converted to carbon dioxid and water. It may also be reduced to ethyl
alcohol, which is ultimately oxidized to carbon dioxid and water.
268 A. I. EIXGEE AXD EMTL J. BAUMANN
It is only from these final oxidations that the cells of the body derive
their energy. All the changes that the foodstuffs undergo, be it in the
process of digestion or later in metabolism, are all aimed to prepare them
for the stage in which the cells can utilize them for energy formation.
Whether we start with the complex protein molecule, the high carbohydrate
molecule or the comparatively simple fat molecule, — they must all be
ground down in the mill of metabolism to fit the finest meshes of the sieve.
They all have to come down to the two carbon stage which is burned with
the liberation of heat and energy.
Fat Formation from Carbohydrate
That animals can be fattened by feeding them large amounts of carbo-
hydrates has been known to stockmen for centuries. Scientific proof for
it has been presented during the course of the last century by a number
of authors.10
The question that confronts us to-day is, how can we picture the trans-
fer of the highly oxidized glucose molecule to the oxygen poor fatty acid ?
It is chemically inconceivable that there is a direct abstraction of oxygen
and that three glucose molecules become converted into an eighteen carbon
fatty acid. We must therefore assume that the fatty acids are built up
from more elementary compounds.
When one makes a survey of all the fats known in the animal and
plant kingdoms, one is struck by the fact that in no place is there a natural
fatty acid to be found that has an odd number of carbons. In milk, for
example, there is present a. variety of fatty acids. There we find,
Butyric Acid, CH3CH2CH2COOH (4 Carbons)
Caproic Acid, CH3CH2CH2CH2CH2COOH (6 Carbons)
Caprylic Acid, CH3CH2CH2CH2CH2CH2CH2COOH (8 Carbons)
Capric Acid, CH3CH2CH2CH2CH2CH2CH2CH2CH2COOH
(10 Carbons)
Laurie Acid, CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2COOH
(12 Carbons)
Myristic Acid, CH3CH2CH2CH2CH2CH9CH2CH2CH2CH2
CH2CH2CH2COOH (14 Carbons)
Palmitic Acid, CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2COOH (16 Carbons)
Stearic Acid, CH3CH2CH,CH,CH2CH,CH2CH2CH0CH2
CH2CH2CH2CH2CH2CH2CH2CO~OH "(18 Carbons)
10 A review of the literature may be found in "Die Fette im Stoffwechsel," by A.
Magnua Levy and L. F. Meyer, in Oppenheimer's Handbuch der Biochemie des Menschen
und der Tiere, vol. 4, part 1, p. 449, 1908.
THE CARBOHYDRATES AND THEIR METABOLISM 269
We have every reason to assume that all the lower fatty acids found in
milk are intermediary in the building up of the higher fatty acids. If
fatty acids were built up by the addition of one carbon we should find
just as many odd carbon fatty acids as even. This consideration led
Nencki as far back as 1878 to suggest that fatty acids are built up by con-
secutive additions of two carbons, and that the two carbon compound is
probably a^cetaldehyde which displays exceptional chemical reactivity.
Support for this assumption may be found in the fact that in their
catabolism fatty acids undergo a series of p-oxidation, whereby they lose
two carbons in successive stages (Knoop (1910, 6), Ringer (1913, a). In
vitro, acetaldehyde will under certain conditions undergo what is known as
aldol condensation, whereby one acetaldehyde molecule combines with
another, forming aldol, which is a four carbon aldehyde. Raper (1907)
has succeeded in building up an eight carbon aldehyde in this way, which
he also easily oxidized to caprylic acid.
CH,
CHO
CH
CHO
Acetaldehyde
CH
CHOH
CH
CHO
Aldol
Smedley and Lubrynzka (1913) bring forth evidence that fat formation
in the body proceeds through the condensation of an acetaldehyde molecule
with that of pyruvic acid, forming first a four carbon aldehyde which
later combines with another pyruvic acid molecule, giving rise to a six
carbon aldehyde. The process thus repeats itself until the sixteen and
eighteen carbon fatty acids are reached.
CH,
CHO
CH?
CH
CH5
CH
Acetaldehyde CH3 Splitting off CH Decarboxilation CH
| of H2O
CO CO CHO
COOH
Pyruvic Acid
COOH
o-Keto-angelic
Acid
Crotonic
Aldehyde
270 A. I. RINGER AND EMIL J. BAUMANN
CH3 CH3
I +H2 |
CH > CH2
1 1 Reduction |
CH CH2
I I
CHO CHO
Crotonic Butyl Aldehyde
Aldehyde
CH3 CH3 CH3
CH2 CH2 CH2
CH2 CH2 CH2
CO
CHO + Splitting off, CH Decarboxilation CH
CH3 of H2O || ||
Butyl aldehyde | , CH CH
CO
| CO CHO
COOH |
Pyruvic Acid COOH
CH3 CH3
CH2 CH2 . Unites with another molecule of pyruvic
CH2 — » 4~ H2 — » CH2 • > acid, and so on until the higher com-
| Reduction |
CH CH2 pounds are reached.
M I
CH CH
CHO CHO
Caproic
Aldehyde
From the ahove we may see that fat formation can only take place in nor-
mal animals that have the power of splitting glucose, for the building stones,
acetalclehyde and pyruvic acid, are mainly products of glucose catabolism
In conditions of diabetes in which there is a loss in the individual's ability
to break down the glucose molecule, fat formation from carbohydrate must
be correspondingly reduced. This helps to account for the extreme and
rapid emaciation in severe diabetes.
THE CARBOHYDKATES AND THEIR METABOLISM 271
The Functions of Carbohydrate in the Diet.— The paramount func-
tion of carbohydrate in the diet is to yield energy to the cells in the process
of its oxidation. It burns in the body apparently with greater ease than
does protein or fat, hence it may be considered as having a sparing influ-
ence on both. With regard to protein its influence is more specific, for
the intermediary products of carbohydrate metabolism, lactic acid and
pyruvic acid have been shown to have the power of uniting with ammonia
in the liver and giving rise to alanin. This conserves nitrogen for the
body, which would ordinarily have been excreted, Knoop (1910), Emb-
den (1910), and Schmitz (1910). For further discussion of the influ-
ence of carbohydrate on protein metabolism see the chapter on Protein
Metabolism, page 118.
Influence of Carbohydrate on Intermediary Metabolism of Fat. An-
tiketogenesis. — Ordinarily when fat burns in the body it is completely
oxidized to carbon dioxid and water. Under certain conditions, however,
the oxidation is not- complete. In cases of absolute starvation "acetone
bodies" (|3-hydroxybutyrie acid, aceto-acetic acid, and acetone) appear in
the urine, the last because of its extreme volatility is also excreted
through the breath. If an individual is kept on a diet of protein and fat
without any carbohydrate, these bodies will also appear in the urine. In
severe diabetes where the combustion of carbohydrates is completely lost,
the amount of acetone bodies formed may be enormous, over one hundred
grams a day. Because the aceto-acetic acid and the acetone have the car-
nonyl (CO) radical, they are known as ketones and their formation in
the body is called ketogenesis. All the acetone bodies originate from the
catabolism of fat and from certain of the amino acids of protein metabo-
lism.
Because it was recognized that whenever carbohydrates burn in the
body ketogenesis stops and that no ketogenesis occurs as long as the body
is capable of oxidizing glucose, antiketogenetic properties were attributed
to glucose.
In normal fasting individuals who develop kctonuria, certain sub-
stances like glycerol, glycocoll, alanin, and aspartic acid have proven to
be antiketogenetic. In diabetic individuals, however, they are without
effect, because they are completely converted to glucose and excreted as
such. Alcohol has proven to be a marked antiketogenetic substance. (().
Xeubauer (1906), Benedict and Torok (1906).)
In 1913 Ringer and Frankel performed a series of experiments on
diabetic dogs who developed considerable ketonuria. After adminis-
tering acetaldehyde to these dogs they found a very marked antiketogenetic
effect. At the same time they also obtained an increase in the glucose
elimination. They suggested the idea that it was possible that acetalde-
272
A. I. KINGER AND EMIL J. BAUMANN
hyde acted by virtue of its combining power with (3-hydroxybutyric acid,
forming a new compound which is glucogenetic. We know to-day that
acetaldehyde is a very important product in the intermediary metabolism
of carbohydrate, and it is very likely that the antiketogenetic effect of
glucose is brought about through acetaldehyde-^-hydroxybutyric acid or
acetaldehyde-aceto-acetic acid combination.
Water as a Dietary Constituent Philip B. Hawk
Introduction — Influence of an Increased Ingestion upon Metabolism — Influ-
ence on Basal Metabolism — Influence of a Diminished Water Intake —
Water Drinking with Meals — Influence on Salivary Digestion — Influence
on Gastric Digestion — Passage of Water from the Stomach — Influence
of Pancreatic Digestion — Influence on Intestinal Flora and Putrefaction
— Influence on Absorption — Influence on Blood Volume and Blood Pres-
sure— Distilled Water — Ice Water — Conclusions.
Water as a Dietary Constituent
PHILIP B. HAWK
PHILADELPHIA
Introduction
The average man who lives among water mains, hydrants, and street,
sprinklers and in the vicinity of rivers and lakes gives little or no thought
to the important part water plays in his life processes, if indeed he
possesses any definite knowledge on the subject. If such a man were
possessed of an introspective hydro-eye, he could quickly convince him-
self that "water" and "life" are synonymous terms so far as the human
body is concerned. If he would flash the rays of this eye upon himself,
he would find that the blood plasma, that important carrier of nutritive
material to every organ and tissue, contains over 90 per cent of water;
that the brain, which regulates and correlates so many intricate activities
and processes, contains from 85 to 90 per cent water ; that the liver cell,
which is associated with so many processes which are vital to the main-
tenance of normal metabolism, contains 75 per cent water; that the
mighty muscle, which is so importantly related to feats of strength, is
three-fourths water; that the saliva, which quickly reduces the complex
and insoluble starch of our foods to a simple soluble sugar, is almost
pure water (99.5 per cent) ; that bone, which has been shown by test to
possess a tensile strength (25,000 pounds per square inch) one and one-
fourth times as great as that of cast iron and more than twice that of
good timber, is 40 per cent water; and finally, if he would put his
150-pound body in an electric oven and drive off all the water, the under-
taker would have to handle only 50 pounds, because the human body as a
whole is about two-thirds water.
Since water is found in such large quantities in all organs, tissues,
and secretions of the body, it is not surprising that water is absolutely
essential to the proper performance of so many bodily functions. For
example, in respiration we have chemical and physical processes which
are dependent upon the presence of water. The surface of the lungs must
be moist before there can be any exchange of carbon dioxid and
oxygen. The regulation of body temperature is facilitated by the presence
of circulating water and the evaporation of water from the surface of the
275
276 PHILIP B. HAWK
skin, whereas an increased water ingcstion has been found to lower body
temperature. The mucous surfaces of the body cannot function normally
unless they are in a moist state. Water is the medium, whereby nutritive
material is carried to the body cells, and the cells of the blood are trans-
ported in a fluid medium. The kidney can more satisfactorily eliminate
toxic substances if such substances are brought to that organ in a well-
diluted form. The normal movement of joints and tendon sheaths is
possible only when fluid is present. Water is also importantly related to
absorption. The end-products of digestion in the intestine are not
efficiently absorbed unless such end-products are properly diluted (see
p. 291). Water also increases peristalsis. It has also been suggested
(Smith and Mendel) that "The large amount of water in the cell may aid
considerably in maintaining the optimum temperature of the cell, for
water has a high specific heat. The large percentage of water in the
tissues in which oxidation is most intense may be correlated with this
unique property of acting as a heat buffer."
Inasmuch, therefore, as water .is so vitally related to man's well being,
it is not strange that water has been the object of considerable investiga-
tion by both the abstract scientist and the practical clinician.
That physicians, as long ago as the early part of the eighteenth century,
were impressed with the dietary importance of water is indicated by a
pamphlet published in London and reprinted in Philadelphia in 1723.
This pamphlet is by John Smith, C. M., and is entitled "Curiosities of
Common Water, or The Advantages thereof in Preventing and Curing
Many Distempers." The author claims that the contents of the pamphlet
were "Gathered from the Writings of several Eminent Physicians, and
also from more than Forty Years' Experience." Among the interesting
excerpts from the volume are the following :
"In the County of Cornwall, the poorer Sort, which did never, or but
very seldom, drink any other drink but Water, were strong of Body, and
lived to a very great age."
In another place the author of the volume quotes a Doctor Manwaring
as saying:
"In the Primitive Ages of the World, Water-Drinkers were the longest
Livers by some Hundreds of Years — nor so often sick and complaining
as we are."
And later Sir Henry Blount is quoted as saying that while in the Levant
"where the Use of Wine was forbid, and where the common drink was
Water, he then had a better stomach for his Food, and digested it more
kindly than he ever did before or since."
To-day practically all up-to-date medical men appreciate fully the im-
portance of water to the human body. This fact is attested by the great
development along certain hydrotherapeutic aspects of treatment. How-
ever, some doctors say to their patients, "Drink freely of water, at all
WATER AS A DIETARY CONSTITUENT
277
times except during meals," and include almost invariably a warning
against ice water and generally against, distilled water. Such advice is
analyzed in the following pages.
Influence of an Increased Water Ingestion upon
Metabolism
That an increase in water intake will produce a change in the metabolic
response of the human body has been repeatedly demonstrated (Eichhorst
Feder(a) (6), 1878, 1881, Falck, E. P. and F. A., Genth, Gruzdiev, Mate-
kevich, Becher, Neumann (a), Panum, Rubner(fr), Schondorff(a), Weige-
lin, Hawk (a) ). The consensus of opinion on this point is that an increase
of 500-5000 c.c. in the daily water intake of a normal man will cause an
increased excretion of total nitrogen, urea, phosphorus, and generally
sulphur in the urine- The increase in total nitrogen and urea is believed
to be due partly to the washing out of the tissues of the urea previously
formed, but which has not been removed in the normal processes, and
partly to a stimulation of protein catabolism. The increase in the excre-
tion of phosphorus is probably due to increased cellular activity and the
accompanying catabolism of nucleoproteins, lecithins, and other phos-
phorus-containing bodies. A typical nitrogen balance from one of the
writer's experiments follows:
TABLE C— INCOME AND OUTGO OF NITROGEN
EXPERIMENT I
Sub-
ject
Experi-
mental
Period
Length
of
Period
Days
Nitrogen (grams)
Nature of
the Diet
In
Food
In
Urine
In
Feces
Gain or Loss
( + or— )
Average
Gain or Loss
per Day
I
I
I
I
II
III
2
2
4
25.68
25.68
51.36
22.13
24.30
44.82
2.95
3.067
4.568
+ 0.60
-1.687
+ 1.972
+ 0.30
— 0.844
+ 0.493
Normal.
4500 c.c. wa-
ter added
daily.
Normal.
Total
8
102.72
91.25
10.585
+ 0.885
+ 0.110
In discussing the influence of water upon metabolism Bischoff, as early
as 1853, wrote as follows:
"Water exercises before all other agencies, apart from the nitrogen
content of the food, the greatest influence upon the excretion of urea
by the urine." . .
And Foster, the eminent English physiologist, said in an early edil
of his "Text-book of Physiology" :
"Water has an effect on metabolism, as shown, among other things, by
278
PHILIP B. HAWK
the fact that when the water of a diet is increased the urea is increased to
an extent beyond that which can he explained by the increase of fluid
increasing the facilities of mere excretion."
The most direct evidence that an increased water ingestion increases
cellular activity was furnished by an experiment made in the writer's
laboratory (Howe, Mattill and Hawk (a), Wreath and Hawk).
A dog was given 700 c.c. of water daily during a 59-day fast, at
which point the water ingestion was increased to 2,100 c.c. for each day
of a four-day interval. The increased water intake caused an increased
excretion of "total purin nitrogen," i.e., nitrogen in the form of purin
bases, uric acid, and allantoin. Inasmuch as this form of nitrogen has its
origin in the cell nucleus, we may consider that an increased output indi-
cates stimulated cellular activity and increased tissue disintegration.
Certain other observations also indicate that water stimulates tissue
changes. For example in the case of the fasting dog just mentioned, the
increased water intake caused the appearance of considerable creatin in
the urine. There had been no creatin in this dog's urine for a considerable
interval before the high water intake. However, as soon as the water
ingestion of the animal was increased, creatin appeared in considerable
quantity in the urine. The creatin was interpreted as having arisen, at
least in part, from disintegrated muscular tissue. The data on this point
are embraced in the following table:
TABLE II
PERCENTAGE EXCRETION IN TERMS OF TOTAL NITROGEN
Day of
Fast
Urea
Ammonia
Creatinin
Creatin
Purin
Allantoin
Undeter-
mined
FASTING 700 C.C. WATER PER DAY
54-57
58-59
85.57
85.28
9.31
8.55
5.76
5.75
0.50
0.57
0.37
0.42
FASTING 2100 C.C. WATER PER DAY
60
79.54
9.20
4.38
0.67
0.10
0.71
5.41
61
80.76
9.81
4.71
1.92
0.11
0.65
2.03
62
78.49
12.63
4.59
1.03
0.06
1.16
2.04
63
78.88
10.17
4.94
1.61
0.07
1.00
3.33
Other observations made on men have been interpreted as indicating
that a high water ingestion causes a partial muscular disintegration result-
ing in the release of creatin, but not profound enough to yield the total
nitrogen content of the muscle. The output of creatin is, therefore, out
of all proportion to the increase in the excretion of total nitrogen (Fowler
and Hawk).
That the chloride content of the urine is increased as a result of an
WATER AS A DIETARY CONSTITUENT 279
augmented water intake has also been demonstrated (Heilner(a), East,
Rulon and Hawk, Foster and Davis, Benedict (a)).
Influence on Basal Metabolism.— Apparently Speck is the only ob-
server who has studied this question after the ingestion of volumes of
water as great as those used in the writer's experiments, i.e., 3,000-4,500
c.c. per day. According to this observer, when 1,250 c.c. of water was
taken, there was a noticeable rise in metabolism. Benedict and Carpenter
(b) conclude that with more than 500 grams of cold water, an increase
as great as 16 per cent above the basal value may be obtained.
Influence of a Diminished Water Intake. — If no water, or an in-
sufficient quantity of water, enters our body, we quickly become abnormal.
This point was emphasized in connection with a metabolism test in the
writer's laboratory. We were to study the influence of an increased water
ingestion. Therefore, in order to have a pronounced difference between
the water intake of the preliminary and experimental periods, the water
quota of the diet of the preliminary period was reduced to a minimum.
The subjects (men) of the experiment soon gave evidence of abnormal
function as shown by headaches, nervousness, loss of appetite, digestive
disturbances, and inability to concentrate on the performance of accurate
chemical work. As soon as the above symptoms appeared, the water con-
tent of the diet was increased, and with this single change the experiment
proceeded satisfactorily. Dennig and Niles have also shown the undesir-
able effect of a diminished water intake.
That man or a lower animal will live longer without food than without
water is well recognized. If we give a dog all the food he wishes but
no water, the beast dies in a short time. If we give the animal no food
but see to it that he receives plenty of water, the animal will live much
longer. In a test in the writer's laboratory in 1912 (Howe, Mattill, and
Hawk(&)), an adult dog (26 kg.), which was given TOO c.c. of water daily,
lived over 100 days without food. Smirnov has also demonstrated that
fasting rabbits which were permitted free access to water were less prone
to show signs of fatty infiltration of the liver than were similar fasting
rabbits which were not permitted to drink water.
Rubner says that a fasting animal may lose all its glycogen and fat and
one-half its protein and still live, but if it loses one-tenth of its water, it
dies. We are continually losing water by way of the kidneys, lungs, skin,
and bowel, and if we do not drink sufficient water to make good these losses,
our body quickly ceases to function properly and death soon follows.
That the loss of water through skin and air passages may be considerable
has been shown by direct determination (Soderstrom and DuBoia
Normal men twenty to fifty years old may lose by these channels 701
grams of water per day, and the water thus lost carries with it i * per
cent of the total heat produced in the Inxly. Typhoid patients with a
rising temperature show a decreased water output, while the reverse
280 PHILIP B. HAWK
true when the temperature falls. In general, however, the output of
water is very little affected in disease.
That a lack of free water in the body may bring about a rapid and
high increase in body temperature has been demonstrated (Balcar, San-
sum, and Woodyatt, Woodyatt(a) ). When sugar, for instance, is injected
intravenously in a dog and the animal is given.no water, high fever and
chills soon follow. Temperatures as high as 120° F. have been obtained
by this method. The sugar produces diuresis, causing a lack of water in
the dog's body, and the fever and high temperature follow.
Certain well known pathological conditions are associated with a loss
of water from the body. In fatal cases of Asiatic cholera, for example,
this desiccation takes place to such an extent that we may have a serum
loss as high as 62 per cent (Rogers). If isotonic saline be injected intra-
venously into such cholera patients, the fluid is immediately and com-
pletely lost by way of the bowel. In cases of poisoning by war gas (Under-
bill), there is also a pronounced loss of water from the blood and the
movement of water into the lungs. The pneumonia crisis in infants
(Lussky and Friedstein) has been shown to be accompanied by decrease
in body weight due to loss of water.
Water Drinking with Meals. — Beginning in 1908, a long series of
studies have been carried out in the writer's laboratory bearing upon the
question of water drinking at meal time. At the time our first study was
made, the consensus of medical opinion was opposed to the mid-meal
use of water. Oertel, who was an advocate of fluid restriction, says, "The
drinking of fluids with meals causes great dilution of the gastric juice,
retards gastric digestion, and favors the development of dyspepsia." The
following quotation (Carrington) will also serve to emphasize, in a
general way, some of the reasons why physicians were opposed to the
drink-ing of water with meals:
"We can lay down the definite and certain rule that it (water) should
never be drunk at meals, and preferably not for at least one hour after
the meal has been eaten. The effect of drinking water while eating is,
first, to artificially moisten the food, thus hindering the normal and
healthful flow of saliva and the other digestive juices ; secondly, to dilute
the various juices to an abnormal extent ; and thirdly, to wash the food
elements through the stomach and into the intestines before they have
had time to become thoroughly liquefied and digested. The effect of this
upon the welfare of the whole organism can only be described as direful."
However, if we search for experimental proof of the above statements,
we fail to find it, no matter how deeply we dig into the musty volumes of
scientific and medical libraries. In all my search I have never found a
single experimental fact which can rightly be interpreted as indicating
that the taking of water at meal time is harmful. In none of our tests
was water used to wash down the products of incomplete mastication ; the
WATER AS A DIETARY CONSTITUENT 281
food was invariably masticated without the aid of .water. Let us follow
the various activities of the digestive tract, from mouth to anus, and see
the actual influence of water taken with meals upon these activities.
Influence on Salivary Digestion.— It is not necessary to believe with
Bunge that the main function of the saliva is one of lubrication, in order
to show that the presence of water aids salivary digestion. The following
table (Bergeim and Hawk) shows that the dilution of saliva with water
facilitates the action of the salivary amylase:
EFFECT OF DILUTION OF SALIVA IN CONCENTRATED MIXTURES
Diluent: Filtered tap water. Time of digestion: 10 min. Temp.: 0°.
No.
Amount of Starch
Paste
^Jo. cc.
Saliva
Amount of
Water
Mg. of
Maltose
Dilution
1:
1
10 cc. of 10%
10
378 6
2
2
7 cc. of 10%
7
6 cc
441 8
3
3
4 cc. ef 10%
4
12 cc
448 6
K
3 cc. of 10%
14 cc
A*R 5
5
2 cc. of 10%
2
16 cc
449 3
10
6
1 cc. of 10%
1
18 0 cc
305 4
20
7
0.4 cc. of 10%
04
19 2 cc
283 0
50
8
0.2 cc. of 10%
0.2
19 6 cr
287 6
100
The diluent in the above experiment was ordinary tap water, and
the optimum dilution was six volumes of water.
Influence on Gastric Digestion. — (Stimulatory Power of Water).—
The most severe indictment brought against the drinking of water with
meals was the claim that water thus taken would dilute the gastric juice
and hence delay digestion. Those who advanced this criticism overlooked
the fact that the gastric juice is manufactured by living cells which are
subject to chemical and psychical stimulation and that water is a
chemical stimulant. The first experiments showing that water possessed
the power to stimulate the flow of gastric juice were apparently made
in 1879 (Heidenhain). This observation was later repeatedly confirmed
by other investigators (Carlson, Orr, and Brinkman, Foster and Lambert,
King and Hanford, Lonnquist, Pavlov, Sanotzky, Sawitsch and Zeliony),
all of whom used lower animals as subjects. Pavlov was not impressed
with the stimulatory power of water — in fact, he found no stimulation
whatever in about 50 per cent of his tests where volumes of water ranging
from 100 to 150 c.c. were introduced into the stomachs of dogs. He
says :
"It is only a prolonged and widely spread contact of the water with
the gastric mucous membrane, which gives a constant and positive result."
Foster and Lambert also claimed that volumes of water below ! 00 c.c.
exerted no appreciable or uniform stimulation in the stomach of the dog.
According to these investigators the increase in the flow of gastric juice
282
PHILIP B. HAWK
which follows the introduction of water is directly proportional to the
volume of water employed. This point is shown in the following data
taken from one of their tests:
300 c.c. water - 7.2 c.c. gastric juice
500 c.c. water = 17.7 c.c. gastric juice
750 c.c. water = 25.7 c.c. gastric juice
Chighin had previously shown a similar proportionality. The ob-
servations mentioned were made by the use of the Pavlov pouch.
The first experiments showing water to be a gastric stimulant in the
human stomach were made in the
writer's laboratory (Wills and Hawk).
The ingestion of water at meal time
by two men was accompanied by an
increase in the excretion of ammonia
which was directly proportional to
the extra volume of water ingested.
Inasmuch as certain experiments have
demonstrated that water stimulates the
flow of an acid gastric juice and as
certain other experiments have demon-
strated that the formation of acid in
the body or the introduction of acid
from without produces an increase in
the urinary ammonia excretion, we
feel justified in assuming that the
increase in the ammonia excretion ob-
served in our experiments was due
directly to the stimulation of gastric
secretion by the ingested water. That
the increase in the ammonia excretion
did not arise from intestinal putrefac-
tion was indicated by the finding of
lowered indican values during the
period of high water ingestion. These
observations were verified by Ivy (a) in experiments on dogs.
Since these observations gave only "indirect" data, the problem was
reinvestigated in the writer's laboratory and "direct" evidence of stimula-
tion obtained. In the latter investigation (Bergeim, Rehfuss and Hawk),
water was introduced into the stomachs of normal men and samples of
gastric contents removed at intervals of ten minutes by means of the
Rehfuss tube (Rehfuss) and analyzed according to the fractional method
of gastric analysis (Hawk (g] ). Figure 1 illustrates a pronounced case of
water stimulation of gastric secretion, and Figure 2 illustrates a'stimula-
Fig. 1. — Curve showing pronounced
stimulation by water and rapid
emptying of the stomach. (Berg-
eim, Rehfuss and Hawk; Jour.
Biol. Chem., 1914, XIX, 345.)
WATER AS A DIETARY CONSTITUENT
283
Fig. 2. — Curve showing moderate stimu-
lation by water (Bergeim, Reh-
fuss and Hawk ; Jour. Biol. Chem.,
1914, XIX, 345.)
tion of moderate intensity, whereas Figure 3 shows but slight stimula-
tion. These tests were made on three men who gave normal gastric his-
tories, and serve to illustrate the fact that all normal stomachs do not
yield the same response to chemical
stimulation. This point has been
emphasized throughout our work on
"Gastric Response" (Miller, Fowler,
Bergeim, Rehfuss, and Hawk). In
other words, water is an important
gastric stimulant, but it does not ex-
ert a pronounced stimulatory effect
in every normal stomach — neither
does any other dietary article. This
same fact has also been brought out
by Ivy (6). Other interesting water
experiments have also been made by
Sutherland, and by King and Han-
ford. The latter investigators say:
" Water given with meals or dur-
ing digestion results in the following
hour in an increase in the amount
of juice secreted over that which would be secreted on the administration
of either water or meat alone."
Niles, as the result of experiments on eight men, each of whom
received one liter of water at each meal for one week, also approves of
water drinking with meals. He says, "Not one of the eight suffered a
single qualm of indigestion,
either gastric or intestinal."
That the water some-
times begins its stimulation
as soon as it comes in con-
tact with the human gastric
mucosa is illustrated by
Fig. 4. In this experi-
ment, after removing the
gastric residuum (Rehfuss,
Bergeim and Ilawk(a) ;
Fowler, Rehfuss. and
Hawk) of a •normal man,
100 c.c. of water was introduced into the empty stomach through the
Rehfuss tube. That there was no latent period is shown by the fact that
an acidity of 15 was registered at the end of one minute, and this value
had risen to 80 at the end of a five-minute interval. Pavlov claims that
the stomach of the dog shows a latent period of five minutes, whereas
/oo
Fig. 3. Curve showing slight stimulation by
water in the human stomach. (Fowler, Rehfuss
and Hawk; unpublished data.)
284
PHILIP B. HAWK
ether observers (Bogen, Hornborg, Kaznelson, Sick, Umber) claim, as
the result of experiments on man, that the latent period varies from 3 to
10 minutes. Carlson says:
"The latent period of the appetite secretion varies indirectly with the
rate of continuous secretion so that when the continuous secretion is
abundant, the appetite secretion shows no latent period at all, while with
the lowest rate of the continuous secretion, the latent period varies from
2 to 4 minutes."
That this latent period does not exist in certain human stomachs after
water stimulation is evident from our data.
Fig. 4. — Curves showing immediate stimulation by water and rapid emptying of the
stomach. (Bergeim, Rehfuss and Hawk; Jour. Biol. Chem., 1914, XIX, 345.)
It has also been claimed that the gastric glands exhibit a pronounced
fatigue when subjected to repeated stimulation (Foster and Lambert).
That this pronounced glandular fatigue is not always in < evidence is illus-
trated in Fig. 5. A normal man was given 500 c.c. city water (10°-12°
C.) at 1 p. m., five hours after breakfast, and samples of juice were
collected at ten-minute intervals until the stomach was approximately
emp»ty. After an intermission of ten minutes the experiment was re-
peated. It will be observed that the stimulation was almost as great in the
repeated test as in the initial one. A similar absence of glandular fatigue,
in the dog, has also been observed by Ivy (6) after the injection of gastrin
every two hours over a period of twenty-six hours.
When gastric stimulants are under discussion, much emphasis is in-
variably placed upon the stimulatory power of meat extract. The com-
parative stimulatory power of water and meat extract in the same normal
Fig 5. — Curves showing no glandular fatigue in human stomach. (Bergeim, Rehfuss
and Hawk; Jour. Biol. Chem., 1914, XIX, 345.)
\—>
As
'dledUa-ber.
10 minuted?
,-Lan,
.100.
CG
. ~BoU
285
286
PHILIP B. HAWK
stomach is illustrated in Fig. G. It will be observed that the gastric
acidity was developed a little more quickly in the case of meat extract, and
the stomach emptied a little more rapidly, but that the general stimulatory
response was very similar to that of water. Fig. 7 shows the com-
parative stimulation produced by water and coffee. Here again it will
be observed that the response is very similar in the two cases. The above
protocols give emphasis to the belief that the stimulation produced in the
stomach by aqueous solutions of various kinds is due many times in large
part to the water alone.
That water may sometimes stimulate the stomach fully as much as
certain common foods is illustrated in Fig. 8. Here we have a direct
comparison with oatmeal, a
good standard food, and it-
will be noted that water ex-
erted a greater stimulation
than the food in question.
That Pavlov's claim,
based on animal tests, that
water stimulates gastric se-
cretion only when there is
"widespread and prolonged"
contact with the gastric mu-
cosa, does not hold, for the
human stomach has been
demonstrated repeatedly in
our work. Pronounced gas-
tric stimulation with high
acid values and rapid stom-
ach evacuation have been
Fig. 7.— Curves showing comparative stimulatory obtained after the introduc-
power of water and coffee in the human
stomach. (Fowler, Rehfuss and Hawk; un-
published data.)
fecc. d/gw.30
.45cc LJat-t
'mine h
60
tion Qf &s small a volimie as
25 to 50 c.c. of water into a
normal human stomach.
Passage of Water from the Stomach. — If water remained in the
stomach for long periods of time after its ingestion, there might be some
argument against its free use with meals. However, there is abundant
evidence that it leaves very rapidly (Cohnheim(a.), Griitzner(a) (&), 1902,
1905, Grobbels, Kaufmann, Leconte, Scheunert, Gabrilowitch). Griitz-
ner says:
"Massiges Getrank wahrend der Mahlzeit stort sicherlich die Tatigkeit
des gesunden Magens in keiner Weise, wie man vielfach angenommen hat."
Leconte, who fed two dogs normally, 2 hours later gave one of them
water, and 15 minutes later examined the stomach contents of both
animals. He found scarcely any difference between the two, the water
WATER AS A DIETARY CONSTITUENT
287
having largely left the stomach and even the duodenum. The general
consensus of opinion is that water leaves the stomach rapidly, the bulk of
it in the first few minutes along the so-called "Rinne," or trough, in the
lesser curvature, this being particularly true of the empty stomach.
Waldeyer and Kauffmann established the presence of this trough on
anatomical grounds, Ernst contributed evidence from a pathological stand-
point, and Cohnheim apparently succeeded in directly observing this
phenomenon in his experiments on dogs. Scheunert, on the other hand,
takes the opposite view and claims, from his experiments on the horse's
8
•f
d. LJairer , /oo QQ.
b. Oatmeal , ~~
t%O
Fig. 8.— Curves showing comparative stimulatory power of water and oatmeal in the
human stomach. (Fowler, Rehfuss and Hawk; unpublished data.)
stomach, that liquid in the distended stomach has a tendency to permeate
along the gastric walls.
The effect of water combined with foodstuffs has also been the subject
of interesting experiments. Grobbels is authority for the statement that
in dogs the digestion of bread followed by water is shorter than that of
bread alone. Gabrilowitch demonstrated that in the administration of a
mixture of meat and water the water passes out of the stomach, allowing
the meat to follow its customary digestion. Certain experiments in
writer's laboratory also furnish evidence that water, at least
cases, leaves the stomach very quickly. In this connection please refc
to Fig 1 p 282 In this experiment, a normal man received
of water six hours after the last meal. Twenty minutes after the water
passed into the stomach, the gastric contents showed an acid value c
and these figures were not subsequently materially altered.
that the data from this test furnish evidence of the rapidity with which
288 PHILIP B. HAWK
the water left the stomach. We may believe that the 500 c.c. of water
upon reaching the stomach at once stimulated the gastric glands to greater
activity, and caused the contents of the stomach to assume an acidity
of 19.0. Some time during the next ten minutes, i.e., ten to twenty
minutes after the water first reached the stomach, practically the entire
500 c.c. had passed into the intestine and left behind a gastric juice of
high acid concentration (111.5). That the stomach was practically
empty in from 10 to 20 minutes, as far as the original water was con-
cerned, is indicated by the uniform values obtained for acidity in the
samples withdrawn from the stomach during the next half hour. In
other words, we believe that the only acidity value which was influenced
by the factor of dilution was the acidity value of the ten minute sample.
Some time before the next specimen was taken the large volume of water
had passed into the intestine and our acidity value (111.5) represents
the true stimulatory power of the water unmasked by the factor of dilution.
This is an example of the hypersecretory type of stomach which we have
discussed in our publications (Kehfuss, Bergeim and Hawk(&)).
Another illustration of a stomach which rapidly emptied after the
entrance of water is given in Fig. 4. Here we have an acidity of 80
developed in five minutes after the entrance of 100 c.c. of water into an
empty normal human stomach. Inasmuch as the acidity values did not
materially change during the next hour and forty minutes we feel safe
in interpreting the data as indicating a practically complete emptying of
the stomach inside of ten minutes. That water and other dietary fluids,
such as coffee and tea, do not delay the emptying time of the stomach,
when taken with food, has also been shown in the writer's laboratory
(Miller, Bergeim, Rehfuss, and Hawk). Four normal men were used
as subjects. The evacuation time after a standard mixed meal had been
eaten was first determined and in later tests the evacuation time of the
same meal plus a liter of water, coffee, or tea was studied. The data are
summarized in Fig. 9.
Summarizing the various experiments which have been made to learn
the influence of water in the human stomach, we may conclude as follows :
The introduction of water immediately stimulates the gastric glands to
increased activity. In a few minutes, the bulk of the water so introduced
leaves the stomach and does not interfere with the evacuation of that
organ while its stimulatory action persists, causing the outpouring of a
highly active gastric juice which insures efficient gastric digestion. It is,
therefore, better to drink water with meals than between meals. If taken
between meals, we have the same stimulatory effect on gastric secretion,
but there is nothing in the stomach to digest, and we have thus a true
economic waste. A summary of the experiments on water drinking with
meals is contained in a publication by the writer (Hawk (e)). -
WATER AS A DIETARY CONSTITUENT
289
Influence on Pancreatic Digestion.— Pavlov has shown that when 150
c.c. of water are introduced into the stomach of a dog, the pancreas begins
to secrete, or augments its flow, within a few minutes after the water has
entered the stomach. Since this investigator found 150 c.c. of water in-
sufficient to excite a flow of gastric juice, the secretion of pancreatic juice
is apparently not secondary to a secretion of the other, but is a direct result
of the presence of water in the stomach. In the case of man, however, we
have shown that water is a pronounced gastric stimulant and causes the
passage of large quantities of acid chyme into the intestine. Inasmuch
as this acid acts as a pancreatic stimulant, we have, therefore, an indirect
Com frieze removal 06 3 Hours.
.K&j,.(Setof four). -Subjects,- Ca,GL,Tti.,Jo.
Fig. 9. — Chart illustrating the evacuation of various fluids from the human stomach.
(Miller, Bergeim, Rehfuss and Hawk; Am. Jour. Physiol., 1920, LII, 28-53.)
stimulation of pancreatic secretion (Hawk(d), 1911). On the basis of the
data gathered in the investigation just mentioned and in associated investi-
gations made in the writer's laboratory and elsewhere, we are prepared
to draw the general conclusion that the ingestion of quantities of water at
mealtime ranging in volume from ^ to 1 1/3 liters stimulates the pan-
creatic function in two ways: first, a direct stimulation of the nervous
mechanism of the pancreas brought about while the water is still in the
stomach and, second, an indirect stimulation brought about on the entrance
of the increased volume of acid chyme into the duodenum,
this augmented pancreatic activity, we would expect to find a more
efficient pancreatic digestion when water is taken with meals. Certain <
our experiments (Mattill and Hawk(&)) have demonstrated this point.
The experiments in question were performed on men living on a uniform
diet; a preliminary period of small water ingestion was followec
290 PHILIP B. HAWK
period of large water ingestion with meals, and this, in turn, by a final
period with the original conditions. When one liter of water additional
was taken with meals the average daily excretion of fat in the feces was
much reduced below that found when a minimum amount of water was
taken with meals ; one and one-third liters had a like effect. A similar but
less marked reduction was observed when 500 c.c. of water were taken
with meals.
The decreased excretion of fat observed during water drinking with
meals was usually evident for a number of days after water had ceased
to be taken in large or moderate amounts with meals indicating that the
beneficial influence of water was not temporary but was more or less
permanent. After several months of moderate water drinking with meals
a pronounced improvement in the digestibility of fat was observed, the
percentage utilization having risen from 94.3 to 96.5. A slight gain in
weight accompanied the water drinking, and this gain was not subse-
quently lost.
The better digestion and absorption of fat was probably due to the
following factors:
(1) Increased secretion of gastric juice and of pancreatic
juice as a result of the stimulating action of water.
(2) Increased acidity of the chyme bringing about a more
active secretion of pancreatic juice and bile.
(3) Increased peristalsis due to larger volume of material
in the intestine.
(4) A more complete hydrolysis of the fats by lipase, due
to increased dilution {Bradley (a)} of the medium and conse-
quently more rapid absorption.
Certain of our experiments on carbohydrate digestion are also of in-
terest in this connection. It has been shown (Mattill and Hawk, 1911),
for example, that in men living on a uniform diet the addition of 1,000 c.c.
of water to each meal causes a decrease in excreted carbohydrate material.
The better utilization of food material thus evident was not temporary
but appeared to extend for some time following the use of water. The
ingestion of a smaller amount of water (500 c.c.) and the use of a large
volume of water (1,333 c.c.) by one accustomed to drinking water with
meals showed a similar but less marked reduction in the excretion of
carbohydrate.
Other experiments on protein digestion and absorption point in the
same direction (Mattill and Hawk(d)). These studies showed that the
drinking of three liters of water with meals caused a more economical
utilization of the protein constituents of the diet. Gains in body weight
were also registered.
WATEE AS A DIETARY CONSTITUENT 291
Influence on Intestinal Flora and Putrefaction.— Since absorption is
more rapid and complete when water is taken with meals, there will be
less food material remaining in the intestine to furnish pabulum for
intestinal organisms. We would, therefore, expect to find a diminished
output of such organisms in the feces and a decreased intestinal putre-
faction. These facts have been emphasized by certain of our experi-
mental findings (Mattill and Hawk(c), Fowler and Hawk, Blatherwick
and Hawk (a) ). In one instance, the excretion of bacterial dry substance
in the feces was reduced from 8.0 grams to 6.2 grams per day as the result
of drinking about a liter of water per meal for a period of five days.
That intestinal putrefaction is reduced when water is drunk freely
at meal time has also been shown using indican as the index (Sherwin
and Hawk, Hattrem and Hawk). The decreased intestinal putrefaction
brought about through the ingestion of moderate (500 c.c.) or copious
(1,000 c.c.) quantities of water at meal time was probably due to
diminution in the activity of indol-forming bacteria following the acceler-
ated absorption of "the products of protein digestion, and the passage of
excessive amounts of strongly acid chyme into the intestine.
Influence on Absorption. — The better utilization of the fat, carbohy-
drate and protein of the diet as just discussed furnishes proof that the
drinking of water facilitates the absorption of the products of the digestion
of our food. The drinking of water dilutes the material in the intestine
and aids in its absorption. Concentrated solutions are not readily absorbed,
as is shown by the experiments of London and Polovzova(a) and others.
The latter investigators showed that when concentrated solutions of glucose
are introduced into the intestine, a diluting secretion begins to flow from
the wall of the intestine. Its amount runs parallel with increasing con-
centration of the glucose solution, and at its maximum it may amount to
one-half the total quantity of bloo4 in the animal. By this dilution and
also by absorption of sugar the concentration of the solution is brought
down to 6-8 per cent, a dilution at which absorption takes place very
readily in the lower intestinal tract. The secretion of the diluting fluid
begins with the coming in of the first glucose solution and continues fairly
uniformly. Since absorption is going on more or less continuously in
the intestine, the water taken with one meal aids in diluting the products
of the previous meal which are in the intestine. Not only is enzyme
action more complete in dilute solutions but such solutions are also bet-
ter adapted to absorption. When the solutions to be absorbed are not
dilute, the organism must first make them so by pouring out a diluti
secretion; if they have been made dilute, the organism is spared this task
Influence on Blood Volume and Blood Pressure.- The practice
drinking large volumes of water is sometimes criticized on the theory that
it increases blood volume and consequently causes a rise in blood pres-
sure. However, some Yale experiments (Bogert, Underbill and Mendel J
292 PHILIP B. HAWK
have shown that there is complete restoration of blood volume of the dog
and rabbit within thirty minutes after the intravenous injection of a
quantity of saline equal to the calculated blood volume of the individual.
Therefore, after one drinks copiously of water, the influence upon blood
volume and blood pressure is both slight and transitory.
Distilled Water. — A belief very widely held by both the laity and the
scientific worker is to the effect that the ingestion of distilled water is a
bad procedure. The absence of inorganic matter in such water is believed
to be the forerunner of various untoward influences upon the processes of
digestion and absorption. So far as I am aware, there is no experimental
basis for such a belief. One scientist (Findlay) says:
"If tissues or cells are placed in distilled water, passage of water into
the cells occurs owing to the difference of osmotic pressure. The cells
swell up and may finally burst and die. A similar poisonous action on cells
is observed when distilled water is drunk. In this case the surface layers
of the epithelium of the stomach undergo considerable swelling; salts
also pass out and the cells may die and be cast off. This may lead to
catarrh of .the stomach."
If this scientist's claims are true, then one of our fasting tests is a
notable exception. This is the fast which continued for over 100 days
and to which reference has already been made (see p. 279). The fasting
dog was given TOO c.c. of distilled water daily by means of a stomach
tube, and yet at the end of the fast the post-mortem examination failed
to show any evidence of a deranged gastric mucosa. Certainly a period
of over 100 days is a sufficiently long interval in which to demonstrate the
toxic influence of distilled water if such an influence is demonstrable.
Particularly is this true of the fasting animal, which may possess a
lowered resistance to toxic influences.
However, if we grant that distilled water, because of the absence of
electrolytes, does possess a pernicious influence upon the gastric mucosa,
it is quite logical to believe that such influence will be exerted to the maxi-
mum by distilled water taken between meals. Because of the electrolyte
content of the average diet distilled water taken along with such a diet
will cease to act as distilled water soon after it reaches the stomach. The
toxic action of distilled water, if such action is demonstrable, must be
more in evidence when the distilled water passes into the relatively empty
stomach. So far as the swelling and ultimate bursting of the cells under
the inflaence of osmotic forces is concerned, it must be apparent that os-
motic phenomena which are exhibited by non-living, excised cells do not
necessarily hold for cells actually functioning in the animal body. Distilled
water in contact with a cell of the living body may, through osmotic influ-
ence, cause a swelling of the cell, but the actual bursting of the cell will, of
course, be prevented by physiological factors which will be called into play,
thus causing the circulation to remove the excess fluid.
WATER AS A DIETARY CONSTITUENT 293
Various clinical views have been expressed as to the influence of dis-
tilled water ingestion. Some clinicians claim to have found it harmful
in certain instances, others claim it is harmless, while still others express
the opinion that the question as to its harmfulness or harmlessness must
be considered an open one. The catarrhal conditions which it is claimed
follow the drinking of water from glaciers, or the excessive ingestion of
ice, may possibly have had their origin in the low temperature rather than
in the absence of electrolytes, although no untoward symptoms have re-
sulted from the ingestion of ice water in the writer's experience (see
below) .
In our own experiments upon the influence of distilled water ingestion
with meals (Bergeim, Rehfuss, and Hawk, Blatherwick and Hawk, Mattill
and Hawk, Sherwin and Hawk), we were able to demonstrate a stimula-
tion of the gastric and pancreatic functions, better digestion and absorp-
tion of ingested food, a decrease in the growth of intestinal bacteria, and
a lessening of putrefactive processes in the intestine.
Ice Water. — When we come to ice water, we are dealing with a slightly
different proposition since the question of temperature must be considered.
In fact, the power of ice water to chill the stomach and to delay digestion
is one of the main arguments advanced against the drinking of the cold
fluid. In order to study this "terrible, chilling effect" of ice water, we
had skilled mechanics construct a very delicate apparatus which enabled
us to follow the temperature changes in the stomach while the food was
actually being digested (Smith, Fishback, Bergeim, Rehfuss, and Hawk).
And this is what we found. In twenty minutes after drinking a glass
of ice-cold water (10° C.) the temperature of the stomach contents
was approximately the same as that of the rest of the body. And in a
like period of time, the temperature of hot coffee (50° C.) was also brought
down to that of the stomach walls. It is truly wonderful how rapidly
the stomach is able to regulate the temperature of the things we put into
it, whether they be cold or hot! And the evacuation time is about the
same for cold and hot drinks. Thus the "chilling effect" of ice water and
the consequent delay in the digestion of our food is seen to be of no real
significance under ordinary conditions. However, there is one time when
we must use discretion in the drinking of ice water. That is immediately
after vigorous physical exercise, and unfortunately that is just the time
we feel like emptying the ice cooler. However, we must not do so for
serious consequences may follow the drinking of large volumes of ice-cold
fluid (water, soft drinks, etc.) at such times.
Conclusions
Before closing this discussion on water, the writer would like to
emphasize the fact that, in all of the water studies made by his associates
294 PHILIP B. HAWK
and himself, normal subjects have been employed. We have made no
clinical studies and have made no clinical suggestions. It may be true
that a person with a deranged circulatory or gastric function, or any pro-
nounced lesion of heart or kidney, should not drink large volumes of
water at any time, either with meals or between meals. The ingestion
of large volumes of water with meals may be contra-indicated in atonic
or dilated stomach, since an excessive water ingestion might promote
further atony and dilation. It may also be contra-indicated in gastroptosis,
where the gastric support is relaxed and insufficient and in certain cases
of pyloric colic and spasm. If contra-indicated in these conditions, how-
ever, we have no experimental evidence to that effect, and it is because a
large volume or weight at any one time is contra-indicated and not because
of the water per se. The writer would say, therefore, that normal persons
may drink freely of water at mealtime, whereas those unfortunate in-
dividuals who possess lesions of heart or kidney or who are troubled with
any circulatory or gastric disturbance, should have their fluid intake regu-
lated strictly according to medical advice. The literature contains at
least two observations (Marcus, Foster and Davis), indicating that the
drinking of considerable water by nephritics causes no undesirable re-
sults, whereas the finding that the introduction of an excessive volume
of fluid into the circulation causes no significant increase in blood volume
or blood pressure (Bogert, Underbill and Mendel) would seem to indi-
cate that patients suffering from cardiac disorders need not necessarily
have their water intake materially restricted.
On the basis of a large number of experiments, made in the writer's
laboratory and elsewhere, we feel warranted in concluding that the
average normal individual will find that the drinking of a reasonable vol-
ume of water with meals will promote the secretion and activity of the di-
gestive juices, and the digestion and absorption of the ingested food, and
will retard the growth of intestinal bacteria and lessen the extent of the
putrefactive processes in the intestine. Furthermore, we would place no
restriction upon the drinking of distilled water and none upon the drinking
of moderate quantities of ice cold water, except when one is overheated
following vigorous physical exercise.
That Nature knew all these things long before we did is indicated by
the fact that milk, Nature's best food, contains 87 per cent water and
by the further fact that the birds and the beasts (Eward) set man a good
example to follow in the matter of water drinking at meals.
There is an old German proverb which reads "Alles Ubel vergeht
durch Wasser und Diat." That is a perfectly good proverb, but I suggest
that it be revised to read "Alles Ubel vergeht durch reichlich Wasser in der
Piat."
The Metabolism of Alcohol Harold I. Higgins
Introduction — Absorption of Alcohol — Excretion of Alcohol — Distribution of
Alcohol After Absorption — Effects of Alcohol on Total Metabolism —
Effects of Alcohol on Protein and Purin Metabolism — Combustion of
Alcohol — Alcohol and Muscular Work — Alcohol in Diabetes.
The Metabolism of Alcohol
HAROLD L. HIGGINS
CINCINNATI
Introduction
Aside from the three important groups of foodstuffs, the proteins,
the fats and the carbohydrates, ethyl alcohol, CH3-CH2OH, is the most
available nutriment the animal organism has to meet its heat requirements.
It is burned in the body to carbon dioxid and water, and each gram of
alcohol when thus oxidized yields approximately 7.2 calories of heat.
But while alcohol thus offers good possibilities from a nutritive point
of view, its status as an altogether satisfactory food is enhanced by its
pharmacological and toxicological action. This action of alcohol at first
is most marked upon the central nervous system; the release of cerebral
inhibition and the anesthetic features 'probably stand out foremost. The
pathological changes as a result of overindulgence in alcohol are well
known. It is quite universally recognized that too much alcohol is harm-
ful to the human organism, and that, to be of any practical use for nutri-
tive purposes, the quantity of alcohol taken must be small. Therefore,
in discussing the nutrition of alcohol in this chapter the effects of mod-
erate or small quantities will be more particularly considered.
Absorption of Alcohol
Alcohol requires no digestion for absorption, but it is absorbed directly
from the gastro-intestinal tract mainly into the portal blood but also by
the lymphatics (Dogiel, 1874). A considerable proportion of the alcohol
taken by mouth is absorbed in the stomach and the remainder in the small
intestine (Bodlander, 1883). The quantities or proportions absorbed in
the stomach and in the different parts of the small intestine vary according
to the rate with which the alcohol passes through the pylorus ; alcohol taken
with food will remain longer in the stomach and a larger proportion of it
will be absorbed there than if the alcohol were taken on an empty stomach.
One observer found that twenty per cent of alcohol was absorbed in the
stomach, nine per cent in the duodenum, fifty-three per cent in the jejunum
297
298
HAROLD L. HIGGINS
and eighteen per cent in the ileum (Nemser, 1907). Alcohol is absorbed
also when given by rectum ( Carpenter (&), 1916) or when inhaled as vapor.
Alcohol is not absorbed so rapidly when taken with food as without; fat
especially seems to delay the absorption (Mellanby (e), 1919) ; the probable
explanation for this is that absorption from the stomach is not so rapid
as from the small intestine.
While alcohol does not require any digestion and is readily absorbed,
it does influence the gastric digestion of other material (Kast, 1906). A
dilute solution of alcohol increases the hydrochloric acid concentration
without affecting the pepsin content of the gastric juice; less dilute solu-
tions act as irritants to the stomach and cause increased mucus formation
and often vomiting. But while alcohol may influence gastric digestion, yet
the net effects on the availability of the fat, protein and carbohydrate in
the diet is not interfered with ; i.e., the amount of undigested residue in
feces is not essentially different when alcohol is taken from when it is
not (Atwater and Benedict -(e), 1902). That is seen in the following
table:
Coefficients o:
Availability
Protein
Fat
Carbohydrates
Energy
Experiments
Without alcohol
%
92.6
%
94.9
%
97.9
%
91.8
With alcohol
93.7
94.6
97.8
92.1
The absorption of alcohol is rapid; this has been demonstrated (1)
by the. early psychological effects from taking the drug (Dodge and Bene-
dict, 1915), (2) by its beginning to be burned in five to ten minutes after
ingestion (Higgins (a), 1916), and (3) by increase in the concentration of
alcohol in the blood (Mellanby (e), 1919). Very soon after taking alcohol
(one-half to two hours), the blood will show the maximum concentration.
Excretion of Alcohol
From two to ten per cent of alcohol taken by mouth is excreted as
such in the urine, the breath and the sweat (Atwater and Benedict, 1902 ;
Voltz, Baudrexel and Deitrick, 1912). The remaining ninety to ninety-
eight per cent is burned to CO2 and H2O. Alcohol is absorbed di-
rectly into the blood without chemical change, and is excreted in part
unchanged by the kidneys, the lungs and the sweat glands. Alcohol is
also excreted in the milk of nursing mothers (Nicloux(a), 1899). The
amount excreted in the expired air and sweat is increased during muscular
work, with the increased respiratory ventilation and sweating. The
elimination of alcohol by the kidneys and lungs, also by the mammary
glands, is by diffusion, the percentage of alcohol in the urine and milk
THE METABOLISM OF ALCOHOL 299
practically equaling that in the blood (Widmark (a), 1915- Nicloux C6)
1900).
Distribution of Alcohol After Absorption
The maximum concentration of alcohol in the blood is usually equal
to or slightly higher than one would find if there were even distribution
of alcohol throughout all the tissues (Mellanby(e), 1919). Analysis of
various organs and tissues of the body after alcohol has been taken show
that alcohol is quite equally distributed everywhere, but apparently there
are some small differences, for the liver and heart muscle in rats have been
reported as containing relatively low while the brain and blood contain
relatively high percentages of alcohol (Pringsheim, 1908). This is shown
by the following experiment:
Alcohol 5 c.c. per kilogram body weight given.
If equally distributed there would be 0.5 per cent throughout the body.
There were found in the
Blood 0.52%
Brain 41%
Kidney 39%
Liver 33%
The percentage of alcohol in the blood, or in the urine, should prove a
good index as to the pharmacological and psychological effects to be ex-
pected; one observer states that intoxication does not appear unless the
concentration of alcohol in the urine exceeds one-tenth of one per cent
(Widmark (6), 1917).
Effects of Alcohol on Total Metabolism
Alcohol in moderate amounts does not increase the total metabolism
of the human body (Atwater and Benedict (e), 1902; Zuntz and Berdez,
1887; Geppert(a), 1887; Higgins(6), 1917). Both the heat production
i.nd the heat elimination are essentially unchanged, for moderate quantities
of alcohol cause no appreciable change in body temperature (Atwater and
Benedict, 1902). However, large quantities of alcohol lead to marked
peripheral vasodilatation with fall in body temperature; this is a cause
of increased heat elimination, which in turn is followed by increased
heat production as the body temperature returns to normal. Alcohol
in being burned acts to replace some other source of energy and
neither a stimulant nor a depressor of the metabolism, and does not serve
merely for "luxus consumption."
300 HAROLD L. HIGGINS
Effects of Alcohol on Protein and Purin Metabolism
Alcohol does not appreciably affect the protein metabolism ; it neither
acts as a protein sparer nor, unless taken to excess, as a protein destroyer
(cell-poison) (Rosemann (a)). This is shown by determinations of the
urinary and food nitrogen (nitrogen balance experiments). There is an
increase in the nitrogen output and a negative nitrogen balance for about
two days after alcohol is added to the diet; this is probably due to the
change in the water balance of the body and non-protein nitrogen content of
the body fluids and is associated with the diuretic action of alcohol; the
nitrogen balance is uninfluenced by alcohol after the first two days. Some
workers report that alcohol increases the uric acid excretion, while others
have claimed that alcohol causes no change at all or an insignificant change
(Rosemann (a) ; Mendel and Hilditch, 1910). Changes in the excretory
action of the kidney rather -than in the true uric acid metabolism seem
to be the cause of the discrepancies found, and supplementary analyses
to determine the uric acid content of the blood will be necessary to deter-
mine if the uric acid metabolism is affected by alcohol.
Combustion of Alcohol
Alcohol is burned by the body up to a certain percentage, when avail-
able in the tissues, in preference to either fat or carbohydrate. Experi-
ments with men and animals show that the rate of combustion of alcohol
is independent of the amount taken and comparatively constant (Mel-
lanby(e), 1919; Voltz and Dietrich, 1912; Higgins(&), 1917). Over
fifty per cent of the total heat production of the body seldom, if ever,
comes from alcohol. When 30 c.c. of alcohol were taken by a man, the
percentage of the total oxygen consumption used in burning alcohol during
the first two or three hours was as high as when 45 c.c. were taken ; about
20 to 40 per cent of the heat production (total metabolism) came from
the alcohol, i.e. with a man in the resting state, about 3.5 c.c. of al-
cohol was burned per hour ; thus if the same rate of combustion of alcohol
continued (which is the case in animals) it would require 8 hours for all of
30 c.c. and 12 hours for all of 45 c.c. of alcohol to be burned (Higgins,
1917). The period during which alcohol will stay in the body when large
amounts are taken is surprisingly long. Thus if a physician desires to
give alcohol to a patient for its nutritive value, he should obtain as satis-
factory results nutritionally and avoid many of the untoward features of
alcohol, by giving it in small doses (10 c.c. or less), which may be repeated.
Alcohol displaces carbohydrate and fat acting to spare them. It prob-
ably displaces a larger proportion of carbohydrate than fat ; i.e., if there
THE METABOLISM OF ALCOHOL 301
is a certain proportion of carbohydrate and fat being burned, and alcohol
is ingested, it will be burned in preference to either up to about forty
per cent of the total caloric expenditure of the body, and the ratio of
carbohydrate to fat displaced in the combustion will 'be greater than the
ratio of carbohydrate to fat previously being burned (Mellanby(e), 1919).
Alcohol and Muscular Work
While experiments have definitely proven that alcohol is burned in
the body, and that it displaces carbohydrate and fat, but not protein, yet
whether the potential energy of alcohol can be changed into the kinetic
energy of muscular work in the body is still a matter of conjecture (At-
water and Benedict, 1902; Chauveau(a) (6), 1901). Experimental evi-
dence is not at all conclusive, although it is generally believed probable, in
the absence of evidence to the contrary, that alcohol can be converted into
muscular energy. It is true that when alcohol is added to the diet of a
person doing heavy muscular work, the work is not so efficiently nor so
easily done (Van Hoogenhuyse and Nieuwenhuyse, 1913; Durig(a),
1906).
Definite and rather startling feats of endurance can be performed after
alcohol is taken ; thus one can hold the breath a longer time after taking
alcohol than before, or one can hold on a bar longer or lift one's weight
from the floor oftener at a given rate, etc. (McKenzie and Hill, 1910). A
patient has been observed to be able to hold his breath fifty-three seconds
before and one hundred and five seconds after alcohol (L. Higgins(fe),
1917). This is probably to be explained on the basis of the dulling of
the nervous centers by alcohol so that the brain does not react to fatigue
so readily as normally, and it is not due to the energy yielded from the
alcohol. But the fact stands out that alcohol gives one the power to per-
form certain feats of endurance of short duration.
Alcohol in Diabetes
Alcohol has been recommended in certain diseases, notably in diabetes.
The diabetic person apparently can utilize alcohol much as the normal
person, and can obtain a food value from it. Alcohol does not, however,
act as an antiketogenic agent, i.e., in being burned, it does not act to pre-
vent the formation of the acetone bodies as do carbohydrates (Higgins,
Peabody and Fitz, 1916). However, if a diabetic has a change made in
his diet so that a given amount of fat is substituted by an isodynamic
quantity of alcohol, less acetone bodies will be formed in the body; i.e.,
alcohol does not form acetone bodies in its intermediary metabolism (Bene-
dict and Torok, 1906).
Mineral Metabolism
. . . . Henry A. Mattill and Helen I. Mattill
Water— Sodium Chlorid — Alkalies — Calcium — Magn esium — Phosphorus —
Iron — Sulphur — lodin — Xeutrality Begulation — Disturbances in Mineral
Metabolism Accompanying Pathological Conditions.
Mineral Metabolism
HENKY A. MATTILL
AND
HELEN I. MATTILL
ROCHESTER
According to Albu-Neuberg the mineral constituents of the adult, hu-
man body amount to 4.3-4.4 per cent. In this ash occur the elements Ca,
P, K, S, Cl, Na, Mg, I, F, Fe, Br, Al, named in the order of decreasing
amounts (Hackh). Any statement regarding exact amounts of the differ-
ent elements is fraught with uncertainty for two reasons : first the paucity
of reliable analytical data, secondly the individual variability due in part
to differences in the organism, in part to differences in food habits and
possibly to the existence of pathological conditions. The ash constituents
of the new-born have been determined by Camerer and Soldner with re-
sults which show considerably more uniformity than do those on the adult.
They find 2.10 to 2.73 per cent ash of which 38.5 per cent is P2O5, 36.1
per cent CaO, 9.1 per cent Na2O, 7.8 per cent K2O, 7.7 per cent Cl, 0.9
per cent MgO and 0.8 per cent Fe2O3. As compared with the adult these
values are characterized by low total ash, CaO and P2O5, and by high Fe.
About 5/6 of the total ash occurs in the bones. Fresh bones contain
about 35 per cent ash, about 84 per cent of which is Ca:{ (PO4)2, 1 per cent.
Mg3(PO4)2 and 7.5 per cent other Ca salts. About 99 per cent of the Ca
in the organism is in the bones, about 70 per cent of the Mg and about
75 per cent of the P.
In a comparative study of the composition of the teeth of man and dog
Gassmann(a) found 74-82 per cent ash. He was not able to recognize F.
He found Ca and P most abundant, organic matter lowest,, in the wisdom
tooth, while organic matter was high and Ca and P low in the dog's tooth.
Cartilage contains only 1-6 per cent of mineral matter and its ash
is higher in Na than that of any other tissue of the body, and is also
characterized by a large amount of sulphates, which probably existed as
organically combined S in the fresh tissue.
It may be safely assumed that the bone portion of the ash constituents
is subject to less rapid metabolic changes than the remaining 1/6, of which
the greater half is found in the muscles, the lesser half in the blood and
303
304 HENRY A. MATTILL AND HELEN I. MATTILL
s *
•§!
cc 2
•* O
03 W
>H O
CO
<N CO
CO CO
ic o oo
co e*s ic i— '
o •* Oi <o
cq «q o <N
rH r-H i— * O
o «o i-H eo «j
O <N O r- O O
C» »j •* o •-; w <N
t~I CO O >-H O O i— i
,eo
i- e-3 o i-! o c o <>i co >
MINERAL METABOLISM
TABLE n
305
100 gm. fat-free, dry substance contain
Cl mg.
Fe mg.
Ca mg.
Mg mg.
Muscle
302
769
1421
529.8
859
' 1087.5
525.4
933
845
848
2545
125
39.6
372
335.5
385.6
82.6
114.6
26.1
34.5
29.0
56.9
33.2
46.8
92.3
39.7
49.6
100.4
116.3
92.2
82.4
169.4
93.6
106.4
102.9
40.9
96.6
75.7
108.2
63.7
97.4
48
107
Heart
Lungs
Liver
Spleen
Kidney
Intestine
Pancreas
Salivary gland
Thvroid
Testicles
other fluids, the nerves and organs. Dennstedt and Rumpf have made an
exhaustive study of previous work on the mineral constituents of the dif-
ferent organs, and from this and their own work have compiled a table (I)
giving what may be considered representative figures. These values are of
interest chiefly in that they give an idea of the comparative abundance
of the different elements, and they are to be considered as only approxi-
mately expressing the composition of any individual normal organ. There
are no fixed relations in the ratio of different elements to each other, and
variations amounting to as much as l/o to 2 times these average values maj'
be found.
Recent work by Magnus-Levy (;') which is summarized in Table II is of
special interest when compared with the values given above, for while the
analyses are calculated to a different basis they allow comparisons of the
relative amounts of the different elements, and show rather wide differ-
ences from the results of Uennstedt and Rumpf. That much of the nor-
mal variation may be due to variations in the fat and water content of
the organs, components which may vary widely under physiological con-
ditions, is very probable, especially in the earlier analyses. Magnus-Levy
has eliminated these variables by calculating to a dry, fat free basis, and
has probably eliminated variables due to pathological conditions, since
his subject was a suicide. Pathological conditions are usually char-
acterized by increased water and NaCl content, and by decreased Ca and P.
In the highly specialized cells the ratio of K : Na is higher than in
supporting tissues (Gerard). In muscle, K phosphate is the predominant
constituent and Mg is more abundant than Ca. As the result of analyses
by Bunge, Aron gives the relationship of K : Na in muscle as 5-6 : 1.
Benedict concludes that there is approximately three times as much Mg as
Ca in the human muscle. Ileubner found 0.15 per cent P in the fresh
muscle of young dogs of which 70-90 per cent was water soluble (phos-
phates), 0.05 per cent P in the skin and 1.5 per cent P in bones. Meigs
and Ryan have found the smooth muscle of the frog lower in K, Mg and
306
HENRY A. MATTILL AND HELEN I. MATTILL
P, and higher in Na and Cl than the striated muscle. Since the K and
P content of muscle is greater than that of the surrounding fluids, blood
plasma and lymph, they conclude that the fibers of muscle are not sur-
rounded by a semipermeable membrane, but that most of the water and
of the K, P, S and Mg in the tissue is held in colloidal combination in a
non-diffusable form. Many of the ductless glands are characterized by
their rather marked content of one of the mineral elements in organic
combination, as the spleen by iron, the thyroid by iodin and bromin
(Labat), the hypophysis by P, the thymus by arsenic (Diesing).
Weil has recently studied the mineral constituents of human nervous,
tissue (Table III). If the concentration of these elements in the fresh
nerve substance is considered, there is a rather interesting classification into
two groups, the first of which, comprising Ca, Mg, P, S, Cl, shows wide
variations in concentration, and the second of which, including Na, K,
and Fe, maintains about the same concentration in the different nerve
tissues. In view of the effect of the Ca concentration on irritability (see
p. 336) it is interesting to note the lower concentration of Ca in gray
matter. If the analyses are calculated to a water-free basis the conditions
are reversed, the concentration .of the first group is nearly constant, of
the second group variable.
TABLE III
1000 gin. Fresh Nerve
Substance Contains
Gray Matter
Cerebellum
White Matter
Spinal Cord
Ca
0.104
0.103
0.142
0.179
Me .
0.196
0.203
0.260
0.380
P . .
2.39
2.58
4.21
5.48
S
0.56
0.61
0.92
0.85
Cl
1.13
1.08
1.51
1.52
Sum (1-5)
4.380
4.579
7.042
8.409
Na
2.03
2.20
2.25
2.01
K
3.45
3.49
3.38
3.61
Fe
0.068
0.050
0.064
0.055
Sum (6-8)
5.538
5.740
5.694
5.675
Total (1-8)
9.918
10.316
12.736
14.084
Water
833
815
702
644
The understanding regarding the mineral constituents of the blood
is even less satisfactory, and is subject to greater confusion than is that
of the organs because in addition to the application of unsatisfactory
methods, there has been confusion as a result of subjecting only a part
of the blood, as the serum, the red blood corpuscles or the plasma, to analy-
sis. Recent work is bringing order out of this chaos, with the result that
the blood is coming to be looked upon as that constituent of the body show-
ing most constant composition with respect to mineral constituents, under
normal conditions (Table IV). From this it is not to be concluded that
MINERAL METABOLISM
307
o
^
0
C« .
fe **
2J CS rH _
o oo oo S
cs os ic
rH rH rH *-«
il
a
' o4
1C
t-
GO be
1C
I-H
P-i be
1C
(M t^ O
CO 1C CO
0 O '
£
"S
1
o
be .
to —'—
g 0 £»U5
2 §SSS
•a
<=> ^ S o 6
o
^0
.S ""• —
'o
0
^ ti)
(M rH
rH rH
^
°
0
"3
S
C
O
^5
o
« <N
bi
o
rH1 bC
OS CO •f OO
CO rH 1^ CO
t^ GO CO CO
£«•'.
30
L?2
0
rH
.S
c
be
ej
O .
as be
oo w o ic ^s
rHCOCO<M CO OHh-COi-HrHgq
COfNiCI"- >C O^OCOOOiCcS
fc
T* Tji HH CO •* '"' •— ' 'C CO >C 1C 1C
„ &,
c
-^ 00 Tj<
Q be
S 00 0
g«<»
0 .
B60
rH ^
-a CO HH Tt< 1C CD
(M Tf rH 001-
g cc i- QO i- r-
'.' '.'.'• V '•'• v ^ '•'"*'•
S % ^-3 :c S
3 C _ § C "H
w ,* £3 o '~l i. a
=a^ K •? •33^-3
S " Hi -P '"^ fl ."to 53"S^ ^~
"1 ifi! •« "« ^ * ^ *'"c C S ra i- ^
S3
*CJ Ctf C ^ OJ """ Qj t-> "^ VN CG "^ "^ *rW ^™* ,22
S
CS
£
ff
J
308 HENRY A. MATTILL AND HELEN I. MATTILL
the composition of the blood is fixed, but rather that it varies within nar-
rower limits than those for the composition of the organs.
Of the less abundant mineral elements Gautier has called attention to
'the wide distribution of F(d) and As(a) in the organism. F bears rather
a striking relation to P ; in the soft tissues and glands P : F is about 450, in
the supporting tissue, bone and cartilage it is 125 and in the epidermis,
hair and nails it is approximately 4. Injection of NaF into rabbits has
been found to have an undesirable effect on Ca metabolism and F in foods
is to be avoided (Schwyzer). Arsenic, Gautier found in the thymus and
thyroid, in menstrual blood, in hair and skin. Bertrand confirmed these
findings, which have been denied by others, possibly because organic As
compounds would escape ordinary analytical methods. Van den Eeckhout
found that ingestion of As promoted growth and well-being in animals.
Bang(/) found that As in the urine varies greatly, depending on the
amount in the foodstuffs, and may reach 0.5 mg. daily. Fish is especially
high in As and on a fish diet he found 0.78 mg. As daily, while on a vege-
tarian diet the urine was As-free.
Silica is normally present in the urine and feces in amounts fluctuating
with the intake (Schulz(a)). It is widely distributed in the body and
comprises 40 per cent of the ash of hair and seems to be an essential con-
stituent of the pancreas. Kahle calls attention to the loss of SiO2 by the
pancreas and its increase in the lymph glands of tubercular cattle, and to
its increase in the pancreas in carcinoma. He found that the administra-
tion of the organic preparation of silica made by Weyland had a beneficial
influence on the formation of connective tissue in the affected organs of
tubercular guinea pigs. Schulz(c) considers that Kahle is not justified
in his generalizations since there is a wide variation in the SiO2 content of
glands of tuberculous and carcinomatous patients. He found 0.0084 per
cent SiO2 in the normal dry thyroid and a larger amount in pathological
thyroids(&). Gassmann(6) has identified selenium in teeth and bones.
Mn (Reiman and Minot; Bertrand and Medigreceanu) is widely dis-
tributed in the human organism and is highest in the liver, averaging
0.17 mg. per 100 g. moist tissue. The blood contains 0.004-0.024 mg. Mn
per 100 g., its function is probably catalytic. Small amounts of Cu and
Zn are widely distributed in the body and always present in the urine and
feces, their sources being undoubtedly the ingested foods (Van Itallic and
Van Eck; Rost and Weitzer).
Older conceptions of the relative unimportance of salts for nutrition
and the easy assumption that a normal mixed diet always supplied what-
ever need there might be for inorganic elements have recently given way to
a recognition of the very definite needs of the body with respect to min-
eral constituents. Forster first established the fact that salt-poor diets
led to faulty nutrition. What little work has been done on the ingestion of
a salt-free diet leads to the conclusion that salts in the food are not pri-
MINERAL METABOLISM 309
marily necessary for the digestion or utilization of the foodstuffs, but
that their lack even over a brief period leads to unpleasant nervous' phe-
nomena such as sweating, lack of appetite, listlessness and disturbed
sleep and to fatal results if long continued (Lunin). Taylor (b) in a 9-day
experiment on himself during which he ingested a ration consisting of 70-
75 g. washed white of egg, 120 g. of fat and 200 g. sugar and containing
less than 0.1 g. of salts, per day, noticed especially the nervous symptoms
and a general muscular soreness. On the 9th day acetone was noticed in
the breath, and acetone and diacetic acid in the urine, whereupon the diet
was discontinued. The elimination of Ca and Mg through the urine ceased
entirely after four days ; Cl reached a minimum of 0.2 g. daily, phosphates
were constant and conjugated sulphates were abnormally high ; urinary
ammonia rose only on the appearance of diacetic acid, suggesting that the
fixed alkalies are required for the neutralization of the strong acids of S
and P. Urinary acidity was constant. Diuresis and a loss in body
weight (which was quickly regained on return to a normal diet) indicated
a loss of water from "the body. Goodall and Joslin repeated Taylor's experi-
mental procedure on two subjects, and in both cases failed to confirm the
appearance of either acetone or diacetic acid in the urine, although the
nervous symptoms were similar, and they agree with Taylor in finding
extremely low urinary chlorin, and considerable loss of weight due to a
loss of body water. Unfortunately no complete study of the mineral bal-
ance was made and the opportunity which these conditions gave for throw-
ing light on the fundamental mineral exchange in the body was lost. That
the undesirable symptoms are in part though not entirely due to the acid-
forming S and P present in the protein seems clear from the early work
of Lunin, who found that Na2CO3 added to a salt-free diet prolonged
the life of mice to about double its duration without the Na2CO3 but did
not prevent death with the usual symptoms.
Fasting experiments have long been used to obtain fundamental infor-
mation upon the metabolism of organic matter. The excretion of inor-
ganic material during fasting gives similar information on mineral econo-
my. In the study of prolonged fasting made at the Nutrition Laboratory
of the Carnegie Institution ( Benedict (/O) it appeared that the excretion
of MgO (per kg. of body weight) was practically constant, especially after
the first six days, and was about one third of the Ca excretion. There was
a notable parallelism between the daily loss of Mg and of body protein
although the Mg was always slightly greater than the calculated value from
catabolized protein, using Magnus-Levy's figure of 0.106 per cent for the
Mg content of dry muscle. Sodium elimination gradually fell during the
first fifteen days, thereafter it was constant at a very low level (about
0.0011 g. Na per kg. body wt.) After the fifth day K2O formed !
per cent of the total alkali excretion (Na and K). If muscle has three
times as much Mg as Ca and 5 or 6 times as much K as Na, mineral ehmi-
310 HENRY A. MATTILL AND HELEN I. MATTILL
nation in fasting cannot be regarded simply as waste products from protein
catabolism. After 15 days Cl elimination was practically constant at 0.15
g. daily and was derived for the most part from disintegrated muscle sub-
N
stance. The ratio was always lower than the accepted value for
*2^5
flesh, 6.6, the excess of P2O5 undoubtedly resulting from the metabolism
of bones. Elimination of S was always less than would be expected from
N
the ratio-— -= 13.3 in protein, and Benedict considers this an indication
k5
of the catabolism of some substance high in nitrogen and low in sulphur.
The elimination of Ca and P, and to a less extent of K, in excess of that
accounted for by muscle catabolism may be interpreted as an indication
of a metabolic need for these elements which when not met by a proper
intake is in normal cases met by the reserves in bone.
In their book published in 1906 Albu-Neuberg repeatedly deprecate
the lack of sufficiently complete metabolism experiments to enable them
to come to any reliable conclusions regarding the mineral requirements of
the adult organism. Most of the work up to that time had been limited
to the investigation of urinary excretion, and because of the lack of any ap-
proximately fixed relation between urinary and fecal output of Ca, Mg
or P, was valueless. They point out that only by a painstaking investiga-
tion not only of the urinary output but also of the fecal output and of the
food intake, can any reliable data regarding minimum requirements for
normal conditions be obtained. Furthermore, in such controlled experi-
ments, in which the intake is varied by the addition to the food of the
mineral constituents sometimes in inorganic, sometimes in organic com-
bination, another element of uncertainty is introduced in that the ab-
sorption and hence availability to the body of the minerals is not inde-
pendent of the form in which they are ingested, and also the absorption of
one -mineral constituent depends to a degree on the quantities of other
food materials ingested, e. g., a condition of Ca equilibrium may be con-
verted to a minus balance by the ingestion of an increased amount of P,
of carbohydrate or of fat. We have only made a beginning in the acquisi-
tion of data which will finally lead to as definite an understanding of
the mineral requirements as we now have of protein and energy require-
ments. With the recently attained success in feeding mixtures of puri-
fied foodstuffs to experimental animals has come a new method of deter-
mining the mineral needs. McCollum and Davis (/) have by this method
shown that a ration in which the acid forming elements far outweigh the
basic elements may support growth but is quite inadequate for reproduc-
tion. Osborne and Mendel (e) have varied the mineral content so as to re-
duce the quantity of one element after another, or of several at once, to a
minimum, and they find that rats grow normally and equally well whether
MINERAL METABOLISM 311
deprived of Mg, Na or Cl or of all three. If deprived of K growth is not
very satisfactory and when deprived of both Na and K it ceases Lack
of Ca or P is promptly followed by a slowing of growth.
Water
Of all the body constituents water is present in greatest proportion
and except in the bones and fat it comprises more than one half the weight
of the fresh substance. Three factors exert their influence on the water
content of the body and of the individual organs. First, the age. The
fetus has the highest percentage of water, at the third' month 94 per
cent, which falls rapidly so that by the fifth month it is approximately the
same as at birth, 66-69 per cent (Camerer and Soldner). In the adult it
is 58-63 per cent. Second, the nutritional condition of the organism.
With poor nutrition the water content of the body increases, as a result of
loss of fat, since water and fat are present in the tissues in quanti-
ties which vary inversely (Voit(fe)). The ingestion of carbohydrates
(Weigert(a)) and of NaCI favors water retention. Strauss(rf) claims
that for every 10 to 15 grams of salt retained iy2-2 kg. of water are
retained, and he considers this a "sero" rather than a tissue retention.
Third, a pathological condition is in many cases, especially in fibrile dis-
eases, accompanied by water retention. Balcar et al. consider this to be the
result of a poisoning of the tissues which causes them to combine with
excessive quantities of water, thus interfering with regulation of body
temperature by surface evaporation. By the injection of a solution con-
taining 5 per cent NaCl and 1 per cent Na2CO3 until diuresis deprived the
body of large quantities of water they were able to produce fever experi-
mentally, and they compare this fever with the salt or inanition fever of
new-born infants, both of which disappear on the administration of water.
Sakai's analyses of the blood of new-born infants as compared with
that of nursing infants and adults show a lower percentage of water, and a
higher percentage of salt in the new-born, H2O : Xa.Cl == 122, than in
either of the others, H2O : NaCl == 140 — 142. The maximum water con-
tent of the blood occurs at about three months of age and a too long con-
tinued liquid diet for babies is apt to prolong the period of high blood
dilution with pathological consequences (Lederer; Widmer(6)). The
normal water content of the blood is occasionally decreased in diabetes but
pathological conditions usually result in its increase.
Edema is a water retention accompanied by salt retention which
Fischer (6) considers the result of an accumulation of acid in the body
(acidosis) since he has shown experimentally that increased II ion concen-
tration promotes the absorption of water and of NaCl by protein. Hender-
son does not consider this explanation adequate because he finds no in-
312 HENRY A. MATTILL AND HELEN I. MATTILL
creased colloidal swelling in H ion concentrations within the ranges that
occur in the body or the urine, and because acidosis is not always accom-
panied by edema.
The requirement of the body for water is of course dependent to a
degree on climatic and occupational variations, but under comparable con-
ditions a child requires more water per kg. of body weight than an adult.
Bartlett is of the opinion that a child 6 months old needs 122 g. water
per kg. and an adult 35 g. Widmer(&) considers that a child 6 months old
should receive 115 g. per kg. ; a child 1 to 2 years old 65-110 g. water per
kg. and that 85 g. is the optimum ingestion for a 2-year-old child. The
daily loss of water through the lungs is 400-500 g. for adults. Lack of
water, if accompanied by the ingestion of food, results in increased pro-
tein metabolism (Spiegler). A fasting animal is supplied with water for
its body needs by the catabolism of its own tissues, and usually shows little
inclination to drink. Excessive water drinking, in fasting or with food,
causes temporarily increased N elimination followed by improved protein
economy (Fowler and Hawk, Orr).
Sodium Chloric!
In how far sodium chlorid is a food and in how far it is a condiment,
is a question which is open to discussion and which is not of particular im-
portance. A certain amount of it must be considered a necessary food
constituent for all but strictly carnivorous animals who suck the blood,
as well as eat the flesh and bones of their prey, but there is no doubt that
habit has resulted in the use of much more NaCl in the human dietary
than is physiologically necessary. Albu-Neuberg state that 1-2 g. of Nad
daily is sufficient. While custom varies considerably the average daily
intake is probably nearer 8-10 gr. Bunge's explanation that the need of
N"aCl by herbivora and animals living on a mixed diet is due to the pre-
ponderance of K over Na in grains, vegetables and flesh and that the ab-
sorption by the blood of the salts from these foods leads to a loss of blood
Na and Cl which must be compensated by ingestion of NaCl, is still gener-
ally accepted. According to this theory the K and Na salts from the food
enter the blood as organic salts or as phosphates and since the ratio of
K to Na is higher than in the blood, the excess of K salt reacts with NaCl
in blood, producing KCL and a Na salt, both of which are excreted by the
kidneys thereby impoverishing the body of NaCl. Koppe has added to
this the theory that salt hunger may be due to a lack of ionized salts in vege-
table foods.
The relation of salt to water retention has already been mentioned
(p. 311). This matter has been attacked experimentally from different di-
rections with interesting results. Cohnheim and his co-workers have shown
MINERAL METABOLISM
313
«
that the water lost on profuse sweating is much more rapidly regained on
a salt-rich than on a salt-poor diet, when water and food intake are other-
wise unchanged. They hold that the largo amount of dilute urine follow-
ing muscular exertion is due to the thirst which prompts water drinking
and since no salt is taken with the water it cannot he incorporated .into
the body. The fact that thirst is only transitorily slaked by water drink-
ing under such conditions is also a result of the lack of NaCl.
Working from the other direction Belli reduced his NaCl intake to
a minimum during 10 days of a metabolism experiment which consisted
of 4 days preliminary period (10.2 g. NaCl daily) 10 days salt-poor
(1.03 g.) and 3 days final (9.32 g.). His decreased water intake during
period II (2000 g.) was enough to account for his loss of weight (1.3 kg. )
since water excretion was practically unchanged, and in the final period
he^apidly regained weight with water balances as follows :
•
Water Intake
Water Loss in
Urine and Fecea
Body Weight, Kg.
Last day, period II
2102
1517
04 g
1st day period III
2279
950
65 6
2nd day, period III
2292
1327
66 2
3rd day, period III
2087
1833
66 2
During period II the urinary Cl fell to 0.04 per cent and in the last five
days there was Cl equilibrium. Klein and Verson in 1867 found a similar
loss of weight in a period without salt and in the following period a large
gain which they ascribed to water retention.
In experimental work on a diet free from all mineral constituents
similar losses of weight have been followed by a rapid gain, in one case
4.1 kg. in 72 hours, on a return to a normal diet or on the addition of
only lSTaCl (Taylor(&) ; Goodall and Joslin).
There is apparently no continuous storage of NaCI in the body, an
increased intake may result in slight retention for a few days, but equilib-
rium is soon established on the higher level. In work on dogs v. Hoesslin
established that on an intake sufficient to exceed the minimum needs all
the ingested NaCl was eliminated by the kidney, not equally on all days
but with daily and periodic variations. On a quantity of salt much ex-
ceeding the minimum needs there was likewise equilibrium over a long
period, but from day to day the capacity of the organism for water and
salt varied within limits which were about 10 per cent each way from the
average. The water content of the feces is less the greater the salt intake,
Cl and water secretion by the kidney run approximately parallel.
Urinary elimination of Cl undergoes a rapid rise upon ingestion of
food (Dobrovici; Hermannsdorfer), due to absorption of NaCl by the
stomach, followed by a fall representing secretion of HC1 in the gastric
juice, which is accompanied by increased alkalinity of the blood (Van
314 HENRY A, MATTILL AND HELEN I. MATTILL
Slyke, Cullen and Stillman), and then, a slow rise representing absorp-
tion from the intestine.
On a salt-free diet and in fasting the salt elimination soon falls to a
very low level, below 0.3 g. chlorin daily, and remains there. It is im-
possible to lose more than 10-14 per cent of the body chlorids and Rose-
mann has shown that the body husbands its supply of chlorids so thor-
oughly that only by removal of the HC1 of the gastric juice by fistula or
stomach tube can symptoms of Cl hunger and malnutrition be produced.
The ingestion of NaCl after fasting is followed by retention for a few
days and then the equilibrium is reestablished. Recent work indicates that
the skin is an important storage place for chlorids (Padtberg(a) ; Wahl-
gren).
Early work on the influence of NaCl on metabolism led to the con-
clusion that it stimulated protein metabolism but later work on sheep, dogs
and men has proven that moderate quantities of NaCl act as a protein
sparer (Belli) reducing the N elimination 2-6 per cent without affecting,
the total energy exchange. Pescheck («)(&) has shown a similar protein
sparing action of Na acetate, citrate, lactate and Mg acetate, in some cases
accompanied by diuresis. The ingestion of NaCl increases the renal and
decreases the intestinal elimination of Ca, probably without changing the
total excretion (Towles; v. Wendt(a)).
The blood is characterized by a greater constancy in NaCl concentra-
tion than is any other body constituent (Biemacki, Gerard). In children,
the plasma NaCl varies between 0:536-0.626 per cent, avg. 0.587 per cent,
and in disease it is usually below normal. Veil found that in adults the
plasma NaCl varied between .575 and .637 per cent with an average of
0.61 per cent. The corpuscles contain about 40 per cent as much as the
serum (Snapper (6)). Authorities differ as to the influence of the diet,
Veil found plasma chlorids decreased on a salt-poor diet, increased on a
salt-rich diet, Arnoldi(fr) found the opposite unless a large ingestion of
water accompanied the high NaCl intake, when chlorids might be in-
creased. Austin and Jonas found chlorids independent of diet and
Barlocco found that the administration of NaCl per os resulted in a transi-
torily increased concentration of blood salt followed by a decrease which
continued until compensated by kidney activity, when it again increased;
while intravenous injection did not produce the preliminary rise, but
caused reduced NaCl concentration followed by a rise unless nephrectomy
had been performed. In view of recent findings on the tendency of the
organism to maintain constant blood volume and concentration (Bogert,
Underhill and Mendel ; Smith and Mendel) the question deserves further
investigation. Gastric secretion does not appreciably affect blood chlorid
concentration (Rosemann(/)). Ingested salt seems to be without effect
on the gastric secretion judging from the work of Rosemann and from
the normal food utilization found in salt-free diets. On the other hand
MINERAL METABOLISM
315
there is evidence that loss of salt through excessive perspiration leads to
hypoacidity (Cohnheim and Kreglinger).
Work by Frouin and Gerard on a dog with Pawlow stomach may bear
upon this. Having usually received 10 g. NaCl daily, the dog was re-
duced to a salt-free diet of 200 g. rice and 700 g. horse meat cooked in
water with the following results :
NaCl
Intake
Gastric Seer.
24 Hrs.
Acidity as g.
HC1 per liter
Total Chlorids
asg. HC1 per 1.
K per
liter
Na per
liter
Jan. 12 0
350 c.c.
2.81
5.55
13 0
275
3.32
5.57
14 0
115
3.28
5.67
15 0
113
1.97
5.57
16 0
96
1.38
5.84
0.15
2.21
17 5 g.
185
3.39
5.98
18 5 g.
190
3.06
5.39
0.22
0.96
19 0
90
1.20
5.90
which are striking for the constancy of the total chlorid content and the
decreased acidity of the secretion with -lack of NaCl in food. The ingestion
of a chlorid, whether NaCl, KC1 or CaCl2 brought the quantity, acidity
and concentration of Na and K in the gastric juice back to normal. Batke
found a similar decreased gastric acidity in salt hunger.
Since ingestion of acids causes loss of alkalies from the body the Na
and K elimination in hypo- and hyperchlorhydria has been the subject of
some investigation, and has been found to be unaffected by such gastric
disturbances (Secchi(6)). Blood chlorid in hypoacidity may be higher
than in hyperacidity (Arnoldi(a), Strauss(c), Veil). However, in dis-
eased conditions which affect kidney permeability, notably in nephritis,
high blood chlorids usually occur and at the same time hyperchlorhydria —
the stomach apparently taking on the excretory function which the kidney
has lost (Goyena and Petit; Crosa).
Alkalies
The alkali metals Na and K are present in all organs and tissues.
Those tissues having important functions, and which are rich in cells
have a higher ratio of K to Na than the tissues of conduction and support
or the body fluids but there is no absolute specificity between Na and K
in any organ, and the blood alone, of all the tissues and fluids, conserves
its ratio of Na : K in spite of regime or food. The ratio of K : Na is
highest in the vertebrates and is normally about 2l/> : 1.
This difference between the quantities of Na and K in the body is
reflected in most foods especially in milk and vegetables, and in infancy
the retention is in approximately the same ratio as the occurrence in human
milk (Cronheim and Miiller(c), Meyer(&)). In the usual mixed
diet the ration of Na : K is reversed, because of the addition of NaCl
316 HENRY A. MATTILL AND HELEN I. MATTILL
to the food and what little metabolism work has been done on alkali
balance, does not give conclusive results regarding their retention chiefly
because the loss of the alkalies, especially Na, through sweat makes the
determination of total excretion difficult.
An abnormally high ratio of K : Na (22:1) in the food of puppies
has been shown to result in a strong positive K balance and a slightly
negative Na balance, and when long continued, to stop growth. The ratio
of K:Na in the liver and kidney was 1.5 to 1 while in control animals (re-
ceiving K:Na 2 :1) it was 1.24 : 1 and in rats a very high K diet brought
the ratio of K : Na in their ash up to 2.41 : 1, when it is normally
1.5 : 1 (Gerard(fr)). Osborne and Mendel(Z) have found K'more essen-
tial than Na in the diet of rats. The bones of calves receiving a high K
diet showed retarded development even with a plentiful supply of Ca and
P2O5 in the diet, though the composition of the bones was normal (Aron
(a)). An effort to confirm these results on children by studying the CaO
balance on diets high and low in K (K: Na 2 : 1 and 1 : IT) has been un-
successful (Adler).
The ingestion of a diet rich in fat affects the alkalies in the same
way that it affects Ca, and may lead to a negative balance (Hellesen). In-
gestion of acids has a similar effect (Secchi(a)). Elimination of the
alkalies is principally through the urine. The feces usually contain more
K than Na, but only in cases of diarrhea does the quantity of either become
a considerable proportion of the total excretion. There are 3-4 grams
K2O, 5-8 "g. Na2O daily in the urine of the normal adult, though these
quantities are subject to wide variations depending on the diet. In starva-
tion the elimination of Na rapidly decreases, of K less rapidly, and after
a few days the K elimination is six to nine times as great as the Na, a
proportion which exceeds that found in muscle substance. On breaking
a fast and in convalescence there is a very marked K retention.
The coincidence of glycosuria and acidosis has resulted in the develop-
ment of an alkali therapy in diabetes for which a considerable success
is claimed ( Underbill (g} ). In opposition to this claim must be mentioned
the findings of others, that NaHCO3 administration is sometimes followed
by retention of chlorids and water resulting in edema, and that the ap-
parently improved carbohydrate utilization may be only a result of its stor-
age in the increased body water (Levinson; Hertz and Goldberg; Beard).
Calcium
The distribution of CaO between urine and feces is too variable to
permit of any even approximate statement. The urinary CaO may com-
prise 5-64 per cent of the total CaO excreted in the normal cases (Neurath,
Towles). A milk diet is apt to result in a lower proportion of urinary
CaO to total CaO than a mixed diet (Secchi(&)) in spite of the fact that
MINERAL METABOLISM 317
urinary CaO is higher on a milk diet than on a mixed diet ; and milk is
more effective than Ca lactate in increasing urinary CaO (Givens(6)).
Breast-fed infants usually show higher urinary CaO, in terms of per cent
of total CaO, than the artificially fed. NaCl and IIC1 increase the per
cent of urinary CaO but do not affect the Ca balance (Givens(6), v.
Wendt(a)) while bases are without effect (Givens) except in pathological
conditions (Eppinger and Ullmann). An increased urinary CaO is
usually accompanied by diuresis (Schetelig).
Calcium in the food is usually in organic combination, as in milk, eggs,
vegetables and cereals, though there is a not unimportant intake of lime
from drinking water, in inorganic combination. The question as to the
relative availability of these two forms has not yet been settled (Bunge(d) ;
McCluggage and Mendel; Rose (6) ; Aron and Frese). Givens found
that 0.34 g. CaO in the form of dried skim milk when added to a
Ca poor basal ration would produce a positive Ca balance, while 1 g. of
CaO in the form of lactate was necessary to accomplish the same end. In
two cases of exophthalmic goiter Towles found that the addition of Ca lac-
tate to a Ca poor diet which was giving a negative balance, resulted in a
positive balance which soon reverted to negative, while the addition of the
same amount of CaO in the form of milk gave a higher and a lasting
CaO retention. That inorganic Ca salts, especially the soluble ones, are
absorbed is indicated by Kost who found notable increased Ca in the
bones of rabbits fed CaCl2 for a long period, as compared with control
animals. Orgler, supplying Ca in the form of Ca phosphate, found equally
good retention whether the salt was given in raw milk or in sterilized milk.
The adult normal requirement for Ca has been variously estimated
3.3 g. (Bunge) to 0.38 g. CaO per day. Bertram maintained equilibrium
on 0.38 g. CaO. Renvall required 1.19-1.26 g. CaO. Von Wendt(a) con-
siders 0.8 g. CaO daily sufficient and Nelson and Williams by studying the
total elimination of four subjects on normal unrestricted diet found 0.95-
1.43 g. CaO excreted daily. Sherman(c) considers 0.9-1 g. CaO per day
sufficient, since it is considerably above the average amount found by him
in a compilation of 97 experiments in which a minimum CaO for equilib-
rium was determined (0.63 g. CaO per 70 kg. body weight) (e). He states
"the case of Ca is the one which would seem to call for the most liberal mar-
gin in intake over the estimated average maintenance requirement if indi-
vidual variability is to be covered by an ample factor of safety." He holds
that 1 g. of Ca should accompany every 100 g. of protein intake. A suffi
cient Qa supply is so important that some investigators have recommended
the addition of Ca salts to bread and others the direct ingestion of 1 to 1.5
g. CaCl, or Ca lactate daily (Heinze; Bertram; Loew). Such an addi-
tion does not affect the arteries (Kost) and has been shown in animal
experimentation, to have beneficial results (Emmerich and Loew(fc) ;
vard ; Dox and Guernsey). Pellagra producing diets have been shown t
318 HENRY A. MATTILL AND HELEN I. MATTILL
be deficient in Ca (McCollum, Simmonds and Parsons). The ingestion of
excessive quantities of fat, protein or carbohydrate increases lime ex-
cretion (Kochmann(a) (6) ). N and Ca balances show no parallelism what-
ever.
Albu-Neuberg state that NaCl increases and that alkalies reduce CaO
resorption: neither v. Wendt nor Givens support this statement Aron
found that high K and low Na intake decreased Ca absorption, but Adler
was not able to confirm this. Dubois and Stolte by adding alkali to the
diet of rachitic children were able to convert a negative to a positive lime-
balance, but if the balance was originally positive the addition of alkali had
little effect. Neither Givens nor Granstrom were able to show any effect of
alkali or acid administration on the lime balance of a dog. Secchi on the
other hand found in dog and man an increased Ca output, especially in the
feces, when HC1 was administered. Undoubtedly the nutritive condition
of the individual at the time such an experiment is initiated influences
the result ; Givens' dogs were on a minimum or even inadequate Ca intake,
while Secchi's subjects showed a positive Ca balance. An addition of
H3PO4 causes an increased CaO output in both urine and feces.
In the adult there is a tendency to Ca equilibrium. Renvall increased
the lime intake over the amount necessary for equilibrium by ingesting
CaCO3 and found a retention of CaO for several days, followed by equilib-
rium on a higher level of intake and output. This is strikingly like pro-
tein and NaCl metabolism, and is confirmed by Sherman and by Herbst.
In infancy and childhood the question of lime metabolism, as of phos-
phorus, becomes one of especial importance because of the need of the
body for these elements in growth and especially in bone formation.
Weiser has shown in work on dogs that gain in weight, on a diet poor
only in Ca, is below normal, and surprisingly enough, the bones make up
a larger percentage of the total body weight than in the control animals.
The water content of the bones was 20-30 per cent higher than that of
the controls, the ash content lower, and the fat content about the same.
The composition of the ash varied from the normal and the variation was
greatest in the ribs and least in the skull, and was characterized by de-
creased Ca, P2O5 and SO3, and by the appearance of 3-5.5 per cent Na2O
and 0.35-1.25 per cent KaO. Aron and Sebauer confirm this. E. Voit
found the breast bone and skull of pigeons to be most affected by a Ca free
diet. Aron(d) and Briining in work on growing rats which they main-
tained at constant weight by underfeeding on an otherwise adequate diet,
or by food containing only carbohydrate, found a markedly increased
percentage of ash in the total body, as compared with control animals of
the same weight but younger.
The amounts of the mineral elements required to make a gain of 100
g. in the body weight of infants have been calculated from various angles.
Camerer and Soldner based their estimate on the composition of new-born
TABLE V
Grams Going to Make
100 g., Gain in Weight
K2O
g-
Na20
g-
CaO
g-
MgO
g-
PA
g-
Camerer and Soldner . .
Cronheim and Miiller
3-4 months old
0.20
1.53
0.24
0 66
1.00
1 07
0.04
1.04
5-6 months old
1 26
0 40
0 4.8
.77
Meyer
0.73
0 17
0 3
0.78
Tobler and Noll, Zy,
months old
069
0 82
0 21
.17
infants, Cronheim and Miiller on the retention found in metabolism ex-
periments extending over 35 days, and Meyer on the metabolism of fast-
ing. Tobler and Noll report a metabolism experiment on a 21/X> months
old baby giving the average retention per day on an average daily gain of
24.3 g., and for the sake of comparison their values for retention have been
multiplied by 4, to make approximately a 100 g. gain in weight, and are
included in Table V. Bartlett's estimate that 1.7 g. ash must accompany
every gram of N laid down is probably within these limits. lie considers
0.05-0.8 g. Ca per day a normal deposit; Herter considers 0.1 g. CaO the
daily deposit necessary for normal growth. Apparently gain in weight
is due to such variable proportions of bone, protein, water and fat that
only an approximate estimate of the mineral need can be made on this
basis. Children 6-7 years old should get 0.3-0.5 g. CaO per day, 14 years
old, 0.6-0.9 g., in order to support normal growth of bones (Herbst).
It is generally conceded that human milk contains the mineral con-
stituents in the ideal proportions for growth, although Dibbelt and Aron(6)
point out that the breast-fed baby's need of lime may exceed its supply in
the first six months of life, and thereafter the supply exceeds the need. In
this connection it is worth while to refer to recent very painstaking analyses
of woman's milk by Schloss(a) and Holt(&) and of cows' milk by Trunz
who show a colostrum period consisting of the first 12 days and character-
ized by high ash content, a transition period to the end of the 4th week after
which the composition remains about constant until the 10th month. This
can best be summarized, and the difference between human and cow's milk
displayed in the following table (VI). Schloss compared the complete
24-hour samples of milk from 8 wet nurses and found a marked paral-
lelism between the N and total ash. The lower content of Ca in human
milk is compensated by a much better absorption.
The feeding of vegetables to young babies (6-7 months old) has recently
been shown to exert a favorable inmience on their growth. The increased
quantity of salts, their especially favorable chemical nature, or the vitamin
content are. variously suggested to explain this effect. Since boiling vege-
tables in water causes a considerably greater loss of salts than steaming, the
latter method of cooking is recommended (Courtney; Fales and Bartlett).
320 HENRY A. A1ATT1LL AND HELEN 1. A1ATT1LL
TABLE VI
G. in 100 cc. Milk.
Aah
CaO
MgO
PA
Na,O
K20
Cl
Human Milk
Holt — colostrum
Holt — early mature,
1-4 mos .»
0.3077
.2056
0.0446
.0486
0.0101
.0082
0.0410
.0342
0.0453
.0154
0.0938
.0539
0.0568
.0351
Holt — middle ma-
ture, 4-9 mos. . . .
Schloas — mature
Cows' Milk
Trunz — colostrum . . .
Trujiz mature,
period II
.2069
.1839
.766
.714
.0458
.0376
.194
.174
.0074
.0086
.027
.019
.0345
.0405
.238
.205
.0132
.0189
.052
.042
.0609
.0529
.174
.176
.0358
.0522
.092
.101
Aschenheim(6) found that the addition of fat to the diet of infants in-
creased the fecal CaO at the expense of the urinary and that if the child
was sick or convalescent the drain on CaO might be so great as to establish
a negative balance. Meyer, and Birk and Rothberg found a like effect of
fat on the balance of Na, K, Mg, and Ca. Herter showed that the loss
of CaO in infantilism was connected with poor utilization of fat, and the
excretion was in the form of a Ca soap. He also concluded that a small
increase of fat in the food might convert a positive CaO balance to a
negative one. Recent work (McCrudden and Fales) has not substantiated
Herter. Niemann(6) in a metabolism experiment on a normal 10-months'
old infant varied the fat content of. milk from 1.13 per cent to 3.97 per
cent and found a constant excretion of CaO throughout, on an intake of
1.8 g. CaO per day. He concludes that in normal infants the change from
a fat-poor to a fat-rich diet, so long as the fat content remains within
physiological limits, does not interfere with CaO absorption and does not
increase the fecal CaO although the typical fat stools are present. Others
confirm this (Wolff; Holt, Courtney and Fales(<i)). Hoobler(a) goes
even further and shows that a high fat content if within normal physi-
ological limits favors retention of Ca and P but this is not the case if the
fat rises above the normal quantity in human milk (Lindberg). For in-
fants on modified cow's milk Holt and his co-workers found the best ab-
sorption of Ca when the food contained 0.045-0.060 g. CaO for every gram
of fat and when the fat intake was not less than 4 g. per kg. body weight.
For young children on a mixed diet the absorption was best when the fat
intake was not less than 3 g. per kg. body weight and there was 0.003-0.005
g. CaO to every gram of fat.
In artificial feeding with cows' milk the intolerance for fat often noticed
may be caused by the excessive amount of calcium present which for lack
of sufficient Cl or phosphate for its excretion as a salt of either of these
acids may be excreted as a Ca soap or may accumulate in the tissues caus-
ing fever and finally being excreted as Ca lactate. The dilution of the
milk with whey, thus supplying a large proportion of acid elements, or
321
"decalcifying" of the casein improves the fat and mineral utilization in
such cases (Bosworth, Bowditch and Giblin; Bosworth and Bowditch;
Forbes(c); Giffhorn).
The mineral requirements of childhood and adolescence have been sub-
jected to metabolism studies by Herbst (a.) and Jundelt with the following
results :
Herbst
Jundelt (2 boys)
(6 boys— 6- 13 yrs.)
5% yrs.
7% yrs.
P205 retention per kg. body weight per day . .
CaO retention per kg. body weight per day . .
MgO retention per kg. body weight per day . .
0.027—0.037 g.
0.01 —0.02 g.
0.002—0.007 g.
.0315
.0029
.0140
.0297
.0294
.0159
In another 12-day study of two rapidly growing adolescent boys Herbst
(&) found a daily exchange per kilogram of body weight as follows:
A
CaO
Retained
g-
CaO
Excreted
g-
PA
Retained
g-
N
Balance
g.
Subject I.
Subject II
0.0075
.0042
.0118
.0093
0.0146
.0204
.0075
.0128
0.0148 •
.0138
.0039
.0111
+ 0.013
+ .045
— .020
+ .029
6 days of muscular ex-
ertion
6 days of rest
6 days of muscular ex-
ertion
6 days of rest
These values are of interest in showing the relation of CaO deposit to
bodily activity and the lack of any parallelism between CaO and N.
Hoppe-Seyler and v. Noorden have noticed increased CaO elimination
in bodily inactivity.
Eecent work has greatly extended our information regarding the cal-
cium of the blood. That calcium, though present in small amount, is
one of the important constituents of the blood because of its effect on co-
agulation and heart irritability, has long been acknowledged. We are in-
debted to Jansen(&) for a review of previous work, the development of an
analytical method and analytical results. Previous investigators have
found 4.0. to 11.9 mg. CaO per 100 c.c. blood (using strictly chemical
methods), with variations for a given species as great as the difference
between various species. Semi-exact methods, devised by Blair Bell and
Wright, have resulted in such wide variations in findings when employed
by different investigators (Katzenellenbogen; Morley; Mullik) that
these results will not be considered in the following summary. Jansen,
Voit, Dhere and Grimme, and Dennstedt and Rumpf agree in finding
a variation in blood calcium dependent on age and independent of sex.
At birth the infant's and mother's blood are about the same in Ca
322 HENRY A. MATTILL AND HELEN I. MATTILL
content. The Ca in infant's blood increases during several mon-ths after
birth; it reaches a maximum which varies but may be as much as double
that at birth, and thereafter there is a gradual decrease. Jansen in the
analysis of the blood of 33 men and women found an average of 12.46
mg. per 100 c.c. of whole blood at 20-30 years of age, 12.25 mg. at 30-40
years, 11.3 mg. at 40-50 years, and 10.95 mg. above 50 years. Dennstedt
and Rumpf found 11.6 mg. the average of many determinations on adults.
Using a nephelometric method Lyman(a) found about half this amount,
and slightly higher in women than in men. There is a difference of opinion
regarding the distribution of the blood Ca between the plasma and cor-
puscles, some (Lamers) considering that all the Ca is in the plasma,
others (Heubner- and Rona; Cowie and Calhoun) that it is in both
plasma and corpuscles. Jansen found that if he washed the corpuscles
free from plasma with isotonic sugar solution they usually contained some
Ca (1-3.5 mg. CaO per 100 c.c. whole blood), but if they were washed with
hypotonic NaCl solution they were free from Ca, and he concluded that
the Ca is dissolved in a diffusible form in the corpuscles. Heubner and
Rona found a similar distribution between plasma and corpuscles in
cat's blood. The fibrin, Jansen found, contained 0.34 mg. CaO per 100
c.c. whole blood. The Ca content of the cerebrospinal fluid is about half
that of the blood and is less subject to fluctuations in pathological condi-
tions (Halverson and Bergeim).
The calcium content of the blood during pregnancy and lactation has.
been the subject of considerable investigation because of the unusual drain
on body^ Ca at such times. During pregnancy and the puerperium Jansen
found an average of 12.5 mg. .CaO per 100 c.c., whole blood, a normal
value for the age. Lamers found 0.8-1 mg. higher CaO in pregnant
and lactating women, but he found high blood CaO in women 4-8 weeks
after delivery, regardless of whether they were lactating or not. Possibly
this illustrates the lag in adjustment after pregnancy which McCrudden
considers an explanation of osteomalacia (see p. 339). Lamers and Mul-
lik suggest that a rise in blood CaO causes the onset of labor. The in-
gestion of a Ca-poor or Ca-rich diet or of Ca salts seems not to affect the
blood Ca (Clark; Denis and Minot(^)).
The important role which the Ca ion plays in controlling the permeabil-
ity of colloidal membranes leads Brinkman(&) to the conclusion that the
Ca ion concentration of the blood is as constant at H ion concentration, and
that the distribution of the Ca in the blood between a protein compound
(25 per cent) and Ca (HCO3)2 and its ions (75 per cent) supplies the
necessary mechanism for its adjustment. Rona and Takahashi place
this Ca ion concentration at 30 mg. per liter- of serum. The increased
blood calcium which has been found on subcutaneous injection or in-
halation of CaCl2 (Clark; Heubner and Rona) and which Voorhoeve
claims to have found on ingestion of large amounts of Ca in food, cannot
MINERAL METABOLISM 323
(according to Eona and Takahashi) affect the Ca ion concentration of the
blood to any degree.
Magnesium
Magnesium has not so far taken on the importance that the other min-
erals have in a consideration of mineral metabolism, possibly because
the body need is relatively small and always sufficiently covered by the
food supply so that the nutritive disturbances which might follow lack
of Mg are not observed. Osborne and Mendel found that a diet poor in
Mg supported growth of rats as well as one richer in Mg but in the Mg-
poor diet they may not have gotten below the minimum requirement The
very small amount of Mg in human milk, which is not compensated by
a storage in the infant's body as is Fe, leads to the conclusion that Mg
needs are at least extremely low. Bertram found that 0.73 per day more
than covered the b9dy needs, and resulted in storage of Mg for a few
days, after which equilibrium was established. Renvall found a balance
established on an intake of about 0.45 g. Mg; on 0.25 g. there was a loss
of Mg by the body. Von Wendt(a) found in one case a slight storage on
0.20 g. MgO daily and in another a loss of Mg on 0.33 g. Sherman in
studies on 150 American dietaries found an average intake of 0.34 g. Mg
per day, which probably expresses a little more than the minimum require-
ment. Neither Mg (Wheeler) nor Sr (Lehnerdt) can replace Ca physio-
logically.
In bones the amount of Ca is 8 to 9 times that of Mg, in muscle the
Mg is 2 to 3 times the Ca, in nerves the amount of Mg is about twice that
of the Ca. In fasting the elimination of Ca is 3-4 times that of Mg, indicat-
ing a catabolism of both bone and body protein.
Absorption of Mg is similar to that of Ca, though it seems to suffer less
interference by the presence of other substances. Its distribution in the
urine and feces is subject to the same variations as that of Ca under similar
conditions though a larger proportion of the total Mg is urinary ; urinary
Mg is usually lower than urinary Ca (Givens(fr) ). The ingestion of large
amounts of Mg salts has been found to increase the Ca elimination, but Mg
elimination seems to be independent of Ca ingestion (Malcolm; Hart and
Steenbock(a). Fats and carbohydrates decrease Mg retention in infants
(Birk).
«
Phosphorus
None of the other inorganic elements has so wide a distribution in
various forms in the animal body as has phosphorus. Its importance in
life processes is reflected in the great volume of literature that has been
contributed upon its occurrence, its nutritive history and its functions.
324 HENRY A. MATTILL AND HELEN I. MATTILL
A compilation and review of the information available in 1914 forms a
compendious monograph embracing about 3,000 titles, and it would seem
unnecessary, indeed, if not impossible to refer individually even to the
more important contributions before that time (Forbes and Keith).
In inorganic form phosphorus is found in animal and plant tissues
chiefly in the form of K and Ca salts of phosphoric acid and in the organic
forms in the generally familiar classification as nucleoproteins, phos-
phoproteins and lecithoproteins or phosphatids. To these should be added
the phosphoric acid esters of carbohydrates and related substances which
may be found increasingly .important as investigation continues; for
example, a phosphorus-containing carbohydrate is regularly found as a con-
stituent of starch (Northrup and Nelson).
The distribution of the different forms of P in the organs and tissues
has claimed the attention of several investigators recently and the resulting
outstanding facts are that inorganic phosphates make up the greater
amount of muscle, bone ancl blood phosphorus (Heubner; Greenwald(f),
that the important substance for muscular activity is a compound of lactic
and phosphoric acids which .is derived from organic P compounds
(Embden), that in smooth muscle the protein P is more abundant than in
striated (Costantino), that lack of P in the food affects first the in-
organic P of the bones and liver and that of the other organs only very
gradually. The brain and heart lose total P under no conditions of dieting
(Masslow(a)), exceptional ingestion of P as phosphates seems to decrease
the P content of the central nervous system, although it does not seem to
influence the deposit of phosphatids in muscle and bone, the percentage
of which is remarkably constant throughout life; possibly it does affect
the nucleoproteins (Heubner).
An estimate of the phosphorus requirement is rendered doubly difficult
because of the uncertainty which surrounds the question of the availability
of the different forms of phosphorus in foods. Unquestionably there is
a difference between the phosphates and the organic P compounds both
in the rate and the percentage of absorption. Experimental studies in
which phosphates have been added to a diet poor in P can therefore hardly
be compared with those in which an ordinary mixed diet has been used.
Sherman found from a study of 95 balance experiments that the minimum
requirement averaged 0.88 g. P per day per 70 kg. body weight, and he
considers 3.50 g. P2O5 per day a sufficient intake. Berg maintained
equilibrium on 2.25 g. P2O5 daily at the same time that Ca equilibrium was
maintained on 0.33 g. CaO, and he showed that the addition of 10 g.
CaHPO4 to this diet not only resulted in no retention of either P or Ca,
but caused a loss of Ca from the body. Von Wendt on the other hand was
able to convert a negative CaO balance to a positive balance by the addition
of 3g. CaHPO4. Any definition of the P requirement without at the same
time taking into consideration the Ca supply, or vice versa, is unsafe.
MINERAL METABOLISM 325
The inquiry into P metabolism is still centered about the question of
the availability of inorganic forms of P for the animal organism. De-
terminations of the P and N exchange usually indicate better retention
when the P is supplied in organic combination (Masslow(a) ; LeClerc and
Cook; Hirschler and Terray) and this is likewise the case for Ca retention,
but in work on cows it has recently been shown that if the ingestion of a
Ca rich food, as hay, is alternated daily with the ingestion of a food low in
Ca and to which inorganic phosphates have been added, there is good
retention of both P and Ca (Meigs, Blatherwick and Cary). Berg in a
metabolism experiment on himself could show no P retention on addition
of Ca(H2PO4)2 or Ca(H2PO2)2 to a diet supplying 3.04 g. HPO4 daily.
On the other hand Forbes (6) in experiments on swine finds orthophos-
phates and hypophosphites as satisfactory forms in which to supply P as
are nucleic acid, phytin or glycerophosphates. Fingorling found the same
for ruminants and ducks. Osborne and Mendel were able to supply prac-
tically all of the mineral constituents in the form of inorganic compounds
and still get normal growth in rats. Experimental work is somewhat incon-
clusive because the effort to prepare a diet supplying enough protein and
energy with a minimum of P in organic combination may result in an
insufficient supply of the animo acids or of the food accessories (vitamins)
and nutritive failure follows irrespective of the form of P. That inor-
ganic phosphates are utilized to a degree is unquestionably established, but
there is still a lack of quantitative work which would establish the percent-
age of absorption from each source. That this is different seems clear from
the fact that the percentage of the ingested P retained by infants is higher
when they are breast-fed (human milk contains about 77 per cent of its
P in organic combination) than when fed on cows' milk which contains
about 27.9 per cent of its P organically combined (Keller; Schlossmann).
Marshall in a review of the subject concludes that inorganic forms are as
satisfactory as organic, but others, notably Sherman and Forbes, take the
more conservative view and (are willing to) grant an advantage, though
possibly not indispensability, to the organic forms.
Of the mineral constituents of the body P is the most universally re-
quired, by bone, muscle, gland and nerve; P retention is the rule and
in this respect and because its retention is frequently independent of the
N" balance, Albu-Neuberg compare P with fat. In infants P retention is
0.02-0.03 g. P2O5 per kg. body weight per day, in growing children
it is 0.027-0.042 g. per kg. (Herbst(a)(6)), in adolescent boys it is
0.004-0.015 and may be said to be independent of the N balance, al-
though the lowest P retention found, 0.04 g. P2O5 per kg., accompanied a
negative N balance. The retention of P2O5 was twice as great as would
have been required by the retained N and Ca for building bone and muscle.
Cronheim and Miiller(6) found a similar retention of P in excess of the
amount required by the retained Ca and N and conclude "P rich nerves
326
HENRY A. MATTILL AND HELEN I. MATTILL
and tissues rich in nuclear material must play an important part in the
growth of the early years." Insufficient P in the food during growth re-
sults in serious under development of the bones (Schmorl; Masslow(6)).
The partition of the excreted P between urine and feces depends
largely on the nature of the diet. A meat diet gives rise to high urinary
P and a vegetable diet to a large excretion through the intestine. The
urinary excretion is normally 2-2.5 g. P2O5 as primary and secondary
phosphates of the alkali and alkaline earth metals. Intestinal excretion
of Ca and P2O5 usually run parallel. Phosphaturia, which is character-
ized by a cloudy urine or one which becomes cloudy on heating, is not al-
ways due to increased amounts of phosphates in the urine, but frequently
to their insolubility in an alkaline urine, and may result from a vege-
table diet or an ingestion of quantities of alkali or following the increased
alkalinity (so-called) of the blood during digestion or loss of the acid
stomach juices by vomiting or by removal with stomach pump. Patho-
logical phosphaturia follows an increased alkalinity of the blood as a re-
sult of disease, or of increased elimination of P and Ca by way of the kid-
neys because of some interference with the excretory functions of the
intestinal membranes (Soetbeer). P is present in the blood in three forms
— lipoid, phosphorus, inorganic phosphates and a form soluble in acids but
not precipitated by the ordinary phosphate reagents. "Acid soluble P"
includes the latter two and is 2-4.5 mg. P (6.4-14 mg. H3PO4) per 100
cc. plasma (Feigl(a) ; Greenwald(/)) of which 1-3.5 mg. P (3.2-12 mg.
H3PO4) is in the form of inorganic phosphates (Marriott and Haessler;
Denis and Minot(^) in normal individuals. The phosphorus concentra-
tion in corpuscles is about 7 times as great as in plasma and shows less
individual variations (Bloor ; Porte). As a result of many analyses using
his nephlelometric method Bloor (g) gives the following table of average
P distribution in the blood of normal men and women :
Mgs. H3PO4 in 1(
10 c.c. Plasma
In 100 c.c.
Corpuscles
Men
Women
Men
Women
Total
32
36.2
248.
249.
Acid soluble
10.4
12.4
188.
187.
Inorganic
8.7
11.2
18.7
15.7
Lipoid
22.1
24.9
57.
56.6
Other forms
1.72
1.26
172.
167.
Iron
Iron occupies a unique position among the mineral constituents of
the body since its presence in hemoglobin endows the blood with oxygen-
carrying capacity. The blood of a man is said to contain about three
grams of iron. The liver and spleen contain perhaps 0.02 per cent of their
MINERAL METABOLISM 327
fresh substance; iron is likewise found in bone marrow and in muscles.
As a constituent of nucleoproteins iron has the function of a catalyst
(Spitzer) particularly of oxidations, and its presence in most (Mouneyrat ;
Jones) if not in all cells (Masing) both animal and vegetable has"gen-
erally been accepted. It has been demonstrated in the liver and other
organs of animals whose blood pigment is not hemoglobin (Baldoni ; Dastre
and Floresco). The cell nuclei of vegetable tissues also contain iron, and
the decorticated and enucleated form in which most cereals are used for
human food makes them relatively poor purveyors of this element. Some
fruits and vegetables, especially the chlorophyll-containing ones, such
as spinach and cabbage, are richest in iron. The amount of iron necessary
to meet the daily requirements of man cannot be stated dogmatically since
it depends on the kind and amount of other foods, organic as well as in-
organic, ingested with it (Kochmann(c) ). In view of our meager knowl-
edge Sherman in his review of the functions of iron in nutrition states that
the daily intake ought to be not less than 12 mg. of food iron, a figure
which should be increased during pregnancy and lactation. Milk is one
of the poorest sources of iron (Jolles and Friedjung; Langstein ; Edelstein
and v. Czonka). The relative amount of iron in the body of an animal
varies with its age; thus Meyer (a) showed that in calves the iron of the
liver decreases with increasing age; he found that the fetus contained
ten times as much iron (relatively) as the grown animal, most of which
is accumulated during the last three months before birth (Hugounenq).
This question was especially dealt with by Bunge(fr) and Abderhalden
(e) (a) (g), who found, in rabbits and in rats, that the relative amounts of
iron and hemoglobin in the body decreased progressively during lactation,
at the end of which it was at a minimum. Thereafter, on the mixed food
of the mother the iron again increased. In guinea pigs whose lactation
period is extremely short, this relation was not observed. Abderhalden
therefore points out the undesirability of restricting an infant to milk diet
beyond the period of lactation, and the necessity of abundant iron-contain-
ing foods for growth and increasing blood volume.
In iron-containing foods the element is usually in complex organic
combination ; only in drinking water and in medicinal iron preparations
is iron ingested in inorganic form. The course which iron follows in the
digestive tract has been of special interest because of a possible difference
in behavior between the two forms, and in contradiction to the first pro-
nouncements of Bunge(» on the toxicity of inorganic iron and the good
fortune of its non-absorption there has come a general acceptance of the
view that both forms are absorbed in the same way. The toxicity of iron
salts given intravenously was demonstrated long ago, but since inorganic
iron per os has no toxic effects unless the doses are large enough to erode
the epithelium, iron salts are in some way modified in the stomach
(Gaule). A part of the ingested iron, either organic or medicinal, is set
328 HENRY A. MATTILL AND HELEN I. MATTILL
free (Schirokauer) forming a loose combination with peptone, perhaps of
the nature of an albuminate. Hemoglobin, nucleic acids, and related com-
pounds, on the other hand, are probably not decomposed until after they
have left the stomach.
The further course of iron has been followed histologically in the in-
testinal tract and in organs and tissues by means of a microchemical
test with ammonium sulphid (and heat), sometimes with the addition of
potassium ferrocyanid and HC1 ; only the loosely combined iron responds
readily to this test, the "organic" iron only after long standing under
ammonium sulphid or not at all (Quincke ; Matzner). While the mechan-
ism of absorption has not been completely outlined it appears that most
of the iron enters the system in the duodenum, either in soluble form in
the plasma or through the phagocytic action of leucocytes. In dogs pro-
vided with various intestinal fistulas it was. observed (Rabe) that 87 per
cent of the ingested (inorganic) iron was absorbed before reaching the
ileum and a large percentage in the duodenum; but such a study of the
absorption of iron is complicated by the fact that iron is also largely
excreted by the intestine; this was shown as early as 1852 by Bidder and
Schmidt (a). They found it in all stages of fasting and later work on
fasting (Lehmann, Miiller, et aZ.), as well as the experiments of Forster and
Voit(a) showed that iron was constantly eliminated by the intestinal tract,
whether iron-containing food was ingested or not. The length of time
elapsing between the ingestion of a given amount of iron and its gradual
elimination extending over a period of days or even weeks (Gottlieb (a),
Hamburger), clearly indicated its absorption and also its excretion.
Direct experiments on isolated loops of the intestine were even more final
in this regard (Kobert and Koch; Honigmann).
The fact that iron in process of excretion cannot be demonstrated mi-
crochemically — the reaction is never obtained in fasting animals (Tarta-
kowsky(a)) and disappears in guinea pigs after 24 hours of fasting
(Swirski) — suggests that all the iron demonstrable by this test is on its
way to absorption. This reaction is regularly obtained in the duodenal
epithelium and in the submucosa of the ascending colon; it is seldom
obtained in the gastric mucosa (Hochhaus and Quincke; Hari(a)) or in
the lower small intestine except in cases of abundant iron feeding
(Macallum(a)) or delayed absorption (Cloetta). Nor was Abderhalden
able to find any essential difference in manner of absorption between or-
ganic and inorganic iron in animals on a vegetable or meat diet and a
more recent investigation by means of the microchemical method (Hueck)
has confirmed these statements. Because of the gradual elimination of
iron the usual balance experiment of short duration (Stockman and Greig)
no matter how accurate, cannot afford far-reaching data on the metabo-
lism of iron.
The intestinal elimination of iron takes place through the epithelium
MINERAL METABOLISM 329
of the colon, perhaps in very small part by way of the bile. That bile
may contain iron has long been known, but the figures given show a wide
variation which may be ascribed in part to faulty methods of analysis, in
part perhaps to a different behavior of various forms of iron (Leone). The
clear connection between hemoglobin and the bile pigments and the place of
formation of the latter, unquestionably the liver, need not be reviewed
here. The iron thus set free is deposited in the organs or gradually elimi-
nated, but whether the amount of urobilin in the feces is a reliable index
of blood destruction in health and in disease is uncertain (Me Cradden(d) ;
Robertson(a) ; Whipple and Hooper(a) ). Bunge's theory of a protective
action of iron salts against hydrogen sulphid in the intestine has been
discarded because of the proven absence of hydrogen sulphid in the small
intestine (Macfayden, Nencki and Sieber).
The urinary elimination of iron has been the subject of many investi-
gations with widely different results (earlier literature cited by Socin) but
by the method of Neumann which gave constant results it appeared to be
about 1 mg. in 24 hours, perhaps much less (Marriott and Wolf), a small
fraction of which is decomposable by (NH4)2S and heat, the rest being
in complex organic combination, perhaps of the nature of a pigment or
of a non-coagulable protein compound (Monier). A small proportion
of intravenously or subcutaneously injected iron appears in the urine
(Damaskin), most of it, however, is eliminated by way of the intestine
(Lipski). The urinary excretion of iron varies in some pathological
conditions (the literature is cited by Goodman), but the kidneys play a
minor part in the excretion of iron (Fini ; Lapicque; Woltering).
Experiments on iron metabolism date back as far as 1849 when Ver-
deil showed that the ash of dogs fed meat contained more iron than that
of dogs given bread (for the early literature see Hall) ; the accumulation
of iron in the liver after intravenous injection (Zaleski; Gottlieb(a)) and
after ingestion in organic or inorganic form (Kunkel ; Salkowski(c) ;
Tartakowsky(fc) ; Oerum(a) ; Bonanni(fc)) especially after the organic
(Samoljoff) not only in liver but also in spleen, muscles and bones has
been determined repeatedly. The iron-free feeding experiments of v.
Hoesslin are the earliest of their kind. By such food and by bleeding he
deprived growing dogs of iron ; their hemoglobin fell and anemia was also
evident in a paleness of the mucous membranes, but growth was not inter-
fered with; similar results were obtained on rabbits. The interesting
experiments of Schmidt on mice showed that iron-poor food did not produce
anemia or a fall in hemoglobin in full-grown animals but that the offspring
of such animals, on the same iron-free food, were retarded in growth am
developed severe anemia, with disappearance of iron stores in the liver and
their diminution in the spleen. According to Fctzer the administration
of iron-poor food to pregnant rabbits and guinea pigs caused a depleti
of the iron supplies of the mother up to a certain point, but the maternal
330 HEKRY A. MATTILL AND HELEN I. MATTILL
organism did not sacrifice the iron required for its own vital functions.
After blood deprivation it appeared (Eger; Haussennan(a)) that animals
returned to normal hemoglobin slowly on inorganic iron, more quickly
on food rich in iron, and most quickly on both. The conclusion of
Abderhalden that the addition of iron preparations to food rich in
iron is more stimulating to the hemopoietic organs than when it is
added to iron-poor food, was not universally accepted ; an interesting
debate ensued between Abderhalden on the one hand and Jaquet and
Tartakowsky on the other, a summary of which is given in Meinertz'
excellent review of iron metabolism. From Abderhalden's own figures
Tartakowsky showed that the differences in hemoglobin produced by
adding inorganic iron to iron-rich and to iron-poor diets were very small,
and when taken absolutely were rather in favor of the iron-poor diet with
the accompanying relatively smaller total amount of hemoglobin. From
histological studies on bone marrow of dogs that had been bled,
Hoffmann concluded that the stimulating effect of iron was in speeding
up the development of red cells, and Miiller(6) indeed found more nu-
clear erythrocytes in the bone marrow of iron-fed animals, but not, he
concluded, as a result of stimulation (similar to that of arsenic, perhaps)
but simply because of the presence of more raw material. Tartakowsky
was able to show that the feeding of iron preparations to anemic dogs on
iron-poor food prevented a fall in hemoglobin ; iron was still present in
liver and spleen two months after beginning the iron-poor food, and he
maintained that the blood of full-grown dogs cannot be deprived of
iron by feeding iron-poor food. Only bleeding accomplished this and
hemoglobin was brought back to normal on iron-poor food by the addition
of iron, but not without it. Lack of material is the whole explanation and
bleeding in itself is the stimulus. Later results reported by Oerum indi-
cated a distinct superiority of organic iron over the inorganic in restor-
ing loss of hemoglobin although the iron content of liver was greatest in
the inorganic iron animals. Zahn on the other hand reports findings in-
dicating that in animals (made anemic by bleeding) hemoglobin did not
increase any more rapidly with than without medicinal iron addition to
the food. He fed iron-rich food to both groups and this he considers the
important difference between his own and previous experiments; perhaps
other dietary factors are also involved (Hooper and Whipple(&)). Chis-
toni(&) found that organic iron preparations possessed a superiority
over inorganic when given intravenously to dogs with experimental
anemia ; hemoglobin and erythrocytes increased less rapidly with inor-
ganic, and the other pathological indications did not disappear under
inorganic iron administration as they did under the organic. More re-
cently the value of inorganic iron in the treatment of secondary anemia
has been questioned because Blaud's pills were found to be inert when
added to various diets whether these favored blood regeneration or not.
MINERAL METABOLISM 331
Hemoglobin, on the other hand, exerted a distinctly favorable influence
(Hooper, Robscheit and Whipple).
V. Noorden points out that artificially produced anemia is not compa-
rable with chlorosis, nor are the conclusions from experimental results in-
terchangeable, because in this disease it is not a matter of lack of food
iron, and the stimulus required by the blood-forming organs seems to
be more powerful in inorganic iron preparations than in iron-containing
proteins. Evidently no general conclusions can as yet be drawn. From
the standpoint of the physiology of nutrition the whole question is, accord-
ing to Albu and Neuberg, of minor importance since the iron of foods
is almost entirely in organic combination. Sherman voices the opposite
opinion and considers that it is of great importance to know whether the
iron in natural waters can supplement an inadequate supply of food iron.
To what extent the full-grown organism can husband its resources of iron
is still uncertain but there is no question as to the need of abundant iron
in growth and in pregnancy. The retention of iron observed at high alti-
tudes and considered as evidence of the need of additional iron supplies
(v. Wendt(&)) requires comirmation (Sundstroem(6)).
The role of the spleen in iron metabolism is uncertain and many of
the conclusions reached are quite contradictory. The iron content of the
spleen is decreased by repeated bleeding and during pregnancy, and is
increased by hemolytic processes and by the administration of iron.
Investigations on splenectomized animals indicated that the fecal iron
in such animals was considerably above normal (Asher and Grossenbacher ;
Chevallier(c) ; Bayer(a)), especially when loss of body protein was caused
by underfeeding, and remained so for many months (Asher and Zimmer-
mann), though these findings have recently not been corroborated (Austin
and Pearce). There was some loss of hemoglobin (Pugliese) or none at
all unless the food was poor in iron (Tedeschi; Asher and Vogel). Such
anemia in dogs was more marked on a diet of cooked meat than when the
meat was fed raw (Pearce, Austin and Pepper). Examination of differ-
ent organs and tissues microchemically and analytically indicated a
changed distribution of iron, the liver of guinea pigs containing less than
normal (Pana) although an increase is also reported; in frogs a decrease
was observed in all tissues and organs (Gambarati) . The various changes
develop gradually, persist for several months, and finally diminish (
lier(a)(6)) as if other organs developed a vicarious activity,
seem that the spleen is an organ for the assimilation of iron, and
necessary for the process of blood destruction (Meinertz(a)), but that
retains for the body the iron that has been set free; but whether i
this for the iron resulting from the destruction of erythrocytes
or for that originating in food is not determined. In cases of porn,
anemia and hemolytic icterus splenectomy has been of advantage ; n
cases, however, a previously abnormally large loss of iron in the feces wu
332 HENRY A. MATTILL AND HELEX I. MATTILL
very greatly reduced (Goldschmidt, Pepper and Pearce; Pepper and
Austin), a result directly opposite to that obtained in normal animals.
In experimental anemia the store of iron in the liver and spleen increases
(Muir and Dunn), but some factor other than blood destruction is opera-
tive, perhaps a derangement of the mechanism for retaining iron (Dubin
and Pearce(a)).
Sulphur
In a discussion of mineral metabolism sulphur requires only a passing
mention, for the amounts of this element ingested in inorganic form are
very small. The various forms of sulphur found in the urine (inorganic
and ethereal sulphates, neutral and basic sulphur), and in the feces (sul-
phids) originate in the processes of digestion and utilization of the sulphur-
containing proteins in the food and from the catabolism of sulphur-contain-
ing tissue proteins. Since sulphates are thus always available in the body
it is obviously impossible to determine the requirements of the organism
for inorganic sulphur. That the organic form is necessary is indicated
by the experiments of Osborne and Mendel (g). It appeared that cystin
was a limiting factor in growth of rats on a diet containing 9 per cent of
casein, since the addition of cystin without any other modification made the
ration decidedly more adequate. The addition of cystin to diets low in
protein, Lewis(a) found, diminished the elimination of nitrogen in dogs
while the equivalent amount of nitrogen in sulphur-free compounds such
as tyrosin and glycocoll had no such effect. It has recently been shown
that rats cannot use inorganic sulphates in place of the necessary amino-
acid cystin (Daniels and Rich).
lodin
lodin was discovered in the thyroid by Baumann in 1895 in amounts
from 2 to 7 mg., in the normal gland; much higher values (3-44 mg.)
have been reported recently by Zunz whose data were obtained during the
war, and the literature contains widely divergent figures. It is present
in the thyroid of cattle long before birth, the female containing more
than the male, and it is present in the new-born infant and in the human
fetus at least during the last three months of intrauterine life (Fenger(a)
(6) (d) ; Pellegrini). The amount of iodin gradually increases with age,
being most abundant at about the age of 50. There is also a seasonal
variation in the iodin content of the thyroid (in cattle, sheep and hogs) ;
in the summer and fall the amount of iodin is considerably greater than
in winter and spring (Seidell and Fenger; Fenger(e)), and is to be
associated with external temperature and change in the size of the gland.
In cattle no difference was found between pregnant and nonpregnant ani-
mals. The iodin content of the thyroid may also be increased by increas-
MINERAL METABOLISM 333
ing the iodin content of the food and is probably closely dependent upon
it normally (Hunter and Simpson; Strauss; Cameron(a)). (For a dis-
cussion of iodin in foods see Forbes and Beegle ; for its distribution in
plant and animal tissues see Cameron.) Its absence in the pituitary has
very recently been confirmed (Seaman) as well as its presence in the blood
(Kendall and Richardson). The complex organic combination in which
iodin is found in the thyroid has been isolated and identified by Kendall
as 4, 5, 6 tri-hydro-4, 5, 6, tri-iodo-2-oxy,-beta indol-propionic acid, con-
taining 65 per cent iodin and to which most if not all of the physiological
effects of the thyroid gland can be ascribed, particularly the stimulation
of basal metabolism (Kendall (a) (c) (d) ; Kendall and Richardson; Cam-
eron and Carmichael). .
Iodin compounds are absorbed by the intestine and since iodids are
sometimes excreted after administration of organic iodin, while ingested
iodids may serve to increase the amount of thyroid complex, the body
possesses the ability to ionize and also to deionize iodin (Buchholtz; Blum
and Griitzner). Inorganic iodids are excreted mostly by the kidneys, and
the time of their appearance after, ingestion may be used as the basis of
absorption tests though marked variation in different individuals is re-
ported. Ingested iodin (element) is quickly bound in the blood by protein
and the absorption of iodids by the thyroid is very rapid, but the iodin
complex is formed more slowly (Sollmann(&) ; Marine and Rogoff(a) (c) ).
The administration of various forms of iodin (non-toxic dose) has caused
temporary infertility in animals (Adler(a)(&) ; Loeb and Zoppritz).
Lack of iodin in food and drinking water is considered the cause of
fetal and maternal athyrosis and as the result of successful treatment in
animals the administration of potassium iodid has been recommended
(Smith; Hart and Steenbock(6) ; Welch). The administration of small
amounts of iodid prevents simple goiter in man (Kimball and Marine),
and while this condition has been associated with a lack of iodin (Hun-
ziker), a voluminous literature has established no clear connection
between endemic goiter and water supplies (Clark and Pierce). The
literature upon metabolism in diseases of the thyroid and in thyroid feed-
ing is reviewed by Halverson, Bergeim and Hawk.
Neutrality Regulation
The maintenance of neutrality is one of the functions of the inorganic
constituents of the body. The production of acids in the body is contin-
uous, and the oxidation products of carbon, sulphur and phosphorus are
neutralized in the body by the alkali metals (to some extent probably by
the alkaline earths), by ammonia resulting from protein decomposition and
by the proteins (Klein and Moritz; Robertson (a)). The eliminatioD of
334 HENRY A. MATTILL AND HELEN I. MATTILL
carbonic acid as such by the lungs does not involve a permanent with-
drawal of alkali from the body, and by virtue of the peculiar ability of
the kidney only a portion of the alkali used to neutralize phosphoric acid
is lost. The inorganic sulphates of the urine, on the other hand, represent
a complete loss to the body of the alkalies required in their formation.
The presence of bicarbonate and of phosphates in the blood in optimum
concentration is the basis for the delicate mechanism of neutrality regula-
tion which Henderson has so fundamentally conceived. Because of this
mechanism assisted by the acid-alkali exchanges between the plasma and
the erythrocytes as well as the tissues (Collip; Haggard and Henderson
(6) ; Henderson and Haggard), an overproduction of acid, even though
it is considerable, does not change the hydrogen-ion concentration of the
blood (Sonne and Jarlov) ; the alkali reserve, as measured by the carbon
dioxid capacity, is decreased (Van Slyke and Cullen) and urinary acidity
and ammonia are increased. The character of the food influences these
relations, foods high in protein and, therefore, containing a preponderance
of acid-forming elements decrease the alkali reserve and increase urinary
acidity and ammonia, those containing a preponderance of base-forming
elements (vegetables, fruits), decrease the latter two and increase the
former (Kastle; Forbes(a) ; Sherman and Gettler; Hasselbalch; Blather-
wick; McClendon, et cd.}.
Prolonged administration of acids or of acid-forming foods tends to
deprive the organism of alkalies. Thus acidosis produced in children by
an acid-forming diet caused a loss of Ca and Mg (Sawyer, Baumann and
Stevens), and in observations on animals with experimental acidosis the
alkaline phosphates, especially the potassium phosphate of the muscles,
and the calcium carbonate of the bones were the first major reserves drawn
upon after the bicarbonates of body fluids (Goto(c)). McCollum(a) (/)
found that rats could grow and be maintained for fairly long periods
on acid-forming and also on base-forming rations though reproduc-
tion was usually not successful. Lamb and Eward determined that
the addition of sulphuric acid to the ration of swine did not inter-
fere with growth but prevented reproduction. Of the ingested sul-
phuric acid only 61 per cent was neutralized by ammonia, and their
conclusion (that there was no marked loss of calcium) is, according to
Forbes, not justified. To what extent these reserves are called into action
in daily dietary fluctuations in man cannot be stated ; in the experiment
of Sherman and Gettler the substitution of isodynamic quantities of rice
in place of potato in an otherwise constant diet caused an increase in
urinary acidity and ammonia, but the combined increase in both could
account for only about two thirds of the acid involved. They suggest
that most of the excess might be accounted for by a change in the balance
of acid and base-forming substances in the feces, but unfortunately they
were unable to make a complete study of the feces. It is significant that
MINERAL METABOLISM 33r,
the increased acidity was not accompanied by an increase in urinary
phosphorus. J
The administration of alkalies to man depresses urinary ammonia and
the urine may be made alkaline like that of herbivora (Janney(a ) Homier
son and Palmer) ; the complete suppression of ammonia cannot be secured
m normal subjects though it is possible in nephritis (Denis and Minot(6) )
The benefit resulting from the giving of alkali in a number of pathological
conditions m which acidosis exists, such as diabetes, infantile diarrhea
(Howland and Marriott), cholera (Rogers), is temporary and the value
of the practice is questioned, but a critical loss of alkali from the blood and
tissues is thereby prevented. The acidosis of nephritis (Palmer and Hen-
derson) accompanied by decreased NH3 excretion is a result not of over-
production but of kidney insufficiency and a consequent retention of acid
phosphate; this may even be increased by giving sodium bicarbonate.
For this reason the value of Ca in this condition is emphasized (Marriott
and Howland (a) ) because Ca leaves the body largely by way of the intes-
tine ; the value of lime in correcting the acidosis of diabetes has also been
indicated (Kahn and Kahn(a)). The influence of alkalies on the course
of sugar utilization and on lactic acid formation, and the effects of acids on
nitrogen metabolism, may be cited as further instances out of many others
indicating a regulation of the processes of metabolism by the alkaline re-
serve of the blood and tissues ( Underbill (t) ; Murlin and Graver; MacLeod
and Fulk; McCollum and Hoagland(a) ; Steenbock, Xelson and Hart).
The important role of ionic substances in life processes, in the be-
havior of the individual cell and in the activity of various isolated tissues,
such as nerves, muscles, and especially the heart, need not be considered
in a discussion of the metabolism of mineral matter. For normal dis-
charge of its functions every tissue seems to require a properly balanced
adjustment of ions in its fluids and membranes and the source of these
mineral substances is the ingested food ; but to what extent the processes
involving ion interactions consume the minerals involved and thereby re-
quire their constant renewal in the food, and where the accumulated body
reserves are stored, and by what mechanism the physiologically proper pro-
portions of the various ions are selected by the tissues from the hetero-
geneous supply brought to them by the blood and lymph, are unanswered
questions. The tetany following parathyroidectomy may be an example
of the unbalancing of ionic equilibrium necessary for normal muscular or
nervous activity. Decreased blood calcium accompanies the tetany and
administration of calcium relieves it ; but the calcium reserves of bone seem
not to be available for this purpose. To calcium has been ascribed a very
important role in correcting almost all kinds of disturbances in inorganic
equilibrium, but the translation of inorganic equilibrium into the language
of inorganic metabolism must await more knowledge of the terms under
which the processes of each are carried on.
336 HENKY A. MATTILL AND HELEN I. MATTILL
Disturbances in Mineral Metabolism Accompanying
Pathological Conditions
Fevers are usually accompanied by a retention of chlorids. Snapper
(a) (c) and Peabody bave shown tbat tbe blood chlorids are below normal,
and the retention is due not to a failure of kidney function but to a change
in cell permeability. A similar retention of chlorids in fever produced
artificially by injection of B. pyocyaneus in dogs has been noticed (Grlin-
baum). Such chlorid retention is not always accompanied by water re-
tention (Leva(&)).
Tuberculosis is accompanied by an abnormal loss of calcium (Croftan;
Voorhoeve(fr) ; Sarvonat and Rebattu).
Typical hereditary hemophilia is not associated with deficiency in'
blood Ca, or with irregular Ca metabolism but there is a type of hemo-
philia "calcipriva" in which the blood calcium is low and in which an
increased Ca intake changes a negative to a positive balance with bene-
ficial effects on the blood coagulability (Hess).
Leprosy seems to be associated with a disturbance in Ca metabolism
(Underbill^)).
The kidney insufficiency in some types of nephritis is marked by re-
tention of chlorids (Gluzinski; Ceconi).
In nephritis without acidosis the inorganic phosphate of the blood is
normal, but with acidosis it may rise to 8-23 mg. per 100 c.c. (Denis and
Minot(<7) ; Marriott and Howland(a)), due to a specific disturbance of
kidney function which prevents the elimination of phosphates; at the
same time there is a marked reduction of blood calcium. Ingestion of
calcium salts, thus diverting the excretory function to the intestine, is
recommended as a therapeutic measure.
Attempts to prove an interdependence of mineral metabolism and the
endocrin glands have not thus far produced proof of any very definite
relationships (Droge) with the exception of a well-established connection
between the parathyroid and Ca metabolism. Underbill, and McCallum
with Voegtlin and with Vogel found that the tetany resulting from thyreo-
parathyroidectomy was accompanied by decreased calcium in the blood and
that injection of Ca lactate would temporarily abolish the tetany. "Nu-
merous researches have shown the important relation of the Ca salts to
the excitability of the central nervous system. Their withdrawal leaves the
nerves in a state of hyperexcitability and tetany may be regarded as an
expression of hyperexcitability of the nerve cells from some such
cause. The mechanism of the parathyroid action is not determined, but
the result, the impoverishment of the tissues with respect to calcium and
consequent tetany, is proven." Injections of Ca or Mg salts check the
337
symptoms of tetany, injection of neutral or alkaline salts of Na or K
intensifies them.
By intravenous injection of phosphoric acid and its Na salts Binger
has been able to reduce the Ca of the serum from 10 mg. to 6 mg. per
100 c.c. Tetany results at this point unless the pH is above 6- if the
solution injected has a pH greater than this no tetany results. A similar
marked reduction of blood Ca to as low as 1.5 mg. per 100 c.c. without
tetany occurs in nephritis where the blood is extremely high in acid
phosphates. Parathyroidectomy is accompanied by an increase in the
acid phosphates of the blood and during a tetanic seizure the ammonia of
the blood is about twice normal, while injection of ammonium carbonate
into normal animals will bring on symptoms of tetany immediately (Green-
wald(a)(&); Watanabe(c) ; Jacobson). That the hydrogen ion con-
centration is a determining factor is clear from the work of Binger and of
Marriott and Howland, and from recent work which showed increased
alkalinity of the blood following parathyroidectomy and just before con-
vulsions began (Wilson, Stearns and Thurlow) ; also from the coincidence
of tetany and increased alkalinity of the blood as a result of intravenous
infusion of NaHCO3 (Harrop(a) ), and of operations on the stomach
which exclude the acid secretion from the duodenum (McCann). On
the other hand, blood which has been dialyzed against a solution contain-
ing everything normal to blood except calcium when transfused into the
isolated leg of a dog resulted in over-stimulation of the nerves (MacCallum,
Lambert and Vogel).
There is some difference of opinion regarding the blood Ca in infantile
tetany, Longo (quoted by Rowland and Marriott), finding a normal con-
tent in eight cases while others have found it much reduced (Neurath;
Brown, MacLachlan and Simpson), and Rowland and Marriott say "con-
vulsions may be expected when the Ca of the serum becomes less than 7
mg. per 100 c.c." They find the Mg and inorganic phosphates of the
blood remain normal. Calcium absorption is little if at all affected in in-
fantile tetany (Schwarz and Bass) and while the Ca content of nervous
tissue has been found (post mortem) below normal (Quest; Weigert(M )
it is not invariably so; but in cases where the Ca is normal the Na and
K are abnormally high, and the ratio ^ + Mg " hign(Aschenheim(a))'
A metabolism study of a baby having rickets and tetany (Fletcher)
has brought out a similar relation in the retention of these elements; while
the disease was in active progress the retention of CaO was •
and the ratio ^ +^ == 1.5, during- the later period during which there
was marked improvement, in the symptoms the retention of CaO was 0.44
g, daily, and the ratio ± = 0.72. Howland and Marriott
338 HENRY A. MATTILL AND HELEN I. MATTILL
have not been able to show alkalosis in cases of infantile tetany,
but medication with NaHCO3 for other causes has in four cases resulted
in tetany convulsions accompanied by low blood Ca, both of which were
corrected when the NaHCO3 was stopped. They conclude "it is apparent
that the symptoms of tetany and the lowering of the Ca content of the
serum may be produced in a variety of ways, but we have not been able to
show that any of these means is operative in infantile tetany."
Administration of Ca salts per os may or may not (Haskins and Ger-
stenberger) have a beneficial effect on infantile tetany. Injection of
calcium lactate gives temporary relief and if accompanied by administra-
tion of phosphorized cod liver oil it speeds the recovery which phosphorized
cod liver oil alone will accomplish (Brown, et al.).
There is apparently an intimate relation between blood sugar and cal-
cium. Thyreoparathyroidectomy is accompanied by a decrease in both,
and the injection of Ca will temporarily restore blood sugar to normal
(Underbill (ft) ; Underbill and Blatherwick). The question as to whether
the hypoglycemia is a result of the thyreoparathyroidectomy or of the re-
sulting reduction in blood calcium is still unanswered. Hyperglycemia
occurs in pneumonia, tuberculosis and especially diabetes, and each of these
diseases is characterized by loss of calcium (Kahn and Kahn; Loeper and
Bechamp) and upon injection of calcium salts the glycosuria is decreased.
Administration of CaCl2 to diabetics is claimed to reduce the glycosuria
(Phocas). Urinary elimination of phosphorus is about normal, that of Ca
and especially of Mg is high in diabetes (Euler and Svanberg; Nelson).
In experimental diabetes in rabbits a decalcification has been observed
(Robert and Parisot). There is possibly some connection between the
diabetes of pregnancy and the unusual drain on calcium (Kahn and Kahn
(a) ) . In the acidosis of diabetes the loss of Ca may be due to the elimina-
tion through the urine of Ca salts of volatile fatty acids (Palacios).
Because of the marked changes in mineral metabolism and in the
composition of the bone in rachitis and osteomalacia (Goldthwaite, et al. ;
Holt, Courtney and Fales(d)(e); Schabad(a) (&) ; Schloss(&) ; Bru-
backer; McCrudden(a) (c)) these have often been considered diseases of
lime metabolism. There is usually a negative lime balance in the active
stage of rachitis, but rachitis does not always result from a low Ca intake
and it frequently occurs in children receiving plenty of CaO. The blood
Ca is not invariably abnormal in rickets or osteomalacia (Stheeman and
Arntzenius). Attempts to establish a relation between the thyroid, thy-
mus, or sex glands and rickets or osteomalacia are not convincing ( Sarvonat
and Roubier; Zuntz(c) ; Bieling; Claude and Rouillard; Rominger;
Aschenheim(c)). The seasonal variation of rachitis, its incidence being
greatest in the spring and least in the early fall months, has been associated
with the increased Ca retention shown by lactating cows when changed
from a dry to a fresh green ration containing the same amount of Ca.
MINERAL METABOLISM 339
Possibly the lack of some food accessory which affects mineral metabolism
(as for example the antiscorbutic vitamin) and which is reduced by dry-
ing, is reflected in the milk and results in the appearance of a pathological
condition in a young animal subsisting on that milk ( Baumann and How-
ard; Hart, Steenbock and Hoppert; Robb).
The disturbance of phosphorus metabolism accompanying that of cal-
cium metabolism in rachitis has been considered a secondary effect. The
fact that phosphorus therapy is frequently successful (Kochmann(d) ;
Meyer (6) ) suggests that phosphorus may be more fundamentally involved
than it is generally thought to be.
Osteomalacia, on the other hand, is more generally considered a disease
of calcium metabolism, occurring usually as a result of the drain on body
lime during pregnancy. McCrudden(c) considers that the normal "flux"
of calcium is increased in pregnancy, that because of functional inertia it
may continue too long after the demand has ceased, and become patho-
logical, and that ovariotomy effects a cure, not because of any functional
relation between the ovaries and Ca metabolism, but because it removes
the possibility of further drain on calcium by pregnancies. The effect
of castration on rats bears this out since the lime content of females is
unchanged by castration, but that of males is reduced 10-20 per cent
(Reach).
The Metabolism of Vitamins Carl Voegtiin
Discovery of Vitamins — Chemical Nature and Physical Properties of Vitamins
— Antineuritic Vitamin (Water-soluble B) — Fat-soluble Vitamin (Fat-
soluble A) — Antiscorbutic Vitamin (C Factor) — Distribution of Vita-
mins in Food — Digestion and Absorption of Vitamins — Intermediary
Metabolism and Physiological Action — End Metabolism of Vitamins —
Special Feature of Vitamin Metabolism.
The Metabolism of Vitamins
CARL VOEGTLIN
WASHINGTON
Discovery of Vitamins
Until a few years ago it was generally assumed that a complete diet
for purposes of proper growth and maintenance of health of the animal
body should consist of proteins, fats, carbohydrates, inorganic salts and
water in sufficient quantities to furnish an adequate supply of energy and
material for the building up of the body tissues. The discovery of certain
other substances not related to the above-mentioned food factors, and
now considered just as essential for the maintenance of normal metabolism,
can be traced back to two distinct lines of investigation; first, the study
of scurvy and beriberi, and, second, feeding experiments with highly
purified diets.
Numerous clinical observations on scurvy and beriberi, and especially
the experimental production of these diseases in the lower animals by
Eijkman(c) (1897), and Hoist and Frohlich(o) (1907), -called attention
to the importance of the diet in the causation of these diseases. Thus it was
found that scurvy does not occur if the diet contains an adequate amount
of either fresh meat, fresh vegetables or fresh fruits, and that the disease
can be successfully treated by the administration of relatively small
amounts of certain fresh fruits and vegetables. These observations, and
the fact that prolonged exposure of these foods to temperatures of 100° C.
destroyed their prophylactic and curative properties, suggested that the
fresh foods contained some hitherto unrecognized food constituents. Ex-
perience with beriberi showed furthermore than this disease appears if
the diet is restricted to highly milled cereals, whereas people living on
foods made from the whole grain are immune against beriberi,
amounts of an extract of the portion of the grain removed in the milling
process proved to be a powerful curative agent. This led to the conclu-
sion that the whole grain and the extracts made from the offal contame,
substance or substances which later on were shown by Funk(<
to be related to any of the well-known food factors.
Independent of this work on scurvy and beriberi, some investigator!
attempted to feed animals on purified diets containing an adequate pro
341
342 GAEL VOEGTLIN
portion of the well-known food factors (purified proteins, fats, carbo-
hydrates and inorganic salts). These attempts invariably resulted in
failure, as the animals after a certain period declined in weight and ex-
hibited symptoms of malnutrition. Pioneer work on this subject was
donebyLunin (1881), Stepp(a)(6) (1909, 1912), Hopkins(a) (1912),
Osborne and Mendel (1911), and McCollum and Davis(d) (1912, 1915).1
The addition of small quantities of milk or certain other natural foods to
the purified diet.rendered the latter physiologically complete. The purified
diet, as the diet which causes beriberi or scurvy, was evidently lacking in
some food constituents which are essential for normal metabolism. These
substances of unknown chemical composition were termed by Funk "vita-
mins." Hopkins refers to them as "accessory food factors," and McCollum
speaks of the "Fat-soluble A" (fat-soluble vitamin), "Water-soluble B"
(antineuritic vitamin), to which Drummond has added the "Water-soluble
C" (antiscorbutic vitamin).
There can be little doubt, if any, about the identity of the antineuritic
vitamin with the water-soluble B. The proof for this assumption is
based upon two well established facts: (1) the solubilities in various
solvents and the resistance towards heat, exposure to alkali and other
agents is identical for both substances; and (2) the distribution of these
two factors in various foodstuffs is the same, whether established by
means of growth experiments on rats or whether the antineuritic power is
determined in pigeons. Both pigeons and rats develop polyneuritis if the
diet is lacking in either water-soluble B or antineuritic vitamin.
All the various terms applied to these substances have been justly
criticized for one reason or another. The terminology adopted in this
chapter should therefore be considered as more or less arbitrary.
Chemical Nature and Physical Properties of Vitamins
The chemical composition of vitamins is unknown, principally on
account of past failures to isolate these substances in pure form from the
natural foods. The work so far done on this subject is, however, not
without interest, both from a theoretical and practical aspect, and will
therefore be briefly reviewed.
Antineuritic Vitamin (Water-soluble B). — The early researches on
beriberi and polyneuritis gallinarum showed that the antineuritic vitamin
can be readily extracted by means of water or hot ethyl alcohol (Eijkman
(e), 1906) from rice polishings, yeast, and other material rich in this sub-
stance. Acetone, ether, chloroform, benzene, and petrolether fail to ex-
1 For a historical review of the earlier experiments, the reader is referred to the
monograph by Osborne and Mendel (1911). The later development of the subject is
admirably presented in the "Report on the Present State of Knowledge Concerning
Accessory Food Factors (Vitamins)," Medical Research Committee, 1919, H. M. Sta-
tionery Office, Imperial House, Kingsway, London, W. C. 2.
THE METABOLISM OF VITAMINS 343
tract this vitamin (McCollum and Simmonds(a), 1918). The addition of
a small amount of hydrochloric acid to alcohol increases the efficiency of
the extraction and the best results are obtained by using acid methylalcohol
(Voegtlin and Myers(d), 1920). If the alcoholic extract is deposited
upon dextrin and the mixture dried, the deposited vitamin may be dissolved
by benzene, but not by acetone (McCollum and Simmonds(a), 1918).
Voegtlin and Myers(d) (1920) showed that olive oil or oleic acid extracts
the antineuritic vitamin from autolyzed yeast, thus proving that at least
under certain conditions this vitamin is fat-soluble, as well as water-soluble.
The great water-solubility of this vitamin suggests that in the cooking of
fresh foods in water a considerable amount of this substance may pass
into the water, and that the latter should therefore be consumed with the
cooked food whenever possible. The active substance diffuses easily
through the ordinary semi-permeable membranes (Chamberlain and Ved-
der(a) (6), 1911, and Sugiura, 1918), a fact which indicates that the anti-
neuritic vitamin very probably has a relatively small molecular weight.
It is safe to regard the antineuritic vitamin as it occurs in the natural
foods as resistant to drying or moderate heating, up to 100° C. Prolonged
heating of foods above 100° C., as used in the process of commercial
canning, appears to destroy a variable proportion of this factor (Grijns,
1901; Eijkman(e), 1906; Hoist, 1907; McCollum and Davis(rf), 1915).
In an alkaline medium destruction proceeds much more rapidly, especially
if the temperature is raised to 100° C. (Cooper(a), 1913; Vedder and
Williams, 1913; Sullivan and Voegtlm(a), 1916; Steenbock(a), 1917;
Drummoiid(a), 1917; Chick and Hume(d), 1919). For example, it was
found that cornbread made from low extraction cornmeal, baking soda,
salt and water was deficient in antineuritic vitamin, whereas cornbread
made without the addition of sodium bicarbonate still contained this vita-
min (Voegtlin, Sullivan and Myers, 1916). The use of baking soda in
cooking is therefore contraindicated unless proper provisions are made
to neutralize the free alkali, as for instance by the addition of buttermilk
in bread making. Several observers (Cooper and Funk, 1911; Sullivan
and Voegtlin(a), 1916) have noted that the antineuritic substance is highly
resistant to acids, as prolonged boiling with 10 p.c. sulphuric or hydro-
chloric acid does not seem to lead to any appreciable deterioration ; on the
contrary, the physiological activity of crude extracts of foods containing
this vitamin was greatly increased by this treatment, as shown by the '
prompt relief of the symptoms in polyneuritic birds (Vedder and Williams,
1913; Sullivan and Voegtlin, 1916).
Zilva (1919) has demonstrated that the antineuritic vitamin in
autolyzed yeast is not destroyed when exposed for six hours to ultraviolet
rays, nor does radium emanation seem to have any deleterious action upon
this substance (Funk(e), 1916). Sugiura and Benedict (1919) claim that
the growth-promoting factors in yeast may be partially inactivated by this
344 CARL VOEGTLIN
treatment, an observation which these observers consider as a possible
explanation of the therapeutic effect of radium upon neoplasms.
Cooper and Funk (1911) discovered that the active substance is
precipitated by phosphotungstic acid, and that the precipitate thus ob-
tained yields a highly active preparation after decomposition of the pre-
cipitate and removal of the phosphotungstic acid. Later work by Funk
(1912, 1913) then showed that this preparation can be further purified
by treatment with silver nitrate and baryta, which precipitates the vitamin.
By repeated recrystallization of this fraction (pyrimidin fraction), a sub-
stance was obtained which melted at 233° C. to which Funk gave the
formula C17H20O7N2. The crystals, for unknown reasons, very often
lose their physiological activity on recrystallization from water, a fact
which has been most troublesome in the isolation of. this vitamin. The
principal observations of Funk were confirmed by Edie, Evans, Moore,
Simpson and Webster (1911-12), Cooper(a)(&) (1913), Vedder and
Williams (1916), Williams (1916), Voegtlin and Myers(d) (1920), and
others. The last two investigators carried the purification a little further
by the use of mercuric sulphate, and obtained a product free of purins, his-
tidin, proteins, albumoses arid lipoids. Suzuki, Shinamura and Odaki
(1912) claim to have prepared a picrate of the antineuritic vitamin, but
their work could not be verified by Drummond and Funk (1914). Hof-
meister(a) (d) (1918, 1920) claims that the antineuritic vitamin belongs
to the pyrimidin series (CgH^NOs) and that it yields a crystalline hydro-
chlorid and gold salt. Williams and Seidell (1916) obtained adenin from
autolyzed yeast, and found that it had powerful curative properties when
tested on polyneuritic birds. The sample lost its physiological properties
on standing. They furthermore found that inactive adenin submitted to
treatment with sodium ethylate assumed antineuritic properties, observa-
tions which led these authors to regard the antineuritic vitamin as an
isomer of adenin. However, Voegtlin and White (1916), and Harden
and Zilva(a) (1917) were unable to confirm these observations.
The active preparations and crystalline fractions hitherto obtained
by various workers are probably mixtures of active material and im-
purities, and the passing over of the active substance into certain fractions
is explained by Drummond (a) (1917) by the assumption that this vitamin
is easily carried down by bulky precipitates. The antineuritic vitamin is
adsorbed by charcoal (Chamberlain and Vedder(a) (6), 1911), by fullers'
earth (Seidell, 1916), by mastic emulsion or basic ferric phosphate (Voegt-
lin and Myers(rf), 1920), and by colloidal ferric hydroxid (Harden and
Zilva(c), 1918). Of these absorbing agents, fullers' earth appears to be
the most suitable one for the purpose of preparing a quite stable concen-
trate from aqueous solutions containing this vitamin. The activated
fullers' earth can be made use of as a source of this vitamin in feeding
experiments (Eddy, 1916). Adsorbing agents have so far not been of
THE METABOLISM OF VITAMINS 345
assistance in the chemical isolation of this vitamin, probably on account of
the fact that other material, especially organic bases, are also carried along
with the active substance. In any attempt at the isolation of this vitamin,
proper consideration should be given to the possible injurious effect of
alkali and heat.
Fat-soluble Vitamin (Fat-soluble A).— This dietary factor was first
discovered in butter (McCollum and Davis (a), 1913 ; Osborne and Mendel
(c), 1913), and is usually found in association with certain food fats in
which it is very readily soluble. It can be extracted from dried spinach or
clover by ether (Osborne and Mendel(r), 1920). In water it is only solu-
ble to a very limited degree. McCollum (1917) has estimated, for in-
stance, that in milk one-half of the substance present is dissolved in the milk
fat, which indicates that the solubility in fat is approximately 30 times
greater than that in water. Osborne and Mendel (h) (q) (1915, 1920)
observed that butter fat treated with live steam for 2y2 hours had not lost
any of its fat-soluble vitamin. More recently Steenbock, Boutwell and
Kent (1918) claimed, however, that the substance is slowly destroyed at
40° to 60° C., and that complete destruction takes place after 4 hours'
exposure to 100° C. These observations were confirmed by Drummond
(e) (1919), who worked with butter and whale oil. The fat-soluble vita-
min in plant tissues is not destroyed by autoclaving for three hours at 15
pounds pressure (Steenbock and Gross (&), 1920). The destructive process
is evidently a reaction of slow velocity, but of suificient magnitude to be
considered from the practical point of view of the deterioration of this
factor in food.
Saponification of butter fat with alcoholic sodium hydroxid does not
destroy the fat-soluble vitamin (McCollum and Davis(c), 1914), whereas
saponification in the presence of water leads to complete destruction
(Drummond(/), 1919). In the commercial "hardening" of certain oils by
means of hydrogen, the physiological activity originally present in the
oil is lost, this being principally due to the high temperature used in
this process (Drummond, 1919). This vitamin is also destroyed when
butter is exposed for 8 hours to ultraviolet rays (Zilva, 1919). There is a
complete lack of knowledge regarding the chemical composition of this
substance, although recently Steenbock (1919, 1920) has called attention
to the possible identity of this substance with a yellow pigment, carotin, a
view which, however, is not shared by Palmer (1919).
Antiscorbutic Vitamin (C Factor).— This vitamin is soluble in water
and alcohol (Harden and Zilva(fc), 1918; Hess and Unger(&), 1918) and
is easily dialysable through parchment (Hoist and Frohlich(fc), 1912) and
porcelain filters (Harden and Zilva(rf), 1918). The substance loses i
physiological activity on drying, sometimes even at low temperature and
more readily at 100° C. (Givens and Cohen, 1918; Givens and McClug-
gage(6), 1919). From the experiments of Delf (1918) it appears that the
346 GAEL VOEGTLIN
rate of destruction of the antiscorbutic vitamin contained in fresh cabbage
is accelerated about threefold when the temperature is raised from 60° to
100° C. The destructive action of heat is more pronounced when the
substance is heated in an alkaline medium (Hoist and Fr6hlich(6), 1912;
Hess and linger (d), 1919), whereas an acid or neutral reaction seems to
stabilize it somewhat (Harden and Zilva, 1918). The effect of canning
on the antiscorbutic factor of vegetables was studied by Campbell and
Chick (1919). Nothing is known concerning the chemical composition
of the antiscorbutic vitamin.
The principal feature brought out by tiiis brief discussion of the
physical properties of vitamins is the fact that these substances must be
considered as relatively unstable, because various influences tend to destroy
their physiological properties. It is readily seen that this lack of stability
has an important bearing upon human nutrition and a proper appreciation
of this fact, combined with further work on this subject, will ultimately
lead to more rational methods of manufacture and cooking of foods.
Distribution of Vitamins in Food
From the standpoint of practical dietetics, it is of great importance
to determine the vitamin content of the more commonly used foodstuffs.
The available data bearing on this point were obtained by means of feeding
experiments on rats, guinea-pigs, pigeons and chickens. To a basal diet,
complete in every respect but lacking the vitamin under consideration,
there were added the foodstuffs to be investigated in such amounts as to
just maintain normal nutrition or growth (Chick and Hume(d), 1919).
The results, which of course are not absolutely accurate, may be briefly sum-
marized as follows : The principal sources of the antineuritic vitamin are
the seeds of plants, eggs, animal tissues, with exception of adipose tissue,
the green parts of plants, pulses, and to a more limited extent, milk, fruits,
and tubers. Brewers' yeast is very rich in this factor. In the case of
cereals, this vitamin is principally, if not exclusively, located within or
close to, the embryo, which accounts for the deficiency of the highly milled
products in this factor, as the milling process removes the embryo and
superficial layers of the seed.
The fat-soluble vitamin is largely found associated with certain animal
fats, and also occurs in the green parts of plants, and to a lesser extent in
the germ of cereals. Butter, cream, fish oils, and egg yolk are rich in this
factor, whereas lard, and the vegetable oils do not contain it in appreciable
quantities. N"o explanation is available for the paradoxical fact that beef
fat contains the fat-soluble vitamin and that the latter is not present
in lard.
The main sources of the antiscorbutic vitamin are fresh, green
THE METABOLISM OF VITAMINS 347
vegetables, certain fruits, and, to a more limited extent, fresh meat, tubers
and fresh milk. In general, dried milk powders (Barnes and 'Hume
1919), condensed and pasteurized milk (Hess(c), 1916) are deficient in
this factor. It is interesting to note that the germination of cereals leads
to the formation of the antiscorbutic vitamin, as shown by the action of
sprouted grains in the treatment and prevention of scurvy in guinea-pigs
(Fiirst, 1912; Weill, Mouriquand and Peronnet, 1918; McClendon Cole
Engestrand, 1919).
An important relationship between the dietary value of the natural
foods was brought out by the systematic investigation of McCollum and
his coworkers (1917), who were able to show that the addition of the
green parts of plants to a diet restricted to the seeds of plants has a
marked tendency to render the diet more complete not only with respect
to the inorganic salts but also the fat-soluble vitamin ; and previous work
had shown that green vegetables supply furthermore the antiscorbutic
vitamin which is absent in cereals. The conclusion is therefore justified
that a proper mixture of the green parts of plants and the seeds does
possess a higher dietary value than either of these foodstuffs alone. A
mixed diet containing, in addition to cereals and green vegetables, also
some milk and fresh meat is the best safeguard against the possibility of a
vitamin deficiency and furthermore insures an adequate supply of in-
organic salts and protein of proper biologic value.
The table on pages 352-355 includes the principal data regarding the
distribution of the three vitamins in the common foodstuffs. The informa-
tion contained therein may be of sufficient practical value until more
accurate methods are worked out for the quantitative estimation of vita-
mins in foods. The relative quantity of these substances is indicated by
the number of plus signs. A zero sign signifies total absence or insig-
nificant traces.
Digestion and Absorption of Vitamins. — In view of the relatively
unstable character of vitamins it is a matter of importance to know
whether these substances are partly destroyed during digestion. Quan-
titative information on this point is completely lacking. However, it may
be safely assumed that the utilization of the vitamins contained in certain
foods (yeast, butter, lemon juice) is fairly efficient, as very small quan-
tities of the latter are required to supply the animal's needs in vitamins.
Whether vitamins are absorbed by the stomach or the upper intestines or
by both of these organs remains to be determined.
Intermediary Metabolism and Physiological Action
After absorption from the gastrointestinal canal, the vitamins are car-
ried, presumably by way of the portal circulation, or possibly also the
lymphatics/ to the tissues of the body, where they are stored up. It is
348 CARL VOEGTLIN
interesting to note that different organs vary considerably in their vitamin
content. Thus Cooper(fc) (1913) has shown that the antineuritic vitamin
content is largest in ox liver, less in ox heart, and still less in ox brain and
skeletal muscle, the latter containing only relatively small amounts of this
substance (see also Osborne and Mendel (j) (fc), 1917, 1918). The pres-
ence of this vitamin was also demonstrated in the spinal cord (Voegtlin
and Towles, 1913), the pancreas (Eddy, 1916), the kidney (Osborne and
Mendel (;') (&), 1917, 1918), and testicle (Schaumanri, 1910) ; whereas it
seems to be absent from adipose tissue generally. These observations are
rather significant, as they suggest that the antineuritic vitamin is needed in
all tissues, more or less in proportion to the magnitude of their metabolism,
but not in tissues which function as a depot for reserve energy. This inter-
pretation is also supported by the fact that the yolk of eggs are rich in this
substance, whereas it seems to be absent in egg white. A similar deduction
may be drawn from the distribution of this substance in plant tissues, as it
was shown that it is concentrated within or in the immediate neighborhood
of the embryo or germ of the corn and wheat kernel and that it is absent in
the superficial layers and endosperm (Voegtlin and Myers (&), 1919).
More recent work has also shown that the green parts of plants contain
sonsiderable quantities of antineuritic vitamin, when due allowance is made
for the high water content of these foods (Osborne and Mendel (n), 1919).
A somewhat different situation is met' with in the distribution in the
body of the fat-soluble vitamin, which is found not only in glandular
organs, but also in certain adipose tissue (beef fat). Strange to say, it is
absent from lard, and skeletal muscle appears to contain only traces.
Again, the liver is relatively rich in this substance, as shown by the
high activity of cod liver oil.
Almost no data are available concerning the localization of the anti-
scorbutic vitamin in the various organs of the body, with exception of the
well established fact that fresh lean meat contains this factor.
The numerous feeding experiments with deficient diets permit us to
conclude that the animal body, under normal conditions, contains a
considerable reserve of fat-soluble vitamin, but not of antineuritic and
antiscorbutic vitamin. Thus susceptible animals survive a much longer
period when supplied with a diet lacking in the former, than on a diet
deficient in the latter* two vitamins.
As regards the role played by vitamins in metabolism, we are still
more or less limited to hypothetical considerations supported to some
extent by suggestive observations. One of the most perplexing questions
is the fact that different species of animals have different vitamin require-
ments. For instance, it is well proven that a diet complete in every respect
but completely lacking the antiscorbutic vitamin will support normal
metabolism, growth and maintenance of health in rats, mice, pigeons and
chickens for considerable periods, whereas this same diet will cause scurvy
THE METABOLISM OF VITAMINS 349
within a few weeka in man, guinea-pigs, monkeys and dogs. On the other
hand, it has been conclusively shown that all of the higher animals need a
certain amount of fat-soluble and antineuritic vitamin for proper
nutrition, maintenance of normal growth, reproduction and life. It has
been suggested by various students of this subject that the antineuritic
vitamin is somehow concerned with the maintenance of the proper function
of the nervous system, an assumption which is supported by the occurrence
of severe paralytic symptoms and degenerative changes in the nervous
system of animals fed on a diet deficient in this vitamin. More recently,
McGarrison has shown, however, that the nervous system is by no means
the only organ affected by this particular vitamin deficiency.2 A few
workers have made the attempt to prove that the antineuritic vitamin
has a stimulating action upon various digestive glands, this resulting in
an iiicEeased production of secretion. Bickel(e) (1917), for instance,
showed that a crude extract of spinach contains a principle with a pharma-
cological action similar to that of pilocarpin. Uhlmann(a)(6) (1918)
studied the effect of the residue of an alcoholic extract from rice polishings
on various digestive glands and the sweat glands. He obtained a marked
increase in secretion, following the parenteral injection of the extract. He
was furthermore able to show that the same extract caused contraction of
intestinal muscle and a fall in blood pressure. The latter effect he attrib-
utes to a direct depressing effect on the heart muscle and to vasodilatation.
Shortly after this paper had appeared, Voegtlin and Myers(c) (1919)
published their findings, which were carried out without a knowledge of
Uhlmann's work. They showed that the intravenous injection of a highly
purified extract from yeast produced an abundant flow of pancreatic and
biliary secretion, resembling in every respect the effect produced by an
extract of the duodenal mucosa purified in the same manner as the yeast
extract. Alcoholic extracts from liver produced the same effect, and all
three extracts were shown to be rich in antineuritic vitamin, when tested
as to their therapeutic action on polyneuritic pigeons. As suggestive and
interesting as these findings may be, it should be emphasized that the
physiological effect noted by all these observers may have been due to some
highly active impurity and not the vitamin per se.
Dutcher (1918) has recently suggested some relation between the
antineuritic vitamin and oxidative processes, as he observed that the tissues
of polyneuritic birds showed a marked reduction in catalase and that the
catalase activity was again restored to normal after the administration of
this vitamin. He believes that this substance increases the production
of catalase. . .
Funk (1919), Braddon and Cooper (1914) claim that the antmeunt
vitamin is essential for the metabolism of carbohydrates, a view which i,
not shared by Vedder (1918).
'For further details see chapter on beriberi.
350 CARL VOEGTLIN
Driunmond(rf) (1918) studied the metabolism of rats fed on an artifi-
cial diet deficient in antineuritic vitamin and noted the presence of ereatin-
uria, accompanied by decrease in food consumption. The addition of the
vitamin to the diet was followed by an increased food intake.
Incidentally, reference is made to the work of Mellanby (c) (d) (1919),
who claims to have produced experimental rickets in dogs by means of a
diet deficient in fat-soluble vitamin, which would indicate that the sub-
stance is concerned in the metabolism of calcium. It is impossible to ac-
cept this view without considerable modification, as Hess and linger (/)
(1920) have shown conclusively that infants develop rickets while receiv-
ing "a full amount of this principle, and that they do not manifest signs,
although deprived of this vitamin for many months, at the most vulnerable
period of their life." McCollum and Simmonds (1920) have also pre-
sented evidence which is not in agreement with Mellanby' s views.
A lack of fat-soluble vitamin in the diet leads to the appearance of
xerophthalmia in rats (McCollum) ; a condition which had previously been
observed by Mori (1904) in young children whose diet was lacking in
certain fats, which are now known to be rich in fat-soluble vitamin.
The antiscorbutic vitamin is probably concerned in the growth of some
species, but not of all, as Hess(c) (1916) observed the appearance of scurvy
in infants in spite of a preceding period of normal growth. Hoist and
Frohlich have described great fragility of the bones in guinea-pigs suffer-
ing with scurvy which on histological examination was shown to be due
to lack of proper calcification. It would thus appear that the antiscorbutic
vitamin has some relation, either direct or indirect, to calcification.
To sum up, very little indisputable knowledge is available as to the
part played by vitamins in metabolism beyond the fact that the antineu-
ritic and fat-soluble vitamin are needed for growth and that all three
vitamins are essential for proper nutrition of man and some of the higher
animals. Taking into consideration that apparently very small amounts
fulfil the physiological requirements, it is quite possible that vitamins act
as catalysts of some metabolic reactions. They may also possess an indirect
effect upon nutrition by stimulating the digestive organs in the way
indicated above. »
End Metabolism of Vitamins
The available evidence regarding the ultimate fate of vitamins in the
animal body does not permit many positive conclusions. The only data
with a bearing on this point are a few observations on the vitamin content
of the various secretions and excreta. Muckenfuss (1918) treated saliva,
ox bile and human urine with fullers' earth and fed these samples of
fullers' earth to pigeons showing acute symptoms, as a result of a polished
rice diet. Improvement was noted when the preparation was given in
THE METABOLISM OF VITAMINS 351
amounts corresponding to 950 to 3,250 c.c. of ox bile, 400 to 1,325 c.c.
fresh saliva or 4,150 to 6,000 c.c, of urine; from which the author con-
cludes that this vitamin is probably present in comparatively small
amounts in saliva, bile and only in traces in urine. Some unpublished
experiments by Voegtlin and Myers also indicate that human urine
obtained from subjects on a mixed diet is very poor in antineuritic vita-
min, as "activated" fullers' earth corresponding to over a liter of fresh
urine, when fed daily to pigeons on a polished rice diet, was not capable
of delaying the onset of polyneuritis.
Cooper(c) (1914) showed that alcoholic extracts of feces of rice-fed
hens and bread and cabbage-fed rabbits relieved the symptoms of polyneur-
itic pigeons. This would indicate that at least part of this vitamin is
excreted with the feces. (See also Portier and Random, 1920.)
That the mammary gland secretes all three vitamins is well established,
as feeding experiments with fresh unheated milk has shown that this
food belongs to the richest sources of fat-soluble vitamin and that it con-
tains also some antiscorbutic and antineuritic vitamin, although the last
two factors seem to be present in relatively small amounts.
The evidence thus far points to the destruction of vitamins within the
body, which renders it necessary to constantly replenish the supply through
a proper diet. The ultimate source of this supply is the plant, as the
animal tissues are unable to produce vitamins.
Special Features of Vitamin Metabolism
A discussion of the metabolism of vitamins would not be complete with-
out a brief reference to the factors which safeguard an adequate supply
of vitamins to the young animal during the period of its life when it
is entirely dependent upon the milk of its mother. On the basis of some
work on rats, McCollum and Simmonds (1918) conclude that milk varies
in nutritive value according to the composition of the food fed the lactat-
ing animal. The mammary gland has no power of synthesising vitamins
(McCollum, Simmonds and Pitz, 1916). An inadequate supply of fat-
soluble and antineuritic vitamin in the diet leads to a corresponding
diminution of these substances in the milk. Similar observations were
made more recently by Hart, Steenbock and Ellis (1920) with regard to
the antiscorbutic vitamin content of milk. They have found that summer
pasteur milk is much richer in this factor than dry feed or winter-produced
milk. (See also Barnes and Hume, 1919.) Osborne and Mendel(g)
(1920) have found little if any difference in the antineuritic vitamin
content of cows' milk during the various seasons, an observation which 11
easily explained by the fact that the drying of feed does not destroy this
vitamin. Further evidence along this line will bo found in the laptc
on beriberi.
352
CARL VOEGTLIN
oT
la
<n
oo _«?
eo
njco
C
03
03
oS
01 eS
O5
oS O
0)
P
o
-w
'd
s
^3
~
C
03
g
1
0
oS
&o c
a cs
a«
0
ff 1
0
3
3
'H y S
O
c ai
Z^
t^
«5
•-«
5 JL; i— t
r^
.~
03
O
OS -
- - Oi
O
OD O C
*
s
o> ^
•
1—1
i
O -rH
W ^?j
)
1—1
CS
1— 1
"o °3
Mt
c
p— i
. ••>
.^ s
r
CD
C
g
W5
OS
i— 1 1— i
4T w^
0
O
c" S
Ej
os
|U
S s
OS OS
r— 1 i-H
OS 2 *rj
~
-
o
o i
•«.?
8
W
1
3
0
•
03
o .
C C
rt c
-T — "eS
4J . -T3 c
g ao a 03
•3
P
C
03
C s~
O> 3
r^ O
^
c ^
CJ w ^ r~l
b*l ^
^ OS ^ ^ ^H .S
C
3
C 0]
^^
1
•
c 2
" "— 1 **^ i— 1
eS
k> '~i
••^'3 rX
a
0
-r
c c
03 03
eS (3 03
§
^ •
S^2
Osborne
1915.
Hallibur
M
McCollui
Mend
Osborne
Osborne
1913.
gl, s §|
II 3
Hallibur
2
Steenboc
Furst
£2 1-
=3 0
ft, O
||
1.1°
0
O
o 1 4-o
O
1
a
,
o
is.g
'
j|m
O
0
O
O
oo | 4-0
+
+ i
ft."*
? s
£
, 4-
+4-4-
°-'a
's
"03,3 |<H
O
oo
04 o
0
O
4-
+
OD K"*
4~
4~
3 =
o
^
iS 03
-w
^
rt
• • w
"oS
SJ
-u
"cS
m
SB
•S
• • w
• • 01
• • S
• • •
_§
'S
tJD
S
s
1
cereals . .
o
i
• • o)
• • S3
a
T3 •
««H
1
, anim
•as
X
o>
0
w
J5
O
o— '"s
»
§11
^^s
g^^
Cocoanut oil .
Cottonseed oil
Margarin pre
oS
— ' oo •
(-. *" '
jg "S'o ;-•
e$ _ « s
*5 |
H "S
PQPQ
i ^ I
a> "g -u
c3 o S S t-l
Margarin pre]
Hardened fats
origin . . . .
1REAL8, PULSi
o>
oS
m
Germinated pi
Lentils, dried
s
O
THE METABOLISM OF VITAMINS
353
R
a.s
38 •&
e o 05
3^05
o so
-s >
« fi
S -0
si
-
oT .. of £ J^
l| its till li
S >• > >• s
«C5
2F|
^ C * 3
U C >H —
+ | O O O O
S c
i t+t
1 ° i
+ 0+0 + +
to
&
« -
S
°° x
-
O
354
CARL VOEGTLIN
a 2
•3 §a
§s
2 eq |
• Is ~
2. °'S
i -! !^
oo'
00 OO 00 00 rt
^H ••sV.J
B •- § «
05 S 0 S C"
C (M ^
.2 -S * c S
i-H !-( i-H rt .„
O5
•k *y ^ fc ^
PH l~^ ^H
r- - r rj
<^3 ^ — — - -[
O £ ^. »^4 Gl
V— / i^i g -*r
00
3 g J
^ -O ^ on
'^ ^^ g t^ ^
Jill ^
8
oo §10 5
"" C5 o" * C5 "^
A "^ .
•^ ifl tj i—j O ^ —
IV
C
V
§' s|g| |
2 ill s li
Ol
— r *-""£. 2"^ ^
.2 — "P-T^ -r ' ^r
o o o o <g\2 -^"-
i Mlf f
1 III 1 11
"3 'aj "S "oi £ cs 'H
. j^j ^; ^ x r5 Q g
r. OJCCCCCC^1"1^
^H 1 ^j '^ h"J o
^H F^l *~^ ^H ^^ (i^
"H P^ .«s^H
_- • ^ ., ._ Sj
•"' o QJ ij Gi c o
5^*2 oi S.r-c^ ^o
rrt ^ 5 'S
— ~ ~ — ^ C
^H PH * .^
^ffi to ffi ^ ^ ""* *
dJ "^ »v 1^ C r.H OD **
^aTCCTS C SI-H
Sa ^' ^J .jT g
^* tJ^ ^ ^ hrH O S •* *^ O
3gJ«(-.C >H >-O5h
^ Lf y *S fc> r* Q ta
_§ "• 'ff &* _§"O£co *^ S
•gv— s 2 c cj o o P— i >
— ' CJ CJ CJ t) QJ •— s O
o ^ o O SwK W.3
c»OtDO O 6
oouSojoo
o
33
3 «
' '
'
•el
|jp
C a> fi
<u C i~ o flj
O rt i L ^ ^ 1
+++1 +
05 .«
1*
-M
00 00
X 03
•i3 "*"*-!- i i
00 '
+++i +
<1
r— <
O
5 c
+
||«
+++ o + ++ ++|
++++ ++ +
+++
?£
oo
<l
o>
"r" QJ
a> e
+ .S
-U ,£2 C
IJJH
-f- i -4- c ^
+ I + O+ ! O * g +
— ^_,
+ + + +
+1
GC£
oo 'O
co C
te
^.. -.43 • ;S v i •
CO
"SI! -'S 1"^ a^'te
> t
.• £ ' .6
£ oj
£ O . . U
CO
S
f :S5 1| ||ll|l§
e «l i* s'*|^Ia'1
2 s .^-g
^ -s -sf;
TJ a) » .S C fe
_OJ t, >- CS J
.2 »
•
CB g&q ^^ 5.2 » 53 "§ § H
«£ w "1
•I, -Sa
0
sg!i||l "|
| 1-2-1 s s s 2
C- Cj O) — —
1- I- 1^.1
h-5 S 02 >< O O r? * ^
fqpqpao o
^ 3 ^l(§
THE METABOLISM OF VITAMINS
355
H
w
O
c5
.M
I
C
s
O)
. CO
cc
22 o
2^g
c^1"1
CO '^ ^
oo
o
o
o
I
V
CQ
JS C
O O
O5 ' "
3 ^H 05
111
soj
B
• =* a?
2 os **
05 ^ 60
"" ^ fcJOoX
3 °0
*
aj hj
m _.j *v oy , — . ^j cw W OH 3 »• vJ
O coQO ScoO OO WO O
cs a
W 3
c ^
.
02,202001
oSooco
+ +
+
S'i
s-M
'•»>
+
Fat
luble
amin
A
o
Vit
S
7. — —
— — —
oS a; o
PH PH PH
.
tl
li!
356
CARL VOEGTLIN
Recent work indicates that the growth of unicellular organisms, such
as yeast and certain bacteria, is dependent upon a supply of vitamin.
As a result of Bachmann's observations (1919), Williams (&)(&) (1919,
1920) has elaborated a promising method for the quantitative estimation
of the antineuritic vitamin, based upon the observation that the growth of
yeast is proportional to the vitamin content of the medium. The relia-
bility of this method should, however, be fairly established before its
general adoption for work of this kind.
Drummond(6) (1917) has made observations on the influence of a de-
ficiency of fat-soluble or antineuritic vitamin in the diet on the growth of
tumors. He comes to the conclusion that a lack of the fat-soluble vitamin
has no effect, whereas the absence of the antineuritic. vitamin causes a
certain amount of inhibition.
As a concluding remark it may be said that the work of this last decade
has resulted in numerous discoveries regarding the physiological and
pathological significance of vitamins. Although some facts have been
pretty firmly established, this does not hold for all observations made in
this field. As a matter of fact, the study of vitamins is still in its infancy
and sweeping generalizations, as so often made in scientific literature, do
not serve a good purpose. We' are fairly well informed as to the distribu-
tion of the three vitamins in the more important foodstuffs. Further
progress will largely depend on the chemical isolation of these substances, a
phase which so far has attracted the attention of a relatively small number
of investigators.
SECTION II
A Normal Diet Isidor Greenwald
Introduction — The Diet of Primitive Peoples — Food and Civilization — Crop
Failures and Famine — Criteria of Adequacy of Diet — Eelative Impotence
of Certain Foods — Dietary Studies — Manner of Conducting Studies and
of Calculating Eesults — Studies of Entire Countries and Cities — Studies
upon Individuals and Groups on Fully Chosen Diets — Influence of Cli-
mate and Season upon Food Consumption — Influence of Work — Amount
of Protein — Amount of Fat — Ash Constituents — Changes in Food Habits
within Recent Times — Vegetarian — Protein Minimum and Optimum —
Neumann's Experiments — Chittenden's Experiments — Fisher — McCay —
Fat Minimum — Carbohydrate Minimum — Minimum of Ash Constituents
— Underuutrition — Conclusion.
A Normal Diet
ISIDOR GREENWALD
NEW YORK
Introduction
The Diet of Primitive Peoples. — From as early a time as we
can discern anything of the life of man we find that this has
been an almost unceasing struggle for food, for enough to enable
him to satisfy his wants. So far as we can judge from the re-
mains, from the habits of the animals most closely resembling man, and
from those of backward or undeveloped peoples, the diet of primitive man
consisted of whatever that was edible that he could secure. The Min-
copies, or inhabitants of the Andaman Islands, regarded as among the most,
primitive, or lowest in scale of civilization, of the human race, live chiefly
on mangoes and other fruit, shellfish .and an occasional small wild pig.
The Fuegians, another primitive people, subsist almost entirely on shell-
fish. Heaps of shells, supposed to be the remnants of the middens of
primitive man, are found in different parts of the world (Avebury, Tyler).
Scott-Elliott believes the food of Pleistocene man to have consisted of
nuts, fleshy fruits, small birds' eggs, honey, insects and shellfish. There
is no evidence that man, except under the influence of a religious or
pseudo-scientific inhibition, dating from very recent times, ever voluntarily
restricted himself to a purely vegetarian diet. On the contrary, amongst
such peoples as the Fuegians, and in the nomadic and pastoral stages
of civilization, his diet was almost exclusively of animal origin. The
relative importance of vegetable and animal foods varied with their rela-
tive availability. Both kinds were frequently eaten raw but the earliest
evidences and the descriptions of the life of the most primitive of peoples
indicate that, from a very earlv stag'e, man has cooked some of his food, at
i/ t/ O '
least occasionally and as opportunity offered. Man has, indeed, been
called "the cooking animal."
Food and Civilization. — The development of civilization depended
very largely upon the kind of food man was able to secure. Semple states :
"In Australia, the lack of a single indigenous mammal fit for domestica-
tion and of all cereals blocked from the start the pastoral and agricul-
tural development of the native." The American continents were more
fortunate for, with beans, maize and pumpkins, it was possible for a
359
360 ISIDOR GREENWALD
limited agriculture to develop. It is, perhaps, in North America that one
can see most clearly how the nature of the available supply affected the
food habits of the natives. The Indians of the plains were essentially
hunters and lived largely on the results of the chase. In the east, agricul-
ture was fairly well established, among some tribes at least, and maize,
beans, pumpkins and other plants constituted a very considerable part
of the diet. But; it was in what is now the southwestern part of the United
States and in Mexico that the greatest progress in agriculture occurred
and it was there that the highest civilization developed. In contrast with
the tribes of these sections, all of whom were fairly well fed, we find
the stunted and emaciated Indians of the northern Rocky Mountains,
denied both the chase of the buffalo and -the cultivation of maize.
It was in the Old World that animals susceptible of domestication, es-
pecially those suited for a nomadic life, were most numerous and it was
there that pastoral civilization reached its fullest development. Cereals
and legumes were also abundant and furnished the basis for a more
settled life. It was no longer necessary for so much time to be given
to the obtaining of food ; more could be devoted to other wants, the satis-
faction of which is the characteristic of civilization.
Crop Failures and Famine. — All through the ages, such margin as
separated man from an actual food shortage has been very narrow. Famine
has always been a very present menace, as the liturgies of the churches
abundantly testify. The yield of the staple foods, from year to year,
is very uncertain even at this time. With a population dependent upon
closely neighboring sources of supply, any failure of the accustomed yield
means scarcity and even starvation. It was only with the development
of transportation, particularly in the latter part of the nineteenth cen-
tury, that a fairly regular food supply could be assured to most of man-
kind. Even then, famine was not unknown in Russia, China and India.
With the breakdown of commerce and transportation and the withdrawal
of large areas of land and of millions of men from food production as a
result of the world war, famine has reappeared in regions from which we
had once believed it banished.
Even in so large and fertile country as our own and one so well pro-
vided with railroads and other means of communication, the failure of a
staple crop may involve, if not deprivation of sufficient food energy, a fail-
ure to secure sufficient of the less well-recognized dietary constituents. To
quote from Hess(e) (1920) : "It is important for us to realize that we are
still dependent on the annual crops for our protection from scurvy; in
other words, the world is leading a hand to mouth existence in regard to
its quota of antiscorbutic food. The truth of this condition has been real-
ized for Ireland, sadly illustrated by numerous epidemics, notably the great
epidemic of 1847 reported by Curran. It was demonstrated by the out-
breaks of scurvy in Norway in 1904 and 1912 and was brought to the atten-
A NORMAL DIET 361
tion of many in the United States in the spring of 1916. In this year our
potato crop fell far below the normal, with the result that scurvy appeared
in various parts of the United States, especially in institutions."
Short of actual famine and the acute distress and suffering due to
occasional crop failures, the development of man may be hampered by
chronically insufficient or improper food. The case of the RockyMountain
Indians has already been mentioned. Ripley regards the low stature and
poor physical condition of the natives of the Auvergne plateau in southern
France as due to the impossibility of obtaining an adequate diet from
the soil of that region. Removed from the district while young, the chil-
dren develop normally.1 The peasants of the Abruzzi seem to furnish an-
other illustration of the damaging effect of an unsatisfactory diet upon a
whole people. These peasants are amongst the shortest in Italy but when
the young men enter the army and receive a more adequate diet, they grow
rapidly and this growth is greater than for any others except the men from
a few districts in which a similarly unsatisfactory diet is employed. (Al-
bertoni and Rossi(&), 1908; Lichtenfelt, 1912, page 34.) The damaging
effects of malnutrition in cities have been much discussed. While these
are generally considered to be occasional, rather than general, there is some
evidence that they may affect a very considerable proportion of the popula-
tion and may, indeed, alter the physical characteristics thereof. Thus,
Collis and Greenwood regard it as likely that the short stature of the cot-
ton operatives in Lancaster is due to a deficient diet. The nature of some
of these supposedly unsatisfactory diets and the criteria of their inadequacy
will be discussed later.
Definition of "Normal." — It is obvious that in any given country
and at any given period, the people living there and then must regard
their diet as the normal. It is the "usual, common or ordinary" as the
dictionary defines "normal." But to the physician, physiologist or hy-
gienist the word "normal" relates to good health and the "usual, common
or ordinary" is employed only as a means of ascertaining what is to be
considered healthy. A normal diet must be capable of maintaining man
in good health and our conception of a normal diet will become more
definite with increasing knowledge of what is to be considered good health
and of the relation between diet and health. It may, then, fairly be ques-
tioned if the "usual, common or ordinary" diet, as it obtains to-day, even
amongst those most free to chose is really a "normal" diet.
• In this chapter an attempt will be made to discuss the subject from
both points of view. The nature and amount of the food materials made
use of by civilized man in different parts of the world will first be con-
sidered. Then the results of more detailed studies upon the diet of groups
and of individuals in different climates, engaged in different occupations
and of different economic status will be presented. An attempt will be
1 Ripley gives Collignon as his authority. I have not been able to find the original.
362 ISIDOR GREENWALD
made to point out certain properties common to all or most of such diets,
to discuss the significance of the differences and to indicate wherein the
evidence shows some of the diets to be inadequate. Finally, the question
of a possible improvement in our dietary habits will be discussed and the
various measures proposed for this purpose will be considered.
Criteria of Adequacy of Diet. — It is obvious from the preceding chap-
ters that the adequacy of a diet may be judged from many different
aspects; energy yield, nature and amount of protein, nature and content
of inorganic material, etc. Probably, the most essential of these is energy
yield. Unless the diet be restricted to a certain few materials, it is, if
sufficient in energy yield, sure to contain a considerable, even if not en-
tirely adequate, amount of protein, inorganic matter, etc. However, it
should be clearly recognized that this primacy of energy requirement may
be due largely to the fact that our means for determining the energy
R/CE
^^^*~
\\ \\\\
^^
BARLEY
POTATOES
3EEF. PORK AMD MUTTON
Chart I. — Total food value of the chief world foods expressed in calories. Rice,
wheat and sugar are practically all consumed as human food. Some of the rye and
barley is distilled or used for animal food. A considerable part of the potato crop
is used for industrial purposes. Data from G. K. Holmes, The Meat Situation in the
United States, Dept. of Agriculture, Office of the Secretary, Report No. 109. Figure
from G. B. Roorbach, The World's Food Supply, Proceedings of the American Philo-
sophical Society, Philadelphia, 1918, Vol. 57, pp. 1-33.
content of the food and the energy requirements of the body are the better
developed. It may yet be found that man's desire for food is directed
primarily to securing, not a sufficient supply of energy, nor even of pro-
tein, but perhaps of some inorganic constituent or of some as yet unknown
or imperfectly recognized organic substance of the kind variously known
as vitamines, protective substances, food hormones, etc. Thus Osborne
suggested that the beneficial results of exercise may be due, in part, to
the ample supply of these substances secured as a consequence of the
hearty appetite thus produced. But, for the present, we will consider
food primarily as a supplier of energy, then of protein and only secon-
darily of other constituents.
Relative Importance of Certain Foods. — The amount, of energy con-
tributed annually to the world's food by the more important food materials
A NORMAL DIET
363
has been calculated by Holmes to be, in trillion calories : rice, 900 ; wheat,
382; sugar, 209; rye, 164; barley, 119; potatoes, 98.6 and meat 62.4!
The chart on page 362 was prepared by Roorbach from Holmes' figures.
Unfortunately, Holmes does not cite his authorities, and the figure for
sugar appears remarkably high. The relative importance of the different
foods shown by these figures is, however, true for no one country. In some
parts of the East, rice is even more largely the predominant food and, on
the other hand, the consumption of meat is concentrated in a very few
countries.
The figures in Table I are taken from Holmes and show, in pounds,
the annual per capita consumption of meat and meat products. No data
are reported .for China, India and Japan but the consumption of meat
there is known to be small. The amount of meat used, per person, is
greatest in the meat-raising countries, in all of which the density of popu-
lation is rather low. (Chart II is taken from Roorbach.)
TABLE I.-CONSUMPTION OF MEAT AND MEAT PRODUCTS (BEEF, MUTTON AND PORK) PER CAPITA OF
POPULATION— Data from Holmes.
COUNTRY
YEAR
POUNDS
COUNTRY
YEAR
POUNDS'
Argentine
.1899
140
Netherlands
1902
70
Austria-Hungary
1890
64
New Zealand
1902
212.5
Australia
1902
262.6
Norway
1902
62
Belgium
1902
70
Poland (Russian)
1899
62
Canada
1900
109
Portugal
1899
44
••
1910
137
Russia (except Poland)
1899
50
Denmark
1902
76
Spain
1890
49
France
1892
77
Sweden
1902
62
••
1904
79
Switzerland
1899
75
Germany.
1894
88
United Kingdom
1893
112
••
1904
112.7
••
1906
119
••
1913
111.8
United States
1900
182
Greece
1899
68
.. ..
1909
171
Italy
1901
46.5
As the population increases, pasture land is put under cultivation,
the production and consumption of meat fall and the use of the cereals
and other foods increases. A fairly high consumption of meat may be
maintained) and even increased, as in Germany and Great Britain, in
spite of an' increasing population in a manufacturing and trading com-
munity if the level of wealth is sufficiently high to secure the importation
of meat or of concentrated feeding stuffs for animals. But, as a rule, the
importance of meat in the diet diminishes as the population increases and
such meat as is consumed falls chiefly to wealthy and powerful classes.
The medieval laws restricting the taking of game seem to have had their
origin not so much in the desire to secure sport to the nobility as to secure
to them an ample supply of meat, or of certain kinds of meat. (Lich-
tenfelt(c), 1913.) The same predominating use of meat by the wealthier
and more powerful classes obtains to-day in all countries except those in
5 N
II
ili
»j a o
s «' .«£
O
J3? ^-2
%) 0)
. M-g
M' -t^^
e^
g.S
cg^
.20 8
-*J o
Bu « C
S §Pn
— p
«— ^
II
rel
-M&H
364
A NORMAL DIET 365
which meat-raising is one of the chief industries. In 1903, the per capita
consumption of meat in Great Britain was, among artisans, laborers and
mechanics, two pounds per week ; among the lower middle classes, paying
from $75 to $125 annual rental, 2.5 pounds; in the middle classes, 3.5
pounds, and amongst the upper classes 5.75 pounds. (Lusk(t), 1918.)
As can be seen from Holmes' figures, the cereals furnish most of
man's food. Certain few are of particular importance. In the earliest
periods, barley was the predominating or only cereal. In Europe, barley
was supplanted by oats and by rye and these, in turn, were in great part
displaced by wheat. In eastern and southern Asia the supplanting cereal
was rice.
In order to make them more available as food, man early learned to
break and grind the grains, to soak the fragments in water and to cook
this porridge. Cereals prepared in this way are to this day a very im-
portant and even a major part of the food of the people in many lands.
Familiar examples are the boiled rice of the East, the oatmeal porridge
of Scotland, the maize polenta of Italy and, in a slightly modified form,
the many flour soups and cooked dough dishes of central Europe. It prob-
ably did not take man long to discover that the uncooked mixture of cereal
and water could be dried in the sun or over the fire and that this then
furnished, with or without cooking, a readily available, yet durable source
of food. Present day examples are spaghetti, etc., noodles of all kinds,
the oat and barley cakes of northern Europe and the unleavened bread of
much of Asia and of other parts of the world. The preparation of an
actual bread came much later and is, in fact, a matter of comparatively,
recent and local development. For this purpose neither rice nor maize
can be used alone and rye and wheat are immensely superior to barley.
This superiority depends upon the peculiar properties of the proteins of
wheat and rye flour. These form a sticky, extremely tenacious mass when
mixed with water. • This mass holds the starch, etc., firmly, imprisons the
carbon dioxid formed by fermentation and thus produces a light, firm
loaf. This will hold its shape in spite of considerable handling and can
be preserved with comparatively little change for a considerable time and
even indefinitely. It is this superiority of wheat and rye for bread mak-
ing that has caused them to so largely supplant the other cereals as sources
of human food. Wheat bread is generally preferred to rye because of its
color and texture and, by some, because they find the taste more agreeable.
But there are many, chiefly those accustomed to it from early life, who
prefer the taste of rye bread. At any rate, it is still the bread of most
of eastern and central Europe, except in the larger cities. (See Table
III.)
However, there seems to have been, until the outbreak of the war,
a gradual displacement of rye by wheat. To a considerable extent, no
doubt, this was due to the increasing proportion of the population living
366 ISIDOK GREENWALD
in cities, which always lead in the consumption of wheat as compared
with rye, barley or oats. But Sherman(&) (1918) has collected figures
showing that in Russia in the period from 1894 to 1899, there were 1.82
bushels of wheat and 4.76 bushels of rye consumed per person per annum.
During the following five years, these figures were 2.46 and 4.78, respec-
tively, and from 1911 to 1913 were 2.86 and 4.47. The magnitude of
these changes in a country with, relatively, so small an urban population
indicates that the use of wheat was increasing in the country as well as
in the cities.
Dietary Studies
Manner of Conducting Studies and of Calculating Results. — The
amount and composition of the food consumed per person may be deter-
mined in various ways. As in the calculations of Sherman and of
Holmes, the total amount of food raised in and imported into a given
area, less that exported and used otherwise than as human food, may be
divided by the number of people. The method is, at best, only an
approximation but it serves very well to indicate the relative importance
of the different food materials. Next, studies may be made of groups
such as families, eating clubs, public institutions, military and naval
organizations, etc., in which the total amount of food is weighed and,
with or without deduction for waste, is divided by the total number of
people participating. Finally, the food consumed by an individual may
be Weighed.
The composition of the food may be calculated in different ways.
For such gross calculations as those relating to the food consump-
tion of an entire city or country, it is obvious that only the average
of a considerable number of analyses can be used. In the other cases,
the same procedure may be followed but it is also possible, and prefer-
able, to secure sufficient of most of the materials to last through all,
or a considerable part, of the experiment and to analyze representative
samples of these. Still greater accuracy may be obtained by taking to
the laboratory and analyzing a composite sample of the food consumed,
weighed as served, and mixed in exactly the same proportion as consumed.
Assuming the trustworthiness of the subjects, many factors influence
the accuracy and significance of the results. Studies made under labora-
tory conditions with accurate weighing and analysis of the food are the
most accurate but are obviously expensive and difficult to make in large
number for a long period. Studies made in the home can be carried out
in larger number, can be continued for a longer period and come nearer
to "normal" conditions but the accuracy of the weighings and the ap-
plicability of the analytical data employed are more questionable. Daily
and seasonal variations in food consumption must also be considered. The
A NORMAL DIET 367
former are generally neutralized in periods of a week or longer but the
latter may be appreciable, particularly in agricultural communities and
in others in which transportation and storage facilities have not been
well developed.
The results of observations upon adults of either sex may be reported
directly as so much per person, per kilo or per square meter of body sur-
face. With groups including both sexes or adults and children, it is es-
sential to have some unit in which to express the results. Omitting the
periods of pregnancy and lactation, women have a lower food requirement
than men because of smaller body weight, lower basal metabolism per kilo,
and, as a rule, less mechanical work performed. Children may eat less
than adults but consume more per kilo of body weight.
Choice of Factor for Calculating Food Consumed "Per Man."-
From time to time, various methods have been proposed for converting
observations made on groups including women or children to a "per man"
basis. The table (Table II) on page 368 is a compilation of the more im-
portant of these, the food requirement of a man of average weight (70
kilos or 154 pounds) engaged in a moderate amount of work being taken
as 100. The first six columns are copied from the report of the Eltzbacher
commission. This was organized in 1914 to survey the food resources
and requirements of the German nation. It included in its membership
both Zuntz and Rubner. For the value of the food energy requirement
of the German people, they used the average of the results calculated by
each of the six series of factors. Most other investigators and reporters
have used Atwater's factors and generally the earlier set. These»are cer-
tainly in error in giving too low a value to the food requirements of grow-
ing children. In fact, recent investigations (Gephart, Holt and Fales)
indicate that all the sets of factors used by the Eltzbacher commission
and by others are erroneous and that rapidly growing boys and girls re-
quire more food than adults. Holt and Fales have tabulated the energy
requirements of children at different ages. They regard that of an adult
male as 3265 calories per day. From their figures, the author has calcu-
lated the factors found in the last column, which are, for American
children, probably more accurate than any others hitherto used. There
must, of course, be variations in the value of the factors in different parts
of the world and among different races due to the variation in the age of
attaining maturity and the rapidity of growth at any given age.
The factor for women is generally taken as 80 (man == 100) though in
compiling the report of the U. S. Commissioner of Labor in 1903 it was
set at 90 and Rubner (Eltzbacher commission) considered it to be 100.
Two series of Russian observations, cited in Table IV, yield the ratios 81.5
and 88, respectively. Slosse and Waxweiler in a series of 6 comparisons
obtained values for 73 to 95, average 85. On the other hand, Sundstrom'
(1908), in his series of observations on Finnish men and women, found it
368
ISIDOR GREENWALD
^•oooc*5t*"»'Hto^-r*.ts"
eoeo^'^'^'^oiocosot*-
Ci Ci C: O5 00 00 OO 00 3O 00 OO OO
§8 o?
888
_ r o
*H H;K
.2 ^
SS
51
.33
H OQ
^1
88
88
o S
88
A NOKMAL DIET 369
to be only 70. His factors for the food consumption of growing children
were also rather low. Probably these low values are due to the fact
that Sundstrom's adult male subjects were all engaged in hard muscular
work, rather more severe than the standard "moderate work" used by others
whereas the women and children were not so unusually active. If this
reasoning is correct, Sundstrom's values should be increased by from
10 to 20 per cent.
Results Reported as Food Consumed Not that Supposed to be Absorbed.
— Some of the observers whose results are summarized in Table III and IV
have reported their findings in terms of "available" calories and "digest-
ible" protein, the values being calculated with the aid of factors obtained in
metabolism experiments in which the nitrogen content and energy value of
the f eces have been regarded as being due to undigested or unabsorbed food.
This does not, to the present writer, appear to be justified. The percentage
of nitrogen in the feces. is approximately the same no matter what the
diet but the amount of feces formed and, consequently, the amount of nitro-
gen excreted therein is greater with vegetable material than with animal.
However, the relation of fecal nitrogen to food nitrogen after the ingestion
of specific foods is not a constant but depends a great deal upon the indi-
vidual, upon the method of preparation of the food and the nature of the
other constituents of the diet. Thus, Albertoni and Rdssi(a) (1908)
found that the addition of meat to the customary vegetarian diet of Italian
peasants, although increasing the total nitrogen of the food, diminished not
only the relative but also the absolute amount of nitrogen in the feces.
On their customary diet containing 75.7 grams protein, three men ex-
creted a daily average of 3.21 grams nitrogen in the feces. On diets
containing 98.7 grams protein, of which only 21.2 grams was meat pro-
tein and the remainder was derived from the customary food, the nitro-
gen in the feces was 2.94 grams; and with 111.13 grams protein, of which
only 40.8 grams were derived from meat, the fecal nitrogen was 2.16
grams. Similar results were obtained with two women, the figures being
55.8 grams protein intake without meat with 2.71 grams nitrogen in the
feces and 92.6 grams protein, of which 43.3 grams were meat, on the
experimental diet, with only 1.533 grams nitrogen in the feces. A similar
though much less marked effect of added glucose was observed by Neumann
(d) (1919) who found that on a diet of 1000 grams of whole rye bread, his
feces contained 2.52 grams nitrogen daily. Upon adding 300 grams
glucose to the diet, the fecal nitrogen fell to 2.44 grams and, after in-
creasing the glucose intake to 500 grams, to 2.41 grams.
Again, Hindhede(d) (1914) found that the addition of plums to a
bread diet increased the nitrogen of the feces by an amount greater than the
total nitrogen of the plums. Hindhede regarded this as evidence of inter-
ference with protein absorption but, since there was no such evidence of
interference with carbohydrate or fat absorption, it seems possible that the
3TO
ISIDOK GREENWALD
TABLE III. — AMOUNT AND NATURE OF
Date
Country
Authority
PER "MAN" PER DAT
Scale used
to convert
population
into "man
equiva-
lents"2
PERCENTAGE DISTRI
Protein
grams
Fat
grams
Carbo-
hydrates
grams
Calories
Meats
Milk and
products
Wheat
Other
grains
1912-7
United States..
Pearl
121
169
542
4290
J
25.5
20.4
28.9
7.2»
114»
127»
433'
3424'
1909-13
Great Britain
and Ireland
Committee of
Royal Society
113
130
571
4009
I
34.8
13 7
34.6
3.6
1894
Germany
Lachtenfelt
(1898)
123
94
528
3800*
A
22 9
13.7
40.5
(104)
(81)
(504)
(3336)1
1907
Germany (rural)
(urban)
Claassen (a) . .
(146)
(195)
(679)
(5193)1
<m.7<;
(16.8)
(25.0)
(2.5)
(31.8«>)
(98)
(141)
(467)
(3633)1
66.7%
(35.4)
(20.6)
(13.8)
(21.7")
1912-3
Eltzbacher
Commission
per capita. . .
per man ....
(93)
(122)
(106)
(531)
(36425)»
average of
A-F=76.2%
(23.5)
(21.2)
(16.6)
(18.1)
(139)
(699)
(47775)1
1890-9
Paris
Gautier, per
'capita
107«
57
314
26067
43.6
14.1
28.0"
per man ....
140
73
408
3385'
77%
1886
Italy
Lichtenfelt (b)
(1903)
151
78
550
3586
A
(138)
(67)
(524)
(3448)i
1904
Russia
Sherman(1918)
per capita . . .
per man
90
2997
11.1
3.4
70.00
1
117
3880
77%
1 Figures in parentheses represent "digestible" nutrients. 2See Table II. 'After deducting waste of 5% protein, 25%
fat and 20% carbohydrate. 4 Includes 254 calories from alcohol. 5 Includes 173 calories per capita, or 228 "per man," from
alcoholic beverages, or 112, and 147, respectively, from alcohol. 6 Gautier gives total as 102 but total of individual entries is
107.5 grams. 7 Includes 354^and 460 calories, respectively, from alcohol. 8 Includes fish, poultry and eggs. » 10.5% from
plums stimulated the excretion of nitrogen into the intestine. Mosenthal
(a) (1911) found that in dogs on a mixed diet, which would be a high pro-
tein diet for man, the excretion of nitrogen into the intestine was about 35
per cent of the intake and that 25 per cent was later reabsorbed. Hind-
hede's results could be explained by an increased excretion of such nitrogen
without compensatory reabsorption. It is quite possible and even probable
that such nitrogen has not been completely metabolized and therefore repre-
sents as real a loss to the body as if it were unabsorbed food nitrogen but
the fact has not yet been fully established. It is just possible that the
material excreted into the intestine is as truly a waste product as urea
or any other constituent of the urine. However that may be, it is evident
from the observations of Albertoni and Rossi and of Neumann that "fac-
tors of digestibility" derived from certain experiments cannot properly
be used in calculating "digestible protein" under different conditions. See
also Rubner(a#) (1918). Therefore, the discussion in this chapter, unless
the fecal or urinary nitrogen has actually been determined in the particular
observation under discussion, will, unless specifically otherwise noted,
be based upon the nitrogen and energy content of the food, the latter
being calculated by the use of Rubner's factors, 4.1 calories per gram of
protein or carbohydrate and 9.3 per gram of fat.
A NORMAL DIET
FOOD CONSUMED IN DIFFERENT COUNTRIES!
371
BUTION or PROTEIN
PERCENTAGE DISTRIBUTION OK CALORIES
Po-
tatoes
Other
vege-
tables
Nuts and
fruits
Other
foods
Meat'
Milk and
products
Other
fats
Wheat
Other
grains
Po-
tatoes
Other
vegetables
Nuts and
fruits
Sugars
Other
foods
3.1
27
2.0
0.3
24.1
15.3
4.0
25.9
8.818
3.4
2.0
3.1
13.2
0.3
8.1
3.7
0.7
0.6
19.6
12.7
1.8
30.9
3.9
12.5
1.9
2.3
12.6
0.1
6.3
13. T9
0.3
2.6
16.2
11.0
43.5
9.3
6.3
0.8
3.9
9.1i»
(9.4)
(13.3H)
(1.2)
(24.9)
(15.1)
(2.9) 1(31.42°)
(15.3)
(5.9)
(2.8)
(1.8)
(4.8)
(3.5)
(0.3)
(25.4)
(17.2)
(15.8) |(22.4n)
(7.4)
(1.4)
(0.7)
(9.6)
(8.0)
(10.4»»)
(1.0)
(1.2)
(17.3)
(13.1)
(1.9)
(16.6)
(22. 2»)
(11.7)
(4.3)
(2.4)
(5.4)
(5.1»)
1.2"
13.0i«
0.1
15.2
15.1
1.1
37.1"
3.415
7.9
0.8
6.0
13. 6*
9.0
6.3"
0.1
4.7
2.2
1.9
75.3
10.2
3. 125
0.6
2.2
legumes. 10 31.7% from rye. u 5.1% from legumes. 1Z 21.0% from rye. ls 5.4% from legumes.- H Does not include rice.
1S Includes rice. w 8.8% from legumes. " 5.3% from legumes. w 7.0% from maize. » 6.7% from alcohol. *> 31.2% from
rye. 81 21.1% from rye. » 15.2% from rye. » 4.8% as alcoholic beverages, 3.1% as alcohol. :t 13.6% from alcohol. "2.4%
from legumes. * 5.55% from maize.
Studies of Entire Countries and Cities
The great part played by food, or by the lack of it, in the World War,
was responsible for very careful studies of the food statistics of some
of the countries involved. Perhaps the most complete of these that has
been published is that made by Pearl for the United States. In Table III,
there are presented figures taken or calculated from Pearl, from a report
of a committee of the Royal Society of London and from the report of
the Eltzbacher commission. There are also included figures obtained
from the reports of Lichtenfelt(a) (6) (1898, 1903) on food consumption
in Germany in 1894 and in Italy in 1886, of Claassen(a) for the urban
and rural population of Germany in 1909, of Sherman(&) (1918), for
Russia in 1913 and of Gautier for Paris from 1890 to 1899. These last,
obtained from the records of the octroi, or customs collected on the impor-
tation of food into Paris are almost certainly too low, probably due to the
very considerable amount of smuggling that was carried on.
The figures show considerable variation, even for the same coun-
try. Claassen reported an intake of 99.8 grams digestible protein and
3633 available calories for the urban population of Germany and 146
grams and 5193 calories for the rural population, whereas Lichtenfelt cal-
ISIDOR GREENWALD
culated them to be only 104 and 3336 for the country as a whole. Claas-
sen's figures agree fairly well with those of the Eltzbacher commission,
but the latter show an increased consumption of wheat at the expense of
rye and a lessened meat consumption in the interval of five or six years.
The total energy consumption is over 3400 calories in all countries.
The average protein intake is always more than 100 grams. Meat,
including fish, poultry and eggs, supplies roughly 20 per cent of the
calories and somewhat more than this fraction of the protein; milk and
its products, from 13 to 17 per cent of the calories and 14 to 25 per
cent of the protein and the cereals, from 35 to 40 per cent of both calories
and protein.
The greatest variation is found in the nature of the cereal used. In
Great Britain and in France, this is almost exclusively wheat; in this
country, maize plays a not inconsiderable role; but in Germany, particu-
larly among the rural population, rye is used almost exclusively. (See
also pages 365/376, 377.)
Except in the United States, in Paris and in the German cities, po-
tatoes furnish 10 or 12 per cent of the total energy content and a some-
BELGIUM
TABLE IV. — SYNOPSIS
Date
Authority
Subjects
Number oi
Studies
Number of
Individuals
Scale for
Con-
version '
"Man
Equiv-
alents"
Average
weight of
adult male
kilos
Duration
days
1853
Engel
Needy families.
48
Families, income just ade-
quate
51
Families, able to save
54
1891
Engel
Workmen's families:
Income less than 280 marks
per man per year
44
282
A
193
30
Income 280-350 marks per
man per year
49
315
A
218
30
Income 350-420 marks per
man per year
47
294
A
205
30
Income over 420 marks per
man per year
48
276
A
202
3C
188
1167
A
818
1908
Slosse & Van
Workmen
33
33
33
66.4
6
der Weyer
Of these, metal - workers
(hard work)
8
8
8
70.0
6
Wood-carvers, shoemakers,
etc. (moderate work)
13
13
13
68.4
6
1910
Slosse &
Weavers
156
C
14
Waxweiler
Printers
36
C
14
through
Miners
115
C
14
Quarry workers
49
C
14
Greenwood
« See Table H.
A NORMAL DIET
373
what smaller part of the protein. The amount of protein contributed by
"other vegetables" is slight in Great Britain and in the United States, is
greater in Russia and is considerable in Germany and in Paris, owing to
the free use of legymes. The part played by sugar is greatest in the
United States and in Great Britain but is considerable in all countries.
The consumption in the form of beverages has generally been included in
that of the materials used for their preparation but in the reports of
Lichtenfelt and of the Eltzbacher commission for Germany and of Gautier
for Paris this has been separately calculated and found to amount to from
5 to 14 per cent. It is not surprising, therefore, that the prohibition of
the use of alcoholic beverages should, as is claimed for the United States,
increase the consumption of sugar and other sweets.
Studies upon Individuals and Groups on Freely Chosen
Diets
We now have a general conception of the character of the diet in these
countries, considered as units. How is it with the individual? What
OF DIETARY STUDIES
BELGIUM
COMPOSITION OP FOOD, PER MAN, PER DAT
PERCENTAGE
CALORIES FROM
PERCENTAGE DISTRIBUTION or PROTEIN
Calcu-
lated or
ana-
lyzed
Protein
grama
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calories
Protein
Fat
Meat1
Milk
and
products
Wheat
Rye
Po-
tatoes
Others
Calcd.
52.6s
17.3s
469s
2341»
10. 9»
6.9s
"
65.1'
29. 2s
504s
2592s
10.1s
10.5s
*'
72.73
39. 3s
5193
2790s
10.7s
13.1s
„
67.9s
56. 4«
458s
2683s
10.4s
19.2s
13.0
5.8
54.3
7.0
14.1
5.9
»
79. S>
70.6s
497s
2985s
10. 9»
22.0s
17.7
6.7
41.8
15.5
11.9
6.3
«
97. 2»
80.6s
572s
3490s
11.4s
21.5s
18.5
9.0
46.7
8.4
10.2
7.2
«
108s
93.1s
571s
3646s
12.1s
23.7s
22.4
10.1
46.8
2.5
9.0
9.2
'*
85. 9s
74.9s
521'
3179s
ll.P
21.8s
Anal.
105s
100
393
2932
14.7
31.6
»
117
115
410
3110
15.4
34.3
••
100
107
381
2815
14.6
35.4
Calcd.
(80.6)4
(86.9)1
(529)«
(3330)'
9.9
24.2
(94.9)«
(103)4
(586)«
(3817)*
10.2
25.1
"
(77.2)<
(127)4
(497)«
(3604)*
8.8
32.8
(86.2)«
(130)4
(658)«
(4314)<
8.2
28.0
1 Includes fish, poultry and eggs.
1 All of the values for food consumption reported by Engel are too low since not all, but only the principal, foods were included.
4 Figures in parentheses represent digestible nutrients.
"Digestible" protein 0.91 to 2.02 gm. per kilo per day, average 1,375. The man who had only 0.91 gin. protein per kilo
lost 3.48 gm. nitrogen per day
374
ISIDOK GKEENWALD
DENMARK
TABLE IV. — SYNOPSIS OF
NUMBER OF
COMPOSITION OF FOOD, PER MAN PER
DAT
Average
Scale
Man
weight
Du-
Date
Authority
Subjects
studies
indi-
viduals
of Con-
version
equi-
valent
of adult
male
kilos
ration
days
Calcu-
lated or
ana-
lyzed
Pro-
tein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calories
1910
Heiberg
Laborers' families
and Jensen
in Copenhagen . .
27
F(?)
83.7
Calcd.
107
105
493
3351
In other towns . . .
23
76.6
"
101
90
464
3153
In islands \
201
,.
„
109
111
516
3595
In Jutland . . . . /
119
103
550
3701
251
749
««
107
105
493
3450
1912
Hindhede. .
Author's family...
1
10
7
"
76
103
3418
FlNtAND
1904
Sundstrom
Students
160
200
391
4126
University
1
100
100
67.6
14
Calcd.
1577
1917
3807
3984'
Agric.. School, men
1
24
24
61.8
14
"
22B7
119?
6857
4836'
" " women
1
9
Not con
verted
S6.8
14
"
/50'.«
92'.'
49&'>
35081*
Families of city
workmen
12
40
C
30.8
14
"
139
130
455
3643
1907
Sundstrom
Farmers, etc., men
17
17
67
7
Anal.
136
83
580
3705»
women
25
25
69
7
"
W«
Bl>
360*
23S5>'W
disregard 6 lowest
19
19
59
7
94*
64»
39&>
245V>>ia
1907
Sundstrom
Households of
farmers, etc
80
559
H
393
7
Calcd.
177
104
688
451610
FRANCE
1906
Gautier . .
Family of farm la-
borer in south of
France
2
14
(fn.11)
12
385
Calcd.
149
79
830
4745
6 Includes oleomargarine. 7 Corrected for waste. 8 Includes other vegetables. * Figures in italics refer to food|consump-
tion per woman, not per man equivalent. 10 Sundstrom gives other figures but he used other factors for energy values of
food. u Gautier calculated food consumption of 2 women and child of 7 as equivalent to that of one man.
variation is there among individuals and what are the factors responsible
for such variation ?
There have been many observations published on the food con-
sumption of individuals and of groups living on their customary diet,
which is sometimes called a "freely chosen diet." In reality there
is no such thing. Man's choice is limited by his geographic and
economic situation, to say nothing of such things as food habits and prej-
udices acquired early in life. Just as was his primitive ancestor, though
to a lesser degree, modern man is limited in his choice by his environment.
Among the earliest reports that are sufficiently accurate to be of any
considerable value are those of Liebig on the1 food of Bavarian woodchop-
pers. Similar studies were made by Playfair, by Meinert, by Moleschott
and by others but the greatest impetus to the study of the food habits of
the people appears to be due to the work of Voit. Basing his opinion
upon the results of previous investigators and upon the actual food con-: '
A NOKMAL DIET
DIETARY STUDIES — Continued
DENMARK
375
PERCENTAGE
CALORIES FROM
PERCENTAGE OP DISTRIBUTION OF PROTEIN
PERCENTAGE DISTRIBUTION op CALORIES
Protein
Fat
Meat2
Milk and
Products
Cereals
Po-
tatoes
Other
vege-
tables
Meat2
Milk and
Products
Cereals
Po-
tatoes
Other
vege-
tables
Sugars
B
5
13.1
29.1
13.1
26 6
12.4
13.2
28.7
25.8
12.7
28.3
9.1
28.0
5.7
34.8
46.2
12.78
0.5
1.6
31. 76
36.9
12.7
14.1
2.7
FINLAND
15.9
45.1
43.4
30.9
19.9
2.3
2.5
21.9
39.5
24.1
4.3
1.6
7.3
16.2'
44.6
19. 17
22.9
17.3
43.2
29.6
5.1
4.8
7.1
13.5
28.8
44.0
10.2
3.5
17.6*
24-4
19.0
38.8
32.2
2.9
13.1
27.0
43.9
13.9
2.2
15.7
33.2
28.1
38.0
28.1
1.7
4.0
11.0
39.0
33.7
7.4
1.7
7.2
15.0
21 6 \
19.0
36.0
37.0
8.0
9.0
28.0
50.0
13.0
16.0*
20. 8*1
15.7*
SO. 5
16.1
21.4
15.0
35.0
41.0
7.0
2.0
10.0
27.0
48.0
1.1
3
FRANCE
15.5
sumption of men of average weight, 70 kilos, engaged in moderate work
in the city of Munich, he concluded that a normal diet for such a man
should contain 118 grams of protein, 56 grams of fat and 500 grams of
carbohydrate. Substitution of as much as 150 grams of the carbohydrate
by an isodynamic amount of fat was considered desirable. This is known
as Voit's standard. As Dunluce and Greenwood say, "It has enjoyed a
vogue which is not so much due to the number or accuracy of the laboratory
experiments carried out by Voit as to this investigator's high and well-
deserved reputation." However, the necessity of so large an amount of
protein has been vigorously denied and as vigorously affirmed. The ques-
tion will be considered later.
Some of the evidence is contained in Table IV, which gives a sum-
mary of some of the results obtained in what seem to be some of
the more important studies of people on their accustomed diets made
since Voit's time. Most of these were made on the poorer classes of the
376
ISIDOK GEEENWALD
TABLE IV. — SYNOPSIS OF
GERMANY
Date
1880-
1892
Authority
Subjects
NUMBER OP
Scale
of
con-
version
Man
equiv-
alent
Average
weight
of adult
male
kilos
Du-
ration
days
COMPOSITION OF FOOD PER MAN
PER D&T
studies
indi-
viduals
Calcu-
lated or
ana-
lyzed
Pro-
tein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calories
Demuth. . .
Pensioners, etc.,
light work
3
3
Calcd. to 70
kilos bodyw't.
Calcd. to 70
kilos body w't.
Calcd. to 70
kilos bodyw't.
Calcd. to 70
kilos body w't.
Calcd.
103
50
546
3130
City laborers
Farm laborer
Families of above,
etc.
2
u
"
131
67
545
3472
1
1
"
137
89
590
3811
20
78
99
57
597
3400
1890
V. Rechen-
berg
Families of hand-
weavers, very poor
28
57"
7
-
65"
4912
485"
2703"
1899
Ranke
Ranke
Physician (self),
Jan. and Feb.. . .
Physicjan (self),
July and Aug . . .
1
1
73
30
H
138
162
351
3512
1
1
13513
162"
372"
3588"
1902
Neumann..
Laboratory inves-
tigator (self)
Laboratory inves-
tigator (self)
Laboratory inves-
tigator (self) ....
1
1
67.5
305
»
66
84
230
2309
1
1
66
15
Anal.
77
156
221
2659
1
1
72
321
Calcd.
76
109
169
2068
1895
Atwater . . .
Bavarian me-
chanics
17
..
134
63
491
3150
farmers
brewery
laborers
5
"
137
55
545
3295
5
149
61
755
4275
1910
Claassen...
Peasant families,
Rhine valley. . . .
30
(")
109
146
669
4537
GREENLAND
1857
Krogh,
A.&M..
Eskimos
65
282*
2604A
" Per adult individual. " See text, page 389. " 12.7% protein in beer, w 1.1% protain in beer. lfl Legumes furnished
4.5% of the protein and 1.8% of the calories. 17 It is not evident just what factors were used, but they were apparently
lower than any of these in Table II. A Not all food included.
population and many of them were undertaken to ascertain whether or
not a condition of undernutrition obtained. For this reason, it is probable
that the values reported are minimal rather than optimal. In order to
facilitate comparison, the results have been grouped by countries and with-
in each group have been arranged chronologically, unless other consid-
erations made some other arrangement appear preferable.1
1 There is much valuable material for the student of nutrition in the series of
family monographs published by Le Play under the title "Les ouvriers europeens"
and continued by the Societe Internationale des etudes pratiques d'economie sociale as
"Ouvriers des deux mondes." These are a series of complete studies of families in many
parts of the world and include the amount paid for food, in money, kind or labor,
and the amount and nature of the food secured. Unfortunately, the character of the
food is not always sufficiently well-defined to permit of accurate calculation. A similar
criticism applies to the reports of the Board of Trade of Great Britain on working-
class conditions in Great Britain, Belgium, France, Germany and the United States.
A NORMAL DIET
DIETARY STUDIES — Con'.inued
GERMANY
377
PERCENTAGE
CALORIES FROM
PERCENTAGE DISTRIBUTION OF PROTEIN
PERCENTAGE DISTRIBUTION or CALORIES
Protein
Fat
Meat2
Milk
and
Prod-
ucts
Cereals
Po-
tatoes
Other
vege-
tables
Others
Meat2
Milk
and
Prod-
ucts
Cereals
Po-
tatoes
Other
vege-
tables
Sugars
Others
14.3
14.7
15.5
17.9
15.7
22.7
12.0
15.7
9.9
17.0
1.1
12.0
61.7
18.4
16.1
42.8
15.4
41.8
11.7
33.6
35.9
27.4
22.5
1.6
12.7"
11.8
54.6
15.1
48.9
47.0
27.6
19.2
1.9
4 215
17.5
18.5
17.0
15.5
14.3
13.3
11.1
30.0
12.8
21.7
41.1
11.2
12.6"
0.6
14.8
18.8
42.0
15.6
5.016
1.9
1.1
GREENLAND
44
48
The first column gives the date of the study if that is available, ii
not that of the publication and the next, the name of the author or other
authority for the data. The succeeding columns give, in order, some idea
of the social and economic status of the subjects, the number of studies,
the total number of individuals, the scale of conversion to "man equiva-
lents," the number of these, the average weight of an adult male and
the average duration of the studies. These fall into two classes, accord-
ing as the data for the composition of the food were obtained by actual
These include the results of questionnaires on family budgets. Some of the additional
difficulties in drawing conclusions from some of the calculations that have been made
from some of the Board of Trade data are discussed in footnote 21 to Table IV, p. 378.
However, cursory examination of the French monographs and of the reports
of the Board of Trade indicates that more detailed consideration would only cor-
roborate the conclusions indicated by the data presented in this chapter.
378
ISIDOR GREENWALD
TABLE IV. — SYNOPSIS OF
GREAT BRITAIN
Date
Authority
Subjects
NUMBER or
Scale for
con-
version
"Man
equiva-
lents"
Average
weight of
adult male
kilos
Duration
days
Studies
Indi-
viduals
1900
Paton, Dunlop
and Inglis
Families in Edinburgh:
Income less than 20a.; av. 17s., 4d
Av. income 22s., 2d
5
32
C
18
7
5
30
-—
17.1
7
Av. income 39 s
4
34
21.4
7
Typical, av. income 25s., lOd
9
50
34.4
7
1901
Rowntree, data
r e c a 1 c d. by
Dunluce and
Greenwood
Families in York:
Av.income 18s., lid. (all under 26s.)
16
87
I
58.5
70
3
17
I
12
19
6
39
I
30
9
1904
Board of Trade;
calcn s. by
Dunluce and
Greenwood
and by Green-
wald
Families of workmen in cities:
Income under 25s.; av. 21s., 4' ad.
Income 25-30 s.; av. 26s.. Il34d.. .
261
See
Note 21
289
Income 30-35s.; av. 31s., llJid....
Income 35-40s.; av. 36s., 6Md
Income 40s. or more, av. 52s., J^d.
416
382
59b
1911
Cameron
i men
4
149
149
7
\ women
1
30
0.8
24
7
1911-12
Lindsay !
Glasgow families:
Income under 20s, average 18s, 14d
Income 20-25s, average 23s, lOd. .
Income 27-31s
5
29
C
18
7-14
10
63
C
39.2
7-14
3
20
C
11.2
7-14
1916
Ferguson
Glasgow families:
Average income 27.2s
6
C
Average income 31.3s
4
C
7
1917
Ferguson
Average income 28.4s
6
C
7
4
C
7
1903
Dunluce and
Greenwood
British Agricultural Laborers
Northern Counties
see
note 21
Midland Counties
Eastern Counties
Southern and Southeastern Coun-
ties
w Includes 2.2% from peas.
w Includes 13.6% from sugar.
*> Figures underlined refer to distribution of calories, not protein.
11 The average number of children in the families in the different groups was 3.1, 3.3, 3.2, 3.4, 4.4 and 3.6, respectively. In
their calculations, Dunluce and Greenwood used the value 0.51 to convert the number of children into "man equivalents." But
A NOKMAL DIET
379
DIETARY STUDIES — Continued
GREAT BRITAIN
COMPOSITION OP FOOD PER MAN PER DAT
PERCENTAGE
CALORIES FROM
PERCENTAGE DISTRIBUTION OF
PSOTEIN
Calcu-
lated or
analyzed
Protein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
grains
Protein
Fat
Meat'
Milk and
products
Cereals
Po-
tatoes
Others
Calcd.
93
69
396
2607
14.6
23.6
27.1
10.6
53.2
9.0
103
82
480
3133
13.5
24.4
34.1
7.0
54.7
4.1
"
115
92
529
3531
13 4
24.3
31.9
10.0
53.0
5.0
108
88
479
3228
13.7
25.5
30.3
10.2
53.0
3.5
3.318
16.32J
12.82J
50.2"
4.6ZJ
6.3" 20
••
82
88
450
3000
11.2
27.3
49. 4»
46 grains meat and 85
grams sugar per day
227 grams meat and
88 grams sugar per
day 280 grams meat
and 113 grams sugar
per day
"
117
130
589
4102
11.6
29.7
45.3*'
I^^BM^^B
112
161
511
4052
11.3
37.0
29.72J
86
59
536
3094
11.4
17.6
61.325
01 grams meat and 73
grams sugar per day
17 grams meat and 85
grams sugar per day
42 grams meat and 93
grams sugar per day
-Ifi prams meat and 98
grams sugar per day
54 grams meat and
110 grams sugar per
day
92
71
565
3348
11.2
19.6
55.2»>
99
82
588
3581
11.3
21.3
55.62J
98
86
582
3589
11.0
22.5
5t.O"
108
100
644
4013
11.0
23.1
53 32->
"
140
138
516
3976
14.4
32 3
"
162
139
495
3990
16.6
32.4
«
98
76
86
385
2689
14.9
26.4
39.5
8.4
46.9
3.8
1.5
118
531
3457
13.9
23.1
29.1
9.9
51.8
4.1
3.6
*'
118
98
506
3648
13.9
26.3
31.4
10.8
50.2
3.6
3.9
..
96
96
467
3198
12.3
27.9
"
98
88
439
3017
13.4
27.2
••
93
72
462
2949
13.0
22.8
**
112
89
498
3331
13.8
24.8
88
113
547
3654
9.9
27.8
14
88
90
537
3698
10.6
24.6
M
92
83
597
3598
10.5
21.5
"
96
84
600
3634
10.8
24.6
in the families with the larger incomes it is probable that some of the family income came from the earnings of some of the chil
dren. These children would be older than the average and would eat more. Even if this effect be disregarded, the familief
with smaller income would be likely to those most recently established, with the younger children whose food consumption
would be lower than the average. The effect of income upon the amount and character of the food consumed is, tn
probably exaggerated in these figures.
380
ISIDOR GREENWALD
TABLE IV. — SYNOPSIS OF
INDIA
Date
Authority
Subjects
NUMBER or
Scale for
Conversion
"Man
equiva-
lents"
Average
weight of
adult male
kilos
Dura-
tion
days
Studies
Individuals
1908
McCay (1908)
Bengali students, ration scale —
Anglo-Indian and Eurasian stu-
1
54
1
1912
McCay (1912)
Bengalese cultivators
" middle classes, not
above indigence
Appro*. 50
Bengalese middle classes, above
indigence
Thibetans, etc., rickshaw men. .
Sikhs, young men
ITALY
Date
Authority
Subjects
NUMBER OF
Scale of
conversion
"Man
equiva-
lents"
Average
weight of
adult male
Duration
days
Studies
Individuals
1886
Lichtenfelt(1903)
Workers in food industries. . . .
Textile workers
5
9
Laborers
7
1894
Memmo
Men at moderate work, Rome,
ordinary diet
3
3
60.7
7
Native of chestnut-eating dis-
trict, chestnut diet, easy
work..
1
1
59.1
7
Acorn diet, very light work . . .
1
1
65.5
1893
Manfredi
Poor men, Naples, cobblers
" man, " mason
" carpenter . .
2
2
51
5
1
1
55
5
1
1
62
7
1906
Albertoni and
Rossi
Peasants of the Abruzzi, men
" " " " women
7
7
60.4
5
5
5
Not
converted
SO.S*
S
JAVA
1892
Eijkman
Malays, Laboratory servants —
4
4
47.5
4.5
(1893)
medical student
1
1
58.1
5
Europeans in Java, physicians,
etc
11
7
65.4
4
' Figures in italics refer to food consumption per woman, not per "man equivalent."
A NORMAL DIET
DIETARY STUDIES — Continued
INDIA
381
COMPOSITION OF FOOD PER MAN PER DAT
PERCENTAGE
CALORIES FROM
PERCENTAGE DISTRIBUTION or PROTEIN
Calcu-
lated or
analyzed
Protein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calories
Protein
Fat
Meat'
Milk and
products
Rice
Other
cereals
Le-
gumes
Other
vege-
tables
Calcd.
67
72
549
3190
8.6
20.8
13.9
30.5
19.9
26.9
8.7
»
95
56
467
2822
13.8
18.5
41.6
4.4
13.4
26.8
12.9
2.1
••
52
25
475
2390
8.9
9.8
9.7
87.3
5.7
2.2
«
50
50
400
2310
8.9
20.5
10.1
7.5
72.5
6.9
2.3
«
70
90
300
2350
12
36
14.4 +
10.7
19.4
41.2
4.3
1.6
••
175-200
6300 +
"
125-130
3750-4000a
0 Includes 16 oz. milk and 4 01. meat per day.
ITALY
COMPOSITION OP FOOD PER MAN PER DAT
PERCENTAGE CALORIES
FROM
Calculated
or
analyzed
Protein
grams
Fat
grains
Carbo-
hydrate
grams
Energy
yield
calories
Protein
Fat
Calculated
143
31
713
3808
15.4
7.6
5
128
29
662
3470
15.1
7.8
"
168
48
909
4866
14.2
9.2
"
227
62
932
5326
17.5
10.8
Analyzed
106
30
495
2745
15.8
10.2
87 grams digestible protein and 2563
available calories
44.4 grams digestible protein and 2171
available calories
98 grams digestible protein and 1892
available calories
„
59
19
464
2521
9.6
7.0
"
124
63
252
2120
24.0
27.4
"
75
38
379
2208
13.9
15.4
"
71
29
391
2155
13.4
12.3
"
94
56
475
2852
13.5
18.3
. "
73
53
450
2746
10.9
18.1
52.9 grams digestible protein and 2480
available calories
42.7 grams digestible protein and 2004
available calories
60>
46>
S48>
2204'
n.x»
19.4'
JAVA
Anal.
70
29
482
3254
8.9
8.3
"
96
64
426
2731
14
22
"
98
92
262
2553
16
34
382
ISIDOK GKEENWALD
TABLE IV.— SYNOPSIS OF
JAPAN
Date
Authority
Subjects
NUMBER or
Scale for
conversion
"Man
equiva-
lents"
Average
weight of
adult male
Duration
days
Studies
Individuals
1886
Eiijkman
(through Oshima)
Prisoners, no work
1
20+
,
47.6
" light work
1
20+
48.0
" hard work
1
1889
Nagase (Oshima)
Military colonist in Formosa. .
1
1
59
7
1890
Tsuboi (Oshima)
1
1
62.4
4
1909
Inaba
Farmers, rice diet
7
" barley-rice diet
7
H
1910
Yukawa
Celibate monks, young, no
work
8
8
44.5
7
Celibate monks, light work
Celibate monks, old, no work .
1
1
52.1
7
3
3
51.8
7
1911
Hinhede (1920)
Diet list of Japanese pavilion,
Dresden, 1911, hard work. .
light wor,k . .
1
7
7
1
5
7
1919
Kobu and
Sokamoto
Workmen
4
2
32
RUSSIA
Date
Authority
Subjects
NUMBER or
Studies
Individuals
1889
Erismann (1889) . . .
Factory workers
50
1670
1904
Smolensky
Factory workers, ordinary diet
3
" fast days
3
Peasants, Government Moscow, poor
2
" well-to-do
2
Laborers, Cronstadt docks, ordinary diet
1
" fast days
1
Laborers and mechanics, Cronstadt, wages 18-24 rubles
per month, 5 spent for food
1
Ditto, 24-28 rubles, 7.5 spent for food
1
Ditto, 30-48 rubles, 13.5 spent for food
1
Fishers at mouth of Volga, men
1
" " " " " women
1
Peasants, 2 districts, men
1
2 (same), women
1
Average of all reported by Smolensky
94
Figures in italics refer to food consumption of women not "man equivalents."
A NORMAL DIET
383
DIETARY STUDIES— Continued
JAPAN
COMPOSITION OP FOOD PER MAN PER DAT
PERCENTAGE
CALORIES
PERCENTAGE OF DISTRIBUTION OP
PROTEIN
Calcu-
lated or
analyzec
Pro-
tein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calories
As
Protein
As
fat
Meat2
Cereals
Le-
gumes
Other
vege-
tables
Anal.
48
6.8
372
1782
11.0
8.6
"
57
7.6
458
2178
11.7
3.2
"
75
9.8
630
2975
10.3
2.9
"
59
7.7
594
2752
8.9
2.3
Calcd.
158
25.6
1031
5113
12.7
4.7
"
78
16.9
530
2676
11.9
5.9
11
126
31.6
663
3529
14.6
8.3
102
24.3
597
3091
13.5
7.2
Anal.
57
14.6
345
1804
12.9
7.5
38 grams digestible protein
and 1651 available calories
63 grams digestible protein
and 2547 available calories
41 grams digestible protein
and 1872 available calories
••
87
21.2
531
2719
13.1
7.3
"
60
12.3
347
2020
12.3
5.7
Calcd.
120
31.5
3536
14.6
8.3
5
63
32
81
18.6
2770
12.0
6.2
7.5
76
7
9.5
96
18.9
766
3766
10.4
4.7
RUSSIA
COMPOSITION OP FOOD PER MAN PER DAT
Calculated
Protein grams
Fat grams
Carbohydrate
grams
Energy yield
calories
Protein
Fat
Calculated
132
80
583
3676
14.7
20.2
133
565
3507
15.5
18.8
121
71
603
3706
13.4
20.0
109
80
542
2935
15.2
92
146
29
669
3784
15.8
11.8
2?0
48
931
5603
16.1
15.7
216
95
1040
6033
14.7
14.6
123
43
563
3207
15.7
12.3
122
52
419
2704
18.5
18.0
146
140
460
3785
15.8
34.4
303
71
462
3797
32.5
17.3
?19»
4S>
48S»
3/94'
ts.i*
1S.S>
138
39
560
3223
17.5
11.2
122*
31 •
6SS»
t84&
17. 6»
10. (fl
149
57
4040
15.1
13.1
PERCENTAGE CALORIES PROM
384
ISIDOR GREEXWALD
TABLE IV.— SYNOPSIS OF
SWEDEN
Date
Authority
Subjects
NUMBER or
Average
weight
of adull
male
kilos
Du-
ration
days
COMPOSITION OF FOOD PER MAN PER DAT
Stu-
dies
Indi-
vidual
Calcu-
lated or
analyzed
Protein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calories
1887
1887
Hultgren and
Landergren
(1889)
Hultgren and
Landergren
(1889)
University students
University professor. . . .
5
5
68
10.4
Calcd.
128
115
300
3034
1
1
96
8
»
137
113
345
3205
1887-8
Hultgren and
Landergren
(1891)
11
9
67
7.5
.<
159
91
610
4023
1893-8
Englund(Tiger-
stedt, 1900)
Lumbermen in north of
Sweden:
• "Rivermen"
17
96
1
17
64.4
22
„
124
214
424
4239
Choppers, etc
96
67.3
65
"
140
284
732
6214
Of these latter
1
72
56
"
181
415
1145
9292
Lumbermen, etc., groups
Of these a group of 2
men
1
119
68
"
130
271
696
5905
2
69
••
152
523
720
8439
SWITZERLAND
1912
Gigon
Workmen
•
8
68.9
7
Anal.
107
93
402
3181
M Beer. >*» Legumes.
analysis of samples of the material used in these studies or were obtained
by calculation from published analyses of similar food materials, with
or without occasional supplementary analyses by the author. The figures
in the following columns represent the daily intake per man (if in italics,
per woman) of protein, fat, and carbohydrate. Then follow the total
energy intake, the fractions of this contributed by protein and by fat,
the contributions to total protein and total energy content made by the
different classes of food materials and other data that appeared to be
of interest.
Some of the figures have been taken from the original publications,
some have been obtained through other authors, as indicated, and some
have been calculated by the writer. Many of the publications cited contain
data that permit of calculations to fill many of the vacant spaces in the
table but the labor of such calculations is onerous, and seems to be out of
proportion to the value of the results to be expected.
From the material presented in .previous chapters, it is evident that the
food consumed must supply energy for the following demands: 1. the
basal metabolism, 2. the increase in metabolism due to the ingestion of
food, 3. the increase ia metabolism due to muscular work, 4, the maiate-
A NORMAL DIET
385
DIETARY STUDIES— Continued
SWEDEN
PERCENTAGE
CALORIES FROM
PERCENTAGE DISTRIBUTION OF PROTEIN
PERCENTAGE DISTRIBUTION OF CALORIES
Protein
Fat
Meat*
Milk and
Products
Cereals
Po-
tatoes
Other
vege-
tables
Others
Meat'
Milk and
products
Cereals
Po-
tatoes
Other
vege-
tables
Others
17.3
35.3
47.7
16.8
15.3
17.5
32.8
52.6
10.6
20.6
16.2
21.6
28.1
21.4
37.8
5.9
4.6
3.P*
14.7
18.8
46.9
10.4
4.2
2.8*
12 0
47.0
31.4
23.5
42.8
0.123.
9.3
42.4
28.2
2.9
60.3
5.2
2.9»«
8.0
41.5
26.2
58.2
11.1
4.5»a
9.7
42.6
8.0
41.5
45.4
54.6
SWITZERLAND
13.8 1 27.2
nance of body temperature. Variations in the amounts of energy required
for these purposes mean variations in the amount of food required and,
presumably, in the amount consumed. This we shall find to be the case.
The many variables involved make direct comparison of the tabulated
figures difficult but by considering only one at a time, fairly regular rela-
tions appear.
Influence of Climate and Season upon Food Consumption. — It is
a generally accepted belief that less food is required in summer than
in winter and less in the tropics than in temperate climates. But there
are very few accurate observations and such as there are do not support
this belief.
In a study of the rations consumed by a battalion of French soldiers,
Perrier found an apparently regular change with the season. (Table V.)
But these soldiers were fresh recruits in October and Perrier ascribed the
large consumption of food in October and November to this fact. The
peak came in November, the consumption of food being then 100 calories
greater than in the following January and February. When the men were
at camp, June 22 to July 11, the new mode of life and, probably, the in-
386
ISIDOR GREENWALD
TABLE IV.— SYNOPSIS OF
UNITED STATES
Date
1920
Authority
Subjects
NUMBER OF
Scale
for
con-
ver-
sion
"Man
equiva-
lents"
Aver-
age
weight
of
adult
male
kilos
Du-
ration
COMPOSITION OF FOOD PER MAN
PER DAT
Stud-
ies
Indi-
vidu-
als
days
Calcu-
lated
or ana-
lyzed
Pro-
tein
grams
Fat
grams
Carbo-
hydrate
grams
Energy
yield
calo-
ries
Pearl
Selected studies in
American families,
with average an-
nual income of
each group
Mother wage earner
$640
8
J
212"
Calcd.
105
65
472
2895
Garm'tmakers $724
Laborers $1497
Retired $1647
7
J
168*
"
109
81
495
3145
6
J
305"
"
94
102
479
3210
5
J
130"
"
81
121
420
3095
Clerks (office) $1934
Mechanics... $2133
Teachers $2160
Profess'l men $2208
Engineers (profes-
sional) $2253
Salesmen $2527
Farmers
11
J
225"
"
92
120
419
3125
8
J
259"
"
97
113
460
3245
32
J
620"
"
88
125
430
3195
17
J
J
J
438"
"
99
148
438
3480
5
97"
»
85
128
395
3070
5
121"
"
90
111
405
2980
12
J
J
384"
"
102
131
506
447
3640
116
11
95
113
3185
1903
Atwater
(1903)
Farmers
14
.
G
G
Calcd.
108
136
493
3767
Athletes
23
"
181
194
506
4617
Business men, stu-
41
G
«
124
142
451
3678
1904
Woods and
Mansfield
Maine lumbermen,
"Chopping and
yarding "
2
47 or 77
75.8
11
Calcd.
206
387
963
8140
Average of all op-
5
174 or
200
73.1
9.4
••
182
337
812
6995
1917-8
Murlin . . .
U. S; soldiers in
training camps
(supplied)"27...
Consumed
427
7
Calcd.
131
134
516
3899
427
7
"
122
123
485
3633
Consumed plus
canteen purchases
Of these
(consumed)27
427
7
..
127
136
545
3998
213
7
"
138
133
527
3963
7
*•
129
121
496
3687
1917
Benedict,
Miles and
Roth
12
12
66.0
3
Anal.
97
3097
1896-7
Atwater
and
Bryant
. B
Workmen's fami-
lies, New York
City, children of
normal weight. . .
Children beJ o w
normal weight. . .
10
No. of
children
in family
3.7
_C_
c
10
Calcd.
101
124
382
3175
11
4.3
10
»
92
95
349
2693
1901-4
Wait....
B
Families, eastern
Tennessee chil-
dren of normal
weight
28
2.8
c
c
14
77
3601
Children below
normal weight. . .
10
2.6
14
«
75
3304
" "Man equivalents" multiplied by number of days.
* Army rations are not generally considered a freely chosen diet but under the system in use at the training camps during
the period of these studies, the rations were, within the limits imposed by geographic and economic considerations, practically
the "free choice" of the mess sergeants. They were supplemented by individual purchases at the regimental exchange. Both
sources of food were included in these studies.
27 Supplied and consumed at army mess. Canteen purchases not included.
A NORMAL DIET
DIETARY STUDIES— Continued
UNITED STATES
387
PERCENTAGE
CALORIES FROM
PERCENTAGE DISTRIBUTION OF PROTEIN
PERCENTAGE DISTRIBUTION OF CALORIES
Protein
Fat
•
Meat'
Milk am
product
[ Cereals
Vegetables
Fruit
Meat2
Milk am
products
Cereals
Vegetables
Sugars
Fruit
15
21
14
24
12
30
11
37
12
36
12
32
11
36
12
40
11
39
12
34
11
33
12
33
11
34
15
39
13
37
10
44
44.8
0.3
26.3
27.8"
0.6
43.1
4.2
24. 3»
13. 8"
11.1
3.5
11
45
14
32
14
32
13
31
14
31
14
32
46.9
4.0
26.4
4.4
5.3
12.3
28.7
3.0
30.3
57
2.9
12.3
16.5
13
13
36
47 2
11.4
31.8
Vege-
tables
8.3
Fruit
1.2
27.9
13.6
39.6
Vege-
tables
7.7
Fruit
0.8
10.3
14
32
46.6
8.3
34.3
10.8
0.2
25.8
13.6
38.2
9.6
1.1
11.6
8.8
11.7
7.3
71.4
8.4
0.3
21.1
6.2
60.4
6.6
1.3
4.5
9.3
12.7
6.8
64.6
14.6
0.2
19.7
5.9
57.4
7.2
6.9
1.8
« Chiefly beans
creased exercise, led to a consumption of 4065 calories, which far exceed-
ed the maximum of the previous winter. During the year, the men gained
an average of 742 grams in weight. It is probable that most of this gain
388
occurred in the first few months and thus accounts for the large food con-
sumption at that time.
TABLE V.— FOOD CONSUMPTION OF SOLDIERS IN DIFFERENT MONTHS OF THE YEAR
Month
Subjects
Oct.
Nov.
Dec.
Jan.
Feb.
Mar.
Apr.
May
June
July
Aug.
Sept.
Oct.
Nov
Dec.
Battalion French recruits
1908-1909
36821
3789
3765
3681
3695
3670
3648
3599
3435»
4065»
3458«
Men in U. S. training camps
1917-1918 No. of studies..
3
19
36
37
30
42
77
30
20
13
14
8
13
7
5
Food consumption
3606
3706
3819
3827
3864
3894
3545
3514
3517
3609
3658
3487
37?7
3918
4145
1 October 10 to 31.
'June 1 to 17.
* This period at camp, June 22 to July 11.
'July 12 to Aug. 12.
During 191-7 and 1918, a series of nutritional surveys were made
in the training camps of the United States Army. (See Table IV.)
Although they were not made upon the same men throughout the year, the
observations were so numerous and each made with so large a number of
men, pirobably over 200, as to furnish useful averages for the present pur-
pose. When the energy content, in calories, of the food consumed per
man per day is calculated for the different months of the year, as in Table
V, certain seasonal changes become evident. Beginning in October, 1917,
the figures showed a gradual increase in food consumption until it reached
3894 calories in March, falling to 3545 in April. This level was con-
tinued in May, June and July. In August, there was a slight rise but
in September there was a return to the summer level, after which there
was a rise to December, 1918, at which time the observations ended.
The peak of the previous years was passed in November and the
food consumption in October, November and December was, respectively,
121, 212 and 326 calories greater than in the corresponding months of
the previous year. Attempts to correlate the curve of food consumption
with variations in local temperature, wind velocity, humidity, etc., were
not successful. It would seem more likely that the higher consumption of
food in the winter was due to the greater muscular activity of the men.
There is, moreover, another factor of possibly even greater importance.
Practically all the men in training gained weight. If this gain did not
occur in summer or was then much smaller than in winter, this differ-
ence alone would account for the differences in food consumption. The
effect of the armistice in modifying the attitude of the men in regard to
the conservation of food may help to account for the larger food consump-
tion during the last two months.
According to Eijkman(&) (1897), the basal metabolism of Europeans
in Java was not lower than in Europe and Dutch physicians there ate
A NORMAL DIET 389
as much food as men of similar occupation in Holland. Similarly, Kanke,
in Munich, found that he required as much food to maintain his body
weight in summer as he did in winter.
The explanation of this uniformity of food consumption over a wide
range of external temperatures appears quite obvious. Except under very
unusual circumstances, man selects his clothing so as to keep the tempera-
ture of most of the body surface at about 30° C. If the customary activ-
ities of the individual involve a heat production which is too great to be
dissipated with maintenance of surface temperature at 30°, the individual
may, and generally does, diminish his food consumption but only at the
cost of loss of body substance or ability to do work. Thus Ranke, in
the experiment above referred to, found that, of free choice, he
would have consumed 400 calories less per day during the summer but
that he then lost weight which, for the purpose of the experiment, was to
be kept constant. He accordingly ate enough to maintain his body weight
but experienced increasing discomfort until, at the end of the month,
there was a definite gastro-intestinal disturbance and, apparently, an
increased susceptibility to infection. It is important to remember, in this
connection, that the average temperature of the room in which Ranke spent
most of his time was 21.9° C. in summer and 18.9° C. in winter. The
humidity is not stated but was probably lower in winter than in summer,
so that the cooling effect of the air was greater in winter than in summer.
Moreover, when indoors, Ranke wore the same clothing in summer as in
winter, so that it seems quite likely that the dissipation of heat was inter-
fered with and that this led to the disturbances he noted.
If external conditions, such as temperature and humidity, do not
permit the removal of the heat produced in ordinary metabolism, the
temperature of the body is raised, the basal metabolism is raised and may
thus be even greater in warm weather than in moderate (Young).
It is quite possible that the inability to maintain a high metabolism
in warm weather and in the tropics is responsible for the indolence and
lack of energy displayed by man under those conditions.
With very low external temperatures, on the other hand, the heat pro-
duced in metabolism may not be sufficient to cover the heat loss, even
though this be reduced to a minimum by means of much clothing. The
feeling of cold is experienced and muscular activity is increased (shiver-
ing), with consequent increase in the production of heat. With short
periods of exposure, shivering may not appear and, in such cases, as
found by Eijkman(d) (1897), metabolism is the same at from 0° to 12°
C. as at 24.5° C. though the clothing be light and the subjects complain
of cold at the lower temperature. There may be some direct stimulating
effect of cold upon metabolism (see discussion in Tigerstedt(Ti), 1919, Vol.
I, page 168), but such action must, ordinarily, play a very inconsiderable
part.
390 ISIDOK GKEENWALD
The effects of season and of climate upon the energy content of the
food may therefore be neglected except as they may affect the body weight
or conduce to, or be unfavorable to, muscular activity.
Relation of Body Weight to Food Consumption. — The basal metabol-
ism is roughly proportional to the body weight (Harris and Benedict)
and, consequently, so is the energy content of the quota of food needed to
satisfy this requirement.
The increase in metabolism due to the ingestion of food depends upon
the amount and nature of the food consumed, the nature of the individual
and upon other factors which seem to make it vary from time to time in
the same individual with the same kind of food (Benedict and Carpenter).
But this constitutes only a small part of the total metabolism and may
therefore also be considered as proportional to the body weight.
The same relation holds for the amount of energy required to move
the body about. That required to supply energy for external work varies
with the nature and amount of the work to be performed and with the
muscular efficiency of the individual. But it is probable that, as a rule,
in occupations involving much muscular work, the individual weighing
considerably less than 70 kilos (154 pounds) will do less than one of that,
or slightly greater, weight.
Except in the case of individuals of unusual body form, the total
metabolism and, consequently, the food requirements of adults leading
about the same kind of life may, therefore, be expected to be propor-
tional to the body weight. With much greater body weights, the proper:
tionality can no longer be expected to hold for an ever increasing part of
the weight is contributed by the comparatively inactive adipose tissue.
And this, in truth, is usually found to be the case. Selecting from Table
IV, groups within which other factors may be considered to be relatively
constant and consulting the original publications for the data, we obtain
the following figures for the food consumption in calories per kilo of body
weight :
Demuth, 3 pensioners, light work, 47, 46, 41 Average 45
Yukawa, Japanese celibate monks, young, no
work, 36.5, 50.0, 41.6, 39.0, 36.3, 40.1, 23.9,
34.1, " 37.7
old, no work, 37.9, 35.6, 35.0 " 36.2
Eijkman (1893), European physicians, etc., in
Java, 32.2, 38.7, 32.0, 44.9, 36.6, 30.5, 31.5,
33.3 " 35.0
Eijkman, Malay laboratory servants, 49.6, 41.7,
55.4, 55.8 " 50.6
Hultgren and Landergren, Swedish students, 40.9,
48.4, 44.2, 38.1, 46.8 " 43.7
A NORMAL DIET 391'
Within any one group, the energy content of the food consumed is
almost as proportional to the body weight as the basal metabolism is found
to be (Harris and Benedict). The factors, such as varying body form,
differences in activity of endocrin glands, that account for the latter will,
probably, also explain the latter. The effect of variations in body weight
in the same individual upon the amount of food required to maintain a
particular body weight will be considered later. (Page 414.)
Influence of Work. — Reference has been made to the variations in
energy requirement with differences in the amount of muscular work
performed. The amount of energy expended in a given task or occupation
by different individuals has been measured in several instances but the
results are rather conflicting. Much depends upon the previous training
and experience of the individual, but even with individuals of similar his-
tory, the amount of energy expended in the same occupation varies tremen-
dously (Becker and Hamalainen, Lusk(/i), 1917, Sherman(c), 1918, Ben-
edict andCathcart andWallerand associates(a) (&) (c)). To a considerable
extent, this variation is probably due to differences in the amount of work
accomplished, but other factors may also play a part. Nevertheless, it still
remains true that typesetters and cobblers do less work than machin-
ists and that business and professional men do not use their muscles as
much as farmers or laborers. And, consequently, men whose occu-
pations involve muscular exercise do not usually eat so much as do
those who do much physical work. In some of the observations con-
solidated in Table IV, this fact may be obscured by three other factors.
Of these, the influence of body weight has already been discussed. Of
possibly equal significance is the fact that the reports are not only for
individuals but for groups and families. The very large food consump-
tion of a laborer doing hard work may no longer be so apparent when the
only report is that for the food consumption of the family. It may be that
the family of a man who is engaged in hard work will be similarly more
active but it certainly is not always the case. (See also discussion of Sund-
strom's results, pages 367-369.)
The influence of mental work upon food intake may be neglected.
There is no evidence that mental work, even of the most fatiguing nature,
appreciably affects the amount of metabolism. Starling(fe) (1919) has
suggested that mental work, while not requiring much energy, may require
that to be supplied at a high pressure. This would justify a liberal pro-
tein and energy allowance in the food of brain workers.
Influence of Economic Status. — Last, but not least, is the economic
factor. Beginning with Engel's figures and proceeding down the table,
one can see that in every instance in which information as to income is
included, except for one or two in the summary by Pearl, food con-
sumption increases with increase in income. It is important to remember
392 ISIDOE GKEENWALD
this and to note that even in the neediest families studied, the energy
content of the food does not fall below about 2500 calories per man per
day, except in the case of those of low body weight, such as the Italians
studied by Manfredi or the Japanese and Malays studied by others.
Amount of Protein. — The character of the food and, consequently, the
relative importance of protein, fat and carbohydrate in making up the total
energy content of the diet varies considerably with different peoples and
different circumstances. But there are some quite evident uniformities
and comparisons. Except in the most needy families, the protein content
of the food anywhere in the world does not fall appreciably below one gram
per kilo or 70 grams for the man of average weight in northern Europe and
in the United States and it is generally as much as 1.3 to 1.5 grams per
kilo, or 100 grams per man. The fraction of the total energy contributed
by protein varies from 8.5 per cent in some Oriental diets and in those
of some of the poorer classes in Europe to as much as 18 or 19 per cent
in some of the Swedish and Finnish diets and even to 32 per cent in the
case of the fishers at the mouth of the Volga who probably subsist largely
upon fish and to 44 per cent among the Esquimaux (Krogh). But except
for people under such unusual .circumstances, the protein rarely contributes
over 18 per cent and generally only from 12 to 15 per cent of the total
energy. This comparatively narrow range is worthy of note.
Effect of Work. — Men at hard work eat more protein than do those not
so engaged, but, apparently, this is due entirely to the greater consumption
of food and not to a specific demand for protein or foods rich in protein.
The fraction of the energy contributed by protein to the diet of men at hard
work is frequently less than in the case of others of similar economic status
and engaged at lighter work. This is most strikingly illustrated in the case
of the diet of the Maine lumbermen in which the protein contributed only
10.5 per cent of the calories, a smaller proportion than was reported for
any other group in the United States, except for some from the southern
states. Similarly, the diet of lumbermen in the north of Sweden con-
tained less than 10 per cent of the calories in the form of protein (only
8 per cent in the case of the man whose total was 9292, and 7.4 per
cent for the two men whose average was 8439), whereas Hultgren and
Landergren reported 16 per cent for Swedish working men and Sundstrom
15 to 16 per cent for the- Finnish agricultural population.
Effect of Economic Status. — The amount of protein consumed is gen-
erally lowest with those of smallest income and grows larger with increas-
ing income. But this increase is not indefinite and probably the total
rarely goes above 160 grams or 2.3 grams per kilo. The relative impor-
tance of protein as a contributor of energy may, however, be slightly greater
among the poor than among those of slightly greater income. A greater
share of the necessary economy in food is attained at the expense of the
fat. . At the other end of the range of incomes, the proportion of energy
A NORMAL DIET 393
contributed by protein is apt to be slightly lowered by the increasing con-
sumption of sugars and fats.
Amount of Fat. — The amount of fat consumed varies with the country,
economic status, occupation and the time. Japanese diets seem to contain
the least fat of any that have been studied, the maximum in the really
native diets being about 30 grams, which is, or was, the recent European
minimum. The fat consumption is also much lower in Italy, particularly
among the laboring classes, than in northern Europe. Probably, this low
fat consumption is, in both Italy and Japan, due to the general operation
of the next factor to be considered, the economic.
In every series in which data are available beginning with Engel's of
1853, the amount of fat eaten increases regularly with the income. There
are a few slight deviations from this rule in the series reported by Pearl
and in the Scotch families of Lindsay but the number of observations in-
cluded in these exceptional cases is rather small. In Pearl's series fat
constitutes 37 per cent of the calories in the diets of the professional men.
There is one group (salesmen) of higher income ($300 or 14 per cent
more) in which fat contributed only 34 per cent of the calories but there
are only five studies included in this group. In Lindsay's series, fat
plays a slightly greater part in the diets of the families with income under
20s than it does in those of families with an income of from 20 to 25s,
and as great a part, as in the group with an income of from 27 to 31s,
but the number of studies in these groups is only 5, 10 and 3, respectively.
The largest amount of fat is found in the diet of American and
Swedish lumbermen, which, in one case, contained as much as 523 grams
fat, furnishing 58 per cent of the calories. American athletes and Fin-;
nish students come next with 194 and 191 grams, furnishing 39 and 45
per cent of the total calories. In general, the amount and relative im-
portance of fat in the diet increases with the total food intake, though
in the diets of sedentary persons with ample income, the effect of the in-
come may outweigh that of the energy intake as is illustrated in Ranke's
and Neumann's observations on themselves (42 per cent and from 34 to
66 percent, respectively).
During the fifty years immediately preceding the World War, there
seems to have been a general increase in the amount of f a t, consumed, at
least in several countries. Thus, Engel estimated the fat consumption in
families whose income permitted saving to be 39 grams per man per day in
1853*, but in 1899 found it to be not less than 56 grams in any group
studied. The averages for all families were 28.5 grams in 1853 and 74.9
in 1891. In 1908, Slosse and van der Weyer found 74 grams to be the
minimum in 33 studies of the diet of Belgian workingmen and Slosse and
Waxweiler found that in only ten out of 1065 Belgian workingmen's fam-
ilies was it less than 35 grams and in only 132 was it less than 60 grams.
Similarly, Lichtenfelt estimated the fat consumption in Germany in 1894
394 ISIDOE GREENWALD
to be 94 grams per man per day, whereas Claassen, in 1 907, estimated it as
141 grams (digestible) for the urban and 195 grams for the rural popula-
tion. The Eltzbacher commission placed it at 139 grams for the popula-
tion as a whole in 1912-1913. The series of reports from English cities
confirm this tendency, though the number of observations is rather small.
Thus in 1900, Paton, Dunlop and Inglis found that Edinburgh families
with incomes of less than 20s used an average of 96 grams of fat per man
per day; those with ample income used 92.3 grams. In Glasgow in
1911-1912, Lindsay found 76.3 grams in families with less than 20s in-
come and 98 grams in those with an income of from 27 to 31s. In 1916,
also in Glasgow, Ferguson found it at the same level, though the wartime
restrictions on the use of fat might have been expected to reduce the figure.
The high value, 88 grams, calculated by Dunluce and Greenwood from
Eowntree's reports for York families with incomes of less than 26s weekly
seems to be due to some local factor. It is greater than that reported for
similar families in Edinburgh or Glasgow and much greater than that
.calculated by Dunluce and Greenwood from the Board of Trade returns
for a large number of cities in Great Britain. It is interesting to note
that the northern counties reported a higher fat consumption among the
agricultural laborers than did the other counties of England. Within
Rowntree's series, the usual economic effect is observed.
The amount of protein and of fat and their contribution to the total
energy of the diet having been discussed, little remains to be said regarding
the carbohydrate, save that it furnishes the remainder of the energy, from
400 to 600 grams per man per day being required. The increasing con-
sumption of cane sugar is discussed on pages 395 and 397.
Ash Constituents. — Comparatively few studies of normal or customary
diets have included determinations or calculations of the amount of the
inorganic constituents. Tigerstedt(e) (1911) had the samples collected
by Sundstrom(&) (1908) in his study of the diet of the Finnish agricul-
tural population analyzed for some of the ash constituents with results
shown in the first part of Table IV. The figures following were
calculated to European body weights from Japanese diets by Rubner
(&&) (1920). These are followed by those obtained by Nelson and
Williams in a study of the calcium content of the urine and feces of
four normal men (U. S.) on their accustomed diets. Then come the
figures calculated by Sherman (c) (1918) for 150 supposedly typical
American dietaries, and, finally, those calculated by Blatherwick for 32
studies in army training camps and by Howe (reported by Blatherwick)
for four others. The enormous difference between the calcium and phos-
phorus contents of the Finnish and the American and the Japanese diet-
aries is due to the great difference in the amount of milk consumed. ( See
also page 415, for Rubner's calculation of inorganic food constituents in
Germany before and during the war.)
A NORMAL DIET 395
Many investigators have observed and calculated the contributions
made by animal and vegetable material to the total food. Particular im-
portance has been attached to the content of animal protein, which has
been regarded as far superior to vegetable protein. More recent investiga-
tion has indicated that this distinction is not altogether justified. It is
true that animal proteins are, as a class, rather more effective as builders
of body protein than are vegetable proteins but there are marked excep-
tions. Thus gelatin is the classic example of an incomplete protein where-
as the protein of the potato is one of the most efficient (Hindhede(c) 1913
Eose and Cooper) . Isolated plant proteins such as gliadine or zein may bo
very inadequate but the mixed proteins of wheat or of maize, as found
in flour or meal, will maintain nitrogen equilibrium at a fairly low level,
particularly if the whole grain be used or if it be supplemented by a small
quantity of other proteins such as those in milk. In any mixed dietary,
even if wholly of plant origin, the proteins are almost sure to be suffi-
ciently varied to compensate for any individual inadequacies if only
the total amount of protein be sufficient. Therefore, no attempt has been
made to indicate in Table IV the quantity of animal protein consumed.
However, in many cases, that can be calculated from the figures given for
protein from meat and from milk and its products.
But the source of the protein, while of itself of not so great significance,
is important as an indication of the amounts of those little known sub-
stances, variously denoted food accessories, food hormones, protective sub-
stances or vitamines, that may be present. Some idea of the inorganic con-
tent of the food may also be obtained in this manner. For this reason,
there have been included in Table IV, where the data were available or
could readily be calculated, the contributions made to total protein and, in
some cases, to total energy also, by each of the classes of food materials, as
was done in Table III. The same differences that were evident in Tables
II and III also appear in Table IV. In addition, there are differences
due to occupation, economic status, etc., most of which have already been
discussed.
In all regions and at all times, man seems to have sought and found
some beverage, other than water, to use with his meals. Meat, ale, milk,
(sweet and fermented), wine, coffee, tea, cocoa and many others have
been used. Particularly striking is the use of four plants of widely dif-
ferent botanical nature but all containing caffein or a related substance.
Changes in Food Habits within Recent Times. — The introduction
of new foods as a result of the importation of new species, the im-
provement of old, or the development of transportation may greatly
modify the food habits of a people. Maize and potatoes, unknown
before the discovery of America, are to-day two of the staple crops of
Europe and are fundamental to the economy »f several countries. The
improvement of the sugar beet has helped to lower the price of sugar and,
396
ISIDOR GREENWALD
TABLE VI.— ASH CONSTITUENTS OF ORDINARY DIETS
FINNISH AGRICULTURAL POPULATION, WOMEN, 25 OBSERVATIONS ON 21 PERSONS, 7 DAYS EACH, ANALYZED. (Sundstrom 1908)
SUBSTANCE
PER WOMAN PER DAY
PER 3000 CALORIES
Calcium
Minimum
Grams
1.13
Maximum
Grams
3.86
Average
Grams
2.28
Minimum
Grams
1.50
Maximum
Grams
4.17
Average
Grams
2.79
Magnesium
0.21
1.14
0.66
0.50
1.11
0.84
Phosphorus
1.69
4.25
2.76
2.52
4.54
3.34
Rest
15.44
43.48
27.75
FINNISH AGRICULTURAL POPULATION, MEN, 14 OBSERVATIONS ON 11 PERSONS, 7 DAYS EACH, ANALYZED. (Sundslrom 1908)
SUBSTANCE
PER MAN PER DAY
PER 3000 CALORIES
-
Calcium
Minimum
Grams
1.92
Maximum
Grams
9.85
Average
Grams
3.79
Minimum
Grams
1.68
Maximum
Grams
5.13
Average
Grams
3.06
Magnesium .-
0.73
1.39
1.09
0.69
1.02
0.85
Phosphorus
2.79
6.00
4.32
2.05
4.21
3.37
Rest
28.92
62.79
42.26
JAPANESE DIETS, CALCULATED TO EUROPEAN BODY WEIGHTS BY RUBNER (1920)
SUBSTANCE
Minimum
Grams •
Maximum
Grams
Average
Grams
Calcium
0.281
Magnesium
0.414
Phosphorus
2.12
2.81
FOUR AMERICAN MEN, Six STUDIES OF FIVE DAYS EACH, ANALYZED. (Nelson and Williams)
SUBSTANCE
Minimum
Grains
Maximum
Grams
Average
Grams
Calcium
0.676
1.016
0.852
150 AMERICAN DIETARIES, CALCULATED. (Sherman, 1918-B)
SUBSTANCE
PER MAN PER DAY
PER 3000 CALORIES
Calcium
Minimum
Grams
0.24
Maximum
Grams
1.87
Average
Grams
0.73
Minimum
Grains
0.35
Maximum
Grams
1.47
Average
Grams
0.73
Magnesium
0.14
0.67
0.34
0.17
0.53
0.34
Potassium
1.43
6.54
3.39
1.63
5.27
3.40
Sodium1
0.19
4.61
1.94
0.22
4.83
1.95
Phosphorus
0.60
2.79
1.58
0.72
2.30
1.59
Chlorin1
0.88
5.83
2.83
0.83
7.26
2.88
Sulfur
0.51
2.82
12.8
0.80
2.35
1.30
0.0080
0.0307
0.0173
0.0090
0.0234
0.0174
1 Does not include salt added to food. Consequently is much too low.
A NORMAL DIET
TABLE VI. -ASH CONSTITUENTS OF ORDINARY DIETS
397
32 ARMY ORGANIZATIONS IN TRAINING CAMPS, CALCULATED. (Blaiherwick)
SUBSTANCE
Minimum
Maximum
Average
Calcium
0.374
1 516
1.060
2 845
0.711
9 171
Iron (only 25)
0.0203
0.0494
0.0291
FOUR INFANTRY COMPANIES OP SAME REGIMENT AT CAMP CODY DURING SAME PERIOD OF 7 DAYS
CALCULATED BY HOWE, PUBLISHED BY BLATHERWICK
SUBSTANCE
Minimum
Grams
Maximum
Grams
Average
Grams
Calcium .-
0.416
0.542
0.493
Iron
0 0210
0 0221
0 0216
in that way, has helped make what was formerly a luxury, a relatively
cheap and common food. The consumption of sugar within the last
century increased tremendously throughout the western world, though
some countries consumed more than others. The United States appears to
lead the world in the per capita consumption of sugar, with Great Britain
a close second. Whether or not this large consumption of sugar is de-
sirable or not is still a moot question. .
As one result of freeing populations from dependence upon local
sources of supply, the development of transportation and refrigeration
has helped to change the character of the food, particularly in making
fresh foods available throughout the year and in giving the rest of the
world access to the products of tropical and semi-tropical countries.
But these beneficial effects have been very largely confined to the cities
and towns. In rural regions, the same causes seem to have led to less de-
sirable changes. Instead of diversified farming, the tendency has been to-
wards a "one crop" or "cash crop" agriculture. Tinder such a system the
farmer no longer raises much of his own food but has only one crop which
he sells for cash, with which he buys his food. He buys the purified, staple
and stable foodstuffs and loses many valuable food constituents. The de-
velopment of transportation and industry has not yet made it possible for
him to buy, in addition to the staple foods, the fresh vegetables, etc., that
he also needs. Sometimes, too, ignorant of the true values of foods, he may
sell his own product to copy, through the village store, the habits of the
city. To quote from Rubner(g) (1913) : "I have noticed a very unfavor-
able influence of urban food requirements on the milk-producing districts of
some regions of Switzerland, Germany, which is so characteristic that it
deserves consideration. The milk-producing regions of the Bavarian
highlands and of Switzerland had formerly an extremely, healthy, strong
398 ISIDOK GREENWALD
and temperate population. Milk was largely used as a food, and the ex-
cess of production was placed on the market. In the course of years the
communities gradually established central creameries in which the fat is
withdrawn from the milk by means of centrifugal machines to produce
cream and butter. The impoverished milk is partly returned to the farm-
ers. The milk producers are paid in cash for their product, but a poor
and insufficient food now takes the place of a former healthy one. The
money now goes to the saloons. The potato conquers a new territory. In-
stead of the butter which was formerly used, cheap fats are now bought ;
in short, the change in diet is exactly such as we find with the poorer
working population in the cities. The effects are exactly the same. Physi-
cal deterioration in such districts becomes more and more pronounced,
reaching finally a low level. This is a very serious condition, which at-
tracts attention and which must be combated by all possible means."
A similar effect seems to have been produced, in a rather different
manner, in our own southern states. Formerly the corn was ground in
small mills and all of it was used. Now much of it is sold for cash and
"'new process" or degerminated meal is purchased. It is quite possible that
the present high freight rates will have one good result in encouraging
diversified farming and the home production of more of the necessary
food.
Indirectly, the improvement of transportation and the development
of industry as a whole have helped to change food habits because of the
improvement in economic condition. It is to this that we must ascribe
the increased consumption of meat and fat in Germany and Belgium, and
the gradual change from rye to wrheat bread. The tendency to copy the
diet of the wealthier classes is everywhere marked. The nature of this
diet is determined largely by taste and fashion. The wealthier can, and
do, secure for themselves the foods which have the more agreeable taste,
and others, as soon as they can afford them, also wish to secure these
foods for themselves. But taste will not alone explain the relative order
of esteem in which foods are held. At one time shad, oysters and lobsters
were so plentiful along the eastern coast of the United States as to be
despised. To-day, they are delicacies. Diminishing supply may be re-
sponsible for this but not for all similar instances. Not all rare edible
articles are highly esteemed foods.- Nightingale tongues and peacock
breast are no longer prized as they were in imperial Rome. Again, it is
not so many years ago since calf thymus glands could be had at New
York slaughter houses for the asking. To-day they are the expensive
sweetbreads. That complex of varying influences that we call fashion has
helped determine man's food habits as it has his other social practices.
(See also Fairchild.)
Canned foods, while adding tremendously to the variety of foods avail-
able, have, to the extent that they have replaced fresh food, tended to re-
A NORMAL DIET 399
duce the narrow margin of intake over requirement of protective sub-
stances or vitamines.
A factor of considerable importance is the effect of advertising in ac-
celerating and initiating changes in the character of the foods employed.
The sales of specific articles of food can be as greatly stimulated as can
those of any other commodity. Some of this advertising may be of quite
a misleading character, even though the specific statements be absolutely
true. Thus, butter substitutes are advertised as "purely vegetable" or as
containing only vegetable fats, as if this were an advantage when it is ex-
actly the opposite for vegetable fats do not contain an important substance
which is present in most animal fats, particularly in butter.
Due to a combination of the factors already considered, grains are no
longer ground at, or near, the place of consumption. The appearance and
the keeping qualities of the product must be carefully considered. As a
result, rice is polished and the germ is carefully removed from wheat
and maize. But the diet that was adequate when more than half of it con-
sisted of the entire grain may no longer serve to maintain the race in
health and vigor if half the food consists of only part of the grain, for
the two parts differ widely in composition. See Chapter on vitamins.
(For further discussion of changes in food habits see Lichtenfelt(c), 1913,
Ruhner(r), 1913, Grotjahn, and Mendel.)
We have now considered the actual food consumption of man in differ-
ent parts of the world as reported by many observers and have noted
certain similarities, many differences and a number of progressive changes
of quite general significance. To what extent are these resemblances to
be considered as evidences of real physiological need ? Is man's appetite
a proper measure of his food requirement ? Need we eat so much or should
we eat more ? Which is preferable, the high meat diet of the English speak-
ing peoples and of those of the Argentine, the bread and milk diet of Fin-
land or the comparatively meat- and milk-free diet of Japan ?
First comes the question of vegetarianism. Space does not permit
a full presentation of the benefits claimed to follow the exclusion of meat
from the diet. There can, however, be little doubt that vegetarians have
performed many feats requiring much muscular energy and have, in sev-
eral races and other competitive sports, made a very striking showing. But
there can also be little doubt that vegetarians, as a class, are not distin-
guished for good physique or for exceptional strength and endurance. Such
showing as they have made seems to have been due largely to the rigorous
training earnest advocates of the cult have imposed upon themselves.
(Caspari, Albu, Hindhede(a) (<?)(<*), 1912, 1913, 1914.)
400
ISIDOK GEEENWALD
The argument that meat is not the "natural" food of man would seem
to be fallacious. (Page 359.) Moreover, any such objection, if valid,
would apply equally well to all cooked foods and, indeed, to all cultivated
varieties of plants and throw us back upon the wild fruits of the forest
and unbroken prairie.
The place of meat, as of any other food in the diet, is to be decided
entirely upon physiological and economic considerations. Physiological
investigations indicate no objection to the use of meat save in so far as
the unduly large consumption of meat, in increasing the amount of
protein, may be unwise. The economic objection is not so readily disposed
of. The animals whose flesh is used for food return in that manner only a
small proportion of the total energy they receive (Armsby). To a great ex-
tent, it is true, this is obtained from materials that are unfit for human con-
sumption but to the extent that animals are fed grain, or other products
of land that could be used to grow grain, vegetables or fruit, they do com-
pete directly with man for readfly utilizable foods. The loss in the ani-
mal in converting energy of the vegetable food into potential energy in the
form of muscle and fat is one of the factors responsible for the compara-
tively high cost of meat in most countries. That is the objection to the
free use of meats. So much of the income available for the purchase of
food is spent for meat, wThich can be dispensed with, that not enough is
left for milk and vegetables which are practically indispensable.
Benedict and Roth have shown that the basal metabolism of vegetarians
is not appreciably less than that of meat-eaters. Unless the muscular sys-
tems of vegetarians are markedly more efficient than those of their fel-
lows, the metabolism due to muscular work must be the same. Such
economies in food consumption as are claimed for vegetarians and which
the observations of Jaffa seem to corroborate must therefore be due to the
operation of some other factor, probably the state of nutrition or level of
metabolism. (Page 414.)
One of the great disadvantages of a vegetarian diet is its bulk. With
the ordinary vegetarian diet, the work required of the digestive apparatus
is considerably greater than with a mixed diet. This objection does not
apply to the so-called lacto-vegetarianism, which permits the use of milk
and eggs. Such a diet has much to commend it. It need not be bulky.
The milk and eggs furnish protein of exceptionally good quality to com-
pensate for possible deficiencies in those supplied by other articles of the
diet. They contain much phosphorus and calcium, the latter of which
is apt to be present in insufficient quantity if milk is not included in the
diet, and furnish a considerable, if seasonably varying, quantity of some
of the vitamines or protective substances. Moreover, the cow and hen re-
turn in the form of milk and eggs much more of the energy they receive
than they do if kept for their meat (Armsby) . In spite of what is often
A NORMAL DIET 401
said to be an uneconomical manner of distribution, milk is, for most people
in this country, a comparatively cheap food.
Protein Minimum and Optimum
The question of the protein minimum and optimum has engaged the
attention of physiologists for many years. While the necessity of a cer-
tain amount of protein has been recognized from the beginning, it has
been believed that the optimum could be, and was, readily exceeded and
that the excess was distinctly injurious. This belief has been due chiefly
to the fact that protein is not completely oxidized to carbon dioxid and
water, as are carbohydrates and fats, but leaves a non-combustible residue
which must be excreted by the kidneys. Other objections are the high
cost of protein foods, their ready susceptibility to putrefaction in the in-
testine and the fact -that only a small part of the potential energy in pro-
tein is available for work, the remainder being excreted as urea, etc., or
useful only as heat. Since, as a rule, the latter is produced in excess of
requirements, this part of the protein energy may also be regarded as
lost.
There have been many experiments on the so-called nitrogen minimum
— the minimum amount of nitrogen in the food required to maintain an
equilibrium with that of the excretions. Sherman(/) (1920) has collected
the results of 109 experiments in 25 different investigations of this nature
and has calculated the values found to a uniform basis of 70 kilos body
weight. There is no difference in the per kilo requirements of men and
women. The average of all 109 experiments is 44.4 grams. The range of
values is very considerable, from 21 to 65 grams, but out of the 109 values,
94 fell between 29 and 56 grams, with an average of 42.8 grams, and 76,
derived from 19 investigations and including 20 men and 4 women as sub-
jects, fell between 30 and 50 grams, with an average of 40.6 grams. Ex-
pressed in terms per kilo body weight, these averages become 0.635, 0.61
and 0.58 respectively. Most of these experiments were of comparatively
short duration and consequently the values obtained must be regarded as
absolute minima and not as satisfactory and altogether sufficient amounts.
The apparently low protein intake of the Japanese and other Oriental
peoples has long been noted but the earliest observations of any degree
of accuracy seem to have been those of Eijkman on the diet of Japanese
prisoners and those of Nagase on the diet of a military colonist in Formosa.
(Both cited from Oshima.) In the latter, the content of protein was about
one gram per kilo body weight. It was about the same in the diets of
the prisoners doing no work but was higher (1.18 grams) in the diets of
those doing light work and still higher (probably 1.5 grams or more) in
the diets of those at hard work. These diets were not "freely chosen"
402 ISIDOR GREENWALD
but were probably not greatly different from those to which the men had
been accustomed.
In 1890 von Rechenberg published the results of his studies of the
families of hand weavers in Zittau, a small town in Germany. The average
intake of protein was 1.14 grams per kilo, but the condition of the people
indicated that they were undernourished. They were very poor and their
diet was not at all what they would have selected had they enjoyed better
conditions.
Neumann's Experiments. — Neumann's studies on himself were really
the first to show that so low a level of protein metabolism could be obtained
on a mixed diet and maintained for a considerable period without evidence
of ill effect. The diets were such as he had been accustomed to, although
necessarily restricted in variety during the course of his studies, for he
analyzed many of the foods himself. The first experiment included 305
consecutive days. In the following year there was a second experiment of
120 days. Three years later (four years after the first) a third study was
begun. With the exception of November, December and January, this
extended from May 1900 to June 1901. While reported as one experiment
of 321 days, it really consisted of two separate studies of approximately
half that length. The protein intake in the first and third studies was
approximately one gram per kilo and, in spate of the rather low content
of energy, Neumann gained slightly in weight. There was no evidence of
any ill effect.
In the second experiment referred to, all the foods used were analyzed
and the nitrogen of the urine and feces was also determined. Neumann
found that he lost nitrogen and weight on the food as he then selected it
and retained both only on a rather higher level of protein and energy in-
take than in the previous experiment. The values now obtained over a
suitable period of 15 days were 1.16 grams protein and 40 calories per
kilo per day. It seems probable that a consistent error was responsible for
the much lower values for energy content in the other, not carefully ana-
lyzed, diets.
Chittenden's Experiments. — Very soon after the appearance of Neu-
mann's paper, Chittenden published the results of his long-continued ob-
servations on himself, his friends and associates, on college athletes and on
a group of soldiers. The experiment on himself was begun when he was
47 years old and weighed 65 kilos. He gradually reduced his diet until,
eight months later, he weighed only 58 kilos. By that time an
arthritis had disappeared, not to return, and he no longer suffered from
headaches and bilious attacks which had formerly appeared periodically.
He was able to do as much physical work as formerly with less than
the customary degree of fatigue and muscular soreness. Observations
during the following year showed that the nitrogen of the urine averaged
5.69 grams per day and that the intake with the food was approximately
A NORMAL DIET 403
one gram more or 6.69 grams per day. Similar experiments on his friends
and associates gave similar results. The body weight fell slightly and then
remained stationary. For long periods the nitrogen in the urine remained
at a fairly constant low level, which was not so low, however, except with
Mendel, as it was with CKittenden. The average for all, including Chitten-
den, was 0.117 gram nitrogen per kilo per day or the equivalent of 0.74
gram metabolized protein per kilo per day.
Experiments in which the nitrogen of the food, as well as that of the
urine and feces, was determined gave similar results. The energy con-
tent of the food was not determined by analysis but was calculated from the
results of published analyses. This involved a considerable degree of error,
with such complex mixtures as were here employed.
In calculating the nitrogen balance, the nitrogen of the perspiration
was not included. With men engaged in sedentary occupations, the
amount of this was probably not great but it may very well have been
large enough in May and June to have wiped out the apparent positive
nitrogen balance (0.38 and 0.35 gm., respectively) in the second experi-
ments with Mendel and Beers and to have increased the nitrogen loss in
the corresponding experiment with Chittenden and Underbill. Moreover,
the small gain of nitrogen, even if entirely real, is none too large when it
is remembered that in other similar periods there was a greater loss.
Taking all nine experiments together there was an average loss of 0.329
gram nitrogen per man per day, with an intake of 0.125 gram nitrogen
and 32.0 calories per kilo per day. Practically the same values, 0.133
gram nitrogen and 32.4 calories, were obtained in the four experiments
with positive nitrogen balance. For a man of 70 kilos, these values would
become 58 grams protein and 2338 calories.
Eight athletes were under observation for five months and during the
last two months of this period the average daily nitrogen excretion in
the urine was 0.127 gram per kilo. Seven of these subjects were used in
a seven day metabolism experiment. Considering all the results, there
was an average daily loss of 0.06 gram nitrogen (not including that in
the perspiration) per man upon an average daily intake of 0.147 gram
nitrogen and 38.4 calories per kilo. Considering only the four experi-
ments in which there was a positive nitrogen balance, the values were
0.158 gram nitrogen and 41.4 calories per kilo'. For a man of 70 kilos,
these would correspond to 69 grams protein and 2898 calories. It is
interesting to note that the ratio of nitrogen : calories was lower in the food
of the athletes than it was in that of the teachers. Notwithstanding the
fact that these athletes had previously been accustomed to a high protein
diet, they suffered no ill effect other than a slight loss in weight which may
even have been advantageous and continued to increase their muscular
strength, as measured by appropriate tests.
A detail of soldiers of the Medical Department of the United States
404 ISIDOR GKEENWALD
Army was sent to New Haven as subjects for Chittenden's experiments.
The observations upon them differed from those upon the students and of-
ficers of the university in that the diet was prescribed. After about two
weeks upon their accustomed rations, the food was selected by Chittenden
to contain less protein and to furnish a rather smaller amount of energy,
while retaining approximately the same bulk and furnishing considerable
variety. Per kilo of body weight, the average" daily urinary nitrogen,
over a period averaging 144 days varied from 0.106 to 0.148 gram, the
average of all being 0.128 per kilo or 7.89 grams per individual. The
weight of the men remained nearly constant, some gained a little, others
lost, but the losses were advantageous rather than otherwise. The men were
regularly engaged in drill and other exercises and improved progressively
in muscular strength and general physical condition during the whole of
their stay in New Haven. »
These observations were confirmed by three metabolism experiments,
In the first, of six days' duration, each man's food contained a daily aver-
age of from 7.71 to 8.23 grams nitrogen, or from 0.111 to 0.153, averaging
0.135 gram, per kilo and furnished approximately 2078 calories, or 33 per
kilo. In all cases the excretion of nitrogen in the urine and feces was
greater than the intake in the food. Six weeks later, a second experi-
ment of seven days was begun. The food now furnished 2509 calories
or 40.4 per kilo and contained from 9.27 to 9.64 grams nitrogen, or from
0.128 to 0.180, average 0.157, grams per kilo. Upon this diet, all the men
but one gained nitrogen, the average retention being 0.591 gram per ma.n
per day. A third experiment of five days came a month later. The
energy content of the food was approximately 2840 calories or 45.9 per
kilo and it contained from 8.14 to 8.67 grams nitrogen, or from 0.112 to
0.157, average 0.139, gram per kilo. Three men retained nitrogen and
eight men lost, the average of all being a daily loss of 0.254 gram per man
per day.
Since these losses occurred in spite of the fact that the diet furnished
300 calories per man, or 5 per kilo, more than that employed in the previ-
ous experiment, it would seem that the nitrogen of the food had been re-
duced to too low a level. The apparent nitrogen retention in the sec-
ond experiment, 0.591 gram per man per day, is probably not much, if
at all, greater than would be accounted for by the perspiration in men en-
gaged in as much exercise as was taken by these subjects. We may there-
fore conclude that the least adequate nitrogen intake demonstrated by those
experiments upon soldiers to be 9.5 grams, equivalent to about 60 grams of
protein per day. Calculated to 70 kilos, it would be 69 grams. Similarly,
the energy content would be 2800 calories. These values are very nearly
the same as those obtained from the experiments upon athletes.
Although some of the food served was not eaten, the entire detail
received practically the same diet. Nevertheless, as Benedict(&) (1906)
A NORMAL DIET
405
pointed out, there was a great variation in the amount of nitrogen in the
feces of the different men, a variation which does not appear to have been
observed in other experiments upon men receiving identical diets. Dur-
ing the first period the ratio of fecal nitrogen to food nitrogen varied
from 9.06 to 24.6, average 18.0 per cent ; in the second, from 10.7 to 24.4,
average 17.6, per cent; and in the third, from 18.9 to 27, average 24.2,
per cent. It varied in the same man in the different experiments. Bene-
dict regarded these variations as evidences of a possible disturbance of
the mechanism of absorption. But the variations in the case of the sol-
diers were greater than were observed with the professional men (from
10.9 to 19.0, average 15.1 per cent) or with the athletes (13.3 to 21.4,
average 16.2 per cent) although the diets within these groups were not uni-
form. It seems to the writer that the irregular, and high, values for the
nitrogen in the feces of the soldiers may have been due to the ingestion of
additional food. That the men should sometimes have "broken diet" seems
quite likely. If they did, they would have been likely to attempt to conceal
their action by failing to collect all the urine or feces. At any rate, varia-
tions in the excretion of nitrogen in the urine such as were recorded in
many instances and some of which are included in the following summary
of the urinary nitrogen excretion on the last four days of the second balance
experiment appear inexplicable except as a result of intentional, or acci-
dental, failure to collect all the urine.
NITROGEN EXCRETED IN THE URINE OF
' g
a
1
S
§
"3
a
tn
MU
cP.3
§
6
'C
£
a
01
p5
3
g
&
9
S)
5 •§
03
§
o
se
o
'3
0
0
.s
0
43
fcM
O
n
3
O
GO
a
N
02
P3
fe
8.750
6.85
7.37 »
6.55
7.18
8.10J
7.83
lost
7.56
7.78 10
6.18
7.05
10.427
7.95
8.22
//.99
7.93
4.66 3
7.35
5.5,9 8
7.51
7.49
7.68
lost
10.483
6.10
8.09
5.38
7.67
8.69 *
4.29"
9.55
7.08
7.54 »
5.56
8.71
10.265
7.96
8.20
7.01
7.95
8.20 5
8.07 7
6.77 9
6.81
8.23
7.69
4.78
Intake the same for each man, except as follows: 1. 8.555; 2. 9.30; 3. 11.107;
4. 10.024; 5. 10.392; 6. 10.654; 7. 10.886; 8. 10.215; 9. 8.164; 10. 8.164; 11. 10.475.
However, in spite of all the objections to some of the details, there can
be no question but that Chittenden's results did show that it was possible
for men to maintain themselves in good health and with a gain, rather
than any demonstrable loss, in physical and mental vigor for a considerable
period of time on diets containing less protein than had previously been
considered necessary.
Fisher. — Chittenden's observations were extended by Fisher in his
studies of the effect of diet upon endurance. It was found that students on
a low protein diet, yielding only a moderate supply of energy, less than
these students had been in the habit of obtaining, regularly increased in
406 ISIDOR GREENWALD
their power of endurance in a number of physical tests. The experi-
ments were not well controlled but they showed that healthy young men
could live in an apparently perfectly healthy condition for at least two
months on a diet containing only 0.97 grain protein per kilo per day.
McCay. — The advocacy of a low protein dietary was severely attacked
by McCay, who based his criticisms chiefly upon the results of his experi-
ence in India. McCay found that Bengalis, as their incomes increased,
partook to a larger and larger extent of protein food. The poorer classes,
who were also in poorer health, subsisted chiefly on rice, with only small
additions of meat, fish, milk or eggs. Some of his data and others calcu-
lated from them are included in Table IV. McCay emphasized the poor
physical condition of those whose diets contained little protein as compared
with that of those who, like the wealthier Bengalis, the Sikhs and others,
ate more protein.
Perhaps the most striking of all McCay's studies is one upon Bengali
and Anglo-Indian and Eurasian students at the same college. The for-
mer received a diet furnishing 3190 calories but only 67 grams protein,
the latter, only 2822 calories but 95 grams protein. The average weight
of the Bengali students was 54 kilos and they gained very little (less than
one kilo) during their stay at the school, in spite of a gain of 1.5 to 2.5
inches in height. There was no increase in the girth of the chest. The
Anglo-Indian and Eurasian students, however, gained an average of 8.2
kilos during the three years and their chest girths were increased by an
average of one inch. While racial peculiarities may have had something
to do with the result, it seems probable the difference in food played an
important part.
However, since McCay's work was published, there has been an in-
creasing recognition of the importance of, not only the amount of protein,
but its kind, the nature of the constituent amino-acids, and of the signifi-
cance of other dietary constituents. The diet of the Bengali (students and
others) may well be criticized as containing not too little protein but pos-
sibly not enough of certain amino-acids, or even more likely, as being de-
ficient in certain vitamines, or protective substances, or in one or more
inorganic constituents.
Hindhede. — In a series of experiments designed to determine the mini-
mum nitrogen intake required to maintain equilibrium, Hindhede ( c} (d)
(1913, 1914) succeeded in maintaining two men for considerable periods
on diets containing rather less protein than those employed by Chittenden.
The foods he used consisted of potatoes, or bread, with butter or margarin,
with or without the addition of onions, plums, rhubarb or strawberries.
The onions helped to make the large quantities of potatoes more palatable.
The other additions acted as vehicles for sugar, thus permitting a reduction
in the amount of bread. The nitrogen they contained did not appear in
the urine but in the f eces. Sometimes, indeed, the addition . of plums.
A NORMAL DIET 407
rhubarb or strawberries to the food led to an increase in the fecal nitro-
gen greater than the total nitrogen of the added food. In this manner,
these additions served to reduce the amount of what Hindhede regarded
as "digestible protein," which he calculated from the difference between
the nitrogen of the food and that of the feces. In this manner Hindhede
was able to arrive at extraordinarily low figures for protein metabolism.
But as pointed out on page 369, this procedure may not be justified and
in the present discussion of Hindhede's results, the nitrogen of the food
will be considered.
The lowest value for nitrogen intake, with maintenance of equilib-
rium, was obtained on the potato diet with 7.59 grams nitrogen or about
47 grams of protein for a man of 70.7 kilos. (The slightly lower value,
6.98 grams nitrogen or 44 grams protein, obtained in period E, was prob-
ably accompanied by a loss of nitrogen for the apparent gain of 0.2 gram
nitrogen per day was scarcely sufficient to account for the loss in perspira-
tion in the case of a man engaged in the hard work Fr. Madsen was then
performing.) This appears to be the lowest protein intake, accompanied
by a positive nitrogen balance, that has been recorded.
The analytical results reported by Hindhede cover a very consider-
able period, two years in the case of Fr. Madsen. It is difficult to ex-
tend quantitative observations over even so long a time as that and any
of longer duration are almost impossible. But it should be remembered
that Hindhede's subjects, particularly the two Madsens, were accustomed
to a very low level of protein metabolism and were, nevertheless, healthy,
vigorous men, well above the average in muscular development and en-
durance. Hindhede's own customary diet contained only 10.34 grams
nitrogen or 64.6 grams protein per day and that of his family, which
included children, only 75.7 grams per man.
The energy content of the food consumed by Hindhede's subjects
appears to be rather high. It is possible that this low level of protein me-
tabolism could be attained only at the cost of a large carbohydrate metabol-
ism. However that may be, it is noteworthy that the very low protein me-
tabolism observed in the case of the Madsens necessitated a very monotonous
and limited dietary. Hindhede himself called attention to the difficulty of
making a potato diet palatable or even endurable for any considerable
period. It required the greatest care in the selection and preparation of
the potatoes. On the bread diets, large quantities of sugar were required
in order to maintain the energy yield of the foo'd while keeping the pro-
tein content low.
As a matter of fact, unless unusual reliance be placed upon more or
less purified foods such as starch, sugars and fats, it is nearly impossible
to obtain 3000 calories without securing at the same time about 70 grains
of protein or one gram per kilo. Reference to Table IV shows that this
level is reached by all the dietaries reported, if only the energy content
408 ISIDOK GKEENWALD
is high enough. From Sherman's compilation (page 401) it is evident
that this is 75 per cent or more above the minimum requirement. The
danger of falling below the minimum protein requirement is, therefore,
slight. As Bayliss said, "Take care of the calories and the protein will
take care of itself." That is certainly true of the minimum for mainte-
nance but it is not quite so evident that the optimum will be thus attained.
Liberal Protein Intake a Possible ' ' Factor of Safety" (Meltzer) . — In a
memorable lecture delivered in 1906, Meltzer called attention to "The
Factors of Safety in Animal Structure and Animal Economy" and sug-
gested that the tendency of mankind to seek a level of protein metabolism
above the minimum might be such a factor of safety. Just as we are pro-
vided with kidney, liver and lung tissue in excess of the apparent minimum
requirement, so, too, the excess of protein above the minimum determined
by experiment might serve as a factor of safety to cover emergencies and
insufficiencies some of which we may not at present be able to recognize.
Aside from its value as a factor of safety, there are not wanting evi-
dences of the desirability of a rather liberal supply of protein. Not only
do the more vigorous and prosperous individuals consume a liberal al-
lowance of protein but so also, do the more vigorous nations. This may be
effect rather than cause and, undoubtedly, is so in many cases with in-
dividuals. Meat and other protein foods are prized for a number of reasons
including their agreeable taste, stimulating action, etc. This has led to
a comparison of the desire for a liberal allowance of protein with the
desire for alcohol. This seems to be based upon entirely too superficial
resemblances. We now have a fairly good conception of how and why al-
coholic beverages came to be so regularly employed by man. We know
fairly well how they act to secure the effect desired. We know what are
the consequences of excessive indulgence and even of the regular use of
small quantities. We also know that not only scattered individuals for a few
months or years but entire peoples for generations have maintained them-
selves in full health and vigor without the use of alcohol. There is to-
day no such body of evidence in respect to the advantages of a low-protein
diet. Some protein is needed. A slight, or even moderately great excess
can scarcely be so very disadvantageous. When overindulgence in protein
shall have been shown to be followed by ill effects at all comparable to
those following the excessive use of alcohol, comparison will be in order
but hardly until then.
Change of diet of whatever character has too often led to improvement
in clinical condition for one to lay much stress upon the fact that Demuth
observed such improvement on increasing the protein content of the diet of
some of his patients. But such results as those reported by Moulinier with
some 72 Indo-Chinese taken from Annam to the Yangtse valley as laborers
are not so readily dismissed. The men first fed themselves as they had been
A NORMAL DIET 409
accustomed to at home, chiefly on rice. After several months, with the ap-
proach of cold weather, they tired easily and did very little work. Thev
were then rationed and received 100 grams biscuit, 800 grams rice, 300
grams meat, 15 grams fat and 10 grams salt, yielding, in all, 3600 calories
daily. Their capacity for work promptly increased and, when the meat
ration was later diminished, the Annamese bought pork and poultry out of
their own funds.
The following account of a similar instance is copied from Starling(fe)
(1919). "Thus Major Ewing relates how on a railway job in Canada,
the Italian workmen were found to become inefficient at about 11 o'clock
in the morning. These workmen were spending only seven to eight dollars
for food at the canteen as against fifteen dollars expended by the Canadian
workmen. The chief difference in the diet conditioned by this economy was
in the meat. The company then insisted on the Italians spending fifteen
dollars a month. With the 'extra money, they bought fat beef and it was
then found that their work was entirely satisfactory." It may be objected
that the favorable results in both these instances were due to the increased
amount of food and not to the increased amount of protein. But, if the
total amount of food had originally been insufficient, the men would, in all
probability, have been hungry and would have eaten more.
Starling believes that the food of the Italians was originally too poor
in fat and that the men felt the lack of this and responded to the addition
of fat in the form of fat beef. But, while it is true that people accustomed
to a liberal amount of fat suffer from lack of it, there is little reason to
believe that its lack should inconvenience those, who like these Italians,
probably never had any considerable amount of fat in their food.
A similar effect of meat feeding upon the laborers engaged in the con-
struction of another railroad is mentioned by Collis and Greenwood (page
254).
Complete data are lacking but it seems to the writer that in all
these cases the improvement was due to the increased protein content of the
food. The original diets, while selected in accordance with previous habits,
were possibly of not so high a protein content as in their native country.
A change from unpolished rice to polished rice in the cases of the Anna-
mese or from one kind of flour (as such or as bread or macaroni, etc.) to an-
other with the Italians would have been quite sufficient to have produced
an appreciable change in the protein content of the food.
It is curious that physiological literature should be so plentiful in
arguments for a low protein diet based on the fact that protein is not com-
pletely oxidized but leaves a residue to be excreted by the kidneys. Win-
there should be so much solicitude for the kidneys rather than for other
parts of the apparatus of metabolism is not entirely clear. Whatever may
be the case in disease, it is yet to be demonstrated that the healthy kidney
is in any way injured by being required to excrete 15, or even 20, rather
410 ISIDOE GKEENWALD
than 7 grains of nitrogen per day. A. and M. Krogh found no evidence of
the prevalence of kidney disease, etc., among the Eskimos. There is
rather more reason to be sparing in our use of the simpler carbohydrates,
for it has now been demonstrated that a considerable number of individuals
who would ordinarily be considered normal have rather a limited tolerance
for sugars and that this tolerance can probably be impaired by continuously
exceeding, or approaching, this limit. Apparently the factor of safety
in the metabolism of glucose is less than it is for protein metabolism.
Fat Minimum. — During the war, and after, the importance of fat in the
diet was greatly emphasized. The lack of fats was most severely felt by the
people of central Europe and there were not a few who ascribed to their lack
of fats the widespread occurrence of nutritional disorders, particularly "war
edema." The Inter- Allied Food Commission adopted 2 oz (57 grams) of
fat per man per day as the minimum upon which the peoples of the allied
countries were to be asked to subsist. The absolute need of even so little
is questionable. Experiments by Hindhede showed that his subjects could
maintain themselves with much less fat. Fr. Madsen's diet included an
average of 10.8 grams fat for 107 days. After a vacation of 21 days, dur-
ing which he confined himself to a fat-poor diet, there was another period of
120 days during which the average fat content of the food was 13.9 grams.
Then came another vacation of 21 days, then a period of 140 days with an
average fat ration of 12.8 grams and then another vacation of 38 days. Dur-
ing both of these vacations, Madsen kept on a fat poor diet. Finally there
was a period of 106 days with a diet containing an average of 14.2 grama
fat. In all, he lived for over 18 months on a diet containing less than 15
grams of fat per day. Similarly, Holger Madsen ate food containing an
average of 6.6 grams of fat per day for 117 days and, after a three weeks
vacation, 7.9 grams fat for 180 days. After a two months vacation, there
was another period of 106 days with an average of 7.5 grams of fat per day.
The vacation diets were also poor in fat.
These results were not obtained in connection with the low protein diets
previously discussed. Except for 30 days, Fr. Madsen's fat-poor diet regu-
larly contained over 100 grams of protein and, during the period in which
it fell below this level, Madsen lost weight. But whether this was due
to the lack of protein and of fat or merely to the deficiency in energy con-
tent, which was at its lowest in this period, it is difficult to determine. Hol-
ger Madsen did not maintain his weight of 70 to 72 kilos on. a fat-poor
diet containing less than 90.grams of protein but, after his weight had fallen
to 65 kilos, he maintained himself at this level and even gained a little on
a diet containing 60 to 70 grams of protein, 6 to 7 grams of fat and furnish-
ing 3000 calories.
Experiments by Osborne and Mendel on rats support these observations
as do the observed dietary habits of Japanese and other Oriental peoples
as well as those of the poorer classes in Europe. However, it seems probable
A NOKMAL DIET 411
that, when the diet ''is deficient in fats, particularly in those of animal
origin, it must contain considerable quantities of the green leafy vegetables
as these and the animal fats appear to be the only sources of the fat-soluble
vitamin or vitamins.
But if fat is not absolutely necessary, it is certainly very useful, for our
whole accustomed cookery is dependent upon the use of fat. Without it.
the housewife of western Europe and of the United States does not know
how to prepare food nor does her husband relish it when it is prepared.
Food prepared without fat leaves the stomach rapidly — it does not "stay
with one." For those who require a large supply of energy, the use of fat
is advantageous in that it supplies energy in a very concentrated form, nine
calories per gram and all of it food, instead of four calories per gram, as
with protein and carbohydrate, with each gram accompanied by from 0.5
to 9 grams water.
Carbohydrate Minimum. — Carbohydrates furnish more than fifty per
cent of the energy content of 'most diets. If greatly reduced in amount,
signs of defective fat metabolism may appear. However, the inhabitants
of the arctic regions appear to maintain good health on diets containing
very little carbohydrate. The possible ill effects of an excess of carbohy-
drate, particularly of the simple sugars, have already been mentioned
(page 410) and are discussed more fully in the chapter on diabetes.
Minimum of Ash Constituents. — The requirements of the body for in-
organic constituents have been, as yet, only scantily investigated and the
demands for phosphorus and calcium have received the greater part of the
attention that has been given to the subject.
Sherman (d) (e) (1920) has compiled the available data for these
elements in a manner similar to that used in the determination of the pro-
tein requirement, to which reference has already been made. In 95 experi-
ments included in 17 investigations (12 of which were by Sherman and his
collaborators), the daily requirement of phosphorus varied from 0.52 to
1.20, with an average of 0.88 gram per 70 kilos body weight. Sherman
states that "in a detailed study of the food supplies of 224 families or other
groups of people selected as typical of the population of the United States
only eight showed less than 0.88 gram of phosphorus per man per day and
in all but two of these cases the phosphorus content would have reached this
figure if the food consumed (without changing its character) had been in-
creased in amount to a level of 3000 calories per man per day. The two
cases which apparently contained less than the average actual requirement
of phosphorus and would still have been thus deficient if the food had been
sufficient in amount to cover the energy requirement amply were both re-
ported from the southern states. . . . Outside of the southern regions where
the food consists too largely of patent flour and new process (degerminated)
cornmeal, the danger that a freely chosen American dietary will be deficient
in either protein or phosphorus does not appear serious, in the light of our
412 ISIDOR GREENWALD
present evidence, so far as the requirement of maintenance is concerned."
The 'compilation of the observations on calcium showed that in 97 ex-
periments belonging to 14 investigations (10 of them by Sherman and his
collaborators), the indicated daily requirement varied from 0.27 to 0.82,
average 0.45, gram per 70 kilos. Sherman pointed out that, whereas only
one out of 224 supposedly typical American dietaries fell below the indicat-
ed protein requirement, one in six was deficient in calcium. If all that fell
below 3000 calories were increased to this level, none would be deficient
in protein, but one in seven would still be deficient in calcium. It is inter-
esting to observe, in this connection, that only one of Blatherwick's 32
army dietaries fell below 0.45 gram of calcium.
The possible occurrence of a calcium deficiency and consequent advis-
ability of "liming the nation" seems recently to have attracted considerable
attention in Germany. Rubner (1920) has considered the question and has
concluded that with such foods as are used in Germany and are now avail-
able, there is no danger of a calcium deficiency for adults, so long as they
get enough food to satisfy their energy requirements.
Rubner also calculated the values for the inorganic content of some
Japanese diets to European body weights with the results shown in Table
VI. The calcium content is much below Sherman's indicated requirement
and is certainly considerably below that which was customarily consumed in
Germany (page 415) but, if the analytical figures chosen by Rubner are
correct, is certainly adequate ivitli Japanese dietaries. It may not be with
European food materials.
It is suggested by Rubner that the low fat content of Japanese diets may
be related to their low calcium content. If they ate more fat (vegetable
oils, etc.), the Japanese would not eat so much of their customary foods
and would thus obtain even less calcium than they do now and might then
suffer from a deficiency.
A certain absolute minimum of calcium and of other inorganic ele-
ments is unquestionably needed, but there are observations that indicate
that this minimum may vary considerably under the influence of different
factors. The first and most obvious of these is the texture of the food and
the ease of digestion of the protein and carbohydrate contained therein.
Hart, Steenbock and Hoppert found that cows and goats lost much less
calcium on rations otherwise identical if they received fresh grass rather
than hay. McCluggage and Mendel found that the calcium and magnesium
of carrots and of spinach were poorly utilized by the dog. While it is
true that Rose found that the calcium of carrots was as well utilized by
women as that of milk, it, nevertheless, seems possible that in some other
foods, less readily digested, some inorganic constituents are not made
fully available for absorption.
The nature of the chemical combination in which the element appears
A NOKMAL DIET 413
may play an important part. Organic iron is generally considered to be
more valuable than inorganic, although the evidence is still conflicting.
Also, although the requirement of the body for phosphorus may be met en-
tirely by inorganic phosphate, it is possible that a larger amount is required
than if some is present in organic combination.
Relation of Ash Constituents to One Another. — The existence of factors
of quite different kind is indicated by the results of Bunge who found that
the ingestion of potassium increased the excretion of sodium and by those
of Hart and Steenbock who observed a similar effect, in swine, of the ino-es-
O
tion of magnesium upon the excretion of calcium. It is possible that some
such action was responsible for the increase of 0.16 gram in the excretion of
calcium in one of Sherman's experiments, following the addition of lean
beef, containing 0.01 gram calcium, to the basal diet. The relation of the
inorganic constituents of the food to one another is evidently of consider-
able importance.
Of all such relations, one of the most obvious, though not necessarily
one of the greatest physiological significance, is the relation between acid-
and base-forming elements. Sherman and Gettler first called attention to
this. Blatherwick(a) (1914) showed that with some foods such as prunes
and cranberries which contain considerable quantities of benzoic acid,
which is not oxidized in the body but conjugated with glycine and excreted
as hippuric acid, this may play a considerable role in the determination of
the acid-base equilibrium of the body. Meats and cereals contain an ex-
cess of acid-forming elements, most fruits and vegetables an excess of al-
kaline, milk a slight excess of alkaline, and an ordinary mixed diet a slight
excess of acid, elements. In his study of 32 army dietaries, Blatherwick(6)
(1919) found a variation from an excess of acid equivalent to 39 c.c. nor-
mal acid to an excess of alkali equivalent to 2.4 c.c. normal alkali per man
per day. The average of all was 2.2 c.c. normal acid.
Medical literature is rich in references to the supposed ill effects of an
acid diet but most of these will not stand a careful examination. The fact
that most organic acids are oxidized to carbon dioxid and water has gen-
erally been disregarded. Moreover, most of the evidence indicates that the
body is able to neutralize the excess of acid that may be formed by neutral-
izing it with ammonia, at the expense of the urea of the urine.
Rose and Berg have reported that an acid-forming diet increases the
need for protein. Their preliminary report is very interesting but accep-
tance of their views must await publication of their detailed results and
confirmation thereof. Such confirmation would appear not to be forthcom-
ing for Jansen (1919) and Fuhge have denied any such influence.
So little is known of the nature of the vitamins or protective substances
that it is impossible to state with any degree of definiteness just what are
the requirements for human nutrition. There seem to be at least three of
these substances that must be supplied but there may be more. To what
414 ISIDOR GREENWALD
amounts these are required we do not know. It is possible that these
amounts will be found to vary considerably with the nature and amount
of other constituents of the diet. Some evidence that this is so is already
available. For a further discussion, the reader is referred to the chapter
on vitamins.
Undernutrition
For years it has been known that fasting reduces basal metabolism but
the significance of this fact as indicating a means of lowering the level
of metabolism does not appear to have been fully appreciated until after
the outbreak of the war. Then it was noted, particularly in Germany, that
large numbers of people maintained themselves in good health and remained
capable of performing their accustomed tasks while eating much less food
than they had previously. They lost weight but not continuously and the
loss was slight "in comparison with the saving in food effected. The energy
content of the food of the city population was probably about 2500 calories
per man per day, but was increased by means of extra rations for those
working in factories, mines, etc. (though still remaining below the accus-
tomed quantity) and by extra foods purchased openly or surreptitiously by
those whose means permitted them to do so.
Loewy and Zuntz showed that this maintenance at a lower level was
due to lowered basal metabolism and not merely to the reduction in the
protein of the food.
The success of the German people in maintaining health and vigor on
such low diets appeared so striking that it seemed almost a foregone con-
clusion that their previous food intake had been greatly excessive.
In this country, Benedict, Miles, Roth and Smith, in a series of experi-
ments, found that a group of twelve young men whose usual requirement
of food was 3090 calories per day lost weight when placed upon a diet fur-
nishing only from 1600 to 1800 calories, until after five weeks they had
lost 10.5 per cent of their body weight. Thereafter, without changing
the character of the food from that to which they were accustomed, they
were furnished an average of 1967 calories, upon which the body weight re-
mained stationary for a period of several months. Examination, by McCol-
lum, of the diet furnished these men showed that it was not deficient in any
known dietary constituent but only in total energy content. At first it
seemed as if this economy in food was accomplished without any untoward
effect but as the experiment continued it became evident that the men were
not capable of the physical exertion that had previously been readily dis-
played. They lacked spirit and were easily tired. To use a colloquialism
which many of them used to describe their condition, they lacked "pep."
There was no clear evidence of lack of mental power but there was a very
decided lessening of sexual desire.
A NORMAL DIET 415
Coincidentally, reports from Germany showed that similar effects, but
greatly intensified, were appearing there. The early favorable results of a
reduced dietary were found to be illusory and a very real failure to accom-
plish the usual amount of work was evident on all sides.
War Edema. — Outbreaks of what came to be known as "war edema" or
"hunger edema" appeared in 1917 and became more and more frequent as
time went on. The mortality figures soon showed an increase, particularly
in the number of deaths from tuberculosis. A very good review of the sup-
posed effects of the war diet on the incidence of disease was published by
Determann.
Many factors have been held responsible for the appearance of "war
edema." It is easy to point out some of these, such as the lack of protein
and of fat (page 410), but there seem to be natural and experimental diet-
aries that share these deficiencies and that have been employed for long
periods without producing -edema. The large amount of water in the
food has also been blamed. But Hawk and his collaborators found no
such ill effect to follow the regular use of large volumes of water.
Rubner(aa) (1920) calculated the inorganic content of the rationed
food of the German people in 1917-8 to be 3.375 grams K2O, 0.226 gram
CaO, 0.290 gram MgO, 0.089 gram Fe,O3 and 1.922 grams P2O5, per head
per day. A similar calculation for the food used before war gave the fol-
lowing values: 4.403 grams K2O, 1.221 grams CaO, 0.576 grams MgO,
0.154 gram Fe2O3 and 4.472 grams P2O5. The difference is marked. The
calcium content of the war-time diet is far below Sherman's indicated re-
quirement and is even less than that of Japanese diets, as calculated by
Rubner.
When we consider how large a part the inorganic constituents of the
body fluids play in determining their osmotic properties, it seems quite
likely that a change in the inorganic content of the food, in which change
the lack of calcium may or may not have been the significant factor, should
have had some influence in the causation of .the edema.
However that may be, lack of food — simple starvation — must be regard-
ed as largely responsible, not only for war edema but also for the other
disastrous effects observed. It is possible that a proper mixture of salts,
vitamins and amino-acids added to the reduced diet would have prevented
some of these, but for the present it seems safe to say that the only practic-
able way to secure these needed substances is to eat enough food of sufficient
variety.
Probably the most complete and most accurate study of nutrition in
Germany during the war, though limited to one individual, was made by
Neumann upon himself. For seven months, from November, 1916, to May,
1917, he confined himself to the rationed articles with only such additions
as were available to the poorer classes in his city (Bonn). This diet
furnished him 45 grams protein, 18.9 grams fat, 287 grams carbohydrate
416 ISIDOK GREENWALD
and 1546 calories daily. His weight fell from 167 to 127 pounds. (The
chart is taken from Starling.) Other studies (Starling, Loewy and Brahm,
Maylander, Mason) indicate that at about this time Neumann's diet was
typical of that available to most of the city population. The well-to-do
town dwellers and the agricultural population fared much better, the latter
reducing their food consumption little, if at all.
The limitation of diet in the investigations of Benedict and in the
experiences of the German people was accompanied by all the stimulation
of war and the fervor of patriotic service. This may have helped to con-
ceal from the subjects manifestations that might otherwise have been more
promptly observed. In his studies of prison diets, Dunlop found that much
smaller changes were promptly noticed by the subjects. He found that
with a certain group on a diet containing 179 grams protein, 54 grams fat,
654 grams carbohydrate and furnishing 3928 calories, there was much
waste and such complaints as there were regarded quality and not quantity.
The ration was then reduced to one containing 165 grams protein, 5.6 grams
fat, 566 grams carbohydrate and furnishing 3517 calories, which was tried
for two months. By that time, 82 per cent of the prisoners of average
weight (67 kilos) had lost weight. There was little waste but there were
many complaints of lack of food. The ration was then increased to one
containing 173 grams protein, 57 grams fat and 602 grams carbohydrate,
furnishing 3707 calories. Complaints as to quantity ceased but there was
no more waste than with 3517 calories.
There seems to be a certain definite level of nutrition to which the
individual is accustomed and from which it does not vary over very consid-
erable periods of time. Thus, Zuntz (Zuntz and Loewy (&)) found his
basal metabolism the same after fifteen years. Any change in food intake
from the amount required to maintain the level, assuming the amount of
physical work performed to remain the same, is promptly indicated by a
change in body weight which is, however, not continuous nor proportional
to the change in the food.
It is interesting to examine in this connection the figures given in
Table IV for two pairs of groups of dietary studies in the United States.
The writer has selected from the studies of Atwater and Bryant in New
York City in from 1896 to 1897 and from those of Wait in eastern Ten-
nessee in firum 1900 to 1904, those in which the weight and age of the chil-
dren were given.2 These were then separated into two groups, one of which
included the studies of those families in which one or more children were at
least ten per cent below the normal in weight as judged by Griffith's stand-
ards and the other in which all, or all but one in the case of large families,
were of normal weight. The distribution of protein and calories is approxi-
mately the same within each pair. In New York, milk and its products sup-
2 These are the only publications in which such information is given that are known
to me.
•?!. =
O O O Q O O O
»0 O «5 O «O O »O
(6 to *o »o 4." V <o~
f- ** b* es. t- ^ **•
3 O O O O O O
3 o o in o *n o
n of of — ~ — ' o o
| f S § S § S 8 8 8 2 § 2 8 3 8 2 g 8 g S § 2 S S §
2 S S S 5 S S S S S i $ J S S S 3 5 S 8 g S 5 2 $ S S
«° * —
r
r'
*r
I
,-.
1
3
A A
A. AAi
* *.*
,-f
-#'
r
i"
—
9
i
^ —
*jj
*- =
*"
\
^
7T
^-
•^
.
\
?
|
//
1
1
0
if
//
o
'
0
L
4
9
//
H
4
£
t.__
-^
<t
i
A
/
4
J
\/
0
J
f1
E
1
'
T
i
!
0
l
i
-c fl
u
X.
•
J
f
!
^
<-
g
t
r
\
i
2 N
r
r
_
.1
.
(j)
\
f
'
f
>j
r
'*•
5
J
-i
S
91
1
/
f
0
|
3 "
c
V
1
/
t
0
ft-
Jl
E
*•
if '
I
fe
/ f
D L
tj
J
,
0^
/
r*
o i
'
9
J
1
!
<
3, *
10
^
<
TO
i
c
3S
"
•
t
H "
"
* J
O
••
c
.
a
*-•
i
^\
*
a-
o
•H
\
c
/
o
3
!
.
L
u in
*
•
1
A
0
„
0
1
7^
t.
i
a .
:
/
i
i
f
1
,
•f
h
y
r
rf
1
L
J
*->
F
•
y
- j
a
;
. V
E _
? ±
••
g ...
•f~
3
z
o
•
•
u
"
"J
V
-j
f ' *
-*
~t
V
i> 3
«O Q W) O »o Q ""
•»» *> W O P" *O «
§in O 10 c
^ IO M C
§10 0 "-> O
•» n M Q
•s |-
s I
oooooooooo o o o oo ooo o
1 1
1
5
417
418 ISIDOR GREENWALD
plied less of the protein to those families whose children were below normal
weight than it did to the other families, but these foods supplied more of the
calories, indicating that the former group used less milk but more butter
than the latter. The two Tennessee groups show no such difference in the
consumption of milk and butter but, apparently, the- families with children
below weight used more peas and beans and less cornmeal than did the fam-
ilies whose children were of normal weight. But these differences are
slight. The striking difference, in both pairs, is that in energy content, 8
per cent in Tennessee and 14 per cent in New York. Food habits that do
lot secure to the ordinary family at least 3000 calories per man per day are,
apparently, not suited to secure the proper development of the children.
Of course, if no work is done, much less food is needed. This is in-
dicated by many of the observations cited in Table IV and also by those
of Benoit on a group of 78 Russian officers, prisoners in Germany, dur-
ing a period of 480 days. Their food contained an average of 48.7 grams
protein, 14.6 grams fat and 332 grams carbohydrate, furnishing 1697 cal-
ories per man per day. During this period, they lost an average of 140
grams. Although they had previously lost weight, they were still of about
the "normal" weight, as judged from the American statistics, the average
weight being 139 pounds (63 kilos) with an average height of 65 inches
(1.65 meters). But they did no work and took very little exercise of any
description. Bread and flour furnished 49 per cent of the protein, milk
and its derivatives 23 per cent, meat and fish 16.3 per cent and vegetables
11.65 per cent. This was a very satisfactory distribution and no disturb-
ances of nutrition were observed.
With the foods ordinarily consumed, the amount needed to maintain
the body in its accustomed condition distends the stomach to a certain de-
gree. If, with a change of diet, this bulk is lacking, the individual may be
hungry, even though the energy content of the food is quite sufficient. On
the other hand, in times of scarcity, the most varied, though indigestible
and worthless materials are used simply to fill the stomach. Such is the
case in Russia and in China to-day.
Bread and flour supply half the food of Europe. They are, ordinarily,
the cheapest foods and in a time of high prices, their comparative im-
portance increases and an adequate supply of bread becomes even more
essential. Thus Miss Ferguson found that the same families in Glasgow
used less meat, potatoes and sugar in 1917 than in 1916 but that they all
used more bread and flour. It is not without reason that "bread" is so
often used as synonymous with "food." A bread-eating people must have
bread or suffer. For this reason, the most diligent attempts were made
during the war to find suitable diluents or substitutes to use with wheat
or rye flour in bread making.
A very complete study of the effect of a large number of such sub-
stances as were used in Russia in times of scarcity was made by Popoff.
A NORMAL DIET
419
An account of his experiments was published by Erismann in the Zeit-
schrift fur Biologie in 1891. Notwithstanding this readily available ac-
count, many of these substances and many others were used in Germany
during the war, some with very disagreeable consequences. Only two
suitable substances appear to have been found. Blood obtained from slaugh-
terhouses was, in this manner, made directly available as a food for man.
Finely milled bran was also found useful. The addition of either of these
made the bread less palatable than it formerly was. (Neumann(d) 1916.)
What is "Normal" Weight? — Such losses of weight as were observed
in Germany and by Benedict and his associates in this country must be re-
garded as pathological but it is probable that if the reduction in the diet
had not been quite so marked the loss in weight would have been much less.
Benedict's subjects at an average weight of 66 kilos, were accustomed to a
diet furnishing 3097 calories. A diet furnishing 1967 calories main-
tained them at about 59 kilos, indicating a loss in weight of 1 kilo for every
reduction of 160 calories in the diet. If they had reduced the energy con-
tent of their food by 320 calories, or approximately 10 per cent, they
would probably eventually have lost almost two kilos. If they had in-
creased it by this amount, they would probably have gained about the same
amount and would then have maintained themselves at this new level of
metabolism and of weight. Which of these, *2777, 3097 or 3417 calories
is the "normal" ? That question cannot be answered until we know more
definitely what is the "normal" weight for these men, 64, 66, or 68 kilos.
Symonds collected and published the height and weight of men and
women at different ages as obtained from the records of accepted applicants
for life insurance in the United States and Canada. The results are in-
cluded in the following tables, the height including shoes and the weight,
ordinary clothing.
TABLE VII.— SYMOND'S TABLE OF HEIGHT AND WEIGHT FOR MEN AT DIFFERENT AGES BASED ON
74,162 ACCEPTED APPLICANTS FOR LIFE INSURANCE
AGES
15-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
5 ft. 0 in
120
125
128
131
133
134
134
134
131
5 ft. 1 n
122
126
129
131
134
136
136
136 -
134
2 in
124
128
131
133
136
138
138
138
137
3 in
127
131
134
136
139
141
141
141
140
140
4 in
131
135
138
140
143
144
145
145
144
143
5 in
134
138
141
143
146
147
149
149
148
147
6 in
138
142
145
147
150
151
153
153
153
151
7 n
142
147
150
152
155
156
158
158
158
156
8 n
146
151
154
157
160
161
163
163
163
152
9 n
150
155
159
162
165
166
167
168
168
168
10 n
154
159
164
167
170
171
172
173
174
174
11 n
159
164
169
173
175
177
177
178
180
180
6 ft. 0 n
165
170
175
179
180
183
182
183
185
185
6 ft. 1 n
170
177
181
185
186
189
188
189
189
189
2 n
176
184
' 188
192
194
196
194
194
192
192
3 n
181
190
195
200
203
204
201
198
420
ISIDOR GEEE^WALD
TABLE VIII— SYMOND'S TABLE OF HEIGHT AND WEIGHT FOR WOMEN AT DIFFERENT AGES BASED ON
58,855 ACCEPTED APPLICANTS FOR LIFE INSURANCE
AGES
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
4 ft. 11 in
111
113
115
117
119
122
125
128
128
126
5 ft. 0 in
113
114
117
119
122
125
128
130
131
129
1 in
115
116
118
121
124
128
131
133
134
132
2 in
117
118
120
123
127
132
134
137
137
136
3 in
120
122
124
127
131
135
138
141
141
140
4 in
123
125
127
130
134
138
142
145
145
144
5 in
125
128
131
135
139
143
147
149
149
148
6 in
128
132
135
137
143
146
151
153
153
152
7 in
132
135
139
143
147
150
151
157
156
155
8 in
136
140
143
147
151
155
153
161
161
160
9 in
140
144
147
151
155
159
163
166
166
165
10 in
144
147
151
155
159
163
16/
170
170
169
From a study of the records of the relation of weight to height and
of the mortality records, Symonds concluded that, below the age of about
30 years, those slightly above the average weight were the more likely to
survive but that beyond this age those slightly under the average in weight
showed the greatest vitality. But the optimum was very near the average.
So that, apparently, the average weight of the people of this country is
just about the "normal" in both senses of the word.
The relation of weight to height as calculated by Symonds is, of course,
a rather crude measure of the state of nutrition or "degree of fatness"
as Sherman calls it. Attempts have been made to devise others (Oppen-
heimer, Oeder) but these have not met with general acceptance.
Conclusion
From what has preceded, it is evident that it is impossible to fix defi-
nitely a "normal" diet. It is clear that its nature will depend upon
geographical location, economic status, degree of muscular activity, habit,
etc. Any diet that will maintain, or, rather, that has maintained normal
health for generations must be considered to be a normal diet.
Judging by the experience of the race, checked by observations under
laboratory conditions, or conditions approaching those of the laboratory,
and by experiments upon animals, such a diet, if of European or American
food materials, will furnish the man of 70 kilos engaged at moderate work
3000 calories and will contain from 75 to 120 grams of protein, at least 0.4
gram calcium and 0.8 gram phosphorus and will include a considerable
amount of fruits and vegetables to furnish "roughage," vitamins, etc.
Success in maintaining individuals upon exceptional diets for even
long-continued periods cannot be accepted as a criterion of the adequacy
of a diet. Failure is piroof that the diet is not satisfactory but success can
only be taken to indicate exactly what was observed, which is merely that
A NOKMAL DIET 421
no deficiency was detected within the period of observation. We now know
that animals may be maintained in a satisfactory condition for periods cor-
responding to many years in the life of man upon diets that finally fail to
continue to do so. Other diets will maintain the animal throughout life
but will not permit reproduction. Experiments of comparable extent upon
man are, of course, impossible. Custom, carefully observed and ana-
lyzed, must remain our chief reliance in deciding what is a normal diet,
As has already been shown, the cereals play a less important part in
American diets than in those of most other peoples. It is probable that we
shall, in the future, approximate them in this regard. Our per capita con-
sumption of meat is almost certain to fall due to its almost inevitable in-
crease in price, relative to other foods. What changes in our diet are physi-
ologically sound and economically justifiable ?
There seem to be two foods, or classes of foods, in which many Ameri-
can diets appear to be deficient or to approach deficiency. These are milk
and its products and fresh vegetables, particularly the green leafy vege-
tables. Students of nutrition appear to be united in this opinion. Thus
McCollum(c) wrote: "Milk is our greatest protective food, and its use
must be increased." "There is no substitute for milk and its use should be
distinctly increased instead of diminished, regardless of cost." "Milk is
just as necessary in the diet of the adult as in that of the growing child."
According to Lusk(^) (1917), the mother of a family consisting of two
adults and three children should buy no meat until she has first bought 3
quarts of milk a day. Sherman (c) (1918) writes: "It therefore seems ad-
visable to spend at least as much for fruit and vegetables as for meat and
fish ; also to spend at least as much for milk as for meat or for milk and
cheese as for meat and fish." . . . "General adoption of a dietary such
as we now believe to be best would call for more milk and perhaps more
vegetables and fruit than now come to our city markets."
To quote again from McCollum: "In the light of facts presented in
the previous chapters of this book, there can be no reasonable doubt that
the importance of poor hygienic conditions and of poor ventilation have
been greatly over-estimated, and that of poor diet not at all adequately ap-
preciated as factors in promoting the spread of this disease." (Tubercu-
losis. )
It is probable that the importance of a faulty diet in reducing resistance
to other infectious diseases has similarly been overlooked. Moreover, when
we consider how slowly the signs of such unquestionably nutritional dis-
orders as scurvy or rickets usually develop, it is not difficult to understand
that a slighter nutritional deficiency may give rise to general inefficiency
and impaired health.
We cannot hope to maintain and improve our standards of health and
efficiency without maintaining and improving the character of our diet.
SECTION III
Body Tissues and Fluids Victor c. Myers
Composition and Significance of Blood — Blood Volume — Total Solids — Spe-
cific Gravity — Eeaction and Hydrogen Ion Concentration — Blood Pro-
teins— Serum Proteins — Fibrinogen — Hemoglobin — Blood Cells — Blood
Nitrogen — Total Nitrogen — Non-protein Nitrogen — Urea — Uric Acid —
Creatinin — Creatin — Amino Acids — Ammonia — Best Nitrogen — Blood
Sugar — Blood Lipoids — Total Fat — Lecithin — Cholesterol — Acetone
Bodies — Mineral Constituents — Sodium — Potassium — Calcium — Magne-
sium— Iron — Chlorids — Phosphates — Sulphates — Blood Gases — Oxygen
— Carbon Dioxid — Muscle — Liver and the Bile — Connective Tissues —
Brain — Phosphatids — Cephalin — Cerebrosids — Sulphatids— Cholesterol —
Extractives — Cerebrospinal Fluid — Saliva — Milk.
Body Tissues and Fluids
VICTOE C. MYERS
NEW YORK
So much attention has recently been devoted to the study of the chem-
istry of the blood that a consideration of the subject of the body tissues
and fluids can hardly be made without undue emphasis on the blood. Some
of the more recent methods, have been applied to advantage in the study
of spinal fluid and milk, and an extended application of many of these
methods to the study of fresh autopsy tissues, muscle, liver, etc., would
probably yield equally valuable results.
Composition and Significance of Blood
During the past decade, 1910-20, the chemical composition of the
blood has been a topic of increasing interest and importance, quite eclips-
ing in significance the studies carried out on the urine during the pre-
ceding decade. In the case of urine the advances were primarily the re-
sult of the impetus furnished by the new methods of Folin and of S. R.
Benedict, and these same workers, together with Van Slyke, are responsible
for many of our new methods of blood analysis. During this latter period
the blood has probably been the topic of more studies than any other body
tissue, fluid or secretion. The practical importance now attached to the
chemical examination of the blood would appear to be rapidly overshadow-
ing the importance formerly attached to the examination of the urine.
Blood has often been referred to as a fluid tissua That the blood
may readily be compared with other tissues from the standpoint of its
solid content is evident by the fact that in perfect health the total solids
are only slightly less than those of the muscle tissue and even more than
those of some of the glandular tissues of the body. According to recent
observations human blood normally constitutes about 8.5 per cent of the
body weight Blood is the common carrier of nutritive materials to the
various tissues of the body and waste products such as carbon dioxid, urea,
etc., to organs of excretion. From this it is apparent that an inability
to properly metabolize certain food materials or properly excrete certain
waste products should result in changes in the composition of the blood.
Owing to the various factors of safety in the body it would seem unlikely
423
424
VICTOR C. MYERS
COMPOSITION OF HUMAN BLOOD
Constituent or
Determination
Calculated as
Normal
Pathological
Range
Average
Range
Blood Volume \ SfT%' ' V
£ Whole Blood
Total Solids
Per Cent of
Body Weight
Per Cent
i( ((
tl It
if n
it it
Per cu. mm.
« ii a
ti ti it
Per Cent
Mg. to 100 c.c.
it it it it
it it it it
ti ti it it
it it it a
it it it it
n ti ii it
ti ti 11 ft
Per Cent
it n
n it
it ft
« ii
If K
11 ft
If It
11 It
11 ft
It ft
T'l as Acetone
Mg. to 100 c.c.
(( it if n
it ti it ti
Mg. to 100 c.c.
it ti i ti
it it i ii
4.5- 5.7
7.6- 9.1
19 -23
6.7- 8.2
4.8- 6.7
1.4- 2.3
0.3- 0.6
12.5-23.0
4,500 000
5.1
8.5
22
7.5
5.6
1.9
0.5
16
3.8 - 6.2
4.3 - 13.7
10 - 25
4.2 - 9.1
3.7 - 7.0
1.7 - 2.6
0.1 - 0.9
3.5 - 24.0
100,000-
12,000,000
500-600,000
1 - 4
20 -400
5 -350
0.5 - 25
0.5 - 35
2 - 35
4-30
0.05- 1.30
10 - 75
to 6.10
to 8.13
0.16-0.46
0.14-0.50
0.34-0.70
0.06-1.00
0.06-1.20
0.10-0.20
2-350
2- 50
1-300
10- 35
50-400
2- 25
350-700
500-850
1- 40
0.5-16
Total Serum Protein
Serum Albumin
Serum Globulin
Fibrinogen ( plasma )
Hemoglobin ( whole blood ) .
i Erythrocytes
Cells J T
] .Leucocytes
5,500,000
3,000-10,000
200,000 500 000
[Platelets .
3.3
30
15
2.5
1.0
• 5
5
11
0.10
15
0.36
0.39
0.32
0.30
0.21
0.42
0.15
0.16
0.14
2
1
1
300
20
200
10
2.5
50
470
600
3
7.5
53
0.7
Total Nitrogen
Total Non-protein Nitrogen.
Urea Nitrogen
3.0-3.7
25 -35
12 -15
2-3
0.5- 2
3-7
4-8
-0.1
4 -18
0.09- 0.12
14 -18
0.29- 0.42
0.30- 0.47
0.27- 0.45
0.28- 0.33
0.17- 0.26
0.35- 0.48
0.14- 0.17
0.15- 0.18
0.13- 0.17
1.3 - 2.6
0.3 - 2.0
0.5 - 3.0
280-320
16- 22
150-250
9- 11
2- 3
Uric Acid
Creatinin
Creatin
Amino-Acid Nitrogen . . .
Ammonia
Rest Nitrogen
Suo'ar (glucose)
Diastatic Activity
Lipoids
Total Fatty Acids (whole
blood )
Total Fatty Acids
(plasma)
Total Fatty Acids
(corpuscles)
f whole blood . . .
Lecithin { plasma
I corpuscles ....
! whole blood .
plasma
corpuscles . .
Acetone Bodies
Acetone }
g-hydroxybutyric Acid . . .
Mineral Constituents
Sodium (serum) asNa ..
Potassium (serum) as K .
Potassium (whole blood) .
Calcium (serum) as Ca ..
Magnesium ( serum ) as Mg
Iron (whole blood) as Fe .
Chlorids (whole blood) as
NaCl
if a i it
It It 1 It
It It I 11
11 It 11 11
It 11 11 11
11 11 11 11
11 It 11 11
450-500
570-620
1.5- 4.5
5 -12
40 -75
0.5- 1.0
Chlorids (plasma) as NaCl
Phosphates as P
Inorganic (plasma) ....
Lipoid (plasma)
Organic ( corpuscles ) ...
Sulphates (whole blood) ..
BODY TISSUES AND FLUIDS
COMPOSITION OF HUMAN BLOOD (Continued)
425
Constituent or
Determination
Calculated as
Normal
Pathological
Range
Average
Range
Blood Gases
Oxygen
Capacity
Volumes
Per Cent
tt «
ii a
u n
19-23
18-22
13-17
45-55
50-65
55-75
21
20
15
50
58
65
7-33
6-32
3-27
5-90
Arterial Content
Venous Content
Carbondioxid
Arterial Content (whole
blood)
Venous Content ( whole
blood)
Capacity (plasma)
that these changes should Toe very marked except in severe pathological
conditions. With sufficiently delicate methods, however, these slight
changes should be readily detected. The development of simple and very,
delicate colorimetric methods has done much to aid in this type of work.
More and more we have come to consider the various changes which
take place in the tody from a quantitative point of view. The various
blood constituents, and certain blood determinations, with the range of
their normal and pathological variations, are given in the table above.
Blood Volume. — Owing principally to the recent work of Keith, Rown-
tree and Geraghty the subject of blood volume has received considerable at-
tention. These investigators have introduced a new method of determin-
ing blood volume and have obtained somewhat higher figures than those
formerly given for man. The principle underlying their method is the
introduction directly into the circulation of a non-toxic, slowly absorbable
dye (vital red) which remains in the plasma long enough for thorough
mixing, and the determination of its concentration in the plasma colori-
metrically by comparison with a suitable standard mixture of dye and
serum. According to this method the plasma normally constitutes ap-
proximately 5 per cent, or one-twentieth of the body weight. The volume
occupied by the corpuscles was calculated with the aid of the hematocrite
and found to average 43 per cent for the erythrocytes and 57 per cent for
the plasma. On this basis Keith, Rowntree and Geraghty have calculated
that blood normally constitutes 8.8 per cent or 1/11.4 of the body weight.
With this method they were able to demonstrate the amount of decrease in
blood volume as the result of hemorrhage and of the increase following
intravenous infusion of saline.
Significant observations were made in a few pathological conditions.
Both the blood and plasma volume are increased in pregnancy, before,
term, but return to normal within a week or two after delivery. In obesity
the plasma and blood volumes arc relatively small. Many cases of anemia
426
VICTOK C. MYERS
exhibit a relatively high blood volume, while in some cases polycythemia in
the sense of a high blood count may be dependent on a low plasma volume.
In anasarca accompanying myocardial insufficiency the blood volume may
be absolutely increased. In many cases of marked hypertension the
volume is small, indicating that hypertension is not necessarily dependent
upon a large blood volume.
More recently a very elaborate study of the question of blood volume
has been carried out on animals by Whipple and some of his coworkers.
Since "vital red" was not available, their earlier experiments were made
with "brilliant vital red." Later they tried out a very large series of
dyes for use in this connection, and discovered a blue azo dye which ap-
pears to be slightly superior to the vital red group, especially as regards
ease and accuracy of colorimetric readings. In the same series of papers
McQuarrie and Davis have employed a method of determining blood
volume which consists essentially in reading refractometrically the serum
non-protein increase after the intravenous injection of a known amount of
acacia or gelatin solution, or a mixture of the two. The results obtained
were quite comparable to the dye methods and an acacia method described
by Meek and Gasser.
The most recent publication on blood volume is that of Bock who pre-
sents some very interesting data, obtained with the vital red method, on
five normal and twenty pathological cases. The constancy of the plasma
volume under widely varying conditions is pointed to as a striking fact
Although the plasma volume remains practically normal in polycythemia
and anemia, as shown by the table below taken from Bock, the total blood
volume is increased in the former and decreased in the latter owing to varia-
tions in the cell content.
DATA ON BLOOD VOLUME
Condition
Number of
Cases
Total
Plasma
Per Cent of
Body
Weight
Total
Blood
Per Cent of
Body
Weight
Hemoglobin
Calculated
from O2
Capacity
Per Cent
Red Blood
Cells in
Millions
Normal
5
5.1
8.2
119
4.8
Polycythemia
3
5 1
137
163
9.1
Pernicious Anemia . .
Miscellaneous
7
7
4.9
4.9
5.7
7 1
47
79
1.6
3.9
Diabetes
8
4.8
7 3
118
4.6
Blood volume methods have been critically discussed by Lamson and
Nagayama, but the authors concede that the plasma volume method of
Keith, Rowntree and Geraghty is as correct as any and the best method
at our disposal for most purposes.
Total Solids. — Where a careful quantitative examination of the blood
is being carried out, the estimation of the total solids is often of consider-
BODY TISSUES AND FLUIDS 427
able value. In the first place, the solid content of the blood is a very
excellent index of the functional condition of the blood, blood proteins and
blood cells taken together, and furthermore is of value in explaining small
fluctuations in the content of the individual constituents. Normally the
total solids amount to from 19 to 23 per cent, although in primary and sec-
ondary anemia, severe nephritis, etc., the amount may be decreased to
nearly one-half these figures. That the total solids may be increased in
cholera, as a result of the severe diarrhea, was recognized by Carl Schmidt
many years ago. An increase in the blood solids was found by Underbill
to result from poisoning by the lethal war gases.
Specific Gravity. — The specific gravity of human blood in the adult
male varies between 1.041 and 1.067, the average being about 1.055. For
the female the figures are slightly lower. The specific gravity obviously
varies in much the same way as the solids. The determination appears
to be little used at the present time. Gettler and Baker have recently
given some new observations on serum. They found the specific gravity
of the serum of both men and women to range from 1.026 to 1.030, the
majority being between 1.027 and 1.029.
Reaction and Hydrogen Ion Concentration. — Normal human blood as
it exists in the body is faintly alkaline in reaction, i. e., it has a hydrogen
ion concentration only slightly less than pure water, and this degree of
alkalinity tends to be very constantly maintained under a variety of con-
ditions. The blood itself, owing chiefly to the "buffer" action of the car-
bonates of the plasma and phosphates of the corpuscles, can take up con-
siderable amounts of acid or alkali without much change in its reaction.
An appreciable change in its hydrogen ion concentration indicates a failure
of this protective mechanism and the presence of a severe acidosis. From
a practical point of view the CO2 combining power of the blood is much
more useful, since the change occurs much earlier (see below).
As the result of a series of analyses on thirty normal individuals by
the gas chain method, as described by Michaelis, Gettler and Baker found
pH to range from 7.52 to 7.60 at 22°C. Levy, Eowntree and Marriott
have described a very simple indicator method of determining the hydro-
gen ion concentration and serum. With this method oxalated blood from
normal individuals gave a dialysate with a pH varying from 7.4 to 7.6,
while that of the serum ranged from 7.6 to 7.8. In a small series of
clinical acidoses, the serums varied from 7.55 to 7.2 and the oxalated blood
from 7.3 to 7.1.
Blood Proteins. — Considerable experimental evidence has recently been
adduced by Kerr, Hurwitz and Whipple (c) which points to the liver as be-
ing concerned in the maintenance of a normal level of the blood serum
proteins (albumin and globulin). The evidence is not so convincing nor
so striking as that obtained by Whipple for the plasma protein fibrinogen
which has such an intimate relation to liver injury. In the case of the
428
VICTOR C. MYERS
blood serum proteins the stability of the normal level appears to be fairly
well maintained under widely varying1 conditions of health and disease.
Serum Proteins (Albumin and Globulin}. — The subject of the serum
proteins in man has recently been very carefully considered by Rowe (&),
who has employed the microrefractometric method of Robertson for their
study in normal and a number of different pathological conditions. In a
series of twenty-two normal cases the serum albumin was found to vary be-
tween 4.6 and 6.7 per cent, the serum globulin between 1.2 and 2.3 per cent,
the total serum protein between 6.5 and 8.2 per cent and the nonproteins
between 1.1 and 1.3 per cent, while the percentage of globulin in the total
•protein varied from 16 to 32 per cent. Muscular activity, even of the
simplest sort, increases total serum proteins, this increase occurring more
in the albumin than the globulin fraction. In three cases with severe
muscular work Rowe (c) found the total protein increased from 1.1 to 1.9
per cent and the albumin from 0.8 to 1.5 per cent, while in one case with
light exercise the total protein was increased 0.5 per cent and the albumin
0.3 per cent.
The following table compiled from data given by Rowe gives a com-
parative idea of the blood serum proteins in the normal human subject and
in a variety of pathological conditions.
BLOOD SEBUM PROTEINS IN HEALTH AND DISEASE (AVEEAGES)
Condition
Number of
Cases
Albumin
Per Cent
Globulin
Per Cent
Total
Protein
Per Cent
Globulin to
Total
Protein
Per Cent
Normal subjects ....
Syphilis
22
19
5.6
5
1.9
2.5
7.5
7.5
22.5
34
Pneumonia
8
3 7
2.5
6.2
40
Chronic nephritis with
edema
3
2.5
1.7
4.2
40
Chronic nephritis with
uremia
5
4.2
2.3
6.5
35
Chronic nephritis
without uremia or
edema
7
4.5
2.2
6.7
33
Cardiac decompensa-
tion
9
4.7
2.6
7.3
36
Arteriosclerosis
9
4.8
2.3
7.1
32
Diabetes
10
5.5
1.9
7.4
26
Anemia
9
3.9
1.7
5.6
30
From the above it is apparent that in syphilis the globulin is definitely
increased, while the total protein remains about normal. In pneumonia
the globulin is increased more in relation to the total protein than in
syphilis, while the total protein is reduced, due probably in large measure
to a dilution of the blood serum by water retention, which occurs in fever.
The lowest values for total serum proteins are obtained in chronic nephritis
with edema, due probably to chronic intoxication as well as hydremia.
BODY TISSUES AND FLUIDS 429
In chronic nephritis with uremia the total proteins may be nearly normal
but the globulin is usually increased. Except in very severe diabetes the
findings are practically normal. In pernicious anemia the total proteins
are not as low as would be expected from examination of the whole
blood, being higher than in nephritis with edema.
Fibrinogen. — According to Whipple the normal fibrinogen limits for
the human subject may be given as 0.3 to 0.6 per cent with an average of
0.5 per cent per 100 c.c. of plasma. In pneumonia and septicemia fibrino-
gen is much above normal, reaching 0.9 per cent, while in acute liver in-
jury it drops to a very low level or even zero in some fatal cases. In chronic-
liver disease fibrinogen often falls markedly and may cause bleeding
(cirrhosis). In general cachexias, such as sarcomatosis, nephritis and
miliary tuberculosis, the fibrinogen may be quite low, 0.1 per cent.
Hemoglobin. — Hemoglobin is the iron containing and oxygen carry-
ing pigment of the red blood cells. It is a conjugated protein, composed of
the histon, globin, and hemochromogen, the iron containing pigment. In
the presence of oxygen the latter body is rapidly transformed into hematin.
Hemoglobin is crystallizable, and peculiar in its high iron content, which
amounts to 0.34 per cent. Under normal conditions it is quite completely
saturated (95 per cent) with oxygen in arterial blood, although in the
case of venous blood the oxygen is ordinarily reduced to about 75 per cent
of saturation. Owing to this fact the hemoglobin of the blood may be
more correctly referred to as oxyhemoglobin. Oxyhemoglobin has a bright
red color but (reduced) hemoglobin is darker and more violet or purplish,
hence the darker color of venous blood. For further properties of hemo-
globin and its many derivatives reference may be made to Hammarsten.
The estimation of hemoglobin was apparently the first chemical de-
termination in the blood to find extensive clinical application. It seems un-
fortunate that most of the estimations recorded should have been made
employing an empirical scale with 100 as the normal, especially since
the 100 is somewhat of a variable factor with different methods owing
to different standardizations. The hemoglobin content of the blood
varies widely not only in disease, but also in different age periods as re-
cently pointed out by Williamson. For this reason it would appear more
logical to record the hemoglobin, as we do other blood determinations, in
grams per 100 c.c. or per cent.
The table below compiled from observations of Williamson well illus-
trates the changes in the hemoglobin content of the blood over different
age periods. The figures were obtained with the accurate spectrophoto-
metric method, fifteen or more of both males and females being employed
for each age group. From this table it will be noted that during the first
few days of life the hemoglobin content exceeds 20 per cent,, but then
drops rather abruptly the third month to below 14 per cent and does not
pass this figure until the tenth year. During the adult period of life in
430
VICTOR C. 'MYERS
HEMOGLOBIN IN NORMAL MALES AND FEMALES DURING DIFFERENT AGE PERIODS
Hemoglobin
Gm. per 100 c.c. of Blood
Male
Female
Both Sexes
1 day
23.3
22.5
22.1
21.4
18.7
23.2
23.1
22.1
21.3
18.0
23.3
22.8
22.1
21.4
18.4
2 to 3 days
4 to 8 days
9 to 13 days
2 weeks to 2 months
3 to 5 months
13.1
13.2
12.8
12.4
13.2
13.3
13.8
14.6
14.5
14.3
14.2
12.2
12.7
13.1
14.0
13.3
13.7
14.9
13.7
13.7
12.5
12.6
13.2
13.6
13.5
14.2
14.7
6 to 1 1 months
1 year
2 years
3 years
4 years
5 years
6 to 10 vears
1 1 to 15 years
16 to 20 years
16.8
17.2
16.4
16.9
17.0
16.9
17.1
17.0
17.0
16.5
15.6
15.0
15.5
15.4
15.4
15.6
15.5
16.1
15.8
15.7
16.3
16.0
15.9
16.2
16.2
16.2
16.3
16.6
16.4
16.1
21 to 25 years
26 to 30 vears
31 to 35 years
36 to 40 years
41 to 45 vears
46 to 50 years
51 to 55 vears
56 to 60 years
61 to 65 years
66 to 70 vears
16.2
15.2
15.7
15.5
15.5
15.0.
15.8
15.3
15.4
7 1 to 75 years
76 and over .
both sexes (from 16 to 70 years) the hemoglobin maintains a fairly con-
stant level of about 16 per cent. From the third month to the fifteenth
year the values obtained in the female appear to slightly exceed the male,
although from 16 to 60 years the reverse is true, the hemoglobin of the
female averaging close to 15.5 per cent, while in the male it reaches nearly
17 per cent.
A few observations taken from Meyer and Butterfield are given in the
table below. They employed the same method as did Williamson and
HEMOGLOBIN CONTENT OF THE BLOOD OF NORMAL AND PATHOLOGICAL SUBJECTS
Subjects
Specific
Gravity
Erythrocytes,
Million per
cu. mm.
Hemoglobin
Content of
Blood, gm.
per 100 c.c.
Normal men, av. 7 cases
Normal women, av. 6 cases . .
Pernicious anemia, I
• 1.059
1.057
1.040
4.92
4.75
0.74
16.60
15.20
3.47
Pernicious anemia, II
1.035
0.87
3.79
Secondary anemia
2.43
5.59
Polycvthemia
1.075
23.90
Color
Index
1.0
1.0
1.5
1.3
0.7
BODY TISSUES AND FLUIDS 431
their figures for normal adults are in substantial agreement with those re-
corded above. The few pathological data are of interest. In the cases
of pernicious anemia it will be noted that the hemoglobin dropped to the
low figure of about 3.5 per cent, while in the case of polycythemia it reached
23.9 per cent.
Since the serum proteins, albumin and globulin, vary only to a limited
extent, as previously noted, it is apparent that hemoglobin is ordinarily
not only the largest but also the most variable factor in the make-up of
the total solids. For this reason hemoglobin estimations provide a simple
method of securing information regarding the total solid content of the
blood. Underbill used the estimation for this purpose to excellent ad-
vantage in the treatment of poisoning with lethal war gases. It may be
assumed that daily fluctuations in the amount of hemoglobin in the cir-
culating blood are slight and that such fluctuations in the hemoglobin con-
tent are due to changes in blood volume. The frequent estimation of the
hemoglobin content of the blood in short series of experiments therefore
constitutes a simple means of following small changes in blood volume.
There would seem to be no good reason why the clinical estimation of
hemoglobin should not be put on a more exact basis, comparable with many
of our other chemical blood analyses. Palmer (6) has recently described a
very simple and accurate method of estimating hemoglobin as carboxy-
hemoglobin, while Van Slyke's (c) method of determining the oxygen ca-
pacity of the blood is valuable in furnishing an occasional check on the col-
orimetric methods and in the preparation of a blood standard. It should
also be noted that several recent papers have shown that hemoglobin can
be accurately estimated by the acid hematin method of Sahli, provided
certain precautions are followed and a good colorimeter employed.
Blood Cells. — The blood cells (erythrocytes, leucocytes and blood
plates) are of interest in this connection only in so far as variations in
their content affect the chemical composition of the blood as a whole. The
figures which are generally given for the erythrocytes of the adult male
and female are 5 million per cubic millimeter for the former and 4.5 mil-
lion for the latter. \7alues higher than these are not uncommon but the
number rarely exceeds six million in perfectly normal individuals. Since
the red cells are composed of hemoglobin roughly to the extent of 90 per
cent it is apparent that, the hemoglobin content, and the total solid content
as well, stand in fairly close relationship to the number of red cells. In
pernicious anemia the number of cells may be reduced to as small a num-
ber as 0.5 million or even less, while in some cases of secondary anemia
very low figures are found. Meyer and Butterfield have pointed out
that the high color index observed in many cases of pernicious anemia is
due to an increase in the oxyhemoglobin content of the red cells (see table
on p. 430). In the secondary anemias the color index is frequently low-
ered, apparently for the reverse reason. As would seem evident from the
432
VICTOK G. MYERS
hemoglobin table of Williamson above, the red cell count is very high at
birth, reaching 7 million in some instances, but drops to a fairly constant
level after the sixth to the tenth day. Owing to the diminished oxygen
tension at high altitudes the number of red cells is increased to maintain
the oxygen carrying capacity of the blood at a normal level, the number
being raised to 7 to 9 million in extreme instances. A relative increase
in the number of red cells, or relative polycythemia, may occur as result of
sweating, diarrhea, etc., while an absolute polycythemia is occasionally en-
countered, particularly in congenital heart disease and in Osier's disease.
The number of leucocytes normally varies between 3,000 and 10,000 per
cubic millimeter, although figures between 5,000 and 6,000 are the most
often encountered in a fasting condition. The leucocytes are subject, to
greater physiological variation than the red cells, but considering their
much smaller number in comparison with the red cells, these variations
have little influence on the chemical composition of the blood as a whole.
In the leucemias, however, the leucocyte count may rise to 600,000 and
even higher. With such a marked leucocytosis, and consequent leucolysis,
the uric acid content of the blood may be greatly increased. Although the
blood plates are normally regarded as amounting to from 200,000 to 500,-
000 per cubic millimeter, on account of their small size, 3 [i, their variation
is apparently without influence upon the chemical composition of the blood.
Blood Nitrogen
Total Nitrogen. — The total nitrogen content of perfectly normal blood
amounts to somewhat more than 3 per cent. Of this, 99 per cent is de-
rived from the various proteins of the blood, about three-quarters being
from the cellular constituents, chiefly the hemoglobin, and one-quarter from
the plasma proteins, albumin, globulin and fibrinogen. The hemoglobin is
obviously the most important as well as the most variable contributor to
the total nitrogen. In pernicious anemia the total nitrogen may be re-
duced to considerably less than half the normal figure, while in severe
nephritis the nitrogen content is frequently very low.
Non-protein Nitrogen. — Although the non-protein nitrogen normally
constitutes only about one per cent of the total nitrogen of the blood, never-
theless greater interest is attached at the present time to variations in the
bodies which form the non-protein than the protein nitrogen. This is due
largely to the fact that the variations in these non-protein constituents
give us an insight into some of the processes of anabolism and catabolism.
The food nitrogen is carried by the blood to the various tissues and the
waste nitrogen to the kidneys, directly or indirectly by the same medium.
After a meal containing protein there is a temporary elevation in the
non-protein and amino nitrogen of the blood. In diseases of the kidney
BODY TISSUES AND FLUIDS
433
there may be at first only a slight rise in the uric acid or urea, although
in the terminal stages of the disease there is generally a very marked ele-
vation in all the forms of non-protein nitrogen. The normal range of the
various non-protein nitrogenous components is given in the table below.
Data are also included indicating the deviations which may occur in gout
interstitial and parenchymatous nephritis and eclampsia.
As will be noted in the table, the normal range for the non-protein
nitrogen is given as 25-30 mg. per 100 c.c. of blood. In discussing the
question of the normal values for the non-protein nitrogen there are two
very important factors which should always be considered, viz., the protein
precipitant employed and the proximity to the last meal, the results re-
ported with the original method of Folin and Denis (/) are probably a little
too low, owing to the use of methyl alcohol as the protein precipitant.
Folin and Denis originally obtained figures of 22-26 mg., while Tileston
and Comfort found 23-25 mg. with a series of five normal adults in a fast-
ing state, and 26-32 mg. two and a half hours after a heavy protein
meal. More satisfactory results are obtained after the trichloracetic
acid precipitation of Greenwald (d) or use of the tungstic acid reagent re-
cently employed by Folin and Wu. After these methods of precipitation
figures close to 30 mg. are generally obtained on a normal individual in
the fasting state.
NONPROTEIN NITROGENOUS CONSTITUENTS, MG. TO 100 c.c. OF BLOOD
Constituents
Normal
Gout
Early
Interstitial
Nephritis
Terminal
Interstitial
Nephritis
Paren-
chymatous
Nephritis
Eclampsia
Non-protein N.
Urea N
25-30
12-15
30-50
12-30
to 350
300
30-60
35-55
7-16
Uric Acid
2-3
4-10
3-10
25
3-10
Creatinin
Creatin
1-2
3-7
2-4
35
30
1-2.5
Amino Acid N.
Ammonia N. . .
6-8
0.1
30
1
4-8
The figures for the normal creatin are taken from observations of Denis, those
for amino-acid nitrogen from Bock, except in the case of eclampsia, where the observa-
tions of Losee and Van Slyke are recorded; other data in eclampsia are from recent
observations of Killian. With these exceptions the data are from the writer's observa-
tions.
The figures for ammonia are very small, but these figures may be taken as the
maximal rather than the minimum values. The very recent observations of Nash and
Benedict on the ammonia content of the blood (made on dogs and cats) give figures
between 0.03 and 0.2 mg. to 100 c.c.
The origin and role which the various non-protein nitrogenous constit-
uents play in metabolism, as well as the ease of kidney secretion, obviously
greatly influence the content of these substances in the blood, both normally
and pathologically. Folin's classic papers on the composition of urine
(for discussion, see Chapter IV) published in 1005, did much to give
434
VICTOR C. MYERS
us a correct appreciation of the significance of the nitrogenous waste prod-
ucts which find their exit through the kidney. He pointed out that the
urea and creatinin stood in marked contrast to each other, since the former
was largely exogenous in origin, while the latter was almost entirely of
endogenous formation. Uric acid stood in somewhat of an intermediate
position, being about half endogenous and half exogenous under ordinary
conditions of diet.
Satisfactory interpretations of variations in these non-protein nitrog-
enous constituents of the blood can scarcely be made without a knowl-
edge of their origin. The following brief statement may be made regard-
ing the formation of these compounds. Urea is formed largely in the
liver from the ammonia resulting from the deaminization of amino-acids
set free in digestion, but not of immediate use to the animal organism.
Uric acid originates as a result of the enzymatic transformation of the
amino- and oxypurins, in which various glands of the body participate.
Creatinin would appear to be formed in the muscle tissue from creatin.
COMPARATIVE NITROGEN PARTITION OF URINE AND BLOOD IN PER CENT OF TOTAL NON-
PROTEIN NITROGEN
Fluid
Uric Acid
N
Urea
N
Creatinin
N
Ammonia
N
Rest
N
Normal urine
1.5
85
5
4
4.5
Normal blood
2
50
2
0.3
46
Blood in gout and
early nephritis . . .
Blood in parenchyma-
tous nephritis (ne-
phrosis )
6
2
50
55
2
2
0.3
0.3
42
40
Blood in terminal in-
terstitial nephritis .
2 to 3
75
2.5
0.5
20
It is of interest to compare the partition of the non-protein nitrog-
enous constituents in the blood with similar partition in the urine. (See
above.) Upon the ordinary mixed diet their approximate distribution
in the urine is 85 per cent urea N, 1.5 per cent uric acid N, 5 per cent cre-
atinin N, 4 per cent ammonia N and 4.5 per cent undetermined N. It is
quite natural to expect a somewhat similar relationship in the non-pro-
tein nitrogenous constituents of the blood, but the above table discloses
quite a different distribution. It will be noted that even in normal blood
the percentage of uric acid nitrogen is greater, if anything, than in the
urine, while the urea is definitely lower, the contrast with the uric acid in
the case of the creatinin and ammonia being even more marked. As Folin
and Denis have pointed out, the human kidney removes the creatinin
from the blood with remarkable ease and certainty, the completeness of the
creatinin excretion being exceeded only by the still more complete removal
of the ammonium salts. The striking difference between the ability to ex-
crete uric acid on the one hand, and urea and creatinin on the other, is
BODY TISSUES AND FLUIDS 435
brought out from an examination of the normal concentration of the blood
and urine. Judging from their comparative composition, the kidney nor-
mally concentrates the creatinin 100 times, the urea 80 times, but the
uric acid only 20 times. Myers, Fine and Lough have pointed out that as
the permeability of the kidney is lowered in conditions of renal insuffi-
ciency, this becomes evident in the blood, first by a retention of uric acid,
later by that of urea, and lastly by that of creatinin, indicating that
creatinin is the most readily eliminated of these three nitrogenous waste
products, and uric acid the most difficultly eliminated, with urea standing
in an intermediate position.
Urea. — As indicated in the table above on non-protein nitrogenous con-
stituents the blood urea of a strictly normal individual taken in the morn-
ing before breakfast appears to fall within the comparatively narrow
limits of 12-15 mg. urea nitrogen per 100 c.c. of blood. Occasionally fig-
ures outside of the limits may be observed such as 10-18 mg., but figures
above 20 mg. can ordinarily be regarded as pathological. These state-
ments apply only to normal individuals on moderate protein diets where the
blood has been taken in the morning before breakfast. As Tileston and
Comfort, and Addis and Watanabe have shown, high protein diets may
considerably raise these figures, especially in certain individuals, while
Folin, Denis and Seymour have conclusively shown that lowering the
level of protein metabolism serves to reduce the non-protein and urea
nitrogen of the blood in mild cases of chronic interstitial nephritis.
Since urea is the chief component of the non-protein nitrogen, and
since its estimation is considerably simpler than that of the non-protein
nitrogen, attention will be directed especially to the urea. Mosenthal
and Hiller have made a careful study of the relation of the urea to the
non-protein nitrogen in disease. They point out that the selective action
of the kidney maintains the urea nitrogen at a level of 50 per. cent or less
of the total non-protein nitrogen of the blood, but that an impairment of
renal function, even of very slight degree, may result in an increase of
the percentage of urea nitrogen. In advanced cases this may be even
higher than the 75 per cent given in the preceding table.
To give a comparative idea of the values observed for urea nitrogen in
various pathological conditions, illustrative findings are given for a num-
ber of different conditions in the table below taken from a recent paper by
the writer, the data being from actual cases. As will be noted, the
conditions in which nitrogen retention may occur are quite numerous.
Marked urea retention may occur not only in the terminal stages of chronic
interstitial nephritis, but also in such conditions as bichlorid poisoning
and double polycystic kidney, and in some cases of acute nephritis. In
parenchymatous nephritis the findings are comparatively low. Kelatively
high figures are frequently noted in malignancy, pneumonia, intestinal
obstruction, lead poisoning, and sometimes in syphilis and cardiac condi-
436
VICTOR C. MYERS
CONDITIONS WITH SIGNIFICANT UKEA NITROGEN FINDINGS
Case
Mg. to 100 c.c. of Blood
Diagnosis
Uric Acid
Urea N
Creatinin
1
15.0
240
33.3
Bichlorid poisoning
2
4.5
75
8.5
Double polycystic kidney
3
14.3
263
22.2
Terminal chronic interstitial nephri-
tis
4
9.5
25
2.5
Early chronic interstitial nephritis;
died 3 years later
5
8.3
72
3.2
Chronic diffuse nephritis; syphilis
6
2.3
28
1.9
Chronic parenchymatous nephritis
7
11.4
106
6.1
Severe acute nephritis; recovery
8
50
2.5
Mild acute nephritis
9
9J
58
3.4
General carcinomatosis
10
5.5
24
3.1
Carcinoma of larynx
11
9.0
46
3.3
Severe pneumonia ; recovery
12
43
2.9
Syphilis
13
5.5
44
3.3
Intestinal obstruction
14
24
2.5
Gastric ulcer
15
3.'s
20
2.0
Duodenal ulcer
16
7.2
18
2.2
Prostatic obstruction
17
14
2.9
Myocarditis
18
e!6
18
2.2
Diabetes of long standing
19
8.4
12
2.9
Gout
20
6.8
7
2.2
Eclampsia
tions, although in the last mentioned this is probably due to renal com-
plications. In uncomplicated cases of prostatic obstruction the findings
do not appear to much exceed 20 mg. urea nitrogen. A slight retention
is frequently noted in gastric and duodenal ulcer, possibly for the same
reason that retention is found in intestinal obstruction. Advanced cases
of diabetes frequently show definitely high figures, apparently due in some
instances to the high protein diet, in others to a complicating nephritis.
The fact that a normal urea is associated with a high uric acid is of prac-
tical value in cases of gout not complicated by nephritis. In normal preg-
nancy, the findings for urea nitrogen are, strangely enough, subnormal,
figures between 5 and 9 having been observed. In eclampsia the urea is
generally subnormal, but the non-protein nitrogen is increased and the uric
acid is generally quite high.
Since urea is largely of exogenous origin, while creatinin is endogenous,
it is subject to much greater variation, especially under dietary influences.
It is of less prognostic value than the creatinin in advanced cases of neph-
ritis, but a much better guide as to the value of the treatment. In cases
of prostatic obstruction the urea is an excellent preoperative prog-
nostic test, much better than the creatinin, for the reason that cases show-
ing creatinin retention already show sufficient urea retention to makt
them very poor risks. The renal factor can be disregarded when the
urea nitrogen is 20 mg. or under, the patient operated on with cau-
tion between 20 and 30, while with figures over 30 the outlook is un-
BODY TISSUES AND FLUIDS 437
favorable. Nephritis in children does not so quickly result in urea
retention as in the adult. On this account it is an especially helpful
prognostic test in the nephritis occurring in early life.
Uric Acid. — No accurate figures on the uric acid content of normal
human blood were available until the introduction of the colorimetric
method of Folin and Denis (e) in 1913. In a series of unselected cases Fo-
lin and Denis (&) found between 1 and 3 mg. to 100 c.c. of blood, the aver-
age being close to 2 mg. Although the accuracy of the method of estimating
uric acid has been considerably improved, still the figures which are now
regarded as normal for the blood uric acid differ very little from those
originally reported by Folin and Denis. Healthy adults most often yield
values between 2 and 3 mg. per 100 c.c. of blood, but figures as low as
1 mg. and as high as 3.5 mg. may be encountered in strictly normal indi-
viduals, the difference probably depending in part upon dietary factors.
High blood uric acids must obviously depend upon either an increased for-
mation or a decreased elimination.
In leucemia the first factor accounts for the increase, but high uric
acids in most other conditions find a probable explanation on the latter
basis. Among these may be mentioned nephritis, acute and chronic (but
not parenchymatous), arterial hypertension, lead poisoning, bichlorid
poisoning, malignancy, acute infections, especially pneumonia, gout and
apparently some cases of non-gouty arthritis. Miscellaneous cases illus-
trating the uric acid findings in many of these conditions are given in the
urea table above. Sedgwick and Kingsbury have made the interesting ob-
servation that the blood uric acid is high during the first three or four days
of life, in harmony with the high uric acid excretion during that period.
That the uric acid content of the blood was increased in gout was
recognized more than seventy years ago by Sir A. B. Garrod. He put
the subject of the uric acid content of the blood on a definite' basis when
he identified this substance in the blood of patients suffering from gout,
and showed that whereas uric acid was normally present in blood only in
traces, it was definitely increased not only in gout, but also in certain
cases of nephritis. He further showed that there is no increase in the
blood uric acid in rheumatism, such as is found in gout, and used this as
a point of differential diagnosis. No noteworthy advance in this subject
was made until the advent of the colorimetric method of Folin and Denis
previously referred to.
In their original paper Folin and Denis (6) found practically no eleva-
tion of the uric acid in a series of eleven nephritic bloods with only mod-
erate nitrogen retention, but later they reported data on cases of advanced
nephritis in some of which very high values were obtained, up to 10
mg. These latter observations were confirmed by Myers and Fine (#), who
noted very high figures for uric acid in several cases of terminal interstitial
nephritis. In one case the uric acid reached the enormous figure of 27 mg.
438 VICTOR C. MYEES
shortly before death, while in several cases figures as high as 15 mg. were
observed, values much higher than any noted in gout. It is perfectly
logical to expect that high figures would be found in the last stages of
chronic interstitial nephritis, with the consequent accumulation of all the
waste products of nitrogenous metabolism. Tnat the retention of uric
acid in nephritis results in a fairly even distribution of this substance
in the various body tissues has been shown by Fine (a) in tissues obtained
at autopsy. The distribution, however, is not quite as uniform as in the
case of the urea or even the creatinin, a fact which might be expected from
their physical properties.
In 1916 Myers, Fine and Lough called attention to the fact that very
high figures for uric acid may be noted, not only in cases of advanced
interstitial nephritis, but also in the very early stages of the disease, be-
fore a retention of either the urea or creatinin had taken place. It was
suggested that, when symptoms of gout were absent, a high blood uric
acid might -be a valuable early diagnostic sign of nephritis, possibly earlier
evidence of renal impairment of an interstitial type than the classic tests
of proteinuria and cylinduria. This point is well illustrated by the stair-
case table on page 439, taken from Chace and Myers. As a result of a
recent study of this question Baumann, Hansmann, Davis and Stevens
conclude that the uric acid concentration of the blood is a delicate, if not
the most delicate, index of renal function at our disposal.
Owing to the fact that the tophi found in gout have long been recog-
nized to contain deposits of sodium urate, it is quite natural that the
uric acid content of the blood in this condition should possess a special in-
terest. Following the investigations of Folin and Denis a number of
different workers took up a study of this question. Among these in par-
ticular should be mentioned Pratt, Fine and their coworkers. From the
normal variations of from 2 to 3 mg. to 100 c.c. of blood, the uric acid may
be increased to as much as from 4 to 9 mg. in gout, but it does not follow
that these uric acid accumulations are infallible signs of gout, since, as
noted above, similar uric acid figures may be found in nephritis. We may
conclude, however, that gout is almost invariably associated with an in-
creased uric acid content of the blood and therefore a high uric acid blood
may be of considerable diagnostic value in cases of gouty arthritis, in which
tophi containing sodium urate are not already present.
High figures for the blood uric acid may be considerably reduced in
many cases, where appreciable urea retention does not exist, by the use
of purin free diets. Such diets will not, as a rule, equally influence the
blood uric acid in gout, although appreciably lowering the initial figures.
It is of considerable interest in this connection that salicylic acid,
phenylcinchoninic acid (cinchophen) and certain of their derivatives have
recently been shown to have a marked influence upon the elimination of
uric acid and upon the uric acid content of the blood. In many cases mod-
BODY TISSUES AND FLUIDS
439
GO
CO
+ I++ +++I
+ + +
+ + +
1 + + +
+ l+ +1+1
+ ± +
+ + + +
o
"3 2 S £
"£ -0- *" s
o o in m m in o o
oo 'n co r— oo oo o in
o o oo in o o
o m o m
•— ' CM (M (M
02
l.s|ss|
PLj fM
SSBS 2SSS
o o in co co N
<D
0 co o ci
^ H
-M -
i^ r-n in Tt< in co <o o
co os (M o m os
i^ in (M
O O> r!
o 5-
<N<N<N<N (MCOCOOJ
<* (N COr-^ CO r-l
03 O <N r-!
r-( (M (N i-l
O ^ OS
00 0
1— 1 ^O JJH ^
i— i i— i r-H XH <N <N 31 CO
%Z^2
CO O CO Tf
(M (N (M I-H
" O TD
in :o m o in co i- co
o os co co m m
•^ O eo i>.
SJD Si 0
o o m o 05 ?o co to
GO^oomotM
C1-! in ^ GO
S
o
0
0
oi» SD ac w> so §) Sj So
Cj-CS CfiCfi
WWW
> > >
o o o
M In (H
PL, O< &
a a a
M M M
5 5 3 5
§!§:!§ -J
as oS oS
•43 C c |
1* fe (H
CO GO CO f3
S S C
^ to to
Diagnosis
Pulmonary tuberculosis . . .
Pericarditis
Interstitial nephritis
Diffuse nephritis
Early interstitial nephritis .
Early interstitial nephritis .
Early interstitial nephritis .
Early interstitial nephritis .
Moderately severe chronic in
phritis
Moderately severe chronic di
tis
Moderately severe chronic di
tis
Tvpical fatal case of chroni
CCS
o o o
«H |4 ««
O Cl «
"0*0*0
W W 4)
CO CC GO
OS OS o!
000
as ?S 03
cc ~tj ^ "eg ^ "cd 2-
"C ^H *s •— i ~c »-< *n
S
XXX* XXXX
a a a" *
a a s
1
zms ssss
t~ •* O5 O
m to ^ m
CO CO CO
09
i-4 M Q Q ^ 05 Q §
0 W B:
M W ^ M 1-5 Q Q O
(4^0* w
H 02 "-5
os m
og
O50OOCO OOt-O50O
i— i
co in m
(M (M IH
CO *~< ^
440 VICTOR C. MYERS
erate doses of cinchophen will reduce a uric acid content of 5 or 6 mg.
to a mere trace in a comparatively few hours. If long continued, how-
ever, the drug loses this influence. This uric acid eliminating effect aj
pears to be quite independent of the marked analgesic effect of these drugs.
Creatinin. — Until the advent of Folin's colorimetric method for the
estimation of creatinin in urine in 1904, we possessed no reliable informa-
tion regarding this interesting nitrogenous waste product. Folin was the
first to show that the amount of creatinin excreted in the urine by a nor
naal individual on a meat free diet is quite independent of either the amount
of protein in the food or of the total nitrogen in the urine, the amount
excreted from day to day being practically constant for each individual,
thus pointing conclusively to its endogenous origin. In 1914 Folin (/) ap-
plied his colorimetric method, slightly modified, to the estimation of
creatinin in blood, and Folin and Denis (g) presented some quite extensive
data on the subject. Almost simultaneously Neubauer reported an ob-
servation on a case of "uremia," while Myers and Fine (g) presented sev-
eral analyses on two cases of nephritis showing marked retention of cre-
atinin.
For perfectly normal individuals the creatinin of the blood amounts to
1 to 2 mg. per 100 c.c., the findings for the strictly normal being nearer
1 than 2 mg. This statement should probably be made with some reserva-
tion as the method does not appear to be entirely adequate for the de-
termination. It is quite possible that the actual content of creatinin may
not be much more than 0.5 mg., the remainder being due to the inter-
ference of other substances in the color reaction. The figures obtainable
with present methods are comparable, however, and serve as a satisfactory
base line. The importance of this source of error would appear to de-
crease proportionately with a rise in the creatinin content of the blood,
so that the absolute accuracy of the estimation is much greater with patho-
logic than normal values.
As soon as one passes to hospital patients values higher than 1 to
2 mg. are found. Although the great majority of cases without renal
involvement show creatinin figures on the whole blood below 2.5 mg. per
100 c.c., occasionally figures as high as 3.5 mg. are encountered that are
not readily explained. It may be noted, however, that a slight retention
of creatinin (figures between 3 and 4 mg.) occurs in syphilis, certain heart
conditions, sometimes in fevers, and in some cases of advanced diabetes.
Creatinin figures above 3.5 mg. are almost invariably accompanied by an
appreciable urea retention and this is generally true of those above 3 mg.
Many of the cases below 4 mg. show improvement, but with over 4 mg. the
reverse is the case. It would appear from this that an appreciable re-
tention of creatinin, i. e., over 4 mg., does not occur until the activity of
the kidney is greatly impaired. That such should be the case is quite
natural to expect, since creatinin is normally the most readily eliminated
BODY TISSUES AND FLUIDS 441
of the three nitrogenous waste products, uric acid, urea, and creatinin
(see staircase table on page 439).
In various studies on nitrogen retention by Myers and associates it
was soon noted that the creatinin of the blood was appreciably increased
only after considerable retention of urea had already taken place and the
nephritis was rather far advanced. It was further observed that those
cases in which the creatinin had risen above 5 mg. per 100 c.c. of blood
rarely showed any marked improvement, and almost invariably died within
a comparatively limited time. The only exceptions were cases where the
retention was due to some acute renal condition. In a recent paper Myers
and Killian (6) have discussed in detail the observations on a series of 100
nephritics with high creatinin findings, while more recently Myers has
again reviewed the general subject. It may be stated that, of 85 cases
having over 5 mg. of creatinin, all the cases, with three exceptions, are
known to be dead. Most of these cases lived from 1 week to 3 months al-
though there were three cases that lived 1, 2 and 3 years respectively.
Of the three exceptions two were acute cases that recovered, while one
was followed for only a short period. Among the cases having very high
blood creatinins there were many who were able to be up and about and
some who showed considerable clinical improvement. In these cases the
blood creatinin gave a particularly good insight into the true nature of the
condition.
• The amount of the increase of the creatinin of the blood should
be a safer index of the decrease in the permeability of the kid-
ney than the urea, for the reason that creatinin on a meat free diet
is entirely endogenous in origin and its formation (and elimina-
tion normally) very constant. Urea, on the other hand, is largely
exogenous under normal conditions and its formation consequently
subject to greater fluctuation. For this reason it must be evident that
a lowered nitrogen intake may reduce the work of the kidney in eliminat-
ing urea, but cannot affect the creatinin to any extent. Apparently the
kidney is never able to overcome the handicap of a high creatinin accumu-
lation. It would seem that creatinin, being almost exclusively of endog-
enous origin, furnishes a most satisfactory criterion as to the deficiency
in the excretory power of the kidneys and a most reliable means of follow-
ing the terminal course of the disease, though it should be noted that
urea, being largely of exogenous origin, is more readily influenced by
dietary changes, and therefore constitutes a more sensitive index of the
response to treatment.
Creatin.— The methods of estimating the blood creatin are considerably
less satisfactory than those for creatinin. Figures obtained with the
original Folin method were apparently too high. Kecent methods and
observations of Denis (6) and Folin and Wu give the normal creatin con-
tent of blood as from 3 to 7 mg., with an average of about 5 mg. The
442 VICTOR C. MYERS
amount does not appear to be increased except in terminal nephritis with
marked nitrogen retention, when values as high as 30 mg. may be attained.
According to Hunter and Campbell (&) the average creatin content of the;
corpuscles lies roughly between 6 and 9 mg. per 100 c.c., while that of the
plasma is not more than 0.4 to 0.6, the blood as a whole containing about 3
mg., and slightly higher figures being found in females than males. Accord-
ing to these investigators there is a distinct correspondence between increase
of plasma creatin and the appearance of creatin in the urine ; but whether
the plasma, in the absence of creatinuria, is creatin-free or whether there
exists a threshold for creatin excretion, has not been positively determined.
Amino-Acids. — That the amino-acids formed in proteolytic digestion
are taken up directly by the blood was first clearly shown by Van Slyke
and Meyer (a), employing Van Slyke's method for«the determination. This
had been made probable from results obtained for the non-protein nitrogen
of the blood by Folin and Denis shortly before, but the work of Van Slyke
and Meyer conclusively proved this point, thus definitely settling one of
the long disputed questions of protein absorption. They found, for ex-
ample, that whereas the amino-acid nitrogen of a normal fasting dog
amounted to 4 to 5 mg. per 100 c.c. of blood, it was increased to 9 to 10
mg. after a heavy protein, meal.
Comparatively few data are available for the amino-acid nitrogen con-
tent of human blood. The normal content of amino nitrogen may be given
a& 4 to 8 mg., with an average close to 5 mg., per 100 c.c. of blood.
In a series of sixty practically normal subjects Hammett (c) found
the amino nitrogen to be relatively constant with an average of 4.9 and
variations of 3.1 to 7.2 mg. per 100 c.c. of blood. Bock has reported anal-
yses on a series of miscellaneous pathological cases. He failed to find
any noteworthy deviations from the normal except in severe nephritis,
where in several cases figures exceeding 10 mg. and in one instance 30
mg. was reached. In' general the findings of Hammett and Bock harmon-
ize very well, though the figures of Hammett average slightly lower, pos-
sibly due to the fact that he used tungstic acid as the protein precipitant,
while Bock employed trichloracetic acid.
Ammonia. — According to the recent observations of Nash and Bene-
dict, the ammonia nitrogen content of the blood (of dogs and cats) under
normal and various experimental conditions is close to 0.1 mg. per 100 c.c.
They express the view that the urea of the blood is the probable precursor
of the urinary ammonia, and that the kidney is the seat of this trans-
formation.
Rest Nitrogen. — The amount of undetermined nitrogen present in
protein-free blood filtrates appears always to be very large. In the table on
page 434 the normal rest nitrogen was given as 45 per cent of the total
non-protein nitrogen. Here the creatin and amino-acid nitrogen were in-
cluded. If deductions of 4 per cent are made for the creatin nitrogen
BODY TISSUES AND FLUIDS 443
and 14 per cent for the amino-acid nitrogen, 28 per cent of the total non-
protein nitrogen still remains unaccounted for. With the rise in the urea
nitrogen that occurs in many cases of nephritis with marked nitrogen
retention there is a corresponding decline in the percentage of the rest
nitrogen, indicating that the actual amount of the rest nitrogen remains
fairly constant under abnormal conditions. As pointed out by Ham-
mett, there is, however, considerable variation in the amount of the rest
nitrogen of practically normal individuals. He found variations of 4
to 18 mg. with an average of 11 mg. to 100 c.c. in sixty cases. These
figures represent the difference between the non-protein nitrogen and the
sum total of the urea, uric acid, creatinin, creatin and amino-acid nitrogen.
While our methods are not sufficiently accurate to make the findings for
the rest nitrogen reliable, still they do indicate that this fraction is quite
large. At the present time we possess no very good information as to the
nature of this material in human blood, although it would seem possible
from the experimental work of Whipple and Van Slyke on proteose intoxi-
cation that a large part of this nitrogen was derived from peptids. From
the work of Abel we also have reason to believe that traces of proteoses are
present.
Blood Sugar. — A sugarlike substance was first recognized in the blood
in a case of diabetes by Dobson in 1775, but it was not until seventy years
later that its presence in normal blood was discovered by the noted French
physiologist, Claude Bernard. By means of his sugar piqure Bernard
first noted the connection between hyperglycemia and glycosuria (gly-
curesis). It remained for Lewis and Benedict in 1913 to introduce a
colorimetrie method for blood sugar estimation so simple that it could be
readily employed for clinical as well as scientific purposes. Earlier in the
same year Bang had described a very ingenious method requiring only
two to three drops of blood, but the fact that it was a gravimetric-volu-
metric procedure precluded any very extensive clinical application. Stimu-
lated by these methods, and several others since devised, many studies
dealing with the sugar of the blood have recently appeared. Previous to
the introduction of these simple methods, however, Bang (d) had written
a very interesting monograph under the title "Der Blutzucker," while
Macleod(&) had discussed the subject of diabetes almost entirely upon the
basis of experimental observations on the blood sugar.
If we may rely upon the findings with the Benedict method, the blood
sugar of the normal human subject falls somewhere between 0.09 and
0.12 per cent, on the average being about 0.10 per cent. Depending upon
the method which is employed for the estimation, one may obtain figures
differing as much as 0.02 per cent in the normal bood, while with patho-
logical bloods the differences, as shown by Host and Hatlehol, may be
somewhat greater. Slightly higher figures appear to be obtained by the
picric acid method of Benedict in its various modifications than by most
444 VICTOE C. MYEKS
of the other methods. That the reducing power of the blood is due in
large part to glucose seems certain, although the various methods appear
to be influenced by other reducing substances. Of the known interfering
substances creatinin is the most often mentioned. In normal blood, how-
ever, it probably does not introduce an error of more than 2 or 3 per cent.
Although the question of the actual content of glucose in normal blood is
one of great theoretical interest and importance, the figures obtained by
the various methods differ so little relative to the variations which occur in
disease that the question of the method scarcely enters into a discussion of
blood sugar findings in disease.
The figure of 0.10 per cent for normal individuals given above applies
to observations made in«.the morning previous to the intake of any carbo-
hydrate. After a meal rich in carbohydrate there may be an appreciable
rise in the sugar content of the blood, 0.12 to 0.14 per cent, while after
the intake of even moderately "large amounts of glucose, the hyperglycemia,
0.15 to 0.16 per cent, may be sufficient to induce a slight temporary (gly-
cosuria) glycuresis. The great majority of hospital cases show practically
normal figures for blood sugar, although occasionally figures of 0.12 to 0.15
per cent are encountered that are not readily explained.
Conditions of hyperglycemia are much more common and of greater
clinical interest than those of hypoglycemia, owing primarily to the fact
that diabetes belongs to the former group. Among other conditions which
frequently show moderate hyperglycemia are pancreatic disease, nephritis
and hyperthyroidism. Hypoeiidocrin function would appear to result in
hypoglycemia, and comparatively low blood sugars have been observed in
myxedema, cretinism, Addison's disease, pituitary disease and other less
clearly defined endocrin conditions such as muscular dystrophy.
All forms of glycosuria are accompanied by hyperglycemia, if we
except the glycosuria produced by such substances as phlorhizin and urani-
um, and the analogous condition, "renal diabetes." In mild cases of dia-
betes the hyperglycemia is not excessive, generally 0.2 to 0.3 per cent, al-
though in severe cases figures up to and even above 1.0 per cent have been
obtained. The normal threshold of sugar excretion (i. e.; the point of
glycuresis) is about 0.16 to 0.18 per cent. With blood sugar concentrations
of 0.15 to 0.20 per cent the appearance of sugar in the urine is apparently
dependent on whether or not diuresis exists, glycosuria appearing especial-
ly in the latter case. When the threshold point has been passed, however,
the overflow of sugar into the urine may continue until the concentration
in the blood has fallen nearly to normal. Mild cases of diabetes usually
have a normal threshold, although some severe cases apparently have a
lowered threshold, increasing the severity of the condition. Ordinarily
in the early stages of the disease there is a fairly direct relationship be-
tween the hyperglycemia and glycosuria. In the later stages of the disease,
however, cases are frequently encountered with marked hyperglycemia and
BODY TISSUES AND FLUIDS 445
only slight glycosuria, showing that the threshold point has been raised,
apparently due in many instances to an accompanying nephritis. The
cause of glycosuria in "renal diabetes" is obviously due to the reverse condi-
tion, viz., a threshold point below the level of the normal blood sugar.
A simple method of estimating the diastatic activity of the blood has
been described by Myers and Killian (a) who have called attention to the
fact that conditions of hyperglycemia are associated with an increased dias-
tatic activity and have suggested that this might be the important factor in
the production of the hyperglycemia in both diabetes and nephritis. The
increase in the diastase of the blood in nephritis finds probable explanation
in the decreased excretion of diastase in the urine, now well known in this
condition, although a satisfactory explanation of the increased activity in
diabetes is not so readily given. So-called alimentary glycosuria is ap-
parently due to an increased activity on the part of this diastatio ferment,
thus impairing the body's power to store glycogen. Hyperfunction on the
part of the ductless glands, hyperthyroidism for example, appears to
result in an increase in the blood diastase, while hypofunction seems to
have the reverse effect,
Blood Lipoids
Material contributions to our knowledge of the blood lipoids and fat
metabolism have been made during the past ten years. The blood lipoids
comprise (1) the true fats — glycerids of the fatty acids; (2) the phos-
phatids — lecithin, cephalin, etc., ordinarily called lecithin, and (3) choles-
terol with its fatty acid esters. Although these substances were originally
grouped together on account of similar solvent properties, it would now
appear that they are closely connected in metabolism.
Bloor (d) has carried out experiments which support the older concep-
tion of fat digestion, i. e., the food fat is saponified in the intestine, ab-
sorbed in water soluble form as soaps and glycerol, resynthesized by the in-
testinal cells, and passed into the chyle and thence to the blood as neutral fat
suspended in the plasma in a very fine condition. About 60 per cent of the
food fat has actually been accounted for in the chyle in this way and this
figure is probably low. The remaining smaller quantity is generally as-
sumed to be absorbed directly into the blood stream by way of the in-
testinal capillaries.
In a study of the blood lipoids during fat assimilation, Bloor (e) has ob-
served that (1) the total fatty acids increase in both plasma and corpuscles
but the increase is generally more marked in the corpuscles; (2) lecithin
increases greatly in the corpuscles, but only slightly in the plasma ; (3) no
definite change takes place in the quantity of cholesterol and (4) a fairly
constant relationship exists between the total fatty acids and lecithin of
446 VICTOR C. MYERS
the whole blood and corpuscles. From this Bloor suggests: (a) that the
blood corpuscles take up the fat from the plasma and transform it into
lecithin ; (b) that most, if not all, of the absorbed fat is so transformed ;
and therefore (c) that lecithin is an intermediate step in the metabolism
of the fats.
Since the question of the blood lipoids has been very carefully con-
sidered by Bloor in a series of papers, an abbreviated table showing his
average normal findings and three illustrative pathological (extremely
severe) cases is given below. It will be noted in the data on the normals
that the lecithin content of the corpuscles is approximately double that
of the plasma, while the cholesterol and total fatty acid values are almost
always lower in the corpuscles than in the plasma. The value for lecithin
in the corpuscles is generally about twice that of the cholesterol, while in
the plasma their values are nearly equal. According to Bloor the ratio
between these constituents is quite constant in normal blood (especially
plasma) and- remains so in most of the pathological samples, suggesting
a definite relationship between these constituents, and making it prob-
able that cholesterol (as its esters ?) has a part in fat metabolism.
The most characteristic feature of pathological conditions is the in-
crease of total fatty acids and fat both in plasma and corpuscles, and the
decrease of lecithin in the plasma. Since the fat is probably to be regarded
as the inactive form of the body lipoids, the form in which they are stored
and the lecithin as the first step in the utilization, an undue accumulation
of fat or a notably decreased value for lecithin, probably indicates a di-
minished activity of the fat metabolism.
In severe diabetes the blood lipoids are all greatly increased but the
ratios between those constituents are practically normal. The fact that
the cholesterol increases parallel with the fat in diabetic blood, even in
severe lipemia, supports the view that probably cholesterol plays an im-
portant part in fat metabolism. Since cholesterol may be rather simply
estimated it affords a practical method of gauging the severity of diabetic
lipemia. In mild diabetes the blood lipoids may be practically normal.
While there is no certain evidence that the abnormalities in the blood
lipoids are responsible for anemia, the low values for cholesterol, which
is an antihemolytic substance, and the high fat fraction, which may indi-
cate the presence of abnormal amounts of hemolytic lipoids in the blood,
are possible causative factors.
According to Bloor (/) the changes in the blood lipoids in severe neph-
ritis are a high fat in the plasma and corpuscles and high lecithin in the
corpuscles. These abnormalities are the same as are found in alimentary
lipemia and may be regarded as the result of a retarded assimilation of fat
in blood, due possibly to a metabolic disturbance brought about by a lowered
alkali reserve of the blood and tissues.
BODY TISSUES AND FLUIDS
447
*3
Is
co O
*~- Cl O 1— 1C
CO CD <M "2 OO
I|XI|-2
H
c3 Pn
o' o I-H o o
1— 1
> ^^. * 3 "%
•8
if
&,
1^ O CO CO
00 l-H i-H
o' o o o'
^1^1^
cS
a
CO
rt< CO t— r-H (M
i— 1 i— 1 i-H (M ••*
.S-g^ * s
a o oS-s
t-t 00 S-* .5 CO ft
S
o o oo" o' o'
"*"" -*-• W p|—l
OQ
si
ess i— i >n co uj
rH (M Od rH (M
r PH "^
O 1=1
ft
00000
I^J^g|
o
CO
03
a
02
<M T)< lr^ CO 00
<M CM CO I-H r-(
1^1|1|
02
g
'o
S
o" o i-i o' o
"Q ri o ^ co
O
M
PQ
O
-Q °
i-^ CO CO CO O5
2s ^^1-
te
2
0 0 1-1 O O
"*" co'S^ ^ a -g
p
W
CO
s|
&
O •* O TH O
TtJ ^ •* CO !>;
"S .S*-g >, « «*H "g
M
O
O
1-3
d
03
Cd Si O •* 00
<N I-H 10 i— I i— I
O O ® "*^
o
W
g
o
2
83
S
0 0 O O 0
Js"gfj§Jjf
S
o
1 §
O CS CO CO "O
CO (M ••* 1-1 (M
O "^ CJ ' O
a; .S g cu ^ 2 3
•5 8 n ^ ft^
R
00000
co ^ q .rt ,J3 >~*
NOBMAL
00
•3
• I— 1
u
•cf1
00
IO Oi !>• CO
CO <M_ W «0
o' o o' o
i^ififi
H
cS
a
CO
OO O CO t~- CO
CO Ti* ,— i CO CO
j|ol1|?
H
S
o o co o' o
^-l.l.c3!
fc
O
0
i
cS
O
H
H
CD CO O t— CO
CO CO i— 1 CO CO
o o' co o" o'
lll^{
3
i!
ft
CO 00 OS O CO
T* CO <N 1-1 i-l
f|§||!|
^li^gi^
Condition
Average, 20 normal men . . .
Average, 16 normal women.
Diabetic lipemia, extreme..
Pernicious anemia
Uremia, death
•^ .2 « cy <« °
>• p -M to Jo -0
•3 "« ° -2 a '3
r.s! 8Ǥ"o
448
VICTOR C. MYERS
For the different lipoid constituents the following statements may
be made :
Total Fat (Plasma Lipoids). — Normally the "total fat" content of the
blood plasma amounts to 0.6 to 0.7 per cent, but in severe diabetes figures
as high as 26 per cent have been observed. In diabetic cases of ordinary
severity, however, the figures amount to about 1.5 per cent. Nephritics
frequently show a moderately increased fat although the figures rarely
reach 1 per cent.
Lecithin. — The normal figures for lecithin may be given in round num-
bers as 0.2 per cent for the plasma, 0.3 per cent for whole blood and 0.4
per cent for the corpuscles. In diabetes there is an increase in the lecithin
of both the corpuscles and the plasma, although in severe lipemia it is
more noticeable in the latter. In anemia the lecithin of the plasma in
particular is lowered, while in nephritis there is a noteworthy increase in
the corpuscles.
Cholesterol. — With the method of Bloor comparatively high figures for
cholesterol are obtained, normals of 0.20 to 0.24 per cent on whole blood,
with slightly higher figures for the plasma. Figures for whole blood ob-
tained with most of the other methods described in the literature are 0.14
to 0.17 per cent for normal individuals. Figures obtained with Bloor's
most recent method are probably too high. The distribution of cholesterol
in blood is well illustrated in the following table taken from Grigaut,
who was the first to suggest and use a colorimetric method for the estima-
tion of cholesterol.
Condition
Cholesterol in Per Cent
Plasma
Whole Blood
Corpuscles
1 Normal man
0.168
0.170
0.170
0.175
0.068
0.098
0.228
0.246
0.270
0.450
0.514
0.840
0.159
. 0.150
0.168
0.165
0.105
0.110
0.198
0.201
0.225
0.285
0.264
0.540
0.141
0.130
0.171
0.140
0.110
0.150
0.170
0.137
0.180
0.150
0.135
0.195
2. Normal man
3 Normal woman . .
4 Normal woman
5. Carcinoma of the pancreas with
jaundice
6. Pneumonia
7. Carcinoma of the liver with jaundice
8. Diabetes
9 Cholelithiasis
10. Nephritis
11. Nephritis
12. Carcinoma of the pancreas with
jaundice
In. general it may be stated that hypercholesterolemia is found in
arteriosclerosis, nephritis, diabetes (especially with acidosis), obstructive
jaundice, in many cases of cholelithiasis, in certain skin diseases, in the
early stages of malignant tumors, and in pregnancy. The chief condi-
tion in which low values are found is anemia.
BODY TISSUES AND FLUIDS 449
As pointed out above cholesterol constitutes an excellent index of the
degree of lipemia in diabetes. The decrease in this antihemolytic sub-
stance in the plasma in anemia would appear to be of considerable sig-
nificance.
That cholesterol is partly present in the blood as an ester (fat) has
long been recognized. Bloor and Knudson have found that in whole blood
the average percentage of cholesterol in combination as esters is about
33.5 per cent, and in the plasma 58 per cent of the total cholesterol.
Acetone Bodies
Owing to the importance which the acetone bodies hold in the acidosis,
or more specifically the ketosis, occurring particularly in diabetes the
quantities of these substances — acetone, aceto-acetic acid and fi-hydroxybu-
tyric acid — present in normal and pathological human blood is of consid-
erable interest. Quite recently methods have been described by Marriott,
(a) and by Van Slyke and Fitz for their estimation in blood. Since acetone
is very diffusible it is natural to expect that it should be fairly evenly dis-
tributed in the various body fluids, such as the blood and spinal fluid. The
concentration in the urine, .however, is considerably greater than that in
the blood. The amount of the (3-hydroxybutyric acid present in both blood
and urine is ordinarily in excess of the combined acetone-aceto-acetic acid
fraction, often exceeding the latter by two or three times.
According to Van Slyke and Fitz the total acetone bodies of the blood
normally amount to 1.3 to 2.6 mg. to 100 c.c. calculated as acetone, while
in diabetes as much as 350 mg. have been observed, although patients
under ordinarily good control show 10 to 40 mg. Allen, Stillman and
Fitz state that there appears to be 110 constant relation between the plas-
ma alkali and the plasma acetone in diabetes. The acetone bodies may
rise greatly even after the carbon dioxid combining power of the blood
has been considerably raised by the administration of alkali, and death
ensue. The acetone bodies in the blood of children have been studied by
Moore. He found in a fairly large series of normal children, that the
acetone plus aceto-acetic acid calculated as acetone averages 2.4 mg. to
100 c.c., while the |3-hydroxybutyric acid as acetone amounted to 3.9 mg.,
a total of 6.3 mg. In one case of ileocolitis with acetonuria the total
acetone bodies rose to 183 mg. per 100 c.c. shortly before death. Moore
states that in a few cases showing acidosis clinically, the acetone of the
blood has been found sufficient to account for the acidosis. From a study
of the acetone bodies of the blood following ether anesthesia Short con-
cludes that the acetone bodies are not formed promptly enough to account
for the decreased plasma bicarbonate.
450
VICTOK C. MYEES
Mineral Constituents
Sodium. — Comparatively few figures are available for the sodium con-
tent of blood. Macallum gives the normal range of figures for normal
human plasma as 220 to 316 mg. per 100 c.c., while more recently Kramer
has found in adults and children 280 to 310 m^f. per 100 c.c. of serum.
Greenwald has obtained quite similar figures for dog serum. It has
long been recognized that sodium was found chiefly in the body fluids,
while potassium was a constituent principally of the cellular tissue. As
might be expected, therefore, sodium is found chiefly in the blood plasma,
and potassium in the corpuscles. Nothing of special importance is known
regarding pathological variations in the sodium content of the blood.
Potassium. — Although the information available at present concern-
ing the potassium content of blood is somewhat limited, considerably
more is known than in the case of sodium. Some years ago Abderhalden
reported analyses of the blood of different animals. The figures obtained
for potassium are of considerable interest. In the dog and cat practically
identical figures were found for the serum and whole blood. This amount-
ed to about 22 mg. per 100 c.c., which is almost the exact amount found
in the serum of the various animals examined. In the ox^ sheep and goat
the figures for the whole blood were about one and one-half times that
of the serum, while in the horse, pig and rabbit the potassium concentra-
tion of the whole blood was about ten times that of the serum.
The potassium content of human blood has recently been considered
by Macallum (c), Greenwald (A), Kramer, and Myers and Short, who are
in close agreement that the potassium of normal human blood serum or
plasma is a relatively constant quantity and amounts to close to 20 mg. K
per 100 c.c. Kramer has suggested a normal range of 16 to 22 mg. to
100 c.c. The potassium content of whole blood depends in large measure
upon the cell content, but appears to vary somewhere between 150 and
250 mg. to 100 c.c. in the normal human subject. In primary and second-
ary anemia the amount may obviously be very low. Pathologically, the
potassium content of the serum or plasma is of greater interest. It has
been suggested by Smillie that uremic symptoms may be due in some
instances to potassium poisoning, while Macallum has obtained some data
which suggest an increased potassium content of the serum in eclampsia.
The data so far reported on pathological cases are too limited to permit
any definite conclusions with regard to the findings. The observations of
Myers and Short make improbable a definite potassium retention in
chronic nephritis with marked nitrogen retention.
Calcium. — As has been shown by Abderhalden and others, the blood
corpuscles are very low in their content of calcium. This being the case
significant changes in the blood calcium are best shown, as pointed out
451
by Bergeim, by analyses made upon the serum or plasma. The serum nor-
mally contains 9 to 11 mg. of Ca per 100 c.c. in the healthy adult, also in
infants. In advanced nephritis with acidosis and phosphate retention Mar-
riott and Rowland (a) have found the calcium of the serum to be mark-
edly lowered, figures as low as 2 to 4 mg. More than ten years ago W. G.
Macallum and Voegtlin recognized the reduction in the calcium content of
the blood following the removal of the parathyroids in animals and the de-
velopment of tetany. The symptoms of tetany were found to be relieved by
the administration of calcium salts. Rowland and Marriott, and more
recently Denis and Talbot, have shown that the calcium content of the
blood (serum) is greatly reduced in infantile tetany, falling to 2 to 3 mg.
in some extreme instances. Rowland and Marriott have shown that cal-
cium administration produces a prompt effect upon the course of the
tetany. In a few hours the spasmodic symptoms disappear. The calcium
treatment must be continued, however, for a long time. Calcium chlorid
administration causes an increase in the calcium of the serum coincident
with the cessation of symptoms, although, in most instances, the calcium
of the serum does not return to quite normal figures. Rowland and Mar-
riott point to the prompt improvement in infantile tetany after calcium
medication and the absence of symptoms when the calcium of the blood
remains above 7.5 mg. as strong evidence of the role that calcium plays
in the production and dissipation of symptoms. Both Rowland and
Marriott, and Denis and Talbot have observed some decrease in the blood
calcium in rickets, while Hess and Killian have noted a reduction in some
cases of scurvy. It is a matter of clinical observation that in fractures
occasionally cases are encountered which very rapidly regenerate bone,
while others do so very slowly. It is natural to link this with deviations
in calcium metabolism, but a few unpublished observations made in the
writer's laboratory on patients of Drs. Albee and Moorhead have failed to
disclose abnormal figures for the calcium of the serum.
Magnesium. — The normal magnesium content of the blood of both adults
and children, (as Mg generally falls between 2 and 3 mg. per 100 c.c.
of plasma or serum, although with pathological bloods a somewhat wider
range of 1 to 4 mg. is found. A considerable number of different patho-
logical conditions have been studied, but the findings differ very little
from those found during health and do not appear to be characteristic
of any special pathological condition.
Iron. — As already pointed out, iron is present in hemoglobin to the
extent of almost exactly one-third of one per cent, which would make the
content of normal human blood about 50 mg. per 100 c.c. calculated as
Fe. Pathologically, it varies directly with the hemoglobin content. Iron
does not appear to be present, normally in the plasma.
Chlorids. — Some of the observations recorded in the literature give
the chlorid content of whole blood, others the content of the plasma or
452
VICTOE C. MYEKS
serum. Normally the chlorid content of whole blood as NaCl amounts in
round numbers to 0.45 to 0.50 per cent, while for the plasma the figures
are about 0.12 per cent higher, i.e., 0.57 to 0.62 per cent. Since the
plasma, rather than the whole blood, bathes the tissues of the body, it
would seem more logical to study the chlorid content of the plasma. Un-
fortunately, unless the plasma is quickly separated from the corpuscles
there appears to be a gradual change (increase) in its chlorid content,
owing to a passage of carbon dioxid from the plasma into the corpuscles
(or its escape into the air) and of chlorids from the corpuscles to the
plasma. This being the case, results obtained on whole blood would ap-
pear to be more trustworthy than those obtained on plasma.
As far back as 1850 Carl Schmidt, in his classic studies on the blood
with special reference to cholera, gave figures for the chlorid content of
whole blood and plasma. Low figures were obtained in many cases of
cholera, apparently as the result of the concentration of the blood, while
in a case of "chronic edema with albuminuria" a definite increase was
observed. McLean has devoted considerable attention to the subject of
the chlorids of the blood working along lines similar to those of Ambard.
In a fairly large series of normal individuals he found the plasma chlorid
to vary from 0.57 to 0.62 per cent with a very constant chlorid threshold
of about 0.562 per cent. The threshold was calculated from the formula
of Ambard and Weill and confirms their observation on this point. Mc-
Lean considered the question of the plasma chlorids in a number of patho-
logical conditions, the lowest observation being 0.50 per cent in a diabetic
and the highest 0.84 per cent in a cardionephritic shortly before death.
In general, relatively increased concentrations of chlorids were found in
the plasma in certain forms of cardiac and renal disease, while decreased
concentrations were noted in certain diabetic and fever patients, also
after the action of digitalis, the decreased concentrations apparently re-
sulting from a temporary or permanent lowering of the chlorid threshold.
Failure to excrete chlorids in pneumonia was found to be associated with
a lowered concentration of chlorids in the plasma, excretion reappearing
with a rise in the plasma chlorid. Edema was usually found to be accom-
panied by a relatively increased concentration of chlorids in the plasma,
which ordinarily returned to the normal state with the disappearance of
the edema.
In general it may be stated that high blood chlorids have been found in
nephritis, certain cardiac conditions, anemia and some cases of malig-
nancy (possibly due to an accompanying renal involvement), while low
values have been observed notably in fevers, diabetes, pneumonia and
Asiatic cholera. The chlorid retention in most cases of nephritis appar-
ently results from impaired renal function. The excretion of chlorids and
nitrogen seems to be a fairly independent renal function. In contrast to
so-called parenchymatous nephritis, the function of excreting chlorids in
BODY TISSUES AND FLUIDS 453
chronic (interstitial) nephritis appears to be much less impaired than ex-
creting nitrogen. Consequently a restriction in the chlorid intake in the
latter condition may fairly quickly restore the chlorids to normal. In fact,
it is sometimes noted that when cases with marked nitrogen retention
are put on a restricted chlorid diet, the blood chlorids fall to a subnormal
level, such as is occasionally found in severe diabetes. A possible ex-
planation for this is that, owing to the large amounts of urea and sugar
present in the blood in these conditions, less chlorid is needed to maintain
normal osmotic conditions. The high chlorid figures for whole blood in
anemia and low figures in Asiatic cholera find probable explanation on
the basis of the relatively high proportion of the plasma in the former dis-
order and the reverse condition in the latter.
Phosphates. — The presence of phosphorus in the blood in lipoid form
has long been recognized, but exact data regarding the inorganic phos-
phorus is of more recent origin. In 1915 Green wald (c) reported observa-
tions on the acid-soluble (largely inorganic) and lipoid phosphorus of hu-
man blood serum. He observed that normally the acid-soluble phosphorus
as P varied between 2 and 6 mg. per 100 c.c., but that in severe nephritis
it might be considerably increased. A year later Marriott and Howland (a)
confirmed these observations and pointed out that the retention of (acid)
phosphate would seem to be sufficient to account for the degree of acidosis
observed. Recently Denis and Minot (#) have studied the inorganic phos-
phates of the plasma in a large series of pathological conditions. In con-
ditions other than nephritis and cardiorenal disease figures varying from
1.2 to 3.1 mg. of P per 100 c.c. of plasma were found, while in one case
of uremia figures exceeding 40 mg. were observed. They believe that
the determination of the inorganic phosphate of the plasma gives promise of
being of considerable prognostic value in renal and cardiorenal disease,
since fatal cases which they examined showed a rapidly rising plasma
phosphate.
An idea of the distribution of the various phosphorus compounds of
normal human blood may be obtained from the table on page 454 taken
from Bloor(/i,) (the figures have been recalculated to terms of P).
As is evident from the table below the phosphoric acid compounds of
human blood may be divided into two classes: (1) the acid-soluble — solu-
ble in dilute acids and precipitated with the proteins by alcohol-ether —
and (2) the lipoid-phosphoric acid compounds — soluble in alcohol-ether
and precipitated with the proteins by dilute acids. These two groups are
apparently sharply defined and since their sum is practically equal to
the total phosphates, the presence of other forms of phosphorus in blood
in significant amounts is doubtful. Inorganic phosphates and an un-
known compiound which on decomposition by heating with acid yields phos-
phoric acid are present in the first group, while substances of the type
of lecithin are found in the second group (lecithin has already been dis-
454
VICTOK C. MYEKS
PHOSPHORUS CONTENT OF HUMAN BLOOD,
MILLIGRAMS P PER 100 c.c.
Sex
*•• . •
Plasma
Corpuscles
"3
-*j
o
H
£
i 3
12 ^
'5 *o
< OQ
0
"a
cS
|
o
a
hH
"2
'S
a,
13
•
S S
5 S
Of*
"~
•s
H
0)
. 3
•3 3
!s3
<^CQ
o
cS
'I
O
C
1— 1
^
'o
&
H
i 05
§5 S
5 S
O PN
Men
7.6
13.6
10.0
2.3
4.3
3.2
1.9
3.7
2.7
5.0
7.3
7.0
0.1
1.2
0.5
57.8
101.5
77.5
43.8
78.1
58.8
3.8
8.5
5.8
13.6
20.8
18.0
40.0
74.2
53.8
Low
High .
Average (16 cases).
Women
9.9
12.6
11.3
2.9
4.5
4.0
2.5
4.3
3.5
6.0
9.1
7.8
0
1.2
0.4
68.1
82.8
77.5
50.0
64.4
58.8
3.0
8.2
4.9
14.7
19.5
17.7
41.8
58.8
52.2
. Low
High .
Average (10 cases).
cussed, see p. 446). As will be noted the average content of inorganic
phosphorus in the plasma of both men and women is about 3 mg. per
100 c.c. and of lipoid phosphorus about 7.5 mg. The corpuscles are rela-
tively richer in all types of compounds than the plasma and there is also
considerably less variation in their composition in different individuals
than is the case with the plasma. The amount of the unknown form, of
phosphorus combination is very small, but in the corpuscles it constitutes
60 to 80 per cent of the total phosphorus. This large amount of organic
phosphorus in the corpuscles is significant considering the fact that Bloor
has shown that "lecithin" formation takes place in the corpuscles during
fat absorption. Furthermore it would appear to be the mother substance
of the phosphoric acid of the lipoid phosphorus compounds. Owing to
the fact that this organic phosphorus compound is relatively unstable, it is
probably easily made available to serve as a "buffer" in case of need.
Sulphates. — According to Green wald(d) the sulphate sulphur of
human blood plasma probably does not exceed 3 mg. per 100 c.c., although
the content in the cells may be as high as 10 mg. The figures appear to be
considerably increased in some cases of nephritis.
Blood Gases
Although we possessed considerable information regarding the blood
gases as a result of observations made with the Barcroft-Haldane method,
the development by Van Slyke(c) of a much simpler method of estimating
the oxygen and carbon dioxid of the blood has given a considerable impetus
to this line of study. For the extraction of the gas to be determined, Van
Slyke makes use of a Torricellian vacuum, with which the gas is easily and
completely extracted in a closed chamber without any loss. Furthermore,
the Haldane apparatus has recently been considerably simplified by Hen-
BODY TISSUES AND FLUIDS
455
derson, and application made to the blood gases by Henderson and Smith.
Very recently Van Slyke and Stadie have introduced a number, of dif-
ferent refinements in the Van Slyke method of gas analysis and it would
seem that this method now left little to be desired in the point of accuracy.
The great practical importance of a knowledge of the factors concerned
in the carrying of oxygen to the tissues and the removal of carbon dioxid
is apparent.
Oxygen. — As has already been pointed out, the ability of the blood
to absorb and take up oxygen depends upon its hemoglobin content. Since
hemoglobin so readily takes up and gives off oxygen, it is obvious that
venous blood should be partly unsat.urated and therefore differ from the
arterial blood in respect to its oxygen content, and further that blood
obtained from different parts of the venous system should differ in its
oxygen unsaturation. Extensive studies on the venous blood from single
organs have been made in animals by Barcroft and his associates,. but in
the human adult the superficial veins of the limbs and neck, particularly
of the arm (vena mediana), are the only sources from which venous blood
can be obtained. This means that in the human only blood coming from
a limited region, consisting chiefly of muscles, can be studied.
Lunsgaard(a) has given the following figures for the oxygen content
and oxygen unsaturation of the venous blood of the normal resting adult.
The results are the average of thirty-eight determinations on twelve indi-
viduals and are given in tabular form below:
Oxygen Content of Venous Blood
Volume Per Cent
Oxygen Unsaturation of Venous Blood
Volume Per Cent
Maximum
18.0
Minimum
9.6
Average
13.6
Maximum
9.0
Minimum
2.7
Average
5.8
In studying this question on circulatory disorders, Lunsgaard(fc) found
that in twelve patients with compensated heart, lesions the unsaturation
fell within normal limits, between 2.5 and 8 volume per cent, while in
four patients with uncompensated heart disease the values for the un-
saturation were all above the normal limits, from 9.7 to 15.2 volume per
cent. In these cases the oxygen unsaturation appears to afford an objective
criterion of the positive effect of digitalis therapy. From studies per-
formed on patients with varying amounts of hemoglobin it. has been shown
that the oxygen unsaturation of the venous blood is independent of the oxy-
gen capacity, unless the latter is reduced below the normal value for oxygen
unsaturation (about 5 volumes per cent). Lunsgaard found, for example,
that in a polycythemic patient with an oxygen capacity of 33.4 volumes
per cent, the Venous oxygen unsaturation was 5.4 volumes per cent, while
456
VICTOR C. MYERS
in an anemic patient, with an oxygen capacity of 6.7 volumes per cent the
venous oxygen unsaturation >was 5.2 volumes per cent, indicating that
the tissues extract from the blood all the oxygen they need with apparently
equal readiness, regardless of whether the extraction leaves a great oxygen
reserve in the blood as in polycythemia, or practically no reserve as in
anemia.
Considerable additional information may also be obtained when
the study of the oxygen content of the arterial blood is included. Such
studies have been conducted on normal and certain pathological conditions
by Stadie and by Harrop(&), the arterial blood being obtained from the
radial artery. Observations obtained by Stadie for the arterial and venous
oxygen, and total oxygen capacity of five normal resting men are given
in the table below. As will be noted the arterial unsaturation amounts to
Individual
•Oxygen Content
Oxygen
Capacity
per 100 c.c.
of Blood
Unsaturation
Arterial
Venous
Arterial
per 100 c.c.
of Blood
Venous
per 100
c.c. of
Blood *
Per 100
c.c. of
Blood
Per Cent
Per 100
c.c. of
Blood
Per Cent
1
c.c.
17.9
21.0
22.1
20.2
19.5
c.c.
12.8
16.7
17.2
15.6
15.4.
c.c.
19.1
21.6
23.3
21.6
20.3
c.c.
1.2
0.6
1.2
1.4
0.8
6.3
2.8
5.2
6.5
3.9
c.c.
6.3
4.9
6.1
6.0
4.9
33.0
22.7
26.2
27.8
24.1
2
3
4
5
Mean
20.2
15.6
21.2
1.0
5.0
5.6
26.8
about 5 per cent while the venous unsaturation slightly exceeds 25 per
cent. Similar studies were made on a series of pneumonia cases (chiefly
post influenza), a high arterial unsaturation being observed in the fatal
cases. A definite relation was found to exist between the degree of cyanosis
and the per cent of arterial unsaturation. With increasing cyanosis the
arterial unsaturation becomes greater. The venous saturation varies sim-
ilarly. Obviously the cyanosis of pnevimonia patients is due to the incom-
plete saturation of venous blood with oxygen in the lungs. The range
of arterial and venous unsaturation encountered in fatal and nonfatal
cases of pneumonia is well illustrated in the table below, taken from
Stadie. As will be noted the arterial uu saturation of the fatal cases aver-
Type of Cases
No. of
Cases
Arterial Unsaturation
Venous Unsaturation
Max.
Min.
Mean
Max.
Min.
Mean
Normal individuals
Nonfatal cases . . .
Fatal cases
5
16
16
6.5
33.0
68.2
2.8
1.6
14.1
5.0
13.9
32.0
33.0
61.2
85.5
22.7
14.4
22.3
26.8
36.3
57.0
BODY TISSUES AND FLUIDS 457
aged 32 per cent and in one case reached 68 per cent, the venous un-
saturation exceeding 85 per cent.
The oxygen content of the arterial blood in anemia and heart disease
has been studied by Harrop, who likewise made a careful study of the
blood gases (oxygen and carbon dioxid) in both. the arterial and venous
blood of fifteen normal subjects, his figures for oxygen agreeing closely
with those of Stadie. With severe anemia the saturation of the arterial
blood did not differ from the normal. Low absolute values were found
for the oxygen content of the venous blood, but the normal oxygen consump-
tion was maintained. No deviations from the normal were found in
arterial and venous blood from cardiac patients without arrhythmias, well
compensated, and at rest in bed. With cardiac cases showing varying
degrees of decompensation the arterial unsaturation is frequently ab-
normally low (sometimes exceeding 15 per cent), although not so low as
that found in pneumonia. It is apparent that in many circulatory diseases
during decompensation, particularly when there are physical signs of
pulmonary congestion, there is a disturbance of the pulmonary exchange,
as indicated by the lowering of the percentage saturation of the arterial
blood with oxygen.
Carbon Dioxid. — Recent studies on the carbon dioxid of the blood have
been devoted largely to the utilization of this determination as a means of
ascertaining the carbon dioxid capacity of the blood. This determination,
as Van Slyke and Cullen have pointed out, furnishes a most excellent
method of ascertaining the degree of an acidosis, since the bicarbonate of
the blood represents the excess of base which is left after all non-volatile
acids have been neutralized and in this sense constitutes the alkaline re-
serve of the body. Before entering into a discussion of this phase of the
subject, however, it may be well to consider the actual content of carbon
dioxid in normal human blood.
Harrop(fr) has presented some interesting figures for the oxygen and
carbon dioxid content (according to the Van Slyke method) of both arterial
and venous blood upon individuals with normal heart and lung findings.
A few of these are given in the table on page 458.
As will be noted the CO2 content of arterial blood in the first
six cases tabulated averages about 50 volumes per cent, while that of the
venous blood is 4 volumes per cent higher. After 15 minutes of brisk
exercise Harrop found the CO2 content of both arterial and venous blood
reduced, with a considerable increase in the venous-arterial whole blood
difference. The oxygen consumption waa, however, only slightly in-
creased.
Smith, Means and Woodwell, employing the Henderson apparatus,
found the CO2 content of eight normal whole bloods to average 50.4 vol-
umes per cent, while the venous blood showed 58.7 volumes per cent, a
difference of 8.3, which is considerably greater than that recorded below.
458
VICTOR C. MYEES
Individual
•
£>
O) °o
bo a
>* —
X OS
oc
Oxygen Con-
tent of Ar-
terial Blood
Percentage
Arterial
Saturation
Arterial
Oxygen
Unsaturation
Oxygen Con-
tent of Venous
Blood
Oxygen Con-
sumption
C02 Content
of Arterial
Blood
C02 Content
of Venous
Blood
1
23 7
23 0
98
0 7
17 6
6 4
51 8
57 2
2
17 2
17 2
100
0 0
14 6
2 6
54 7
56 7
3
16 3
15 3
94
1 0
10 5
4 8
52 9
55 9
4
20 6
19 8
96
0 8
13 5
6 3
46 5
51 7
5
18 7
17 8
95
0 9
15 1
2 7
44 8
48 3
6
20 6
19 8
96
0 8
12 7
7 1
49 7
54 6
Average
195
18 8
96
0 7
14 0
50
50 1
54 1
Normal adult,
resting
220
21 1
96
0.9
15.1
6.0
53.3
56.9
After exercise ....
22.4
19.2
86
3.2
12.9
6.3
32.3
41.1
According to these workers, as the blood passes from the arterial to the
venous side of the circulation in normal man its cells gain from 4 to 11
volumes per cent of CO2, while the corresponding gain in the plasma is
only from 0 to 1.8 volumes per cent, indicating that the transport is ac-
complished mainly by the cells. Theories regarding the ability of the
blood to take up and hold oxygen and carbon dioxid and the equilibrium
between these two gases in the blood have recently been presented by L.
J. Henderson (c) and Y. Henderson and Haggard (&).
Although the removal of carbon dioxid from the tissues may be ac-
complished mainly through the agency of the cells, still the bicarbonate
of the plasma is ordinarily in equilibrium with that of the cells, as Van
Slyke and Cullen have pointed out. Consequently the carbon dioxid capac-
ity of the plasma may be used as a simple practical method of measuring
the alkaline reserve of the body. (Whole blood may be used, and theoret- •
ically is to be preferred, but it easily gums up the Van Slyke apparatus.)
Acidosis may result from an abnormal formation of acid substances
such as is found in diabetes, or from a decreased elimination of normally
formed substances as in nephritis. The carbonates of the blood have
been called by L. J. Henderson the first line of defense against acidosis.
Increased pulmonary ventilation as occurs with dyspnea or hyper-
pnea, serves to increase the excretion of carbon dioxid, thus keep-
ing the reaction of the blood within normal limits. In conditions
of acidosis, other acids may combine with the bicarbonate, robbing the body
of its alkaline reserve. In diabetes this is brought about by the abnormal
formation of ketone bodies, while in nephritis the breakdown in the ex-
cretion of acid phosphate apparently brings about the same result.
The range of the carbon dioxid combining power of the blood plasma
of the normal resting adult, with the Van Slyke(e) method, is from 55 to
75 c.c. of CO2 per 100 c.c., with an average of 65 c.c. For normal in-
BODY TISSUES AND FLUIDS 459
fants the figures are about 10 c.c. lower than in adults. With moderate
acidosis, in which symptoms may or may not be apparent, CO2 combin-
ing power figures of 30 or below are found. In the terminal stages of dia-
betic coma figures of 10 to 15 c.c. are encountered, and similar figures
are sometimes observed in "uremia." In such cases death may be di-
rectly ascribed to the acidosis. Extremely low figures are encountered in
many cases dying from pneumonia. Low figures may likewise be obtained
in the diarrhea! acidoses of infancy. All cases of chronic nephritis with
marked nitrogen retention show a moderately severe or a severe acidosis,
while occasionally severe acidosis is encountered in acute nephritis. Ether
anesthesia is accompanied by a fall in the CO2 combining power of the
blood, amounting to 2 to 20 volumes per cent. The introduction of a
simple method of estimating the CO2 combining power of the blood has
placed the diagnosis and treatment of cases of acidosis on a rational basis.
Muscle
The muscle tissue of the human adult has been variously estimated
as comprising from 30 to 40 per cent of the body weight. Of the total
body metabolism about 50 per cent takes place in the muscles during rest
and 75 per cent during activity. Physiologically, muscle tissues are di-
vided into voluntary or striated and involuntary or non-striated muscle,
heart muscle belonging to an intermediate group. The involuntary muscles
comprise only a comparatively small part of the total muscle tissue. The
muscle fibers of which muscle tissue is chiefly composed are elongated,
spindle shaped cells. Muscle tissue in the adult contains from 22 to 28
per cent solids with an average of 25 per cent. Of this about four-fifths
is protein and the remainder largely extractives and inorganic salts.
The proteins of the muscle are ordinarily divided into two groups,
the muscle plasma and the muscle stroma. This division or separation
is a more or less arbitrary one, since the muscle plasma simply represents
the amount of protein which can be expressed (about 60 per cent) from
fresh muscle. In the muscle plasma there are two distinct proteins, as
may readily be shown by the fractional coagulation of the plasma. Para-
myosinogen (Halliburton (a)) or myosin (von Fiirth(a)) coagulates at 46-
51°C., while myosinogen or myogen coagulates at 55-65° C. The former
constitutes about 25 per cent of the protein in the plasma and the latter
75 per cent. The first of these proteins is definitely a globulin, but the
latter is not a typical globulin since it is soluble in water, and belongs
rather to the class of albumins. The proteins of different muscles do not
differ widely in their content of amino-acids. The phenomenon of rigor
mortis, according to the now generally accepted view, first suggested by
Meigs, is due to the swelling of the muscle cells (taking up of water)
460
VICTOR C. MYERS
as a result of the post-mortem formation of lactic acid, increasing the
hydrophylic properties of the protein colloids of the muscle.
The so-called extractives of muscle are of considerable interest and
importance. Including the inorganic salts they constitute about 2 per
cent of the tissue, the organic material amounting to 0.7 per cent and
the inorganic to 1.3 per cent. The organic material is ordinarily divided
into two groups, the non-nitrogenous and the nitrogenous. To the former
group belong glycogen, glucose, para- or sarcolactic acid and inositol,
and to the latter such substances as creatin, the purin bases, xanthin, hypo-
xanthin and guanin, carnosin, amino-acids and traces of creatinin, uric
acid and urea.
Glycogen is a polysaccharide carbohydrate possessing some of the
properties of starch and dextrin. It is present in normal human muscle
tissue to the extent of about 0.5 per cent. From experiments on animals we
know that the amount may be markedly reduced by muscular activity.
Glycogen constitutes the muscles' reserve supply of energy. The glycogen
of the muscle together with that of the liver is apparently transformed to
glucose as needed. Judging from the observations of Palmer the glucose
content of the muscle is only about half that of the blood. Hopkins has
recently presented some interesting views regarding the transformation of
glycogen into mechanical and heat energy. The facts which he has brought
together indicate that there are two phases in muscular activity, the first
anaerobic and the latter aerobic. During the first, in which muscular con-
traction takes place, lactic acid is formed. During the second phase a part
of the lactic acid is oxidized and transformed to carbon dioxid and water,
while a part is apparently reconverted to glycogen. The heat liberated
during this (second) period, however, is less than that required by the
oxidation of the lactic acid, and is apparently stored in the muscle in a
latent form for the next (first) phase of the reaction, when it is liberated.
The formation of lactic acid (producing changes in the hydrogen ion of
the muscle) apparently plays an important role in initiating the contrac-
tion of the muscle, while a combination of the glucose with phosphoric
acid is necessary to its cleavage into lactic acid. Rigor may take place in
the muscle as a result of severe exertion or from poor oxidation as in car-
bon monoxid poisoning, while rigor mortis may be prevented if a suffi-
ciently high concentration of oxygen is maintained to bring about an oxida-
tion of lactic acid. However, after a time irritability is lost apparently
as a result, of the stabilization of the inorganic ions by the tissue. Although
inositol possesses the same empirical formula as glucose, it is a hexahy-
droxybenzene. However, it probably stands in fairly close relationship to
sugar since lactic acid may be formed from it.
Of the nitrogenous extractives of muscle, creatin is present in much
the largest amount and is of the greatest interest, especially since it is
apparently the precursor of the creatinin of the urine. In 1913 Myers and
BODY TISSUES AND FLUIDS 461
Fine called attention to the fact that the creatin content of the muscle
of a given species of animals was very constant (obviously that of a given
animal) and suggested this as a possible basis of the constancy in the
daily elimination of creatinin first noted by Folin. Later they pointed out
that the creatinin content of muscle was greater than that of any other
tissue, and also that in autolysis experiments with muscle tissue
the creatin (and any added creatin) was converted to creatinin at
:i constant rate of about 2 per cent daily, which is just about the normal
ratio between the muscle creatin and urinary creatinin. They also found
that, when creatin was administered to man or animals, there was a slight
conversion to creatinin which corresponds well with the above figure. These
facts all go to support the view that creatinin is formed in the muscle
tissue from creatin, and at a very constant rate, although no explanation
of the physiological significance of this transformation can as yet be
offered.
For the rabbit Myers and Fine(c) found a creatin content of 0.52 per
cent, for the white rat 0.4Y per cent, for the dog 0.37 per cent and for two
human cases 0.39 per cent. This figure for normal human muscle was
likewise confirmed by Denis (e) who has reported data for the muscle cre-
atin on nearly a hundred human cases. In a series of determinations made
on persons dying from various chronic diseases the creatin of the muscle
was found to be reduced absolutely and relatively in many cases, especially
those in an emaciated condition. These are the type of cases which ex-
crete creatin and show low creatinin coefficients. Denis likewise found
the percentage of muscle creatin in children to be lower thani that of
adults, which is in harmony with the observation that children excrete
creatin.
Of the nitrogenous extractives carnosin stands next to creatin in point
of quantity. It is a dipeptid containing histidin and alanin. By its syn-
thesis Baumann and Ingvaldsen(fr) have shown carnosin to be (3-alanyl-
histidin. Figures given for its contents in muscle vary from 0.035 to 0.30
per cent. About 0.05 per cent has been reported for human muscle.
The amount of purin base nitrogen found in the muscle of mammals
is generally given as about 0.05 per cent. This is partly combined and
partly free. From the observations of Davis and Benedict on a combined
uric acid compound present in beef blood, it is apparent that purins may
even be oxidized to uric acid before they are split off from the sugar with
which they are combined in the nucleic acid molecule. Of the different
purins hypoxanthin is generally stated to be present in the largest amount,
although both xanthin and guanin are also present.
As was pointed out by Marshall and Davis urea is so diffusible that it
is very evenly distributed throughout the tissues of the body, and this
has been amply confirmed by the observations of Mosenthal, Clausen and
Hiller on human muscle tissue in cases with and without nitrogen retention.
462
VICTOR C. MYERS
Normally muscle tissue contains rather more creatinin than the blood,
but in cases of marked nitrogen retention the blood may slightly exceed
that of the muscle (Myers and Fine (c)). The uric acid of the muscle
scarcely keeps pace with the rise in the blood uric acid which occurs in
some cases of advanced nephritis. The figures for the non-protein nitrogen
of muscle are much higher than those of the blood, owing chiefly to the
much larger amounts of creatin and amino-acid nitrogen present in muscle
than in blood.
The table below compiled from observations of Mosenthal, Clausen and
Hiller, and Myers and Fine (b) gives an idea of the distribution of the
various non-protein nitrogenous constituents in the muscle tissue of
normal individuals and those suffering from severe nephritis.
CONTENT OF NITROGENEOUS CONSTITUENTS IN HUMAN MUSCLE
Determination
. Normal
Severe Nephritis
Total solids
er ce
30 gn
<
<
i
nt
is.
24
3.5
185
125
35
13
1
0.5
375
125
30
200
5
2
Total nitrogen
Total nonprotein N
. .mj
5.t
. 1
<
<
<
t
Creatin N . . .
Amino-acid N
i
Urea N
Creatinin N
tt
Uric acid N
- t
It is very difficult to completely free muscle tissue from adherent fat.
Figures as low as 0.6 per cent have been obtained in lean oxen and as high
as 9 per cent in fattened pigs. Less is known concerning the cholesterol
and phosphatids of the muscle, although the latter are present in much
higher concentration, especially in heart muscle.
One may obtain an idea of the inorganic constituents of muscle from
the following table taken from Katz ( b ) . Of the different constituents tabu-
lated potassium and phosphorus are present in by far the largest amounts.
MINERAL CONTENT OF THE MUSCLE OF MAMMALS
Constituent
Range in Mammals
Man
Potassium
Per Cent
0.254-0.398
Per Cent
0.320
Sodium
0.065-0.156
0.080
Iron
0.004-0.024
0.015
Calcium
0.002-0.018
0021
Magnesium
0.021-0.030
Phosphorus
0 170-0 253
0 203
Chlorin
0.040-0.081
0070
Sulphur
0 186-0 227
0 9(18
In striated muscle the phosphorus is present largely in inorganic form,
but in heart muscle organic phosphorus may constitute more than half
of the phosphorus present. In the voluntary muscle of the rabbit, which
BODY TISSUES AND FLUIDS 463
Las a relatively high content of creatin, Myers has observed that the potas-
sium is present in fairly high concentration, 0.46 per cent calculated as
K (average for 8 animals). In conditions such as starvation, which ulti-
mately bring about a reduction in the creatin, it is of interest that the
potassium, as a rule, shows a proportionate reduction.
Without further discussion it may be said that there are many observa-
tions which lead one to believe that glycogen, creatin, phosphoric acid and
potassium are closely associated in active muscle.
Liver and the Bile
An appreciation of the importance of the liver to the animal organism
may be gained from the following facts. The liver is the largest gland
of the body. Its extirpation in mammals quickly results in death. The
blood from the digestive tract first passes through the liver before reach-
ing the general circulation. The liver appears to be a temporary store-
house for all classes of foodstuffs, carbohydrate (glycogen), fat and pro-
tein (ammo-acids). Many poisons both inorganic and organic are retained
by the liver, many of the latter being detoxicated. Numerous chemical re-
actions, in which deamidization, hydrolysis, oxidation and reduction occur,
take place in the liver. The liver also appears to be chiefly concerned in
the synthesis of urea (uric acid in birds), sugar from protein and the
ethereal sulphates. The formation of fibrinogen and also serum albumin
and globulin has been ascribed to the liver.
Less is known concerning the proteins of the liver than of the muscle.
There are two proteins, apparently globulins, which coagulate at 45° and
75° respectively, and a nucleoprotein which coagulates at 70° C. Besides
these proteins which are soluble there are others in the cells which are
difficultly soluble. The fat (fatty infiltration) of the liver is derived
not only from an excess of fat in the diet, but also by transportation from
other parts of the body. The phosphatids (lecithin) are normal constitu-
ents of the liver and are subject to much less variation than the fat.
Cholesterol is also a normal constituent but found in small amounts. As
in the muscle, phosphoric acid and potassium are the mineral constituents
which are present in the highest concentrations. Compared to other tis-
sues iron appears to be present in fairly large amounts. It. is of interest
that considerable iron is stored in the liver during fetal life, apparently
to provide for the deficiency in the diet during the period of lactation.
The storing of carbohydrate in the liver in the form of glycogen
is one of the liver's many important functions. The credit for the dis-
covery of glycogen and this glycogenic function of the liver, i. e., the
ability of the liver to convert glucose to glycogen and glycogen to glu-
cose, is due to Bernard. In normal animals the quantity of glycogen in
464 VICTOR C. MYERS
the liver depends essentially upon the food intake. In starvation the gly-
cogen may almost disappear from the liver, but after food very rich in
carbohydrate it may in exceptional cases reach nearly 20 per cent. Ap-
parently only the fermentible sugars of the six carbon series or their di-
and polysaccharids are true glycogenformers. The di- and poly saccha rids
must, however, first be broken down into monosaccharids in digestion.
Glucose is apparently more readily converted into glycogen than fructose,
and much more readily than galactose. These transformations are ap-
parently brought about by the diastatic ferment of the liver. The liver
is the probable source of the blood diastase. It is of interest that in dia-
betes, where the reserve supply of glycogen in the liver is very small, the
diastatic activity of the blood is generally markedly increased. It is
further significant that when the liver is cut out of the circulation in
animals, the blood sugar rapidly falls and may almost disappear. The in-
fluence of the- various internal secretions and also Bernard's sugar puncture
are of considerable interest and importance in this connection. As regards
the formation of sugar from protein it would seem probable that the liver
was chiefly concerned in the deamidization of amino-acids and the trans-
formation of the carbon moiety to sugar. Not all amino-acids are sugar-
formers, although it may be noted that practically all the amino-acids with
straight chains, except lysin, yield sugar. Prolin is the only cyclic amino-
acid which produces an abundance of sugar.
That urea formation, takes place in the liver is unquestioned as a
result of the well-known experiments of von Schroeder and others. That
the liver is the only organ in the body where urea formation takes place
seems improbable, still the actual demonstration of the formation of urea
elsewhere than in the liver has not been made. In autolysis experiments
M. Ringer was able to demonstrate urea formation in liver tissue but
not in muscle tissue. Muscle tissue added to liver tissue was found, how-
ever, to augment the urea formation. It would appear that the liver was
the chief organ concerned in the synthesis of urea, apparently deamidizing
the amino-acids no longer of use to the body or in excess of the body's
requirements. In the case of the amino-acid, arginin, Kossel and Dakin
have shown that a specific liver enzyme, arginase, converts the arginin
to ornithin and urea.
The liver has its own secretion, bile, which it continuously secretes ; a
reservoir, the gall bladder, being provided, so that the bile need not be
discharged into the intestine except as required. The discharge of bile is
brought about by the same stimulus that initiates the secretion of pan-
creatic juice, namely secretin. Bile may be regarded not only as a
secretion but also as an excretion, since it carries to the intestine certain
metals, cholesterol, lecithin, decomposition products of hemoglobin, and
certain foreign organic substances, for example, tetrachlorphthalein.
In man bile is usually a golden yellow, rather viscid fluid, amounting
BODY TISSUES AND FLUIDS
465
to roughly 500 to 1000 c.c. in 24 hrs. It is usually alkaline in reaction to
litmus, and ordinarily possesses a decidedly bitter taste. The specific
gravity varies between 1.010 and 1.040. As secreted by the liver bile is a
rather limpid fluid, but the addition of mucus and the abstraction of
water in the gall bladder raise both the specific gravity and the viscosity.
The table below, compiled from analyses given by Hainmarsten, gives* a
good idea of bladder and liver bile.
Constituents
Liver Bile ( Hammarsten )
Bladder Bile (Frerichs)
I
II
III
I
II
Water
Per Cent
97.48
2.52
0.53
0.93
0.30
0.63
0.12
0.06
i 0.02
0.81
0.25
Per Cent
96.47
3.53
0.43
1.82
0.20
1.62
0.14
0.16
0.06
0.10
0.68
0.05
Per Cent
97.46
2.54
0.52
0.90
0.22
0.68
0.10
0.15
0.07.
0.06
0.73 )
0.02 f
86.0
14.0
2.7
7.2
6!l6
0.32
0.65
85.9
14.1
3.0
9.1
026
092
0.77
Solids
Mucin and pigments.
Bile salts
Taurocholate
Glycocholate
Fatty acids and soaps
Cholesterol
Lecithin
Fat
Soluble salts . .
Insoluble salts
The most important constituents of bile are the bile acids and bile
pigments. The bile acids may be divided into two groups, the glycocholic
and taurocholic acid groups, the former being considerably in excess in
human bile as indicated in the table above. The bile acids are conjugate
amino-acids, in which glycocoll or taurin are joined to cholic acid. This
latter acid exists in several forms. There is- some reason for believing
that cholic acid is derived from cholesterol. The bile acids generally exist
in the bile in the form of sodium salts. The bile salts have the power of
holding the cholesterol and lecithin of the bile in solution. They also act
as a coferment to the pancreatic lipase, thus facilitating fat digestion.
The bile salts have a strong hemolytic action on the red blood cells.
The bile pigments are derived from the decomposition of the hematin
portion of hemoglobin, after the removal of the iron. (Whipple and
Hooper (6) have recently suggested the possibility of another origin.)
Although the liver is apparently chiefly concerned in this transformation,
the formation of the bile pigments may take place elsewhere in the body.
Bilirubin and biliverdin, an oxidation product of bilirubin, are the two
chief bile pigments, the one possessing a golden yellow and the other an
emerald green color. Bilirubin is identical with the hematoidin of old
blood clots, and isomeric with the hematoporphyrin of pathological urines.
Under the action of intestinal bacteria bilirubin is reduced. It would
appear that hydrobilirubin prepared by the chemical reduction of
bilirubin, the stercobilin of the feces and the urobilin of the urine were
466 VICTOR C. MYERS
practically the same substance. It has become customary to refer to the
pigment of both feces and urine as urobilin. Urobilin is generally excreted
to a large extent in the form of a chromogen, urobilinogen, which on ex-
posure to light is converted to urobilin. Normally a considerable part of
the urobilin (ogen) of the intestines is reabsorbed and reconverted to
bile pigments. In certain diseases of the liver, the liver cells partially
lose this capacity, thus giving rise to an increased excretion of urobilinogen
in the urine. Owing to the greatly increased destruction of red cells in
pernicious anemia (but not in secondary anemia) the output of urobilin
in the stool is greatly increased, an observation which is of considerable
value in differentiating the two forms of anemia.
Human biliary calculi or gallstones are as a rule composed largely of
cholesterol in man. Occasionally the stones are pearly white, indicating
that they are almost entirely cholesterol, although more often they are
somewhat pigmented, sometimes very much so, indicating a mixture with
calcium salts of bilirubin and biliverdin. Stones made up largely of
pigments are not often found in man. The etiology of gallstone formation
is not as yet clear.
Connective Tissues
The cellular elements of typical connective tissues and gelatin-yielding
fibrils are imbedded in an interstitial or intracellular substance. The
fibrils consist of collagen^ while the interstitial substance contains chiefly
mucoid, besides small amounts of albumin and globulin. In yellow elastic
tissue, fibrils containing elastin are also present. Four types of con-
nective tissue will be mentioned, (1) white fibrous tissue, (2) yellow
elastic tissue, (3) cartilage and (4) bone.
The tendo Achillis is generally taken as a typical example of white
fibrous tissue. According to the analyses of Buerger and Gies, the
tendo Achillis of the ox contains 31.6 per cent of collagen in the fresh
tissue and 85 per cent in the dry tissue, together with 4.4 per cent of
elastin and 3.5 per cent of mucoid.
The ligamentum nuchse of the ox is the classic illustration of yellow
elastic tissue. Vandegrift and Gies give the content of elastwi in the
fresh tissue as 31.7 per cent, and in the dry tissue as 74.6 per cent, together
with 17 per cent of collagen and 1.2 per cent of mucoid.
Cartilage is closely related to white connective tissue, since it con-
tains a relatively large amount of collagen. In addition it contains an
albuminoid, chondroalbuminoid, and chondroitin-sulphuric acid. Chon-
dromucoid differs from the mucoids found in other connective tissues in
the large amount of chondroitin-sulphuric acid obtained on decomposition.
This acid is also found in bone, ligament and other tissues. Under the
action of acid hydrolysis, chondroitin is first formed, then later chondrosin.
BODY TISSUES AND FLUIDS 467
*
Chondrosin has a very strong reducing action, which is due to a hexosa-
mine, named by Levene and La Forge chondrosamine, since it is isomeric
but not identical with glucosamine. Levene (c) has recently shown that it
is a derivative of galactose. Glucuronic acid is also present in the molecule
of chondroitln-sulphuric acid.
The organic intracellular substance of bone is very similar to cartilage.
It differs in its very large deposit of inorganic salts, which normally con-
stitute about 40 per cent of the dry weight of the tissue. The ossein of
bone differs in no essential from the collagen of the other tissues men-
tioned. Likewise the osseomucoid and osseo-albuminoid are similar to
those found in tendon and cartilage. The inorganic material of bone is
chiefly calcium phosphate and carbonate, but magnesium is present and
also traces of fluorid and chlorid. McCmdden has given the following
figures for the important inorganic constituents of normal human bone
and bone from a case of osteomalacia :
Constituents
Normal
Osteomalacia
Calcium as CaO
Per Cent
28.85
Per Cent
15.44
Magnesium as MgO
0.14
0.57
Phosphorus as P20s
19.55
12.01
Sulphur as S
0.14
0.55
Brain
The adult human brain weighs about 1200 to 2000 grams, of which
approximately 19 per cent is water. It contains from 100 to 120 grams
of protein after the extraction of the various lipoids. The brain as a
tissue is characterized by its very high content of lipoids, i.e., alcohol and
ether soluble material. The first worker to make real progress in the
chemistry of the brain was Thudichum, who published a most important
monograph on the subject in 1884. Of more recent work the studies of
Waldemar Koch (a) deserve special mention, while very important con-
tributions regarding the constitution of many of the lipoid compounds
of brain tissue have recently been made by Levene and his coworkers.
Among the solid constituents of brain tissue are proteins, phosphatids
(lecithin, cephalin, etc.), cerebrosids or galactosids (phrenosin and cera-
sin), cholesterol, collagen, extractives and inorganic salts. Three dis-
tinct proteins, two globulins and a nucleoprotein, have been isolated from
the brain. The globulins coagulate at 47° C. and at 70-75° C., while
the nucleoprotein coagulates at 56-60° C. The lipoids are of particular
interest and will be specially considered. These bodies, as their name
would imply, resemble fats in some of their physical properties and
468
VICTOE C. MYERS
reactions, but are distinct chemically. The content of lipoids in the
white matter of the brain is very much higher than in the gray matter.
A general idea of the distribution of these various substances in human
brain tissue may be obtained from the table below taken from Koch.
It will be observed that the brain of the adult differs very materially
from the child, notably in its higher content of lipoids, particularly
cholesterol. With this increase in lipoids there is a corresponding re-
duction in protein, extractives and ash.
COMPOSITION OF THE SOLIDS OF THE HUMAN BRAIN
Constituents
In Per Cent of Dry Matter
Whole Brain
(Child)
Whole Brain
(Adult)
Corpus Callosum
Protein
46.6
12.0
8.3
24.2
6.9
0.1
1.8
37.1
6.7
4.2
27.3
13.6
0.3
10.9
27.1
3.9
2.4
31.0
18.0
0.5
17.1
Extractives
Ash
Phosphatids
Cerebrosids
Lipoid sulphur •
Cholesterol
Possibly a better notion of the changes in the composition of the
brain during growth may be obtained from data given by W. and M. L.
Koch on white rats at different age periods. As will be observed well-
marked and characteristic chemical changes occur in the rat during its
growth which may be correlated with its anatomical differentiation. The
principal changes are: "(1) A general decrease in the per cent of the
water which is not due entirety to medullation, since the decrease begins
before medullation; (2) a diminution in the relative per cent of protein
in the total solids due to the formation of a large amount of lipoid matter ;
(3) the lipoids which appear coincident with medullation and of which
the development is pari passu with medullation are the cerebrosids and
phosphatids. These, therefore, are chiefly found in the medullary sheaths.
(4) There is a great outburst of phosphatid formation at the very be-
ginning of medullation. The phosphatids are present, therefore, in the
cells as well as the sheaths."
The chemistry, so far as known, of the various lipoid substances
present in brain is of considerable interest. From the studies of Posner
and Gies, and others, it is apparent that the nitrogenous phosphorized
substance isolated by Liebreich and named "protagon" is a mixture.
Phosphatids. — The best examples of the phosphatids are lecithin and
cephalin. Recently Levene and West have shown that it is possible to
prepare perfectly pure lecithin. The lecithin molecule is known to be
made up of two molecules of fatty acid, one of glycerol, one of phosphoric
acid and one of the base, cholin. The lecithin of brain tissue appears to
BODY TISSUES AND FLUIDS
469
THE RELATIVE PROPORTIONS OF THE CONSTITUENTS OF THE BRAIN OF THE ALBINO RAT
AT DIFFERENT AGES
Age in
Days
1
10
20
40
120
210
Solids in per cent
10.42
125
17 5
90 <*4
91 fi-\
01 o
Number of brains in each
sample
100
40
54
35
OA
01
CONSTITUENTS IN PER CENT OF TOTAL SOLIDS
Proteins
58 25
56 5
53 3
48 4
47 fi
AO e:
Phosphatids
15.2
12 3
21 4
21 8
21 6
99 n
Cerebrosids
3 0
5 9
8 4
u 4
Sulphatids
1.45
2.6
2.5
2 55
3 55
4 5
Organic extractives )
Inorganic extractives .... 5
Cholesterol (by difference) .
Total sulphur
17.9
7'.2
1.00
15.1
13.5
0.83
14.55
5.25
070
14.85
6.5
0 55
9.75
9.1
056
9.8
6.8
0 58
Total phosphorus
1.87
1.48
1.66
1 52
1 42
1 39
DISTRIBUTION OF SULPHUR IN PER CENT OF TOTAL S
Protein S
30.5
44.2
56.4
63.75
61 8
638
Lipoid S
3.0
6.1
7.1
9.65
12.7
15.6
Neutral S
48.2
45.4
28.6
18.15
18.7
14.5
Inorganic S
18.3
4.3
7.9
8.45
6.8
6.1
DISTRIBUTION OF PHOSPHORUS IN TERMS OF TOTAL P
Protein P
Lipoid P
Water Soluble P.
13.3
33.2
53.5
13.45
34.95
51.6
5.9
52.85
41.25
8.7
57.3
34.0
7.3
64.1
28.6
6.8
67.6
25.6
contain one molecule of oleic and one of palmitic acid as the fatty acids.
The formula would thus be written :
H2C — O — COC17H33
I
H C — O — COC15H31
H2C — O — P = O
H(T^ O— CH2.CH2
\
(OH.)t-N
HO
Cephalin differs from lecithin chiefly in containing as its basic sub-
stance amino-ethyl alcohol instead of cholin. Levene and Rolf have shown
470 VICTOR C. MYERS
that the glycerophosphoric acid of cophalin is identical with that of lecithin.
It also appeal's to contain another unsaturated fatty acid, namely,
cephalinic acid, in place of oleic acid. The formula would thus be :
H2C — O - COC17H31
I
H C — O — COC17H31
I
H2C — O — P = O
/\
HO O— CH2.CH2.NH2
Two other monaminophosphatids found in brain tissue are paramyelin
and myelm, the latter being present only in very small amounts. Diamino-
monophosphatids are also present in brain tissue. Two have been
recognized, amidomyelin and sphingomyelin. In the case of this latter
compound Thudichum recognized that it did not contain glycerol. Levene
has recently obtained on hydrolyzing sphingomyelin, phosphoric acid, two
fatty acids, cerebronic and lingoceric, and three basic substances, cholin,
sphingosin and a base of the composition C17H35NO.
Cerebrosids. — The cerebrosids are nitrogenous substances free from
phosphorus, which yield galactose on boiling with dilute mineral acids.
They also contain a complex fatty acid. As would seem evident from
the table above they are not found in the embryonic brain, but develop as
medullation comes on and are found chiefly in the medullary sheaths in
the white matter of the brain. The most important of the cerebrosids
are phrenosin and cerasin. On hydrolysis phrenosin apparently yields
cerebronic acid, galactose and sphingosin, while cerasin yields ligno-
ceric acid, galactose and sphingosin. Thus the important difference in
the two substances appears to be in the fatty acid they contain. Phrenosin
has been somewhat more studied than cerasin.
Sulphatids. — It has been suggested by Koch that the oxidized sulphur
always present in cerebrosids when impure has a union in the form of
sulphuric acid with a cerebrosid and a phosphatid as follows:
O
Cerebrosid — O — S — O — Phosphatid
II
O
Its nature is unknown.
Thudichum has also isolated in small amounts two amino-lipotids,
crinosin and bregenin.
Cholesterol. — Cholesterol is the chief sterol present in brain. Choles-
terol melts at 145°. There is another sterol present which melts at 137°,
BODY TISSUES AND FLUIDS 471
which has been called phrenosterol. Cholesterol is present chiefly in
the free state.
Extractives. — The most important nitrogenous extractives recognized
are hypoxanthin, and creatin, which is present to the extent of about 0.1
per cent. Among the amino acids isolated have been tyrosin and normal
leucin, or caprin. Lactic acid and inositol are also present About 1 per
cent of ash is present and thisi is composed in great part of alkaline
phosphates and chlorids. Potassium is probably the most important base.
Cerebrospinal Fluid
Normally the cerebrospinal fluid is a perfectly clear and colorless
fluid with a specific gravity of 1.005 to 1.008, and a solid content between
1 and 2 per cent The normal amount of spinal fluid has been estimated
roughly as 60 c.c., but pathologically the amount may be much larger,
especially in hydrocephalus. The trace of protein present in the fluid is
globulin in character. Fibrinogen and albumin are absent. The fluid is
hypertonic. It is probably formed by the secretory cells covering the
choroid plexus, according to recent studies of Gushing and his coworkers.
Its function is unknown. It would seem probable that the secretion of
the pituitary passes into the fluid. Normally not more than 3 to 5 white
cells per cu. mm. of fluid are present.
From time to time many studies have been carried out on the spinal
fluid, although scarcely as accurate data are available as in the case of
blood, for the probable reason that the work has been carried out less
systematically. In the table below are given figures for the average normal
content of the various constituents in the spinal fluid, the data being taken
from various sources. From the figures given it is apparent that the
spinal fluid may be considered as a dialysate or ultrafiltrate of the blood
plasma. It contains very little protein so long as the fluid remains normal,
but nearly as much urea and glucose, and rather more salt than the blood.
In pathological cases the properties may change, particularly in
meningitis. The fluid may be greatly increased in amount, under high
pressure, and have a considerable increase in protein.
Denis and Ayer have presented recently some quantitative figures on
the protein content of spinal fluid. Normally they found the fluid to
contain from 0.04 to 0.1 per cent of protein. In active tabes, moderately
active syphilis of the nervous system and lethargic encephalitis the protein
content ranged from 0.1 to 0.2 per cent, in recent cerebral vascular
disturbances such as hemiplegias and cerebral embolus from 0.1 to 0.3 per
cent, in acute syphilis of the nervous system and general paresis from 0.2
to 0.6 per cent, while in tubercular and acute meningitis such high figures
as 0.2 to 1.0 and 0.4 to 1.3 per cent respectively were observed. By taking
472
VICTOR C. MYERS
COMPOSITION OF NORMAL SPINAL FLUID
Determination, Recorded in
Range
Average
Total solids, per cent
08-1.6
1.0
Ash, per cent
0.88
Protein, per cent
0.04- 0.1
0.7
Nonprotein nitrogen, mg. to 100 c.c
17.0 -26.0
21.0
Urea nitrogen, mg. to 100 c.c
7.0 -14.0
10.0
Creatinin, mg. to 100 c.c
0.7 - 1.5
1.0
Uric Acid, mg. to 100 c.c
trace
0.1
Sugar, per cent
0.07- 0.1
0.08
CO2 combining power, volumes per cent
58.0 -63.0
60.0
Chlorids as NaCl, per cent
0.60- 075
0.7
Phosphates as P, mg. to 100 c.c
2.5
Sulphates as S, mg. to 100 c.c
trace
Sodium as Na, mg. to 100 c.c . .
320.0
Potassium as K, mg. to 100 c.c
14.0 -28.0
20.0
Calcium as Ca, mg. to 100 c.c
7.0
Magnesium as Mg, mg. to 100 c.c. . '
3.0
pH ( when first drawn )
7.4
pH (on standing)
8.3
advantage of the changed reaction of the fluid in the last mentioned
conditions and the rate of change of alkalinity on standing, Tashiro and
Levinson have devised a very valuable method of differentiating tubercular
from epidemic meningitis. If to 1 c.c. of spinal fluid there is added 1 c.c.
of 3 per cent sulphosalicylic acid, and to another 1 c.c. of fluid a like
amount of 1 per cent mercuric chlorid, then in tubercular meningitis the
protein which settles down on standing 24 hrs. is more voluminous in
the mercury tube, whereas in epidemic meningitis it is more voluminous
in the sulphosalicylic acid tube.
The nonprotein nitrogen of spinal fluid averages only about TO per
cent of the figures obtained in blood, but this statement does not apply to
its chief component, urea. It is now well known that the various mem-
branes of the body are very permeable to urea, resulting in an even
distribution of this waste product throughout the tissues of the body, as
shown by Marshall and Davis. Cullen and Ellis have strikingly pointed
this out in the case of spinal fluid. Myers and Fine(n) likewise have found
this to be true in nephritis with marked nitrogen retention. In their
series of fifteen cases the spinal fluid urea averaged 88 per cent of that
of the blood. The concentration of creatinin averaged 46 per cent of
that found in the blood in the same series, indicating that it did not
diffuse as readily as the urea. In one case with the high blood creatinin
of 14.5 mg., the spinal fluid content was 4.8, while in a similar case the
figures were 11.0 and 4.2 mg. respectively. Uric acid does not readily
pass into the spinal fluid, if one is to judge from observations on the same
cases, since the amount present averaged only about 5 per cent of that
found in the blood. In a few exceptional cases the figures for the spinal
fluid reached only about 1 mg., and this despite the fact that the blood
content was about 10 mg.
BODY TISSUES AND FLUIDS 473
The sugar normally amounts to 0.07 to 0.09 per cent, in comparison
with figures of 0.09 to 0.11 per cent for the blood. Sugar appears to be
fairly readily admitted to the spinal fluid, since in diabetes comparatively
high figures may be found. Myers and Fine ( n ) observed a sugar content of
0.30 per cent in a case of diabetes showing a blood sugar of 0.44 per
cent. In meningitis the sugar content may be either very low or entirely
absent, negative findings more often being observed in epidemic and
pneumococcus meningitis than in tubercular meningitis. The estimation
of the sugar in meningitis may therefore be of considerable practical
value.
The CO2 combining power of spinal fluid averages 60 volumes per
cent, which is slightly lower than that of normal blood plasma. It like-
wise seems to vary within narrower limits.
Of the mineral constituents of the spinal fluid the chlorids are by
far the most significant in point of quantity. Calculated as NaCl the
chlorids normally appear to average 0.7 per cent, more than half of the
total solid content. The content is considerably greater than that of the
blood plasma. It is ordinarily stated to be hypertonic to lymph, but
theoretically it would seem more likely that the high content of salt was
required to render this fluid isotonic with the blood. The chlorid content
of the spinal fluid is apparently increased in those conditions in which
an increase is found in the blood.
.The phosphates of the spinal fluid, which normally amount to about
2.5 mg. per 100 c.c., calculated as P, are increased (8-10 mg.) in certain
mental disorders, notably paresis. In view of the importance attached
at the present time to the increase in the inorganic phosphates of the
blood in nephritis with acidosis, it may be of interest to note that Myers
in 1909 observed a P content of 19 mg. in the spinal fluid of a patient
dying from "arteriosclerosis." In view of the close relation of both
phosphoric acid and cholin in lecithin, note may be made regarding
cholin at this time. The presence of cholin in the spinal fluid of paretic
patients was first claimed by Mott and Halliburton, and confirmed by a
number of workers in this and other conditions involving nerve de-
generation. Later, however, the presence of cholin was disputed.
The metallic elements, sodium, potassium, calcium and magnesium,
with the exception of the first named, apparently exist in the spinal fluid
in practically the same concentration as in the blood. Sodium appears
to be present in somewhat larger amounts as the high chlorin content
of the fluid would indicate. Some years ago Rosenheim reported that
potassium was present in relatively large amounts in cases of acute
degenerative insanity where cholin was present. In reinvestigating this
question Myers (6) found that the potassium content of the fluid in demen-
tia paralytica and several other conditions during life averaged 20 mg. per
100 c.c., but that after death the figures amounted to slightly more than
474 VICTOR C. MYERS
80 mg., indicating that the high figures for potassium were due to post-
mortem causes and possessed no pathological significance. This post-
mortem increase is quite striking, however, since as high figures are
found one-half hour post mortem as at any other time. This very rapid
post-mortem rise in the potassium is significant. The findings for calcium
and magnesium differ little from those obtained in blood. Levinson(&) has
found that the pH determined immediately on withdrawing the fluid
varied between 7.4 and 7.6. It. was normal in all pathological conditions
observed, except epidemic meningitis, where figures of 7.3 to 7.4 were
generally observed.
Saliva
Mixed human saliva is composed of the secretion of three pairs of
glands, the submaxillary, sublingual and parotid, supplemented by the
secretion of numerous small glands called buccal glands. The saliva
secreted by the different pairs of glands possesses different characteristics,
the secretion of the parotid being thin and watery, while that of the
sublingual and submaxillary, particularly the former, is thick and viscid,
owing to the large amount of mucin present. The amount of saliva
secreted by an adult in twenty-four hours has been variously estimated
as between 1000 and 1500 c.c., the exact amount depending, among other
conditions, upon the character of the diet. The specific gravity varies
between 1.002 and 1.008, with an average of 1.005.
According to Frerichs mixed saliva has the following composition :
COMPOSITION OF HUMAN SALIVA
Constituents
In Per Cent
Water .'....' . ...
9941
Solids
0.59
Mucin and epithelium
0.213
Soluble organic matter
0.142
Inorganic salts
0.219
Potassium thiocyanate .
0 to 0.010
formally saliva is alkaline to litmus and acid to phenolphthalein, the
reaction being practically the same as that of the blood. The chief con-
stituents of the ash are potassium, phosphate and chlorids, which together
constitute about 80 per cent of the mineral content.
The important organic constituents of the saliva are the mucin (a
glycoprotein) and the salivary amylase, ptyalin, the former aiding in
swallowing and the latter in the digestion of starch. At one time it
was argued that ptyalin could be of little value in starch digestion since
it was probably destroyed by the hydrochloric acid of the gastric juice as
soon as it reached the stomach. It has been shown by Cannon, however,
BODY TISSUES AND FLUIDS 475
that salivary digestion may proceed for a considerable period after the
food reaches the stomach, owing to the slowness with which the food
contents are mixed with the acid gastric juice. Ptyalin acts best in a
neutral or faintly acid medium (combined acid), but is readily destroyed
by a trace of free hydrochloric acid. It acts more efficiently when some-
what diluted.
It has been shown by Chittenden and Smith that the diastatic action
of human saliva can be taken as a definite measure of the amount of
ferment present, only when the saliva in the digestion mixture is diluted
at least 50 or 100 times. They have found that the limit of dilution at
which decisive diastatic action manifests itself with formation of reduc-
ing bodies is 1 to 2000 or 3000. Myers and Dellenbaugh, working with a
very delicate method, have recently observed that when 0.01 c.c. of normal
human saliva is allowed to act on 10 mg. of soluble starch in a volume of
2 c.c. for 30 minutes at 40° C., 30 to 45 per cent of the starch is con-
verted to sugar when the diluent is water and 46 to 50 per cent when
the diluent of the saliva is 0.3 per cent sodium chlorid. The Cl ion has
long been recognized to have a pronounced facilitating action. Essentially
the same range of figures were found in such pathological conditions as
diabetes, nephritis and gastric ulcer. A few individuals were encoun-
tered, however, who for periods showed low activities, figures 10 to 20,
that were not readily explained, although it may be noted that they
complained of gastric distress. Representatives of different nationalities
were found to vary within the same normal limits, which opposes the
view advocated by some of the adaptation of salivary secretion to diet.
As shown by Chittenden and Richards, saliva secreted after a period of
glandular activity, as before breakfast, manifests greater amylolytic power
than the secretion obtained after eating. Corresponding with this in-
crease in amylolytic power occurs an increase in the proportion of alkaline-
reacting salts, but the increased amylolysis is due primarily to an increase
in the amount of active enzyme contained in the saliva.
Marshall has suggested that the ratio between the mathematical ex-
pressions for the total neutralizing power of normal resting saliva and
normal activated saliva from a given individual is a "salivary factor"
the magnitude of which appears to be indicative of immunity from caries
or the reverse. Shepard and Gies were unable to substantiate this claim.
The thiocyanate content of human saliva has been the topic of a
number of studies. The saliva of smokers has been shown to have a much
higher content of potassium thiocyanate than that of nonsmokers. Schnei-
der found that the average content for six smokers was 0.013 per cent,
while for ten nonsmokers it was 0.003 per cent. Sullivan and Dawson
have studied the thiocyanate content of the saliva in pellagra. With
active symptoms the thiocyanate content is lower1 than later when the
characteristic symptoms have disappeared. The thiocyanate content of
476
VICTOR C. MYERS
eighteen patients on admission averaged 0.0035 per cent, while on dis-
charge it was 0.0047 per cent.
Milk
Milk is a product of the secretory activity of the mammary gland.
It is the most satisfactory food material elaborated by nature. As a food
it is deficient in only one respect, viz., its iron content. This is without
significance when milk is used as a food for infants, since a considerable
quantity of iron is stored up in the liver during fetal life. Milk contains
the proteins, casein and lactalbumin, such fats as olein, palmitin, stearin
and butyrin, the disaccharid, lactose, together with phosphates of calcium,
potassium and magnesium, citrates of sodium and potassium, and chlorid
of calcium. In addition it is evident from recent observations that milk
is well supplied with the water soluble and fat soluble vitamins, to-
gether with a sufficient quantity of the antiscorbutic element.
The physical appearance of milk suggests that the various constituents
are not all in solution. Fat is present in a finely divided suspension,
while casein is either in suspension or in a colloidal solution. Van Slyke
and Bosworth have been able to separate the insoluble portion of milk
by filtration through a Pasteur-Chamberland filter. With the aid of this
method they have been able to divide the constituents of milk into three
groups as shown by the table below:
MILK CONSTITUENTS
In True Solution
in Milk Serum
Partly in Solution and
Partly in Suspension or
Colloidal Solution
Entirely in Suspension
or Colloidal Solution
Lactose
Citric acid
Potassium
Sodium
Chlorid
Lactalbumin
Inorganic phosphates
Calcium
Magnesium
Fat
Casein
Perfectly fresh milk, both human and cow's, is amphoteric in reac-
tion toward litmus and acid to phenolphthalein. The acidity to phenol-
phthalein is due in considerable part to acid phosphates, although acid
caseinates may be responsible for some of the acidity. The specific gravity
of milk most often varies between 1.028 and 1.032. Milk has a very
slight yellow color, which is more noticeable in the cream on standing.
The yellow pigments of butter fat are the vegetable pigments carotin and
xanthophylls. They are present in the colostrum in much higher con-
centration than in mature milk.
The milk of different species of animals differs very materially, the
animals with a rapid rate of growth secreting a milk with a much higher
477
content of protein and salts and a somewhat lower lactose content. The
following table, compiled largely from analyses made in Bunge's labora-
tory, nicely illustrates this point :
RATE OF GROWTH AND COMPOSITION OF MILK
Species
Number of Days
Required to
Double Weight
at Birth
Percentage Composition of Milk
Protein
Ash
Lactose
Human
180
60
47
22
15
14
9
6
1.6
2.0
3.5
3.7
4.9
5.2
7.4
10.4
0.2
0.4
0.7
0.8
0.8
0.8
1.3
2.5
7.0
6.7
4.9
4.4
4.0
4.0
3.2
Horse
Cow
Goat
Sheep
Swine
Dos
Rabbit
Holt, Courtney and Fales have recently made a quite elaborate study
of the composition of human milk. A summary of some of their results is
given in the table below. As will be noted in the colostrum period human
PERCENTAGE COMPOSITION OF HUMAN MILK BY PERIODS
Period
No. of
Analyses
-P
e)
PH
H
9
be
CO
Protein
Casein
Albumin
•a
•<
1C
*2
o o
HOC
Colostrum ( 1-12 days)
5
2.83
7.59
2.25
0.31
13.4
Transition ( 12-30 days)
6
4.37
7 74
1.56
0.24
13.4
Mature ( 1-9 mos. )
17
3 26
7 50
1 15
0 43
0.72
0.21
12.2
Late ( 10-20 mos. )
10
3 16
7.47
1.07
0.32
0.75
0.20
12.2
milk has a high protein and high ash with rather low fat, in the transition
period the protein and ash are lower while the fat is higher, but after
one month the composition of normal milk does not vary in any essential
or constant way quite up to the end of lactation. The only striking
feature of late milk is a decline in quantity, though there is noted a
slight fall in all the solid constituents except the sugar. Of the different
constituents of milk, the least variation in both individuals and periods is
seen in the sugar. It will be observed in the table that the sugar amounts
to about 7.5 per cent, which is higher by a half per cent than the generally
accepted figure of 7 per cent. The greatest individual variations are
observed in the fat (figures from 1 to 6 per cent), although as recorded
above, the period variations in the fat are not marked. The protein is
highest in the colostrum period and falls to a little over half the propor-
tion in mature milk, during which period it is seldom over 1.25 per cent;
of this about one-third is casein and two-thirds lactalbumin.
Meigs and Marsh give the following table as representative of the
478
VICTOK C. MYERS
limits of normal variation in the constituents of human and cow's milk
from the beginning of the second month of lactation onv/ard, the figures
representing percentages of whole milk:
Fat
Lactose
Protein
Human milk
2-4
6-7.5
0.7-1.5
Cow's milk
2-4
3.5-5.0
2.5-4.0
It is apparent that human milk contains less protein but more sugar than
cow's milk. The protein of human milk differs from that of cow's milk
in one very important respect, quite aside from the total quantity of
protein. It contains much less casein but rather more lactalbumin. Ac-
cording to Meigs and Marsh, both human and cow's milk contain im-
portant non-nitrogenous substances of an unknown character. Early
human milk .contains about 1 per cent of these unknown substances ; milk
from the middle period of lactation about 0.5 per cent. Cow's milk from
the middle period of lactation contains about 0.3 per cent of the unknown
substance.
Denis, Talbot and Minot have studied the nonprotein nitrogenous
constituents of human milk. They summarize the results of the examina-
tion of 71 samples as follows:
Minimum
Maximum
Total nonprotein nitrogen
20.0
37.0
Urea nitrogen
8.3
16.0
Amino nitrogen
3.0
8.9
Preformed creatinin
1.0
1.6
Creatin
1.9
3.9
Uric acid
1.7
4.4
mg. to 100 c.c.
In some of the cases the nonprotein and urea nitrogen were also deter-
mined in the blood and practically the same figures obtained as in the milk.
In a series of about forty cases Denis and Minot (c) found the choles-
terol content of human milk to vary from 10 to 30 mg. per 100 c.c., figures
of 10 to 20 mg. being obtained chiefly in milk with a low fat content and
figures of 20 to 30 mg. with a high fat content. According to Bosworth
and Van Slyke, cow's milk contains 0.052 per cent of potassium citrate
and 0.222 per cent of the sodium salt, while in human milk the potassium
salt, 0.103 per cent, is in excess of the sodium salt, 0.055 per cent. Sommer
and Hart have shown that the citric acid of cow's milk (0.2 per cent)
is not destroyed or changed on heating.
The mineral content of milk is of great interest and importance.
Holt, Courtney and Fales(fr) have given the average composition of the
BODY TISSUES AND FLUIDS
479
ash of human milk for different periods and also for cow's milk, their
figures being given in the table below. As will be noted the high ash of
AVERAGE PERCENTAGE COMPOSITION OF THE ASH OF HUMAN AND Cow's MILK
CaO
MgO
PA
Na20
K20
Cl
f Colostrum
14.2
3.5
12.5
13 7
28 1
20 6
1 Transition
17.0
2.4
16.5)
109
30 8
22 9
Human I Mature
23.3
3.7
16.6
7.2
28 3
16 5
[ Late
19.8
3.6
15.5
10.1
28 8
22 3
Cow's milk
23.5
2.8
26.5
7.2
249
13 6
the colostrum period is due chiefly to the amount of NaaO and K2O. Of
the salts which make up the ash, the greatest individual, as well as the
greatest period, variations are seen in the Na2O. The largest constituent
of the ash of human milk is K2O, this with the CaO together making up
more than half the total ash. Although in amount the total ash of cow's
milk is about three and one-half times as great as that of human milk,
the proportion of different salts which make up the ash is nearly the
same, the only exception being that cow's milk has more Pa^
less iron.
SECTION IV
Excretions Victor C. Myers
Urine — Physical Properties — Organic Constituents — Inorganic Constituents
— Feces — Sweat.
Excretions
VICTOE C. MYERS
NEW YORK
There are four mediums for the excretion of waste products from
the body, viz., urine, feces, perspiration and expired air. Under normal
conditions and on a readily digestible diet, nearly 100 per cent of the
carbohydrate, about 95 per cent of the fat and more than 90 per cent
of the protein — if no correction is made for the "metabolic nitrogen" of
the feces — are completely digested and absorbed. The carbohydrate and
fat absorbed are almost entirely converted to carbon dioxid and water,
and this is also true of the carbon moiety (about 80 per cent) of the
protein. The carbon dioxid thus formed is excreted by way of the
lungs, as is a large amount of the water in the form of water vapor.
Considerable water may be lost from the body by way of the perspiration
but the amount of solids excreted in this way is never large, although with
severe exercise and sweating from 0.3 to 0.5 gram of nitrogen and 0.5 to
1.5 grams of sodium chlorid may be eliminated. The chief paths for
the excretion of solids are the kidney and intestine, the daily elimination
by these two channels in the adult amounting to about 50 grams in the
urine arid 30, grams in the feces. The nitrogenous waste products find
their principal exit through the kidneys, but in the case of the mineral
elements the kidneys and intestines both take part, the salts of sodium
and potassium being largely eliminated in the urine, while the salts of
calcium, magnesium and iron are excreted in the feces. Although the
excretion of the latter compounds in the feces may be due in part to lack
of absorption, still there is likewise a definite selective action regarding
their excretion. An excellent illustration of how changes in compounds
may affect their mode of excretion is the elimination of the two phenol-
phthalein derivatives, phenolsulphonephthaleiii and tetrachlorphthalein.
The former is eliminated entirely by the kidneys, while the latter after
being secreted in the bile by the liver is excreted by way of the intestines.
Urine
Since the end products of the metabolism of nitrogenous and mineral
substances find their principal exit through the kidneys, a study of the
481
482
VICTOR C. MYERS
secretion of these glands under various conditions may be expected to
throw light upon the processes involved in the metabolism of the above
substances. With a knowledge of the principal constituents of the urine
and a partial understanding, at least, of their history in the body, the
appearance of any unusual substance or the presence of a normally
occurring constituent in an amount inconsistent with the attending con-
ditions may bring to light derangements of body functions.
The mechanism of kidney secretion has been a much controverted
question. The view (modified Heidenhain) which has been most, gen-
erally held for some years past is that the renal cells actively participate
in the secretion, the water and inorganic salts being eliminated in the
capsular region, while the urea, creatinin, uric acid, etc., find their exit
through the uriniferous tubules. Quite recently our conception of urine
secretion has undergone material change partly as a result of advances
in our knowledge of physical chemistry and partly from added anatomical
data. From "a study of the blood vessel structure of the glomerulus, it is
apparent that the blood pressure in the glomerular capillaries must be
high, much higher than that of the fluid in the capsule. According to
the "modern theory" (Cushny (&)), the secretion of urine consists of two
distinct processes differing not only in site but also in nature. The first
of these, the filtration, occurs in the glomerulus, and is purely physical ;
the second, the reabsorption, occurs in the tubules, and depends upon the
vital activity of the epithelium. By the first process the protein colloids
of the blood plasma are filtered off. By the second process water and so-.
called threshold bodies such as chlorids and sugar are largely reabsorbed,
while no-threshold substances, such as urea, are rejected and can only
escape by the ureter.
That the cells of the tubules actively participate in the secretion of
urea, however, seems apparent from recent experiments of Oliver. With
the aid of xanthydrol he has shown that urea is present in the cells of
the proximal convoluted tubules in a concentration higher than that of
the blood or that of the cells of any of the other kidney tubules, which
condition can only be reconciled to an assumption of an active secretion
(excretion) on the part of these cells.
Physical Properties. — Volume. — The volume of urine eliminated de-
pends in great part upon the volume of fluid ingested. Under normal con-
ditions 1000 c.c. may be taken as the average volume of urine excreted in
24 hrs. This, however, is subject to great variations under both normal
and pathological conditions.
The volume of urine is diminished by conditions wh.ich cause an
increased elimination of water through other channels, for example
through the alimentary tract during diarrhea and vomiting, or through
the skin as perspiration. On the other hand during cold weather, when
cutaneous evaporation is reduced, the volume of urine is increased. Thus
EXCKETIONS 483
in warm weather the volume may be as low as 350 c.c., while a volume of
1500 to 1800 c.c. may be encountered during cold weather.
The condition of the cardiovascular system and kidneys has much to
do with the volume of urine eliminated. In interstitial nephritis, the
volume of urine is usually large, frequently 2000 c.c. .or over. Of par-
ticular interest is the observation that in this condition an abnormallv
large volume of dilute urine is eliminated during the hours from 8 P.M. to
8 A.M. This night polyuria commonly results in an elimination con-
siderably in excess of 400 c.c., the usual output during these hours. In
parenchymatous nephritis, the relations are not so constant, but in general
the urine is concentrated and the volume reduced. The variations in
volume in such cases are usually referable to the formation or disap-
pearance of edema. A very large volume of dilute urine (5000 c.c. or
more) may be eliminated in diabetes insipidus, due probably to dilatation
of the renal vessels. The 'volume is increased when it is necessary to
eliminate a large amount of material, as is the case with sugar in diabetes
mellitus. A temporarily increased output of urine may result through
nervous influences.
Color. — The color of urine may vary under normal conditions from a
very pale yellow to a reddish yellow or deep amber, depending upon its
density. The color is due principally to a pigment called urochrome,
although small amounts of urobilin, and occasionally traces of uroerythrin
may be present. Pathologically the color may vary from a perfectly
colorless fluid to dark brown or black. A red color may be due to blood,
occasionally to hematoporphyrin ; very dark colored urines may arise
from taking carbolic acid ; the excretion of melanin from pigmented
tumors may likewise be the cause of a dark color, especially after being
exposed to the air for some time or on the addition of an oxidizing agent.
A green or brownish yellow color may be due to bile, also recognized by
the yellow tinged foam. In alkaptonuria the urine may become dark
owing to the presence of homogentisic acid. This is especially so if the
urine is allowed to become alkaline.
Specific Gravity. — The specific gravity of normal urine most commonly
falls between 1.015 and 1.025. It may, however, be as low as 1.008 or as
high as 1.040 without necessarily indicating pathological conditions. Nor-
mally the specific gravity is inversely proportional to the volume. In
diabetes mellitus one may observe both a large volume and a high specific
gravity owing to the presence of sugar. In interstitial nephritis the
specific gravity is persistently low and fixed regardless of variations in
volume.
Odor. — Normal urine has a faint but characteristic aromatic odor. As
urine undergoes alkaline fermentation, a disagreeable ammoniacal odor
develops.
Reaction and Acidity.— The principal factor involved in the regula-
1sl VKTOK C. MYKKS
lion ,,f IIIIIKIIV acidity i. the pi-upm-lion between the ncjd -odium
phosphate ( IL.\';il'< >, ) ;iml (In- basic sodium phosphate ( 1 1 N'^-PO., ) , ||,e
former raising tho acidity ;in<l the littler lowering it. Tin- principiil iicid
supply is found in the metabolism of protein, during which sulphuric ;I.-K|
JH formed froin tli<- oxidation of (lie Hidplinr of iln- protein, while plm
phorir neid is set free. The organic ncids, uric, hippuric, oxalic, ;md
certain of the lower fatty acids also contribute to the acidity. The |,:i ic
rudicalH concerned are sodium, |M>lassium, ammonium, calcium and ma-
neHinm. The excretory function of the kidney normally prevents any
undue accumulation of either acids or liases in the hod\ , thereby ni:iin
i. iinnr- a remarkable constancy in (he reaction of the body fluids.
I'rine is most commonly acid to litmus. Tho reaction and decree of
acidity may, however, experience marked change unde.r both physiolo«:ir;il
and |iatholo^ical conditions. The diet is ono of the inosl importaiil factors
involved. In general, the metabolism of animal foods, except mill<, results
in an ineroaHcd acidity, while vegetable foods, except the cereal [{rain .
tend to diminish the acidity or even yield alkaline mine The re;i on
for tliiw general diU'erenc*^ hctweeii animal and ve^etahle food materials is
due, an jxiirited out by Slienman and (JiMtler, to their execHH of acid- or base-
forming elementH. ThcHe considerations probably account for the fact
that tho urine of dogs is normally acid, while that of rabbits is habitually
alkaline.
The pathological formation of acids (as in diabetes) is coiinleriiele.l
in a measure by the neutralising action of the bases, sodium, poln mm
calcium and inagtiesium. When the acidity .is so great that an adequate
.•supply of those elements can no longer be economically furnished by the
Ixidy, ammonia is called upon to meet this need. This accounts for the
increased elimination of ammonia in diabetic kotosis. Tho proximity to a
meal may alTwt the reaction of the urine. For example, the secretion of
hydrochloric acid in the stomach during the process of digestion may so
reduce tho store of acids in the body that for a time after a meal the
urine may be neutral or even alkaline, giving rise to tho so-called "alka-
line tide."
Quantitative expression may he given to the acidity of the urine by
determining the number of cubic centimeters of tenth normal sodium
hydroxid required to neutrali/e the total volume of urine eliminated in
24 hr». This represents tho liiralahlc acidity, and may range from 2<><>
to f»0(), with an average of about MM).
The tUratahli' an<lHi/ should be distinguished from the Inn- n<-/</i/i/.
tho latter depending upon the concentration of ioni/.ed hydrogen (IP).
From this point of view, a solution is acid, neutral or alkaline, depending
upon tho relative concentrations of hydrogen ions (IT) and of hydroxyl
ions (Oil"). An acid solution therefore contains a greater concentration
of (IP) than of (Oil"). For convenience in recording the hydrogen ion
EXCRETIONS 485
concentration a simplified logarithmic notation is generally employed.
Pure water, our standard of neutrality, contains - of a trram of
10,000,000
H+ to a liter, and is therefore a 1() QQQ (m N solution of H. For con-
venience the logarithmic notation is employed thus-
1 1
= '" ' >Smce the baso is alwas 10 and
10,000,000 N (10)7
the Ingiirithm always negative the expression is further simplified by
ilmpping both the figure 10 and the minus sign. The hydrogen ion con-
centration of pure water, then, is expressed in terms of its exponent,
pll = 7. Since the sum of the logarithmic expressions II and (Oil) ion
concentrations is always 14, it will be readily seen that the concentration
of either ion may be estimated when one is known. In practice the
determination of the hydrogen ion has been found simpler.
Normally the urine appears to vary from an acid solution of
pH = 4.82 to an alkaline solution of pll == 7.45, the average being close
to a solution of pH — 6.0. By the administration of sodium bicarbonate
and sodium citrate (which is oxidized to the earlxmate), Henderson and
Palmer(a) were able to lower the pll to 8.70, a condition of alkalinity. As
pointed out by Blatherwick(a) foods yielding basic ashes may likewise re-
duce the urinary acidity to that of neutrality (pll == 7), or even beyond
this to alkalinity. Among 30 vegetarians the pll varied from 5.$0 to 7.48,
averaging 6.64. Palmer and Henderson (6) have shown that in cases with-
cardiorenal diseases, the acidity of the urine is usually increased. The
average pH of 57 cases was 5. J3JJ, representing a five-fold increase in
urinary acidity over the normal average of 6.0.
Transparency. — When voided the urine of a normal individual is
usually perfectly clear. On standing a few hours a cloud or "nubccula"
forms, even in normal urine. This cloud consists of mucus threads,
epithelial cells, etc., from the urinary passages. Under pathological con-
ditions, the latter may be greatly increased and accompanied by casts or
blood. If the acidity of the urine is somewhat diminished (as after a
mi-ill) a turbidity due to phosphates will form. This will disappear on
adding a little acetic acid. On standing in the cold, urates may settle
out but will again go into solution on warming.
Organic Constituents
By far the greater number of organic compounds present in normal
urine contain nitrogen, and those that do not contain nitrogen constitute
an extremely small% part of the total solids. Fifty grams may bo given
as a rough figure for the solid content of urine and of this amount about
486
VICTOR C. MYEES
60 per cent is ordinarily organic and the remainder inorganic. Since the
organic constituents of urine are chiefly nitrogenous and since the nitro-
genous waste products are eliminated principally in the urine, i.e., to the
extent of 85 to 90 per cent, a study of their elimination in the urine
under different conditions of diet should furnish considerable insight
into the controlling factors in protein metabolism.
The most satisfactory discussion of this subject has been given by
Folin(&) in his now classic papers published in 1905. With the aid of
many new methods which he'had developed, Folin found it possible to make
fairly complete analyses of single 24 hr. specimens of urine. By a study of
the comparative distribution of the nitrogenous compounds in the urine on
two diets, one containing rather more than 100 grams of protein and
the other (starch-cream) containing about 1 gram of nitrogen, he was
able to differentiate between the endogenous and exogenous origin of the
different waste products. As a result of these observations he evolved a
new theory "of protein metabolism, which quickly supplanted the un-
tenable theories of Pfliiger and Voit.
The important components of the total nitrogen of the urine are the
nitrogen of the urea, creatinin, ammonia and uric acid. The following
data taken from Folin illustrate the distribution of these compounds (like-
wise the various sulphur compounds which are also derived from the
protein) in the urine of the same individual on a high and on a low
protein diet.
Normal Protein Diet
July 13
Low Protein Diet
July 20
Volume of urine
1170 c.c.
16.80 gi
14.70
0.49
0.18
0.58
0.85
3.64
3.27
0.19
0.18
n.
' =87.5%
' = 3.0
' = 1.1
' = 3.6
T = 4.9
' =90.0
' = 5.2
' = 4.8
385 c.c.
3.60 gn
2.20
0.42
0.09
0.60
0.27
0.76
0.46
0.10
0.20
a.
= 61.7%
—11.3
= 2.5
= 17.2
= 7.3
= 60.5
= 13.2
= 26.3
Total nitrogen
Urea nitrogen
Ammonia nitrogen
Uric acid nitrogen
Creatinin nitrogen
Undetermined nitrogen
Total S03
Inorganic S03
Ethereal S03
Neutral S03
From the above data it is apparent that the distribution of the nitrogen
in the urine among urea and the other nitrogenous constituents depends
on the absolute amount of total nitrogen present (the distribution of the
sulphur likewise being dependent upon the amount, of the total sulphur).
As will be noted urea is the only nitrogenous substance which suffers a
relative as well as an absolute diminution with a decrease in the total
protein metabolism. On the other hand, as Folin was the first to point
out, the absolute quantity of creatinin eliminated in the urine on a
meat free diet is a constant quantity, different for different individuals,
48Y
but wholly independent of quantitative changes in the total amount of
nitrogen eliminated. It may be observed in the case of the uric acid
that when the total amount of protein metabolism is greatly reduced the
absolute quantity of uric acid is diminished, but not nearly in proportion
to the diminution in the total nitrogen, and the per cent of the uric acid
nitrogen in terms of the total nitrogen is therefore much increased. From
these observations Folin pointed out that urea and creatinin stand in
marked contrast to each other, since the former is largely exogenous in
origin, while the latter is almost entirely of endogenous formation. Uric
acid stands in an intermediate position, being about half endogenous and
half exogenous under ordinary conditions of diet.
Since urea is largely exogenous in its origin the amount of its excre-
tion in the urine obviously depends upon the protein intake. With the
dietary standards of Voit and of Atwater calling for 118 to 125 grams of
protein, the urea output should be 30 to 35 grams. Comparatively few
healthy adults appear to eliminate as much urea as this at the present
time. Probably 25 grams may be taken as more nearly representing the
average output of urea in the human adult, although judging from the
very extensive data given in the Referee Board reports, many individuals
average hardly more than 20 grams, corresponding to a protein intake
of 75 to 80 grams. It is obvious, therefore, that the daily excretion of
10 to 15 grams of urea by many hospital patients finds explanation as a
rule, not in defective kidney function, but in a low protein intake. Even
here the urea excretion represents a protein consumption of 40 to 60
grams, an amount which Chittenden(&) has shown may quite adequately
supply the requirements of the average individual.
Assuming that the average urea output of the human adult is 25
grams, the content of the various nitrogenous constituents with their dis-
tribution in the total nitrogen may be represented as given in the table
below. With this output of urea the urea nitrogen would probably con-
stitute about 85 per cent of the total nitrogen, thus making the figure for
AVERAGE CONTENT OF THE NITROGENOUS CONSTITUENTS IN THE URINE OF THE HUMAN
ADULT
Constituent
Weight of
Substance
Nitrogen
Equivalent
Relation of
Nitrogen Equivalent
to Total Nitrogen
Total nitrogen
Grams
Giams
13.8
Per Cent
100.0
Urea
25.0
11.7
85.0
Ammonia
0.5
3.6
Creatinin
1.5
0.56
4.1
Uric acid
0.5
0.17
1.6
Undetermined N
0.79
5.7
Hippuric acid
0.7
0.06
Amino acids
0.5
0.10
Purin bases
0.03
0.01
488
VICTOR 0. MYERS
total nitrogen 13.8 grams. If allowance is made for a fecal nitrogen
excretion of 1.5 grams, the nitrogen intake would be 15.3 grams, which
corresponds to about 05 grams protein. The output, of creatinin for the
average human adult is about 1.5 grams and of uric acid 0.5 gram.
Urea. — Urea, ammonia and ammo acids are intimately related in their
physiological history. It will be recalled that the amino-acids, resulting
from the digestion of protein in the intestine, are absorbed and carried
to all the tissues of the body. The greater part of the amino-acids thus
absorbed and disseminated are deaminized, i.e., the amino group (NH2)
is split off, forming ammonia. This process of deaminization may be illus-
trated as follows, taking alanin as a typical amino-acid:
NIL
OH
CH3 . CH . COOH + HOH -> KH3 -f CH3 . CH . COOH
"Alanin Water Ammonia Lactic Acid
The ammonia unites with the carbonic acid of the blood and tissues to
form ammonium carbonate. Two molecules of water are then split off
from the ammonium carbonate, yielding urea. The formation of am-
monium carbonate and its subsequent dehydration to form urea are indi-
cated below:
OH
OH
NH,
KEL
H9O
C = O
Carbonic Ammonia
acid
ONH4
Ammonium
Carbonate
Urea
H2O
Water
Kossel and Dakin have also shown that arginin may be directly
split into ornithin and urea under the action of a liver enzyme, arginase.
The deaminization of amino-acids and the transformation of ammonium
carbonate into urea takes place in the liver and possibly in other tissues.
(See preceding article, p. 464.) Because of the prominence played by the.
liver cells in these processes, considerable importance has been attached
to apparent abnormalities in the elimination of urea, ammonia and amino-
acids. In acute yellow atrophy of the liver, interstitial hepatitis and
cirrhosis of the liver, there is a very extensive degeneration of the liver
cells. The association of hepatic disturbance with increased elimination
of ammonia and amino-acids, and diminished output of urea has not been a
constant finding (Fiske and Karsner), and in many instances has been
the result of employing old and inadequate methods. However, there is
EXCEETIONS 489
generally some reduction in the amount of urea in the urine, and an
increase in the ammonia content.
Urea is an extremely soluble and relatively non-toxic substance.
These two properties have a particular significance in view of the fact
that urea is the chief end product of protein metabolism, and is almost
wholly eliminated through the kidney, the portion excreted through other
channels such as the skin being relatively unimportant. The quantitative
output of urea is closely proportional to the amount of protein ingested.
Variations of 10 to 40 grams may be encountered in perfectly normal indi-
viduals. The percentage of urea is dependent upon the volume of urine
in addition to the protein of the diet, and when it is considered that the
former may vary from 500 to 2000 c.c. it is evident that but little informa-
tion concerning the quantity eliminated can be gained from a knowledge
of merely the percentage of urea. The urea nitrogen in ^proportion to
the total nitrogen excreted may likewise be greatly influenced by the
amount of protein in the diet. Thus with a high protein intake, the urea
nitrogen may make up as much as 90 per cent of the total nitrogen;
while with a diet containing relatively little protein but considerable
carbohydrate and fat, the proportion may be as low as 60 per cent. (See
table on p. 486.) With a nitrogen intake of 20 grams the urine would
contain approximately 18 grams of nitrogen, of which about 16 grams
would be in the form of urea ; whereas with a nitrogen intake of 7 grams
the excretion of urea nitrogen may be as low as 4 grams. An average
quantitative output of urea with its nitrogen equivalent and the relation
of the latter to the total nitrogen output is given in the table on page
487. It will be readily seen that it is quite essential in considering
the excretion of total nitrogen and urea to compare these values with
the nitrogen of the food, because only when the nitrogen output is out
of proportion to the intake can an abnormal condition be presumed to
exist.
When the rate of metabolism is accelerated as in fevers, exophthalmic
goiter, etc., or by, the consumption of large amounts of protein as in
diabetes, the total nitrogen and urea may be greatly augmented.
Although the function of excreting urea may be much impaired in
nephritis a recognition of this fact simply from the output of urea is
difficult. Information in this regard may be more readily secured from-
an analysis of the blood.
Ammonia. — Under ordinary conditions the nitrogen of ammonia, in
combination with urinary acids, is present in the urine to the extent of
2.5 to 4.5 per cent of the total nitrogen eliminated, i.e., about 0.5 gram per
day. A considerable portion of this probably represents urea which has
been reconverted into ammonia so that it might be utilized to neutralize the
sulphuric, phosphoric, uric acid, etc., formed in the process of normal me-
tabolism or introduced with the food. This procedure probably operates to
490
VICTOR C. MYERS
prevent undue strain upon the body's supply of sodium, potassium, calcium
and magnesium. As shown by Janney(&), if sufficient fixed alkalies or al-
kali-earths are administered, so that ammonia is not required for neutral-
izing the acids, then the ammonia excretion may be greatly reduced,
cr in fact almost completely disappear from the urine. On the
other hand, the ammonia output may be greatly increased when there is an
abnormal acid production, as occurs in severe diabetes. Sherman and
Gettler have demonstrated that the ammonia output is dependent to a-
considerable extent upon the" balance between the acid-forming and base-
forming elements of the foods. Increased elimination of ammonia has
been observed in pernicious vomiting of pregnancy, but it is important
to note that here the individual is essentially in a condition of inanition,
which itself is characterized by a relative increase in ammonia elimina-
tion.
Amino-Acids. — Small amounts of amino-acids normally escape deam-
inization and appear in the urine. They represent about 0.5 per cent
of the total nitrogen, and, unless specifically determined, are recorded as
undetermined nitrogen. In severe liver disease, i.e., yellow atrophy,
phosphorus poisoning, the output of amino-acids, may be increased, and
occasionally certain amino-acids, such as leucin and tyrosin, actually
crystallize out in the urine. As already noted, however, increased amino-
acid excretion and hepatic disturbances are not constantly associated.
In certain individuals the amino-acid cystin is eliminated in considerable
amounts. This is regarded as an anomaly of protein metabolism.
Creatinin. — Creatinin is the anhydrid of creatin. It is the second
largest nitrogenous constituent of urine, the daily elimination in the
healthy human adult ordinarily varying between 1 and 2 grams.
JIN— CO
— CH
Our accurate knowledge with regard to the elimination of creatinin
dates from the introduction of the Folin colorimetric method in 1904.
As the result of his original studies on the elimination of creatinin, Folin
considered the excretion of this substance from the standpoint of a new
theory of protein metabolism. He was the first to point out that the
amount of creatinin excreted in the urine on a meat free diet is quite
independent of either the amount of protein in the food or of the total
nitrogen in the urine, the amount excreted from day to day being prac-
tically constant for each individual, thus pointing conclusively to its
endogenous origin. The constancy of this creatinin excretion has been
EXCRETIONS 491
fully confirmed by many subsequent investigators and Shaffer(a) has fur-
ther observed the same uniformity in its hourly excretion. (According to
Neuwirth the hourly creatiniii excretion is generally slightly decreased
during one hour in the later afternoon or early evening). Even a con-
siderable diuresis has little effect on this hourly output, while a great
increase or decrease in the amount of total nitrogen excreted per hour is
likewise without effect. Furthermore, neither increased nor decreased
muscular activity, uncomplicated by other factors, has any effect upon
the creatinin elimination. Such results are a definite indication that
the regularity of the creatinin excretion can be explained only on the
basis of a similar regular formation.
While the creatinin excretion is practically constant for each healthy
individual, different persons excrete different amounts, and Folin early
pointed out that the chief factor determining this appeared to be the
weight of the person. He further noted that the fatter the subject, the
less creatinin is excreted per kilo of body weight and concluded from this
that the amount of creatinin excreted depends primarily upon the mass
of active protoplasmic tissue, or as Shaffer has expressed it, ''Creatinin
is derived from some special process in normal metabolism taking place
largely, if not wholly, in the muscles, and upon the intensity of this
process appears to depend the muscular efficiency of the individual." It
has been found convenient to express the daily creatinin elimination in
milligrams of creatinin nitrogen per kilo of body weight and this has
been called the creatinin coefficient. For a strictly normal individual
Shaffer has shown that this coefficient is between 7 and 11. Women elimi-
nate less creatinin than men, and thus have slightly lower creatinin
coefficients. The creatiniii excretion of children is much lower than that
of adults.
That the creatinin elimination is affected by different pathological
conditions has been shown by numerous observations. A low creatinin
elimination has been found associated with a large number of abnormal
conditions, especially those accompanied by muscular weakness. Benedict
and Myers observed creatinin coefficients as low as 2 in two very old
decrepit women, while Levene and Kristeller found coefficients of 1.5 in
several cases of muscular dystrophy in young male adults. A marked
decrease in the excretion of creatinin has been observed to be associated
with such conditions as exophthalmic goiter, the leucemias, diseases of
the liver, especially carcinoma, muscular dystrophy, anterior poliomyelitis,
certain cases of nephritis, etc. An interesting fact to note in this con-
nection is that most of these subjects eliminate considerable amounts of
creatin.
Only in the terminal stages of chronic nephritis is a decreased elimi-
nation of creatinin due to retention. Creatinin appears to be the most
492 VICTOR C. MYERS
readily eliminated of the three nitrogenous waste products, uric acid, urea
and creatinin, and it is only in chronic nephritis or acute nephritis with
partial or complete suppression of urine that retention occurs. A blood
content of more than 5 mg. of creatinin to 100 c.c. has been found to be a
very unfavorable prognostic sign (see preceding article, p. 441).
The excretion of creatinin has been found to be increased in fevers —
typhoid, pneumonia and erysipelas. Here the rise in temperature is
followed by a corresponding rise in the creatinin output. Myers and
Volovic have shown that the excretion of creatinin follows closely the
rise in temperature during fever, whether the hyperthermia is of infective
origin or artificially induced. From this it would appear that the rise in
the creatinin elimination was due entirely to the hyperthermia.
That the creatinin of the urine has its origin in the creatin of the
muscle would seem obvious on a priori grounds, but a definite proof of
this hypothesis has been beset with many difficulties. The older inves-
tigators stated that both administered creatin and creatinin reappeared
in the urine as creatinin. When Folin first reinvestigated this question
with accurate methods and pure creatin and creatinin, he found that 80
per cent of the administered creatinin did reappear as creatinin, but that
when creatin was given in moderate amounts (1 gram to man) it not
only failed to reappear as creatinin, but completely disappeared. From
this Folin quite naturally concluded that creatin and creatinin were rela-
tively independent in metabolism. In 1913 Myers and Fine(c) called
attention to the fact that the creatin content of the muscle of a given
s-pecies of animals was very constant (obviously also that of a given
animal) and suggested this as a possible basis of the constancy in the
daily elimination of creatinin first noted by Folin. Later they pointed
out that the creatinin content of muscle was greater than that of any other
tissue, and also that in autolysis experiments with muscle tissue the
creatin (and any added creatin) was converted to creatinin at a constant
rate of about 2 per cent daily, which is just about the normal ratio
between the muscle creatin and urinary creatinin. They also found, as
did Rose and Dimmitt, Lyman and Trimby, and others, that when creatin
was administered to man or animals, there was a slight conversion to
creatinin although a considerable percentage of the creatin reappeared in
the urine unchanged if large amounts were given. These facts all go to
support the view that creatinin is formed in the muscle tissue from creatin,
and at a very constant rate, although no explanation of the physiological
significance of this transformation can as yet be offered. Excepting
possibly the kidney, the muscle normally contains more creatinin than
any other body tissue and is followed by the blood which indicates that
after its formation in the muscle the creatinin is carried to the kidney
by the blood stream.
EXCKETIONS 493
Creatin. — Creatin is methyl guanidin acetic acid.
HNH
CH3.N — CH2 — COOH
It is a constant constituent of striated muscle, the concentration in man
being about 0.39 per cent. The creatin content of striated muscle appears
to be both constant and distinctive for a given species (see preceding arti-
cle, p. 461). Creatin is also present in heart muscle in about two-thirds the
concentration of striated muscle and in the testis, brain, smooth muscle
and liver in much lower concentrations, the figures varying from about 0.1
per cent in the testis and brain to 0.3 per cent in the smooth muscle of
the intestine and uterus, and slightly less in the liver.
Folin, in his original discussion of the subject, pointed out that
although creatin is normally absent from urine, occasionally small amounts
may be detected. This phase of the problem received renewed interest
when F. G. Benedict (c) noted in starvation experiments on man that con-
siderable quantities of creatin appeared in the urine. Following up this
observation, Benedict and Myers observed the elimination of varying
amounts of creatin in a large number of undernourished insane patients.
Subsequent observers have shown that creatin is regularly excreted par-
ticularly in carcinoma of the liver, diabetes, muscular dystrophy, exoph-
thalmic goiter, anterior poliomyelitis, pernicious vomiting of pregnancy,
typhoid fever and pneumonia. In all except the last two conditions
mentioned (fevers) this is accompanied by a lowered creatinin output,
and even in fevers this is true during convalescence. Judging from the
observations of Denis on the creatin content of human muscle obtained at
autopsy, it would appear that the excretion of creatin was generally
associated with a low muscle content. In carcinoma of the liver the
creatin elimination may be very large, 1-1.5 grams.
From the foregoing, it would appear that the excretion of creatin
was pathological, but Kose, and also Folin and Denis (6), have recently
observed the interesting fact that growing children excrete creatin while
according to Krause normal women periodically excrete small amounts
of creatin.
Muscle creatin has quite generally been regarded as the source of the
urinary creatin in starvation and pathological conditions associated with
undernutrition, although some workers have opposed this view. In the
case of starving rabbits Myers and Fine(rf) believed that they were able to
account for the creatin lost from the muscle on the basis of urinary
findings, but these observations can hardly be directly compared with
pathological conditions in the human subject. McCollum and Steenbock
494 VICTOR C. MYERS
have shown that the pig on a high protein diet from certain sources will
excrete creatin, while Benedict and Osterberg(a) have found that the phlor-
hizinized dog may eliminate very large amounts of creatin when fed on a
diet of thoroughly washed meat.
Different hypotheses have been advanced to explain the excretion of
creatin in children, such as under carbohydrate feeding, high protein
feeding and acidosis, but the experimental evidence advanced in their
support is not entirely convincing, although all these factors undoubtedly
exert an influence under certain circumstances. It is now well known
that the administration of carbohydrate in starvation causes a disappear-
ance of the creatinuria. Denis and Kramer believe that the creatinuria
in normal children is due to the relatively high protein intake which is
the rule with practically all children, also that creatinuria may be pro-
duced in women by very high protein diets. In this view they are opposed
by Rose, Dimmitt and Bartlett. Denis and Kramer further suggest that
the excretion of creatin in children may also be due to the low saturation
point of immature muscle owing 'to the low creatin content of the muscle
of children and the relatively low level of protein consumption at which
appreciable quantities of creatin appear in the urine. In support of this
argument Gamble and Goldschmidt(a) have observed a practically complete
elimination of ingested creatin in an infant on a high protein diet.
Granting that creatinin does come from creatin, the natural question
is: What is the precursor of creatin ? For this we have as yet no definite
answer. On account of its guanidin group, arginin naturally suggests
itself. The very close chemical relationship between arginin and creatin
is apparent from the formula of arginin.
- CH2 - CH2 -Clio - CH(NH2) - COOH
Arginin, or guanidin-amino-valerianic acid.
If arginin is the source it is transformed only in small part to creatin,
since the amount of the daily creatinin excretion could account for only a
small part of the arginin normally metabolized. From the studies of
Kossel and Dakin it appears that the greater part of the arginin is
hydrolyzed to ornithin and urea by the enzyme arginase, but experimental
data to show that creatin is derived from arginin are inconclusive. That
creatin is not present in invertebrate muscle has long been known, although
the presence of arginin and likewise betain has been shown. The possi-
bility that betain, and also the closely related cholin, are the percursors
EXCRETIONS 495
of creatin in the vertebrate has been suggested by Riesser(6), who has pre-
sented evidence in experiments on rabbits suggesting that both the
creatin content of the muscle and the creatinin elimination are increased af-
ter the administration of these substances. Myers and Fine(/) found that
the creatin content of the muscle of rats was very slightly increased (2.5
per cent) as a result of feeding with edestin, a protein relatively rich in
arginin. Bauman and Hines(fc) have perfused arginin, sarcosin, methyl-
guanidin, betain and cholin through dog muscle (hind leg) without
obtaining conclusive evidence of their being creatin formers.
Uric Acid. — Uric acid results from the cleavage and oxidation of
nucleoprotein, which is the chief constituent of all cell nuclei. Nucleo-
protein is split into protein and nucleic acid. When the nucleoprotein
is present in the food, this process takes place in the alimentary tract
under the influence of trypsin ; when the body cells are the source of the
nucleoprotein this transformation takes place in the tissues probably
through the agency of a similar enzyme. The protein fraction is digested
in the usual way, and the nucleic acid is further transformed, ultimately
yielding uric acid. Nucleic acid is a complex substance containing phos-
phoric acid, carbohydrate, pyrimidin and purin groups. In the molecule
there is a union of 4 complex radicals called nucleotids. A nucleotid is
a combination of phosphoric acid, a carbohydrate and a basic group which
may be purin (e. g., adenin or guanin) or a pyrimidin (e. g., cytosin,
uracil or thymin). In nucleic acids of plant origin, the carbohydrate is
usually a pentose (d-ribose), while a hexose is the carbohydrate found
in animal nucleic acids. Animal nucleic acids further differ from the
plant variety in having the pyrimidin, thymin, instead of uracil.
The nucleic acid is split into its component nucleotids, which experi-
ence another cleavage resulting in the liberation of phosphoric acid,
leaving carbohydrate-purin and carbohydrate-pyrimidin combinations. The
latter compounds are known as nucleosids and are eventually split, liberat-
ing the free purin and pyrimidin bases. The purin bases, adenin and
guanin, are then converted respectively into hypoxanthin and xanthin, this
change being accomplished by the enzymes adenase and guanase. Finally
by means of an oxidizing enzyme, xanthin is transformed to uric acid.
This process is graphically represented on the following page, the en-
zymes being enclosed in parenthesis.
The pyrimidins, especially cytosin, have been suggested as possible
purin precursors by Kossel, but no experimental evidence has been ad-
duced in support of this hypothesis. The fate of the pyrimidins appears to
be quite uncertain. Mendel and Myers found that when the three pyrim-
idins found in nucleic acid were administered to man or animals they
reappeared in the urine unchanged, and Wilson has made similar observa-
tions regarding the pyrimidin nucleosids.
496
VICTOR C. MYERS
Nucleic Acid
(nuclease)
I
Nucleotids
(nucleotidase)
Nucleosids
I nucleosidase)
Nucleoprotein
(protease)
Adenin
(adenase)
4
Hypoxanthin
(oxidase)
Guanin
(guanase)
4
— » Xanthin
(oxidase)
Protein
-» Uric Acid
We are familiar with the chemical structure of the purins owing
chiefly to the researches of Emil Fischer and his pupils. An apprecia-
tion of the chemical structure of this group of compounds is of material
aid in obtaining an adequate understanding of purin metabolism.
IN— 60 N = C(NH2) HN— CO
20 5C — N7\ HO C — NH (NH2)C C — NH
| | C8 || || \CH || || \CH
O-IN \tVy " -IN i/ f -i- 1 ~ ~~~ v-/ " -LN // j^\ "~ " \*j "* _IN //
Purin Nucleus or Adenin Guanin
Skeleton ( 6-amino-purm) (2-amino-6-oxy purin)
— CO HN — CO HN — CO
C
HO C — NH 00 C — NH -» OC
|| \CH
r— c — N/
Hypoxanthin
(6-oxypurin)
|| \CH C(
HN — C — N/ HN — C — NH/
Xanthin Uric Acid
(2, 6-dioxypurin) 2, 6, 8-trioxy-purin
It has been claimed that in man about half the uric acid is subject to
a further enzymatic change (uricolysis). This, however, is still a dis-
puted question although in animals the greater part of the uric acid is
undoubtedly converted to allantoin.
EXCKETIONS 497
UN -CO HISF-CO
OC C — NH
:CO
OC
\
CO
/
-C--NH- HN-CH-NH
Uric Acid Allantoin
The difference in the fate of uric acid in man, on the one hand, and in
the dog, rabbit, etc., on the other, is probably a quantitative one. Qualita-
tively there is no dissimilarity, for traces of allantoin do appear in human
urine, and the urines of the lower animals do contain small amounts of
purins (Hunter and Givens(c)). It is especially significant from the
standpoint of comparative physiology to learn that as far as their purin
metabolism is concerned, the monkey ranks with the lower animals rather
than with man. The purin metabolism of man, then, is unique in that uric
acid represents the principal excretory product. It is of further interest
to note that human blood contains from 10 to 60 times as much uric acid
as the blood of the rabbit, cat and sheep. Whereas the blood of these ani-
mals contains from 0.05 to 0.2 mg. of (free) uric acid per 100 c.c. of blood,
normal human blood contains 2 to 3 mg. A similar difference has been
found in the tissues of man and animals (Fine). This furnishes addi-
tional evidence pointing to the relative indestructibility of uric acid in
man.
From the fact that in birds the end product of nitrogenous metabo-
lism in general is uric acid, apparently of synthetic origin, the attempt
has been made to demonstrate a similar formation in man, but without
conspicuous success. For the present, uric acid must be regarded as aris-
ing solely from the oxidative transformations of the purin bases, whether
they already exist in the body or have been introduced from without.
The precursors of uric acid, nucleoprotein and purin bases, may be
present in the food or disintegrating cellular material of the body. In the
former case, the uric acid is said to be of "exogenous origin," in the latter,
of "endogenous origin." The output of endogenous uric acid will be de-
termined by the extent of the body cell activity. During starvation, for
example, the 24 hr. uric acid elimination may vary from 0.1 to 0.2 gram,
which may be increased to 0.2 to 0.4 gram on a purin-free diet. This
diet contains no uric acid precursors, and could, therefore, cause the in-
creased uric acid output only indirectly. It. is quite generally accepted
that the augmented output of uric acid following the ingestion of a purin-
free diet is due to the necessarily increased activity of the digestive glands,
thus raising the level of endogenous purin metabolism (Mares, Mendel and
Stehle). The administration of drugs, such as pilocarpin, which stimu-
lates glandular activity, also increases the uric acid output, while atrophin,
498 VICTOR C, MYERS
a glandular depressant, causes a reduction. With uric acid yielding- foods
as meat, meat extracts, pancreas, liver, thymus, peas, beans, etc., the out-
put will, of course, be the sum of endogenous and exogenous uric acid.
Mendel and Wardell have demonstrated that uric acid excretion may be
very definitely increased by the taking of methylated xanthins in coffee,
tea and cocoa, obviously indicating a demethylation of these purins. On
a mixed diet 0.5 to 0.6 gram of uric acid may be taken as the average
output of the human adult.
The greatest increase in uric acid elimination is observed in leucemia,
as much as 12 grams having been found to be excreted in 24 hours. This
high elimination of uric acid is without doubt to be referred to the enor-
mous increase in the number of leucocytes and consequent leucolysis.
An increased uric acid excretion is observed in other diseases associated
with a high grade of leucocytosis. Although in gout deposits of sodium
urate may be found in certain of the articular cartilages, and the blood
uric acid increased owing to faulty elimination, still the quantitative ex-
cretion of uric acid in gouty individuals does not differ markedly from that
found normally. It may, however, be noted that for two or three days
preceding an attack of acute gout the uric acid elimination is diminished ;
while during and for a few days after the attack it may maintain a level
somewhat above normal.
It has been recognized for some time that the excretion of uric acid
was stimulated by the administration of salicylic acid and phenylcincho-
ninic acid and their derivatives, and they have frequently been referred to
as "uric acid eliminants." Myers and Killian(c) have recently pointed out,
however, that this action is not specific for uric acid. It has been found
that in suitably selected cases, having slightly increased blood urea (and
possibly also creatinin) findings, administration of the above compounds
will lower the blood concentration of these constituents as well as the uric
acid.
Ordinarily uric acid is present in the urine in combination with sodium,
potassium or ammonium. Only when the urine is especially acid does
uric acid itself separate out. When the urine is concentrated or after the
ingestion of considerable meat, pancreas, etc., urates may be deposited
shortly after the urine is voided. In other cases such deposits may form
on standing in a cool place.
Purin Bases. — A small portion of the purin bases, adenin, guanin,
hypoxanthin and xanthin escape conversion to uric acid, and appear un-
changed in the urine. About 0.02 to 0.05 gram of such compounds may
be eliminated.
Hippuric Acid. — Hippuric acid is a combination of glycocoll and ben-
zoic acid. By this conjugation which takes place in the kidney, although
it may be formed elsewhere (Kingsbury and Bell), the body is able to de-
fend itself against the more toxic benzoic acid. For this reason small
EXCRETIONS 499
amounts of benzoic acid or sodium benzoate would appear to be harmless.
Hippuric acid is found in the urine of herbivorous animals, such as the
horse and cow, in large amount, but only about 0.7 gram per day occurs
in human urine. Certain fruits and berries, cranberries in particular,
contain appreciable amounts of benzoic acid, while certain aromatic sub-
stances of vegetables are ultimately converted to benzoic acid. It may also
be formed by the putrefactive decomposition of the phenylamino acids in
the intestine. Benzoic acid or sodium benzoate is often used as a pre-
servative in canned fruit and catsup. All these factors contribute to the
hippuric acid output. It is stated that hippuric acid is decreased in fevers
and in certain kidney disorders where the synthetic activity of the renal
cells is diminished.
Oxalic Acid. — Oxalic acid in the form of calcium oxalate usually oc-
curs in the urine in very small amounts, about 0.02 gram in 24 hrs. Oxa-
lic acid is probably formed from the metabolism of proteins and fat. Its
output may be increased by the ingestion of foods which contain oxalic
acid. Such foods are cabbage, spinach, apples, grapes, etc.
Aromatic Oxyacids and Derivatives.— Under this heading may be men-
tioned phenol, p-cresol, indoxyl, scatoxyl, indol acetic acid and homogen-
tisic acid. These substances are all formed from the amino-acids, trypto-
phan, tyrosin and phenylalanin. Homogentisic acid is apparently formed
as a result of abnormal oxidation of the last two amino-acids men-
tioned. It occurs in alkaptonuria, a comparatively rare anomaly of metab-
olism. In this condition the excretion may amount to as much as 16
grams per day, although ordinarily it is less, i. e.} 3 to 5 grams. Intestinal
putrefaction (in rare instances, putrefaction elsewhere in the body) gives
rise to the formation of the other bodies mentioned. Phenol, />-cresol, and
indoxyl are eliminated in the urine partly in combination with sulphuric
acid, constituting the ethereal sulphates. Indoxyl-potassium-sulphate, or
indican, appears to depend upon the amount of intestinal putrefaction,
and to be an excellent index of it, but the same can hardly be said of the
ethereal sulphates as a whole, indicating that in part they have another
origin. Under normal conditions from 5 to 20 mg. of indican are excreted
per day, but in conditions showing excessive intestinal putrefaction as
much as 200 mg. may be eliminated. In certain of these cases indol acetic
acid is excreted, giving rise to the so-called urorosein reaction. According
to the recent studies of Folin and Denis the larger part of the phenols
(phenol, p-cresol, etc.) are excreted in the free form. The daily elimina-
tion of phenols appears to average about 300 mg., of which about 60 per
cent is free and 40 per cent conjugated.
Sugar. — Sugar appears to be present in normal urine in very small
amounts. As a result of the recent studies of Benedict, this subject has
attracted considerable interest, Normal urine apparently contains from
0.02 to 0.2 per cent of sugar with an average of about 0.07 per cent. Of
500 VICTOR C. MYERS
this sugar roughly half is fermentable. The 24 hr. elimination may vary
from 0.5 to 1.5 grams, but from a large series of analyses made by Croll
on hospital cases the daily average would appear to be about 0.7 gram.
Unless the carbohydrate tolerance is definitely disturbed, larger amounts
do not appear to be excreted. Even in hyperthyroidism comparatively
normal values are found.
Inorganic Constituents
The inorganic constituents of the urine are chiefly the sodium, potas-
sium, calcium, magnesium and ammonium salts of hydrochloric, phos-
phoric and sulphuric acids. The salts of sodium and potassium are elimi-
nated almost exclusively in the urine, but, as pointed out in the section
on feces, much more calcium and magnesium are eliminated by the intes-
tine than by the kidneys, these elements being largely in combination
with phosphoric acid. The average inorganic solid elimination in the
urine amounts to about 20 grams daily, sodium chlorid ordinarily con-
tributing considerably more than half of the total. The average elimina-
tion of these different constituents for the human adult may be given as
follows :
Grams
Sodium as ]N"a2O 6.0
Potassium as K2O . , 3.0
Calcium as CaO 0.3
Magnesium as MgO 0.2
Ammonium as NH3 . 0.6
Iron as Fe 0.003
Chlorids as Cl 7.0
Phosphates as P2O5 2.5
Sulphates as S03 2.0
Long and Gephart have made fairly complete mineral analyses on
the composite urines of six healthy adults. They found that they could
obtain an almost exact balance between acids and bases, if they assumed
that four-fifths of the phosphoric acid was held as dihydrogen phosphate
and one-fifth as monohydrogen phosphate. On this basis they suggested
the arbitrary salt combinations given in tabular form on the next page.
Chlorids. — The amount of chlorids, chiefly sodium chlorid, excreted
per day is dependent upon the food chlorids. The elimination is quite
variable but ordinarily falls between 10 and 15 grams. Some people
ingest very large amounts of salt with their food. This salt is absorbed
and passes rapidly through the kidneys into the urine. In starvation the
sodium chlorid excretion is reduced to a minimum. The same conditions
EXCRETIONS 501
Grams
Sodium chlorid 13.00
Potassium chlorid . . 4 23
Calcium sulphate o.52
Magnesium sulphate 0.61
Ammonium sulphate 1.52
Ammonium urate 0.58
Potassium urate 0.03
Potassium phenyl sulphate 0.42
Potassium dihydrogen phosphate 2.56
Potassium monohydrogen phosphate. . . 0.86
obtain in cases of carcinoma of the stomach, resulting in stenosis of the
pylorus, essentially a condition of starvation. The sodium chlorid elimi-
nation is decreased «by those conditions which favor its removal from
the blood through other channels, e. g., cases of diarrhea, rapidly formed
transudates and exudates, such as pleurisy with effusion. It may be
pointed out that for several days after the reabsorption of an exudate,
the chlorid excretion may be greatly increased, and is here a favorable
diagnostic sign. Diminished chlorid elimination is observed during the
crises of acute febrile diseases, especially pneumonia and in nephritis
with edema, in the latter case because of the relative impermeability of
the kidney to salts. In febrile diseases it is worthy of note that the elimi-
nation of chlorids progressively decreases as the febrile process approaches
its crisis, and tends to rise to its original level during convalescence. It
has been observed that in pneumonia there is, if anything, a decreased
chlorid content of the blood, while in exceptional cases of nephritis with
marked edema, the chlorids of the whole blood may rise from the normal
of 0.45-0.50 per cent to as high as 0.7 per cent. Such cases do not gen-
erally show marked nitrogen retention.
Phosphates.' — Two types of phosphates are present in urine, the alka-
line phosphates, salts of the alkali metals, and earthy phosphates, salts
of the alkaline earth metals. In the normally acid urine the larger part
cf the phosphoric acid is generally present as l^a or KH2PO4, the dihy-
drogen phosphate. The urinary excretion of phosphates as P2O5 amounts
to 1 to 5 grams, with an average of 2.5 grams. This originates to a small
extent in the setting free of phosphoric acid in protein metabolism, but
to a greater extent in the phosphates of the foods. The extent to which
the latter control the phosphate excretion in the urine depends upon the
relative abundance of alkali and alkali-earth phosphates. The alkali-
earth phosphates are difficultly absorbable and hence are in great part
eliminated directly through the feces, thus contributing but little to
urinary phosphate. Ordinarily about two-thirds of the phosphorus is
eliminated in the urine, but a diet containing a very large amount of
502
VICTOR C. MYEES
milk, for example, will increase the fecal excretion. The alkali phosphates
are absorbed and add to urinary phosphate to a large extent, but even
these may be converted into alkali-earth phosphates in the body and be
in part excreted into the intestine, reappearing in the feces. About
1 to 4 per cent of the phosphorus excreted is in an organic combination
of unknown nature. The phosphate elimination is said to be increased
in periostosis, osteomalacia, rickets and after copious water drinking;
and decreased in acute infectious diseases, pregnancy and diseases of the
kidney. Sherman and Pappenheimer have recently shown that phos-
phorus may be made the limiting factor in experimental rickets in rats,
while a number of investigators have observed a retention of inorganic
phosphorus in the blood in nephritis. The retention of acid phosphate,
or rather the inability to excrete acid phosphate, is probably a very impor-
tant factor in the latter condition. At times a turbidity due to phos-
phates may be observed. This is sometimes erroneously interpreted as
indicating an increased elimination of phosphates, uphosphaturia." It
is more likely due to a condition of decreased acidity and is more properly
termed "alkalinuria." This precipitation of phosphates may also be due
to an unusual amount of calcium which would form one of the less soluble
phosphate combinations.
Sulphates. — Sulphur is excreted in three forms : oxidized or inorganic
sulphur, e. g., the sulphates of sodium, potassium, calcium and magnesium;
ethereal sulphur, e. g., sulphates of phenol, indoxyl, scatoxyl, cresol, etc. ;
neutral sulphur, e. g., cystin, cystein, taurin, hydrogen sulphide, etc.
The greater part of the sulphur of the urine is present in the oxidized or
inorganic form, averaging rather more than 2.0 grams calculated as SO3,
this as a rule being about 10 times the amount of ethereal sulphates ex-
creted. The ethereal sulphates normally amount to 0.20 gram and the
neutral sulphur to about the same amount, although sometimes being more
and sometimes less. The neutral sulphur elimination is relatively unin-
fluenced by the diet, and Folin regards it as being analogous to the crea-
tinin. An idea of the distribution of the sulphur on a high and on a
low protein diet may be obtained from the table on page 486. The inor-
ganic sulphur of the urine arises mainly from the oxidation of the sul-
phur of the protein, and is thus increased by those conditions which stimu-
late protein metabolism such as acute febrile diseases, and decreased when
the rate of metabolism is lowered. The ethereal sulphates of the urine
are increased by excessive formation and absorption from the intestine of
products of putrefaction, e. g., phenol, indol, skatol, or by the administra-
tion of similar aromatic bodies such as phenol, cresol, resorcinol, etc.
Sodium and Potassium. — The quantity of sodium ordinarily present
in the urine parallels quite closely the amount of chlorin. The excretion
in the healthy adult may be given as 4 to 8 grams with an average of
about 6 grams calculated as Na2O. The proportion of !N"a to K is fairly
EXCKETIONS 503
constantly maintained at about 5 :3. It is well known that foods rich in
potassium, such as meat and potatoes, require more salt than other foods.
The quantity of both of these elements excreted depends chiefly upon the
food. In starvation or during fever the potassium of the urine may be in
excess owing to a destruction of the body's own tissues.
Calcium and Magnesium. — Since the larger part of the calcium and
magnesium eliminated are excreted in the feces it is always necessary to
have data on the fecal excretion of these elements to make satisfactory de-
ductions (see discussion on page 511). Under different conditions of diet
the calcium excretion in the urine may vary from 0.1 to 0.5 gram calcu-
lated as CaO, and the magnesium from 0.1 to 0.3 gram calculated as MgO
depending upon the diet ; sometimes the calcium is in excess in the urine
and sometimes the magnesium. In a series of 25 healthy adults Xelson
and Burns found the calcium in excess in IT and the magnesium in 8.
The figures for the CaO ranged from 0.13 to 0.49 gram and for the MgO
from 0.12 to 0.30. In this connection they state that either calcium or
magnesium may be excreted by way of the urine in the larger amount,
in the normal individual. Whichever element predominates does so con-
stantly, or very nearly so, and seems to be independent of the character
of the food ingested. The excretion of calcium and magnesium does not
necessarily run parallel pathologically, since there may be a retention
of magnesium in certain bone disorders accompanied by a loss of calcium ;
for example, osteomalacia. Very little is known, however, about the
pathological excretion of these elements. The lime salts absorbed are in
great part excreted again into the intestine, and the quantity in the urine
is therefore no measure of their absorption. The introduction of readily
soluble lime salts or the addition of hydrochloric acid to the food may
therefore cause an increase in the quantity of lime in the urine, while
the reverse takes place on the addition of alkali phosphate to the food.
In other words, the balance between the acid- and base-forming elements
in the foods has a very important bearing upon the excretory path of these
elements and phosphorus.
Iron. — Iron exists in the urine only in very small amount (1 to 5 mg.
per day) and that in organic form. It is largely eliminated by the intes-
tine.
Feces
It has long been the common notion that feces are composed of the
residues of undigested food. In health, however, this is far from the
truth. It is easy to comprehend that the nitrogenous waste products of
the urine are derived from the catabolism of protein in the body, but
since the intestinal canal is a long tube open at both ends through which
undigested material may pass, it has been difficult to appreciate that
504 VICTOR C. MYERS
under normal conditions the feces are composed largely of intestinal
secretions and excretions, together with bacteria, cellular material from
the intestinal walls and food residues. Furthermore as Mendel (a) and his
coworkers have shown, the feces is the normal path for the elimination of
a number of foreign inorganic elements, such as strontium, barium, etc.
As a proof that feces are a true secretion, it has been shown by F. Voit
that the material secreted in an isolated loop of the intestine of a dog-
is of similar composition, and contains the same amount of nitrogen as
the feces of the normal intestine through which food is passing. Espe-
cially significant are the observations of Mosenthal(a), who also worked
with isolated intestinal loops, and estimated that the succus entericus con-
tained nitrogen equivalent to 35 per cent of the nitrogen ingested, and 300
to 400 per cent of the nitrogen of the feces. Nitrogen equivalent to at least
25 per cent of that of the intake must therefore have been reabsorbed.
Prausnitz has pointed out that the nitrogen content of the feces of the
same individual on a meat and on a rice diet are practically identical,
indicating the metabolic origin of the nitrogen. He defines normal feces
as those resulting from the eating of any food that is completely digested
and absorbed. Such foods as milk, cheese,- rice, eggs, meat, macaroni and
white bread are largely available for the use of the organism and conse-
quently yield a comparatively small amount of feces. On the other hand,
the cellulose containing vegetables do not possess this availability and
therefore yield a much more copious fecal output. Cabbage is an excel-
lent illustration of such a vegetable. It is logical to expect that on a diet
whose constituents are not entirely available, not only would the amount
of feces be increased by the undigested cellulose, but also the nitrogen
content would be increased because of the large amount of digestive juices
secreted, the large volume of food and the accompanying increased peri-
stalsis. Although the exact composition of a large part of the organic
material eliminated in the feces is unknown, still it is now recognized that
bacterial substance forms a considerable part of this material.
The fact that about one-third of the dry matter of normal human feces
consists of bacteria, and at least one-half of the nitrogen of the feces is
bacterial in its origin, serves to emphasize the importance of bacteria in
the intestinal canal, though experimental evidence would indicate that
the presence of this large number of bacteria is a normal and even useful-
condition. MacNeal, Latzer and Kerr, who have devoted considerable
attention to the bacterial content of the feces, find that in normal subjects
the bacterial dry substance varies between 1.8 and 9.2 grams with an
average of 5.3 grams per day, while the bacterial nitrogen ranges between
0.2 and 1.0 gram with an average of 0.6 gram, this latter figure constitut-
ing 46.3 per cent of the fecal nitrogen. Of the fecal bacteria they find
that 80. Y per cent are Gram negative (45,0 per cent B. coli type), 17.0
EXCRETIONS 505
per cent Gram positive and 2.3 per cent free spores. Mattill and Hawk(a),
who employed the MacNeal method slightly modified (no ether extrac-
tion used), obtained slightly higher results on two subjects who were
followed for several weeks. They found that the bacterial nitrogen aver-
aged 53.9 per cent of the fecal nitrogen and the bacterial dry substance
8.27 grams. Tinder normal conditions the bacteria probably derive their
sustenance in considerable part from the intestinal secretions and excre-
tions, but pathologically they may decompose appreciable amounts of par-
tially digested protein and carbohydrate.
In nurslings the bacterial flora is relatively simple, though later in
life the number of these bacterial forms becomes very large. The dominant
organism in nurslings is B. bifidus (B. acidophilus of Moro is also
present), but this is ultimately replaced by B. coli and B. ladis
acrogenes. Other organisms which may be observed are coccal forms,
B. welchii, and in certain cases, B. putrificus (Herter(d)). These last two
organisms Herter is inclined to associate with conditions of excessive putre-
faction in the intestines. MacNeal has pointed out, however, that B.
welchii can generally be detected in normal stools. In early life the prod-
ucts of intestinal decomposition are very small in amount, and, as would
be expected, the number of putrefactive bacteria are few. One finds,
however, in middle life a large number of persons in whom the putre-
factive conditions in the intestine are distinctly more active than was the
case earlier in life. Apparently the most important factors in bringing
about this strongly proteolyzing type of bacterial flora are the consumption
of an overabundance of protein food, combined with inadequacy in the
digestive juices, delayed absorption, and insufficient motility in the ali-
mentary canal. Very little decomposition takes place in the large intes-
tines under the action of B. coli, however, if the absorption in the small
intestine has been good. Rettger and his coworkers have recently pointed
out that the daily administration of 150-300 grams of lactose or dextrin
to adults will, with few exceptions, bring about a marked change in the
bacterial flora in which the usual mixed types of bacteria give way to
B. acidophilus, which is a normal intestinal organism, but which is pres-
ent in the intestine after early infancy in relatively small numbers only.
This method would appear to possess interesting possibilities of thera-
peutic usefulness.
Amount. — Upon the ordinary mixed diet, the daily fecal excretion of
the adult, male averages from 100 to 150 grams, with a solid content vary-
ing between 20 and 40 grams. Upon a vegetable diet the fecal output
will be much greater, reaching 350 grams with a solid content of 75
grams, and even more. This being the case, data on variations in the
daily excretion are of little practical significance, except where the com-
position of the diet is accurately known. Lesions of the digestive tract,
a defective absorptive function, or increased peristalsis, as well as admix-
506 VICTOR C. MYERS
ture of mucus, pus, blood and pathological products of the intestinal wall
may cause the total amount of feces to be markedly increased.
Consistency— The form and consistency of the feces is dependent, in
large measure, upon the nature of the diet. Under normal conditions the
consistency may vary from a thin, pasty composition to a firmly formed
stool. Feces which are exceedingly thin and watery generally have a path-
ological significance.
Color. — The fecal pigment of the normal adult is hydrobilirubin, also
called stercobilin. It has its origin in the bilirubin of the bile, being
formed by the reducing action of certain bacteria. Hydrobilirubin is
probably identical with the urobilin of the urine. This pigment is pres-
ent in both the urine and feces, partly in the form of its chromogen,
urobilinogen. This is transformed to urobilin under the action of light.
Normally hydrobilirubin appears to be largely reabsorbed and converted
to bilirubin. • In pernicious anemia the destruction of red cells is so rapid
that it cannot be reabsorbed, thus leading to a marked excretion of the
reduced pigment in the stool, a very valuable point in the differential
diagnosis of primary and secondary anemia. (It is not. increased in sec-
ondary anemia.) In certain liver diseases there is sometimes a breakdown
in the ability to reconvert urobilin to bilirubin, which leads to the appear-
ance of the pigment in the urine in abnormal amounts. Neither bilirubin
nor biliverdin occur normally in the feces of adults, although bilirubin
sometimes occurs in the stools of nursing infants.
The diet is the most important factor in determining the color of the
feces. On a mixed diet the stools may vary in color from light, to dark
brown, on an exclusive meat diet the stools are brownish black, while on
a milk diet they are invariably light colored. Cocoa produces reddish
brown feces, while with certain berries the feces may be almost black.
Pathologically, absence of bile, or any condition producing a large amount
of fat, gives clay colored stools; blood from the upper part of the ali-
mentary tract yields "tar feces."
Odor. — The odor of normal feces is generally stated to be due to skatol
and indol. However, these aromatic putrefactive substances are generally
found in such small amounts as to be an insufficient explanation on this
point. Hydrogen sulphid and methylmercaptan probably play a certain
part in the disagreeable character of the odor. The intensity of the odor
depends to a large extent upon the diet, being very marked in stools from a
meat diet, much less marked in stools from a vegetable diet, and often
hardly detectable on stools from a milk diet. The stool of the infant is
ordinarily quite odorless, and any decided odor may generally be traced
to some pathological source.
A simple division of fecal material may be based upon the separation
afforded by the customary procedures, viz., the estimation of the total
nitrogen, ethereal extract, carbohydrate residues and ash. The results
EXCRETIONS 507
obtained with these methods have yielded data of great scientific impor-
tance, though the time required and the nature of the results render
them of comparatively little value diagnostically.
An idea of the approximate composition of feces in the normal human
adult may be obtained from the tabular data below. Except for the
moisture content, the percentage figures are on a dry basis.
Grams Per Cent
Moist feces 120
Air dry feces 30
Moisture content '. . . 75
Nitrogen 1.8 6
Ether extract 6.0 20
Carbohydrate 1.0 3
Ash 4.5 15
Nitrogenous Substances. — Three sources are usually considered as
contributing to the nitrogenous material excreted in the feces ; food resi-
dues, residues of the digestive juices and cellular material from the
intestinal wall, and bacteria and their products. The quantity of this
nitrogen normally amounts to from one to two grams and from four to
eight per cent of the dry feces. As already pointed out 0.5 to 0.8 gram
of nitrogen is daily eliminated in the form of bacteria. This constitutes
just about half of the fecal nitrogen and corresponds almost exactly with
what is ordinarily spoken of as the "metabolic nitrogen." Upon a meat
diet the food residues represent almost nothing under normal conditions,
i. e., the muscle protein is practically 100 per cent utilized, and further-
more the fecal nitrogen is almost wholly "metabolic" in origin. In the
case of vegetable proteins it has been a matter of common observation
that the utilization was not so good as with animal proteins. This in
part at least is explained by the inaccessibility of certain of the vegetable
proteins to the digestive juices, for as Mendel and Fine have shown, the
proteins of the wheat, and probably also of the barley and corn, are as
well utilized as meat, when taken in pure form or freed from extraneous
cellular substance. With legumes the utilization does not appear to be
quite so good. In order to calculate the digestibility of various proteins
and make allowance for the "metabolic nitrogen" Mendel and Fine pro-
pose the determination of the volume and nitrogen of feces resulting from
the material under investigation, with the subsequent determination of
the fecal nitrogen resulting from a nitrogen-free diet to which has been
t'dded an amount of indigestible non-nitrogenous matter that will yield
approximately the same volume of feces as in the first instance. The
excess of fecal nitrogen of the first test over the second is presumably due
to the undigested or unabsorbed nitrogenous matter of the food material.
508 VICTOR C. MYERS
With regard to the elimination of fecal nitrogen under pathological
conditions, observations show that it is increased in biliary obstruction,
intestinal fermentative dyspepsia, and diarrhea ; and decreased in chronic
constipation.
A great variety of substances may be formed by bacterial action upon
protein or its cleavage products. Among such may be mentioned indol,
skatol, phenol, indol acetic acid, various oxyacids, in certain instances,
putrescin and cadaverin, etc. That intoxication may result from poisonous
products formed by bacterial action can hardly be questioned, though
just what the substances are that exert this action cannot be stated at
the present time. Mulsh attention has been devoted to the products of
bacterial action on tryptophan, viz., indol acetic acid (urorosein of
urine), skatol and indol. Myers and Fine found comparatively large
amounts of skatol and indol in the stools of pellagra patients. In many
of the patients the stools were rather soft. Ordinarily skatol appears
to be observed in the feces much less frequently than indol, but the reverse
was true in these cases. In the case showing the most severe putrefaction,
the skatol of the feces averaged 51 mg. and the indol 21 mg. per day.
The indican of the urine was much lower in this case than in several other
subjects who excreted much smaller amounts of skatol and indol in the
feces. It seems questionable whether the skatol and indol in the amounts
absorbed in this way have any toxic properties. The presence of large
amounts of indican in the urine, however, is excellent evidence of in-
creased intestinal putrefaction.
Ethereal Extract. — The bodies which go to make up this ethereal
extract are the neutral fats-, free fatty acids (and fatty acids in the form
of soaps when an acidified solvent has been employed), and coprosterol
(stercorin of Flint) formed from cholesterol by the action of reducing
bacteria. Myers and Wardell found the coprosterol (and cholesterol) of
dry feces to vary between 0.5 and 1.5 per cent, the high figures being
found in soft stools. The ethereal extract ordinarily forms from 12 to
25 per cent of the dry weight of the feces. The utilization of fat varies
under normal conditions from 90 to 95 per cent, depending upon the
source of food. The higher fats such as stearin are much less readily
assimilated. In biliary obstruction as much as 70 grams of fat may be
eliminated in the feces, forming 50 per cent of the dry weight of the
material. In various conditions associated with defective fat digestion
(pancreatic disease) or defective fat absorption increased amounts may
be eliminated, while in chronic constipation the amount may be decreased.
In both biliary obstruction and pancreatic disease the fat utilization has
teen found to be as low as 25 per cent.
Carbohydrate Residues. — Normally feces may yield on hydrolysis
reducing substances equivalent to from one-half to two grams of glucose
or from two to six per cent of the dry weight of the feces. Although the
EXCKETIONS 509
utilization of carbohydrate has generally been given as about 98 per cent,
it is evident from these figures that on a diet of 300 to 400 grains carbo-
hydrate it is above 99 per cent. As Langworthy and Deuel have recently
pointed out, contrary to the general assumption, even raw starch may be
quite well utilized. Ordinarily starch digestion does not seem to be inter-
fered with, though the amount of carbohydrate eliminated in the severer
catarrhal conditions of the intestine may be slightly increased. One,
question to be asked with regard to all carbohydrate material is, are the
enzymes of the alimentary canal capable of hydrolyzing it ? As Mendel
and certain of his pupils have pointed out, there appear to be no enzymes
in the digestive tract capable of attacking certain of the more complex car-
bohydrates, such as agar agar, Iceland moss, inulin, certain galactans, etc.
Ash. — The inorganic constituents of the feces are derived partly from
the intestinal secretions and partly from the food. The proportion which
comes from the food varies with the nature of the diet. A purely meat
diet results in a lowering of the ash content, of the feces, while with a
milk diet the ash is increased, owing to the presence of unabsorbed lime.
On an ordinary mixed diet the ash of the feces generally falls between
10 and 15 per cent of the dry weight, but on a milk diet values of 25 to
35 per cent are found, about 40 per cent of which is due to calcium.
Pathologically, Cammidge has occasionally observed cases of chronic
colitis in which as much as 45 to 50 per cent of the dry weight of the
feces consisted of inorganic ash.
A general idea of the composition of human feces may be obtained
from the table on the next page taken from Myers and Fine, giving the
fecal analyses of a series of pellagra patients. Except for Case 5 (a male)
the patients were all rather small women. It is not believed that the
findings differ very materially from what would be found in other hospital
cases on similar diets, and with similar fecal movements. The cases have
'been divided into two groups, the first group having well formed stools,
and the second group soft or diarrheal stools. The diet in all cases was
lacto vegetarian, which probably explains the rather high ash figures ob-
tained. Estimations of iron and sodium were not made. The figures
recorded in the literature for the daily excretion of .sodium (as Na2O)
in the feces amount to 0.25 to 0.35 gram, and for iron (as FeO)
to 25 to 40 mg. (The daily excretion of iron in the urine varies from
1 to 5 mg.) An idea of the comparative importance of the intestines
and kidneys as paths for the elimination of various elements may be
obtained from the table on page 511. The figures are computed from the
previous table and urinary data for the same period.
An inspection of the table shows that in the first group of cases the
total nitrogen and total sulphur parallel each other very closely, as prob-
ably might be expected from their common origin (protein). With diar-
rhea, sulphur does not appear to be quite as well absorbed as the nitrogen.
510
VICTOR C. MYERS
O
t— «O CO «O M
00 t~ <M J^ US
CO
t—
Oi-i^-^l^C^OOOO
co-*Ti<inc5int^cso
O
i— 1
M
00000
o
f-!i— i o o o I-H o o' ci
I-H
0
bo
I-H TJ< oo co m
co m i— i co <N
00
CM
ocointNin^ooo
(M-^CM^HcocotNCO'*
OB
(M
S
00000
O
1
0
01
3
O
cd
O W CO T* O
o t^ oq a ••*
t^
0
omcsot--O5aOTt<o
t^COTfOOnHCSOTf^t
10
t~
t*
o
O
(M i-H i-H rt i-H
^
l-HIMl— lO<Mf-Hi— li-H(M
1-1
S
0
l-H Tj< ,-H O5 00
o Tt< t^ co o
CO
cocot^iMt^cscoaoo
r^OC5CO^H-*l^OOCO
t—
o
OJ
bo
PH
«H 1— 1 O t-H 1— 1
I-H
^Hr-lO'CJrHi-HOOrH
1-1
cj
t
O
cj
GO CC O CO OD
f-l (M i— l !O CO
o
CO
r-HoommmtMOt--'-1
t^com<MaOTt<t^cO'-i
CO
O
<!
£
00000
o
OOOOOOOO-H
0
j>>
O
CO •* U5 rH O
i-H i-H r— I CO f~H
o
aooaoeor— aoocjeo
cococo"— iincoco-^co
05
CO
Q
OQ
00000
o
o o o o o o o o o
o
£
co in >— i cs <-H
i— 1 1— m T»< o
CO
CS
Tt*i— io-^int— cooao
oo-'t^mco^co^fN
•*
»n
rH O O .-1 rH
o
rH^Ht— iO(M'-i'— 1 1— ioa
I-H
q
CO Tt< Tjl O5 ^
» m •* co oo
r--
SD
OSOCOC51— C3O(MCO
i— iCMO-^CJCOCOt-fM
00
m
M
fcj-g
O 00 CO t^ 00
t"
t— eo«NlcocoO5OOTj<
w
3 ?,
oL ^ •
i-H CO 5J O o'
r-<
mi— ico<Ninccooo5i—
CO
,C
<!
K
cS
m IM ;o in o
O5 m o o •*
1— 1
•*
os-^^coaocococoin
Ttaot--'-icocco5co'— i
o
ao
O
•^ -^ co m •*
•*
-<tinco(MinincoTjtr-
•<*
*
-p
oj
-tJ
»-. C
<J> S
o I-H oo m o
i-Hinocooocci^TjH
O
in
H3
p»i
PM u
CO •* (M (M (M
CO
•*-HHrt*<MOSCOt^mcO
in
O
,0
39
a
C2 CO •* CD O
t»
i— i(MOS(MCO(M»--cOTti
•*
03
o
eS
tH
C3
00000
o
i— l>-HOOCOi— ll-H^Hi-H
r^
•p
o
03
£
X
fel
^cS
i-l Tt< CO 00 Cvl
i— I (M <M T— i CO
<N
(N
(MC5OsJ3ooiomTjtin
(NrHi-lIN cOrt^Hcg
o
(M
$5
OD
i
t^ m <M in os
•*
•^eo-^rtosciiNcoin
•*
5
W
eS
>i
O
03 ^ co "^ to
•*
cdin'^ojojococoo
m
a~H
11 —
an ^
ro
OO O I— 1-4 t~
!>.
•^^H»nin»ncocooco
CS
-
>
•" '—
i o>
50,
Tj< Tj< CO to if
•*
co'irssomcOT^co'coin
m •
Moisture
+a
•s c
C (V
^0
§fe
^cS
•* •* to oo os
CO
t>.
O5i-H(M-*Tj*inaoooc5
t—oooooooooooooooo
•*
oo
-t-T
SB-
1C
^b?
CO O t^ Tj< ?O
•*
CO-^i-Hl—rJHOOOOi— i
OS
'S"
£
"05
CO OS CO T}< i— 1
(M •-> 1-1 (M (M
0
<M
OOl^COOSCOi-HG'lfM'-H
(N(M(M COCO(M(M'*
CO
(M
m
09
si
O
1-1 <M n •* w
i
<
cot^aoosO'HfNco'*
I-H I-H i-H I-H I-H
%
511
COMPARATIVE IMPORTANCE OF THE INTESTINE AND KIDNEYS AS EXCRETORY CHANNELS
Case
Percentage Output of Material Eliminated in Feces
of Total Output of Both Urine and Feces
H20
N
S
Cl
P
Ca
Mg
K
1. M. F. (b)
7
4
6
6
8
13
7
6
14
10
9
7
10
15
10
3
2
2
4
6
33
43
28
40
35
90
92
89
88
89
76
83
69
66
65
23
18
9
18
20
2 M. L
3. M. F. (a)
4. C. T
5. J. A
Averages
6
10
10
3
36
90
72
18
6. E. C
7
6
7
14
20
13
33
17
32
18
10
12
8
22
14
21
11
21
19
10
15
12
29
18
26
15
26
8
7
5
13
9
4
18
7
16
35
23
27
31
35
44
33
30
42
80
90
85
85
94
93
92
81
92
46
59
54
60
74
81
84
77
77
28
28
11
34
24
30
29
24
38
7. A. N
8. M. T
9. M. McH. (a)
10. R. N
11. L. G
12. M. McH. (b)
13. M. S
14. B. B
Averages
16
15
19
9
33
89
68
27
Although normally very little chlorid is eliminated by the intestine, the
amount found in the stools may be considerably increased in diarrhea.
About one-third of the total phosphorus output of the intestine and
kidneys is found in the stools. The percentage output in the feces of
both calcium and magnesium is high, due probably to the lactovegetarian
diet, which resulted in a poor absorption of compounds of these elements.
On a mixed diet about 60 per cent of both calcium and magnesium are
ordinarily eliminated in the feces of adults, although on milk diets the
stools of infants may contain considerably more than 90 per cent of
these elements. As might be anticipated from our knowledge of potassium
salts, a very appreciable amount of this element is eliminated in the
feces, and diarrhea considerably accentuates this elimination. Although
diarrhea very definitely reduces the absorption of nitrogen, sulphur,
chlorin and potassium, it appears to be almost without influence on the
phosphorus, calcium and magnesium.
It is evident, therefore, that calcium, magnesium and iron are nor-
mally eliminated chiefly by the intestine. Failure of absorption is par-
tially responsible for this, but in part these elements are secreted into the
intestines, as are such similar elements as strontium and barium '(Mendel).
The elimination of calcium and phosphorus are interrelated both as to
total excretion and path of elimination. An increased ingestion of either
causes an increased elimination of the other at the expense of the body's
store, if necessary. Proportionate increase in the intake of both increases
the fecal excretion. Marked deviation in the balance of calcium and
phosphorus partially diverts the elimination of the more abundant through
512 VICTOR C. MYEKS
the kidney. The excretion of magnesium and calcium are likewise inter-
related.
Sweat
Next to the kidneys, the skin is, in man, the most important channel
for the elimination of water. The volume eliminated varies widely under
different physiological and pathological conditions. Obviously the elimi-
nation in warm weather is much greater than in cold weather, also during
muscular activity than during rest. The specific gravity varies between
1.001 and 1.015, ordinarily amounting to about one-half the latter figure.
The solids range from about 0.4 to 2.0 per cent. The reaction may be acid,
neutral or alkaline to litmus, although under normal conditions it is most
often acid. Protein is generally present in traces.
The skin excretes, qualitatively, practically the same substances as
occur in the urine, namely, urea, ammonia, uric acid, amino-acids, crea-
tinin, chlorids, phosphates and sulphates. Probably for this reason it
has been more or less generally accepted that the skin and kidneys can
act, to a certain extent, vicariously. At one time the use of sweat-baths
in the treatment of nephritis was common. The quantity of substances
excreted by the skin, however, is quite insignificant in comparison to that
excreted by the kidney. In addition to their power to excrete water, the
sweat glands do appear to possess the power of excreting salt, the quantity
of sodium chlorid amounting to from 0.2 to 0.5 per cent.
A variety of methods have been employed to collect sweat. Probably
the most satisfactory procedure is to place the patient . in a rubber bag
during the sweating period. Sweat obtained in this way is a cloudy,
nearly colorless liquid, which settles or niters nearly or perfectly clear.
In the comparatively recent experiments of Riggs, and Plaggemeyer and
Marshall this was the method employed. In his work on the cutaneous
excretion of nitrogen, where an attempt was made to determine the
twenty-four hour excretion, Benedict extracted the nitrogen from specially
prepared underwear.
An idea of the composition of sweat obtained from normal subjects
and nephritic patients may be obtained from the table on the next page
compiled from the observations of Riggs. The sweat was obtained by
placing the subject without clothing in a rubber bag which enclosed the
entire body except the head. Sweating was induced by covering with a
pack of hot blankets for thirty to forty-five minutes.
The observations on the nephritic patients are not especially signifi-
cant. It is of interest, however, that in the first two cases where the
volume of sweat is large the percentage of nitrogen is low and the chlo-
rids high, whereas in the last two cases where the volume is small, the
reverse is true.
EXCRETIONS
COMPOSITION OF HUMAN SWEAT
513
N itrogeii
Urea
Specimen and Subject
Quan-
tity
Total
Ammonia
Urea
monia
Nitrogen
Terms of
Total N
Total
Solids
Sodium
Chlorid
1. Normal
c.c.
216
%
0.074
%
0 006
%
0 035
%
57
%
0 49
%
0 36
2 Normal . .
117
0.077
0 007
0 049
73
0 51
0 14.
3. Normal
246
0.050
0 007
0 026
66
0 3()
0 2'>
4. Normal
96
0.126
0 007
0 069
60
0 59
0 36
5. Normal
170
0.085
0 006
0 049
58
0 56
0 33
6. Normal
140
0.083
0 006
0 040
55
0 55
0 35
7—16. Nephritic on ro°'iilai
diet
324
0.064
0 05
t
82
0 52
0 46
17-23. Nephritic
221
0.077
0.05'
I
69
0 65
053
24-26. Nephritic
90
0.215
0.24
0.12
27-29. Nephritic
77
0.158
0.11
}
65
0 43
0.15
The total nitrogen content of sweat appears to vary from 0.05 to 0.20
per cent, from 50 to 80 per cent being in the form of urea and ammonia.
According to the observations of Benedict(a) the average daily loss of
nitrogen in the perspiration when the subject performs no muscular work
amounts to 0.07 gram, but during hard muscular work as much as 0.2
gram may be excreted in a single hour.
From the data of both Riggs and Plaggemeyer and Marshall the urea
content of sweat appears to amount in round numbers to 0.1 per cent.
As the latter workers have pointed out, the relationship between the differ-
ent forms of nitrogen in sweat and urine are entirely different. The con-
centration of urea in sweat is from three to ten times as high as that of
the blood but only one-tenth the concentration in the urine.
Uric acid occurs in swreat in much smaller amounts than in either blood
or urine, the concentration being about, one-twentieth that in blood and
one-five-hundredth that in urine. If creatinin is present it exists in very
small amounts.
The greater part of the total solids is made up of sodium chlorid,
although according to the observations of Riggs sufficient potassium is
present to combine with twenty per cent of the chlorin. For example,
with a vsolid content of 0.5 per cent one might expect a salt content of
0.35 per cent. The salt excreted in the sweat may readily amount under
certain conditions to two or three grams per day, a quantity ten times
that normally present in the feces. Phosphates are present only in traces.
A diastatic ferment is present in the sweat in appreciable amount.
Such dyes as phenolsulphonephthalein are not excreted by the skin nor does
the injection of phlorhizin result in the excretion of sugar by the sweat
glands.
SECTION V
Normal Processes of Energy Metabolism
John R. Murlin
Indirect Calorimetry — Methods of Measuring the Eespiratory Exchange by
Means of a Respiration Chamber — Methods for Measuring the Respira-
tory Exchange by Diract Connection with the Respiratory Passages —
Methods of Calculating the Heat Production from the Respiratory Ex-
change— The Non-protein Respiratory Quotient — Direct Calorimetry —
The Heat of Combustion — Animal Calorimetry — Basic Principles of
Energy Metabolism — The Energy of Muscular Work Is Definitely Re-
lated to the Potential Energy of the Food — The Energy Metabolism Is
Determined in Part by the Environing Temperature — The Indigestion
of Food Increases the Metabolism — Basal Metabolism — Energy Metab-
olism of Growth — Energy Metabolism of Pregnancy — Energy Metab-
olism of the Newborn Infant — Energy Metabolism from Two Weeks to
One Year of Age — Energy Metabolism of Children up to Puberty —
— Energy Metabolism of Old Age.
Normal Processes of Energy
Metabolism
JOHN R, MURLIN
EOCHESTER
It is a familiar fact that the temperature of what we call "warm-
blooded" animals is not only several degrees higher than the average tem-
perature of the atmosphere, but it is held constantly at this level despite
fluctuations of the environing temperature. So-called "cold-blooded" ani-
mals likewise produce heat, the difference being that in these the body
temperature is not regulated but is dependent upon the external temper-
ature. All animals therefore are transformers of energy. In fact experi-
ence and theory are in accord in regarding the production of heat as a neces-
sary consequence of the phenomena of life; it is a sign, indeed, of vital
activity.
There are two general methods of measuring the production of heat:
(1) by determining the intensity of the chemical processes (combustion)
by which heat is liberated in the organism; and (2) by registering directly
the heat disengaged by the organism in a calorimeter. The first is known
as the indirect or chemical method ; the second, the direct or physical
method.
A. Indirect Calorimetry
The indirect or chemical method depends upon the successful measure-
ment of the respiratory exchange. We must, therefore, consider at
some length the technology of this subject. In the meantime it may
be stated that the indirect method of calorimetry offers certain ad-
vantages over the direct method. When the latter subject is con-
sidered (page 567) it will be evident that in order to measure all of the
heat discharged from the animal body by the several routes of escape a
rather complicated apparatus is necessary. In time this may be simplified,
but at present an accurate calorimeter is far more complex and far more
costly both in initial cost and for operation than a respiration machine.
Secondly, the indirect method is more accurate as matters now stand.
Krogh(c) finds that he can measure oxygen absorption with his micro-
respiration apparatus to an accuracy of 2 cu.mm. of O2, equivalent to 10
515
516 JOHN K. MURLIN
milligram-calories in ten hours, while the highest accuracy attainable by
Bohr and Hasselbalch with their egg calorimeter was 100 milligram-calo-
ries. The percentage difference is not so great as this in applying the two
methods simultaneously to the study of the human organism; but one
comes very soon to rely upon the indirect measurement more than the
direct (see page 586). Furthermore, and in the third place the two meth-
ods agree very closely in the best forms of respiration calorimeters. This
being true and the indirect method being both simpler and more reliable,
greater space will be given to. its description and to the methods of calcu-
lating energy production from the fundamental data, than for the direct
method.
I. Methods of Measuring the Respiratory Exchange
by Means of a Respiration Chamber
The methods of measuring respiratory metabolism are of two general
kinds: (a) one requiring a chamber in which the subject is confined, and
(b) a method so devised that the respiratory passages are connected di-
rectly with the measuring apparatus.
JTwo general types of ventilation also have been used, one known as the
open-circuit and the other as the closed-circuit type. The classical instance
of the first type is the apparatus of Pettenkofer first described in 1863 and
later improved by C. Voit. The classical instance of the closed-circuit type
is the Regnault-Reiset apparatus first described in 1849. Only the more
important constructions of each type will be described here.
1. Open-circuit Type of Apparatus. — a. Pettenkofer Apparatus.—
The original apparatus of Pettenkofer consisted of a chamber containing
12.7 cubic meters which was ventilated by means of air pumps drawing
air from the outside. The air was aspirated through the chamber and at
the point of exit samples were measured after having been passed through
pumice stone saturated with sulphuric acid thence through barium hydrate
for the absorption of the carbon dioxid. In the earliest experiments per-
formed with the apparatus by Pettenkofer the efficiency of the absorption
system was checked by burning candles in the apparatus and an error of
1.96 per cent was found as the average for a considerable number of tests.
The error on the water absorption was somewhat higher, varying from 2.5
to 3.5 percent.
This apparatus was used exclusively with the human subject. For
obtaining the oxygen absorption Pettenkofer and Voit(c) employed the fol-
lowing method : Adding to the original weight of the subject the amount
of food consumed and the amount of water drunk a sum was obtained which
was subtracted from the final weight of the subject plus all of the excreta
(urine, feces, carbon dioxid and water vapor). The difference between
these two sums was taken as the oxygen absorption.
<3 a) cS £;
5?*5 5
a n-
3 &otȣ g . 8 8P B
3 ^ g" P « .
i gj w _. w -*-^ -*-* -+j w
i ±S > ^ £ «, * ^ -tj •
03 _ C-1- ^ "i IM HMJ w
C H-JJ 02 OS^o
^ 8 « -2 5^ g^
I « ^ S cS = &,
S
o g oi
I •» c "
^ c^ a; * aj
^ te 52 « 5 -£>
: u ^^
1 X! T3 &i
S B ft
-JJ ,2 ^H Q}" J_|
Jfl.!".!
! " *» -B J
»- B •
--
CD
« -• «8 .S * ta », .S, 3 S
« S ^ M S "^ "* k>r-S ^ S
o
a
-5 'S ^ £ ^H ^^ ^
S^-2^0 = -2^.
is* 1*1
- P 02 03 £X< ^
C3 P^
^2^0,5
^500
517
518 JOHN R MUKLIN
In the modified form of apparatus devised by Voit(d) for experiments
on small animals the suction pumps were replaced by a large meter- driven
by a water wheel which served at once to aspirate the air through thej3ham-
ber and to measure its volume. The chamber devised by Voit was of small
capacity containing only 64 liters. Larger chambers, however, were used
as, for example, the chamber in the accompanying figure which had a ca-
pacity of 340 liters.
The construction of the small suction pumps also was somewhat modi-
fied in the Voit construction and a very useful type of valve with mercury
seal known as the Voit valve was employed to give direction to the air
sample. (See figure 1.) With this type of apparatus in five control ex-
periments in which pure olein was burned in the form of a candle or tal-
low dip, an average error of 1.75 per cent was found for the CO2, and for
the absorption of water an error which varied from 1.4 to 5.5 per cent.
Wolpert(a) working under the direction of Rubner also made some
improvements on the Pettenkofer type of apparatus. His chamber
measured 1.5 x 2.5 x 2 meters with a cubic capacity of 7.5 cubic
meters. The measuring drum was driven by. means of a water motor.
The apparatus differed otherwise in only minor details from the Voit
construction, but Rubner (/) succeeded in measuring the water vapor
with a much greater degree of accuracy.
b. The Apparatus of Sonden and Tigerstedt. — This apparatus erected
at Stockholm and first described in 1895 was so constructed as to accommo-
date a number of individuals employed as subjects at the same time. The
chamber consisted of a room measuring 5x5x4 meters and had a total
capacity of approximately 100 cubic meters. The walls were sealed with
sheet metal carefully soldered together and the room was ventilated through
a zinc pipe measuring 14 cm. in diameter which was carried up above
the roof of the room and capped with a ventilator containing a valve to
guard against aspiration of air from the room by action of the wind. The
room was heated by steam and the air was kept stirred by means of an
electric fan. Ventilation was accomplished by means of pumps gauged
to three different speeds which could be adapted to the number of indi-
viduals serving as subjects. Samples of air were withdrawn from the
exit tube near its mouth and were analyzed by means of the Sonden-Petter-
son apparatus. Check experiments with burning candles or petroleum
gave an average error of 1.16 per cent on the CO2. In other series of ex-
periments performed later by Rosenberg the error was reduced to 1 pei
cent. This apparatus and a later one on the same principle at Helsingfors
( Tigerstedt (^r)) have been used especially for the study of metabolism in
school children.
c. The Apparatus of Atwater and Rosa. — This apparatus constructed
with the aid of the U. S. government in the chemical laboratory at Wesley-
an University, Middletown, Conn., was first described in 1897. It con-
NORMAL PROCESSES OF ENERGY METABOLISM 519
sisted of a chamber 2.15 x 1.22 x 1.92 meters or a cubic capacity of 5.03
cubic meters. It was ventilated by means of a so-called Blakeslee pump of
a reciprocating type. By means of a toothed wheel containing 100 teeth,
the first and fiftieth of which were longer than the others, samples of air
could be diverted from the main stream at each fiftieth stroke of the pump.
These samples were collected in pans for analysis.
The apparatus was not long used in this form. Realization of the
necessity for accurate determination of the oxygen absorption led to its
modification to the closed-circuit type as will be described later.
The apparatus was at once a respiration chamber and a calorimeter for
direct measurement of the heat. The method of heat measurement will
be described in a later section.
d. Apparatus of Jaquet. — This apparatus in its original form has a
cubic capacity of 1393 liters. The subject can either sit or lie down during
the observation. It is ventilated by means of a bellows driven by a water
motor, the air being withdrawn from one end through an exit tube and
being replaced by pure air from the outside which enters at the other end.
The air is passed through a gas meter after withdrawal from the apparatus.
Samples are aspirated from the exit tube by means of a mercury pipette,
the leveling bulb being lowered by means of a pulley connected with the
axle of the measuring meter so that the rate of sampling is proportional
to the rate of ventilation.
The air analyses for CO2 and O2 are accomplished by means of the
Petterson apparatus.
Precaution against change of composition of air in the apparatus is
taken by analysis of the air just before the beginning and just at the end
of an observation period.
By burning alcohol in the apparatus an average error of 1.8 per cent
was attained. An experimental period could be prolonged with this ap-
paratus for some 12 to 13 hours.
e. Apparatus of E. Grafe(b}. — This is a modification of the Jaquet
type of apparatus so constructed as to accommodate a man in a standing,
sitting or lying position. The respiration chamber consists of a rectangu-
lar base bordered by a groove into which the superstructure of the chamber
is made to fit air-tight by means of a liquid seal. The whole upper part of
the chamber is suspended from the ceiling of the room by means of pulleys
and a counterpoised weight. Entrance to the apparatus is gained by rais-
ing one end of the superstructure. The rectangular section of the ap-
paratus measures 0.9 meter at the head and foot ends and 2 meters in
length. In the vertical section one end is higher than the other, measuring
1.7 meters at the head end and 0.75 meter at the foot end. The frame
is constructed of wood covered with sheet metal painted with an oil paint.
Ventilation of this apparatus is accomplished in exactly the same man-
ner as in the original Jaquet construction, air being drawn through and
520
JOHN E. MUELIN"
measured simultaneously by means of a gas meter driven by water power.
Samples taken by the aliquot method of Jaquet are analyzed for oxygen
and CO2 by means of the Petterson analyser.
The apparatus used by Krogh and Lindhard at Copenhagen is of the
Jaquet-Grafe type (Fig. 2).
f. Apparatus of Haldane(a^). — A convenient form of open circuit type
of apparatus devised for observations on small animals is that of Haldane
described in 1892. The respiration chamber (Figure 3) consists of a large
Fig. 2. Diagram of the Jaquet-Grafe respiration apparatus used by Krogh and
Lindhard. The floor is made from a single sheet of galvanized iron with the edges
bent down into a U-shaped rectangular groove ( 1 ) which is filled with water. As
shown at (2) one end can be lifted to let in the subject and put in the apparatus;
(3) small tubes introducing wires, etc., for the working of the ergometer; (4 and 5)
ventilating tubes for use with a meter; (6) inlet for outside air; (7) side tubes
drawing air from points 50 cm. from the outlet; (9 and 10) fans for mixing the air;
(11) wet and dry bulb thermometers; (12) bottle of water keeping water level in
the meter; (13) hand sampling apparatus; (14) automatic sampling apparatus; (15)
tube leading from outlet to the automatic sampling apparatus; (16) thermometer in
the meter.
bottle of 16 liters capacity. Air is aspirated through the bottle by means
of an ordinary laboratory water suction pump. The ingoing air is passed
over sulphuric acid in pumice stone and another bottle containing soda
lime. The outgoing air is likewise passed through three absorbers, the first
containing sulphuric acid, the second soda lime and the third sulphuric
acid. The gain in weight of the first gives the amount of water vapor
exhaled by the animal. The gain in weight of the second two gives the
amount of carbon dioxid exhaled. After passing the absorbers the air is
again saturated with moisture and measured by a gas meter.
The apparatus is of such a size that the chamber with the contained
animal can be weighed. Loss in weight of the animal during an experi-
NORMAL PROCESSES OF ENERGY METABOLISM 521
z..
ment less the gain in weight of the absorbers gives the amount of oxygen
absorbed.
2. Closed Circuit Type of Apparatus. — In most of the open-circuit
types of apparatus thus far described the determination of oxygen is in-
direct, being based upon the loss of body weight of the subject. The absorp-
tion of oxygen can be determined directly, however, provided the subject is
enclosed in an air-tight system of known capacity. The simplest system
of this sort consists of a respiration chamber only of large enough capacity
to supply oxygen and permit respiration of ordinary atmospheric air with-
out discomfort for at least an hour. By analysis of a sample of air at the
beginning and the end of an observation it is possible to learn from the
changed composition the amount of oxygen absorbed and the amount of
C02 given off.
Fig. 3. Haldane respiration apparatus. Ch, chamber; 1 and 2 absorbers for
ingoing air; 3, 4, and 5, absorbers for outgoing air; M, meter; J, safety bottle; P,
air pump.
A more physiological arrangement, however, is to provide for the ab-
sorption of the carbon dioxid approximately as rapidly as it is produced
and its replacement by oxygen. The observations can then be prolonged
for many hours.
a. The Apparatus of Regnault and Reiset. — This is the original closed-
circuit apparatus. The respiration chamber consists of a glass bell of 45
liters capacity (A, Fig. 4). The bell is fitted by an air-tight seal into a
metal base which serves at the same time as the base for the surround-
ing water jacket. Entrance to the chamber is gained by means of a circu-
lar opening in the base. The top or handle of the bell is perforated by
several tubes one of which connects with a mercury manometer (a, b, c)
for recording the pressure inside the chamber. A second connects with a
sampling apparatus d'. Two others connect with the CO2 absorbers C and
C', and a fifth with the oxygen supply (the flasks N, W and N"). The
CO2 absorbers have a capacity each of about three liters. The absorbing
fluid is an assayed solution "of KOH. Movement of air from the chamber
to the absorbers is accomplished by alternately raising and lowering the
absorbers. For example, when C is raised as in the figure the fluid runs
522
JOHN R. MURLIN
from C into C', thereby aspirating the air into C and returning air from
C' to the respiration chamber. By thus absorbing the CO2 produced by
the subject the volume of the contained air is reduced and its place is
taken by oxygen driven from the flask N by water pressure. The experi-
ment is continued until all the oxygen contained in the three flasks is used
up. The last 300 or 400 c.c. of oxygen is driven over under pressure and
the experiment is continued until the atmospheric pressure is again
reached. At this moment samples of the chamber air are drawn off for
analysis.
The CO2 is discharged from the KOH by weak sulphuric acid and is
again caught in a KOH absorber to be weighed. It could not be obtained
> i
Fig. 4. Respiration apparatus of Regnault and Reiset. A, chamber for animal;
B, water jacket; C, carbon dioxid absorbers; a, b, c, manometer for recording pressure
inside respiration chamber; 2V, 2V', N", flasks containing oxygen; T, T', thermometers.
by direct weighing of the absorbers because they contain some water ex-
haled from the animal as well as CO2. To the amount of CO2 contained
in the KOH is added the residual amount found in the chamber air by
analysis at the end of the observation.
The oxygen absorbed is found by measurement of the contents of the
flasks corrected by analysis of the chamber air.
b. The Apparatus of Hoppe-Seyler(c). — Similar in principle to that
of the original construction of Regnault and Reiset this apparatus con-
sists of a horizontal cylinder two meters in length, 1.66 meters in diameter
and a total capacity of 4.480 cubic meters. It is, therefore, large enough
for observation on the human subject.
The respiration chamber rests on the ground floor of the laboratory,
523
the driving mechanism, absorbers and gasometers being set up in the
cellar immediately below the respiration chamber (Fig. 5). The air
of the chamber is cooled by means of a stream of water passing through
a grid of pipe placed near the ceiling of the chamber. Besides the main
ventilating tubes which connect with the CO2 absorbers (b) other tubes
penetrate the walls of the apparatus for recording the internal pressure, for
admitting oxygen and for withdrawing a sample of air for analysis. The
CO2 absorbers are alternately raised and lowered by means of a walking
Fig. 5. Respiration apparatus of Hoppe-Seyler. A, respiration chamber; B,
apparatus for raising and lowering carbon dioxid absorbers; C, engine; D, gasometer
filled with oxygen ; G, meter for measuring sample.
beam operated by a gas motor. Air is thereby alternately withdrawn and
returned to the chamber after absorption of its carbon dioxid.
Oxygen is admitted from the gasometer D through a gas meter G after
passing first through a water flask to prevent evaporation of water from
the meter.
The carbon dioxid absorbed is determined exactly as in the Regnault-
Reiset method by discharging the CO2 from the KOH and collecting it
again and weighing. This amount obviously must be corrected by analysis
of the air residual in the chamber at the end of an observation.
Oxygen is determined by reading the gas meter and correcting the
524
JOHN R. MURLIN
amount so indicated by the residual analysis. The quality of the oxygen
supplied is likewise controlled by analysis.
c. Apparatus of Atwater and Benedict (d}. — These authors introduced
the use of an eccentric blower (Fig. 6) for driving the air through the ab-
sorption system and back to the respiration chamber. The original cham-
ber described on page 518 for the open-circuit apparatus was adapted
to the new type of ventilation shown in Fig. 6. In the upper part of the fig-
ure the respiration chamber is shown and below it is the blower and ab-
sorbing or purifying system. Air from the chamber containing nitrogen,'
carbon dioxid, water vapor and a somewhat diminished percentage of
oxygen passes through the blower and enters the absorption system. Here
it is forced through sulphuric acid to remove the water vapor and through
a specially prepared soda lime which takes out the carbon dioxid; the
soda lime, however, con-
tains water some of which
is taken up by the dry
air. A second sulphuric
acid absorber to catch
Vhis water is therefore
necessary and the total
CO2 absorption is found
by the gain in weight of
these two vessels. The
air is now freed of car-
bon dioxid and water,
but is still deficient in
oxygen. The latter in
requisite amount is ad-
mitted from a cylinder of
compressed oxygen through an opening in the ventilating pipe (see Fig.
6) and the air now restored to its original composition re-enters the respi-
ration chamber.
The respiration chamber of the original construction continued to be
used as a calorimeter. In later patterns of this respiration calorimeter
which have been constructed at the Nutrition Laboratory of the Carnegie
Institution at Boston (Benedict and Carpenter (a)), at Cornell Medical
College (Williams, H. B.) and at the U. S. Department of Agriculture
(Langworthy and Milner) some slight modifications of the original plan
have been made and these will be described here so far as the arrangements
for ventilation and determination of the respiratory exchange are con-
cerned as if belonging to the original construction at Middletown.
The metal walls of the chamber and the ventilating pipes which con-
sist of metal or heavy rubber confine the air to a definite volume and to
allow for expansion or contraction of the air volume as the result of pres-
Fig. 6. Diagram of the system of ventilation in
the closed-circuit apparatus of Atwater and Benedict.
The direction of the air is indicated by arrows.
NORMAL PROCESSES OF ENERGY METABOLISM 525
sure and temperature changes a compensating device in the form of a
spirometer is inserted (see Figs. 7 and 8).
The approximate amount of water vapor coming from the subject's
hody and the amount of carbon dioxid exhaled from his lungs is found
by direct weighing of the absorbers. Likewise weighing of the oxygen
cylinder gives within a small margin the amount of oxygen absorbed by
the subject. These amounts would be absolutely correct if there were no
change in barometric pressure or temperature of the confined air, and if
the composition of the air at the end of an observation period were exactly
the same as at the beginning.
Barometric pressure and temperature are readily determined from ac-
curate instruments and corresponding corrections in the volume of the
contained air are readily made. For detecting alterations in the composi-
tion of the air resulting from inefficiency of an absorber or from unusual
production of COj or water vapor, known volumes of the circulating cur-
rent are diverted from the main pipe and are made to pass through a
smaller channel over sulphuric acid and soda lime and sulphuric acid again
(exactly as in the main circuit) contained in TJ tubes which can be weighed
to a high accuracy on a sensitive balance (Fig. 8).
As an illustration of a compact form of this apparatus constructed for
determination of the respiratory exchange alone (without direct measure-
ment of the heat) either in laboratory animals or in infants, the design
of Benedict and Talbot may be described.
This apparatus was originally described by the authors in a preliminary
publication in 1912. Later it was somewhat modified and was employed
in most of their observations on the infant in the form shown in Fig. 7.
In this form it was capable of determining the oxygen directly, exactly on
the same principle as that described above for the respiration calorimeter.
The chamber C, in which the infant reposes, is provided with a water
jacket, W. W. for temperature control. The air leaves the chamber (Fig.
7) near the right hand end at O, and is drawn by the rotary blower over a
wet and dry bulb psychrometer, Z, which gives the amount of moisture in
the air of the chamber. A can, 1ST, filled with dry cotton batting is also
placed in the air-current between the blower and the chamber to act as a
muffler. After leaving the exhaust side of the blower, P, the air is forced
through an empty glass bottle, A, which serves as a trap should any back-
pressure take place and sulphuric acid be forced back from the water-ab-
sorbing vessels, B and C. These latter vessels are of peculiar construction.
They were designed by Williams for the small respiration calorimeter at
Cornell Medical College. The air passes along a pipe to a 2-way valve, V,
where it may be deflected through either of the soda lime bottles Dt or D2
in which the carbon dioxid is absorbed. Since the reagent must be some-
what moist to facilitate the absorption it gives up water-vapor to the dry
air-current, which must in time be absorbed by suh nuric acid in the Wil-
526
JOHN R. MURLIN
Hams bottles Ej or E2. The air next passes through the 2-way valve, V2,
and enters a small can, F, which contains dry sodium bicarbonate, where
the unweighable and nearly imperceptible sulphuric acid odors are effec-
tually removed. The air then returns to the chamber through the by-pass
J, or, if it is desired to moisten the air, the current can be deflected by
closing the valve, R, in the bypass, J, so as to pass all of the air through
distilled water in the Williams bottle K. The air is now free from carbon
dioxid and contains the water vapor added in passing through K, but is
still deficient in oxygen. This deficiency is made up by admitting oxygen
from the pressure cylinder L. The air thus enters the respiration chamber
I somewhat moist and with approximately normal percentage of oxygen.
r--^= :^=i=r— _•==_-.
-^~
£
L
— — !T
Fig. 7. Diagram of the respiration apparatus used by Benedict and Talbot in
their study of the gaseous metabolism of infants. Description in the text.
Either series of absorbers may be used as desired, fou if the air current
has been passing through the series Dx and EA, for a given experimental
period, the air can be instantly deflected through the series D2 and E2 by
turning the valves Vx and V2. These valves are connected by a long rod so
that they may be thrown simultaneously by one movement of the hand.
Since the air-current is entirely closed a small spirometer S is attached
at the upper right hand corner of the respiration chamber, thus providing
for an expansion or contraction of the air. A thermometer, Ta, in the cover
of the chamber and a second thermometer, T2, in the outgoing air serve
to indicate the temperature changes while the manometer, M, shown be-
low the spirometer indicates the pressure of the air in the chamber.
By noting the increase in weight of the absorbers Dx and Ej or D2 and
E2 the amount of CO\ absorbed is known. It is possible that the amount
NORMAL PROCESSES OF ENERGY METABOLISM 527
of water vapor given up by D! or D2 to the dry air passing through it may
be actually more than the amount of carbon dioxid absorbed, or that the
bottle D! or D2 may be losing weight; on the contrary, the water vapor
given up is immediately absorbed by E, . and hence the algebraic sum of the
difference in weight of the two bottles gives the weight of the carbon dioxid
absorbed. Usually both bottles are weighed on a balance at the same time.
The loss in weight of the cylinder, L, gives the amount of oxygen absorbed
by the subject, corrections being made for any variation in temperature
and barometric pressure. Corrections for changes in composition ;of air
inside the chamber may be made by withdrawing samples through a by-pass
not shown in the figure.
The infant is placed inside a wire crib supported at one end upon a
stout spiral spring, IT, and at the other end upon a knife edge, G ; this
mode of suspension affords a means of recording the muscular activity of
the infant. Alongside the spring, IT, is a pneumograph, II, the distention
or contraction of which compresses the air inside of the pneumograph
tube, thus transmitting to a delicate tambour outside a record of the light-
est motion of the cage.
The respiration chamber is constructed of galvanized iron or copper,
and is 77 cm. long, 25 cm. deep, and 37 cm. wide. To insure temperature
control the whole respiration chamber is surrounded by a water jacket
consisting of a second shell of galvanized iron or copper with a space of
5 cm. between the two walls. The water jacket which is filled with water
to within a few centimeters of the top acts also as a seal when the cover is
placed upon the apparatus. In the cover are a window securely fastened
and an opening for the air thermometer.
The psychrometer is essential for indicating the degree of moisture in-
side the respiration chamber. This is of value not only for the comfort
of the infant, but also for computing the amount of oxygen inside the cham-
ber at the end of the experimental period. Experiments carried out with a
very delicate instrument have shown that the depression of the wet-bulb
thermometer can be measured with great accuracy and the amount of water
vapor in the air computed with an exactness sufficient for all practical pur-
poses. The two thermometers are graduated to 0.1° C. but are capable
of being read with a lens to .02° C. It is necessary to make sure that
the cloth around the wet bulb thermometer is kept thoroughly drenched
with distilled water, also that the capillarity of the fiber is good as other-
wise the cloth may become partially dried and inaccurate results obtained.
Prior to each experiment the wet bulb is drenched by using an elongated
medicine dropper filled with distilled water.
The blower, P, is connected with a leather belt to a small electric motor
and can be provided with a safety clutch to prevent reversing the wheel
through carelessness, and the drawing over of sulphuric acid from the water
absorbers. The safety trap, A, is an additional security against this mis-
528 JOHN K. MUELIN
hap. The blower used with this apparatus gives a ventilation of about 35
liters of air per minute when rotating at a speed of 270 revolutions p. ni.
Experiment with an alcohol flame shows that this rate of ventilation does
not produce a draft which would be perceptible by the infant. The fact
that the relative humidity does not become unduly low, even without use
of the water bottle, is proof that the infant is sojourning in an atmos-
phere approximately normal.
To remove the moisture coming from the lung and skin of the infant,
and any additional moisture from water bottle K, one large-sized Williams
bottle B is usually sufficient. However, a second bottle C removes the last
traces of water vapor. To facilitate the handling of these bottles in weigh-
ing and to prevent breakage, they are usually enclosed in a small wire
basket with a handle by means of which they may be suspended directly
from a hook on the arm of the balance.
The Williams bottles as well as the soda lime bottles are fitted with short
lengths of rubber tubing of good quality to which are attached respectively
male and female parts of ordinary garden hose couplings of standard %
inch size ; with a standard rubber hose gasket, the couplings are made air-
tight by a single twist of the hand.
For infants weighing not less than 3 to 5 kgm. the soda lime container
holding in the neighborhood of 2 kgm. soda lime is capable of absorbing
all the carbon dioxid. This amount of soda lime will take up as much as
To gm. C02 without renewal.
The direct determination of oxygen may be made either by weighing
the small cylinders of gas L, and noting its loss in weight during the ex-
periment, or by passing the gas, under reduced pressure, through a delicate
and accurate gas meter. With oxygen made from liquid air a corrective
for argon has usually to be made amounting to about 1 per cent. The vol-
ume of air inside the respiration chamber is about 75 liters. Correction
for temperature change is therefore necessary in order to determine the
actual volume of air at the end of every experimental period. Two care-
fully calibrated mercury thermometers, one in the cover of the chamber,
the other the dry bulb thermometer of the psychrometer, are used to record
such changes. While the two thermometers barely read alike, their fluctu-
ations are usually parallel. The average of the readings of the two is taken
as representing the average temperature of the air in the chamber.
It is important that the respiration chamber shall not be subjected to
sudden fluctuations of temperature during the experimental periods. The
water-jacket serves to damp any changes in the room temperature, and by
supplying either heat or cold to maintain the chamber at a temperature
either above or below that of the room. During cold weather a mercury
thermo-regulator placed in the water and connected with a small burner
placed underneath, secures a constant temperature which may be regulated
NORMAL PROCESSES OF ENERGY METABOLISM 529
at any desired level. In the excessively warm days of summer, it is neces-
sary to place ice in the tank.
An apparatus devised by the writer, and constructed simultaneously
with the last for use in Bellevue Hospital, New York, follows the same
general principles as that just described, but employs as a means of con-
trolling the temperature the electrically regulated incubator of Freas.
Fig. 8. Respiration incubator (Murlin).
For this reason it has been called a "respiration incubator," and can
be used as an incubator for premature infants independently of its features
as a respiration machine (Murlin (d) ).
d. Apparatus for Very Small Animals. — With very small animals, their
eggs or larval stages it is not necessary to circulate the air through absorb-
ers. The absorption of oxygen can be recorded by a change of pressure and
the carbon dioxid can be readily absorbed by means of a suitable solution
of alkali. Several forms of apparatus constructed on these principles have
>30
JOHN R. MUELIN
been invented. Some of them should be described briefly under the head-
ing of closed-circuit apparatus.
An original form described bj Thunberg was a gas-analysis apparatus
of the Petterson type for the determination of very small percentages of
CO2 in which the animals to be experimented on could be introduced into
the gas-measuring pipette. Any change in volume with the animal in the
confined space would be due to the difference between O2 and CO2 given
Fig. 9. Micro-respiration apparatus of Winterstein. 5 and 6, duplicate air
chambers. The small animal is placed in chamber 6 and chamber 5 is used as control,
the two chambers being connected by a sensitive oil manometer. The absorption of
oxygen from chamber 6 is measured by the pressure of mercury necessary to restore
the balance on the oil manometer.
off. This volume having been noted the air could then be driven over into
potash bulb and the CO2 absorbed. Changes in volume this time would
give the CO2 produced by the animal and the oxygen could be found by
adding the difference-volume first noted.
Winter stein (a) improved upon this apparatus by employing the prin-
ciple of the compensating vessel first introduced into gas analysis by Petter-
son and connecting the two vessels (the animal chamber and compensating
chamber) by means of a very sensitive graduated manometer containing a
drop of kerosene. The oil-drop being set at zero, the level of the mercury in
the U-tube manometer at the left which is graduated in cubic millimeters is
NORMAL PROCESSES OF ENERGY METABOLISM 531
read. By absorption of oxygen from the animal chamber the oil-drop is
shifted toward that chamber and whenever a reading is taken a drop is
brought back to the zero mark by means of the pressure screw on the mer-
cury column. The volume of mercury moved upward then is equal to the
volume of oxygen absorbed when corrected from the original temperature
and barometric pressure to 0° and 760 mm. The carbon dioxid is absorbed
as rapidly as produced by a drop of caustic soda placed in the bottom of the
animal chamber, the animal of course being protected from contact with
the solution. The production of carbon dioxid can be determined if, in
a control period, a small amount of water is used instead of the alkali.
The pressure change will then indicate the difference between the volume
of oxygen absorbed and the carbon dioxid given off. If the oxygen absorp-
tion is determined just before and just after this under conditions other-
wise the same, the volume of carbon dioxid will be found by substracting
the difference-volume from the volume of oxygen. The respiratory quotient
is then available.
It is obviously necessary to keep the two chambers in the same water or
oil bath in which the liquid is sufficiently stirred so that the two chambers
shall be of exactly the same temperature.
The micro-respiration apparatus of Krogh follows very similar prin-
ciples. With it Krogh was able to follow the oxygen absorption of a single
insect egg weighing about 2 mgm. in ten-hour periods from immediately
after it was laid until the hatching of the larva ( Krogh (&)).
II. Methods for Measuring the Respiratory Exchange
by Direct Connection with the Repiratory Passages
The first observations upon the respiratory exchange of man made by
Lavoisier provided for the direct examination of the expired air. A copper
mask was used fitting tightly over the subject's face and by some means
not clearly understood the inspired air was separated from the expired air,
which was passed into alkali, thereby removing the carbon dioxid. Many
different modifications of the original method of Lavoisier have been de-
vised. Those which employ means to separate the inspired air from the
expired air and provide for the collection or automatic analysis of the latter
should be described under the rubric of "open circuit" or air-current types
of apparatus. Other methods employ some form of "closed circuit" ap-
paratus.
1. Open Circuit Instruments, a. Mouthpieces, Nose-pieces, Masks.—
For connection of the apparatus to the respiratory passages of the subject
a rubber mouth-piece originally constructed by Denayrouse for the use of
divers has been widely employed. It consists of a wide rubber disc which
fits in between the lips and the teeth of the subject. In the middle of this
disc is a 2 cm. opening leading into a rubber tube of the same size. On
532
JOHN R. MUELIN
7.
the two sides of the opening are thick rubber projections which may be
held between the teeth. Sometimes the mouth-piece is supplemented by a
band of rubber tied
around the head and
pressing against the
lips from the outside.
In the use of this device
the nose must of course
be closed by some form
of clip or clamp (Reg-
yl, nard) (Fig, 10).
Glass nose-pieces
have been described by
Tissot and these have
been improved by Car-
penter (a). A pneu-
matic nose-piece de-
scribed by F. G. Bene-
dict (d) (Fig. 11) is
much to be preferred to
the all-glass construc-
tion. They can be made
very secure by inflation
of the pneumatic por-
tion particularly if the
outer rubber which fits
against the nose is cov-
ered with mucilage.
Many subjects, how-
ever, find the nose-
pieces quite uncomfort-
able and prefer the
mouth-piece described
above. Benedict him-
self has recently recom-
mended the mouth-
Fig. 10.
clip attached.
Mouth-piece of Denayrouse with nose
(1) brass tube connecting to apparatus;
(2) collar supporting stand (3) which in turn sup-
ports nose piece; (4) brass collar; (5) frame of nose-
piece with adjusting screw for regulating pressure on
nose; (6) nose pads; (7) rubber of mouth-piece which
fits in between teeth and lips ; ( 8 ) opening from mouth-
piece into brass tube; (9) rubber lugs which may be
grasped between the teeth ; ( 10 ) rubber tube continuous
with mouth-piece; (11) strap for holding mouth-piece
firmly in place.
piece with a clinical
respiration apparatus in preference to the nose-piece (Benedict and Col-
lins). When nose-pieces are used the mouth should be sealed shut with an
adhesive tape.
Various types of masks have also been used from the crude copper mask
covering the entire face employed by Lavoisier, to the modern so-called half
mask employed in mine rescue work. The gas masks, perfected from force
of necessity during the recent war, have also found a useful field in con-
NORMAL PROCESSES OF ENERGY METABOLISM 533
nection with respiration experiments. A form of mask described by Bohr
consists of a funnel-shaped piece of tin plate coated on the edges with
a substance used by dentists, known on the market as Stent's compound.
This substance softens at a temperature a little above the body temperature
and may, therefore, be molded to fit the face of each subject. The mask
can be made perfectly air tight by covering the molded surface with vase-
line or lanolin and binding it securely to the face (Krogh(c)).
The half mask employed by Boothby is made of rubber on a flexible
wire frame so that it may be bent to conform to the shape of the nose, cheeks
and chin. It is bordered by a pneumatic cushion. Boothby finds' that it
is much safer not to inflate this cushion for the air-valve tends to leak thus
altering the pressure against the face and causing leakage. He recom-
mends the use of tapes fastened to a towel
which lies upon the pillow under the neck of
the subject. The tapes may be drawn for-
ward and tied about the mask transversely
and obliquely in such a way as to apply the
pressure just where it is most needed.
(Boothby and Sandiford.) (Fig. 12.)
Hendry, Carpenter and Emmes have shown
that the oxygen consumption is practically
identical with the different types of breathing
appliances adapted to the subject.
b. Valves. — Universally the separation of
inspired air from expired air is accomplished
by some type of valve. One of the simplest
is the well known fluid vahTe of Miiller de-
scribed in 1859 (Tigerstedt(/)). Formerly
they were much used filled either with water
or mercury; but they offer considerable
resistance to the air and have now been very generally displaced by
valves of lighter construction. One form which has been widely used
is the valve of Loven consisting of two round brass boxes each enclos-
ing a thin membrane of gold-beater's skin or condom rubber (Fig. 13).
Small circular apertures suitably spaced and arranged in a circle round
the peripheral attachment of the membrane serve for passage of air. The
mechanics of this valve will be evident from the figure. Another favorite
form is the metal valve of Thiry used by Tissot (Fig. 14). Boothby
prefers the so-called flutter valve used in the most recent form of British
and American army gas masks. He has devised a metal housing for the
rubber flutter and finds the valve in this form perfectly competent. In
case of doubt regarding the competency of a valve Boothby recommends
the use of two valves one after the other in the inlet or outlet tubing
(Boothby and Sandiford).
Fig. 11. Pneumatic nose-
piece of Benedict, a, glass
tube to which is fastened a
rubber finger-cot, 6, which is
drawn over a rubber stopper,
c. A capillary rubber tube,
d, serves for dilating the cot
6 ; the clamp e closes d after
b is inflated.
534
JOHN R. MURLIN
Fig. 12. The half mask as used by Boothby.
c. Collecting Apparatus. — The expired air can be collected either in
a spirometer (Speck(&), Tissot), in a bag (Regnard, Douglas, C. G.), or
Fig. 13. Air valve of Loven.
it may be measured by means of a gas meter and simultaneously sampled
for analysis (Geppert(a)).
In the original spirometer method of Speck the inspired air was drawn
from one spirometer and the expired air forced into another so that the
difference in volume of inspired and expired air could be recorded and the
NORMAL PROCESSES OF ENERGY METABOLISM 535
inspired air could also be readily measured at the same temperature and
pressure preliminary to analysis. The bell of each spirometer was counter-
poised and provision was made by mechanical means for compensating
the increase or decrease in weight of the bell according as it was lifted
from or depressed into the water jacket. The Tissot method as used in the
French laboratories has been fully described by Carpenter (a). The spi-
rometers are of special design and used principally in two sizes, one of 50
liters and another of 200 liter capacity. The height of the bell in the
former is 60 cm. and the diameter 33 ; while in the 200 liter instrument
the bell is 73 cm. high and 65 in diameter (Fig. 15). Air is admitted
to the bell through a tube which terminates at the bottom of the spirom-
eter in a 3-way stop-cock, A. The major portion of the weight of the
spirometer bell is counterpoised by the weight R. The automatic adjust-
ment of the counterpoise for the spirometer bell is accomplished by means
of a water siphon. A glass cylinder, C, is made of such size that when
Fig. 14. Metal air valve of Thiry.
filled to the level of the spirometer the weight of the water in the cylinder
exactly equals the increase in the weight of the spirometer bell due to its
new position. When the bell rises or falls water is added to or taken from
the cylinder C, by means of the siphon tube, D. Any increase or decrease
in the weight of the bell due to the varying displacements of the volume
of water by the mass of metal in the spirometer bell is thus exactly counter-
poised by a like increase or decrease in the weight of water in the cylinder.
The upright position of the counterpoised cylinder, C, is determined and
maintained by means of two brass rods on which the cylinder travels. This
siphon tube, D, is so arranged that it does not touch the cylinder, C, at any
point.
A clinical form of spirometer or gasometer used by Boothby differs
from the original form of Tissot in only minor features. A spirometer
mounted on wheels as used in the Mayo clinic is illustrated in Fig. 16.
The counterpoise of the bell in this instrument is hung over ball bearing
wheels by means of steel piano wire. The main weight of the bell is bal-
anced by a long hollow brass tube at the upper end of which are placed
the necessary lead weights to counterbalance the bell exactly. The siphon
arrangement of the original Tissot spirometer is used, but instead of draw-
ing water from the gasometer itself to the counlerposed cylinder, water is
drawn from a special receptacle.
536
JOHN R MURLIN
Fig. 15. Tissot Spirom-
eter with capacity of 50
liters. A, three-way valve
connecting air in bell of
spirometer with outside
air; B, tube leading to in-
side of bell; C, counterpoise
tube compensating for
change in weight of bell;
D, siphon tube connecting
C with water in tank; E,
flat steel band supporting
spirometer; F, wheel over
which runs E; H, rubber
tube connecting siphon tube
with supply tube J; /,
branch of supply-water tube
leading to tank at L ; M,
N, overflow tube from tank;
O, pointer; P, cock for
emptying tank; Q, Q, level-
ing screws; R, lead counter-
poise; Z, opening for gas
sampling.
to counterbalance the
tubes.
In this form of apparatus the scale for read-
ing the volume of expired air is attached to the
back side of the counterpoise tube.
In carrying out an experiment by the Tissot
method the valves are first tested for tightness.
Boothby carries out this test by filling the gas
mask with water and letting it stand for a time
for detection of leaks. A three-way valve at.
the side of the spirometer permits breathing
from the subject into the room air or into the
spirometer according to the position of the
handle. The mask is attached securely to the
face and the subject breathes for a time into
the room air with the bell at its lowest posi-
tion. The subject continues to breathe into
• the apparatus for a definite period of time, the
inspired air being drawn through a pipe from
outdoors. The valve is again turned at the end
of an experiment. The temperature of the air
is recorded by the thermometer in the top of the
bell and a reading of the barometric pressure
is taken.
With the Boothby apparatus several of the
lead weights are slotted so that they may be
readily removed. When all the weights are in
place the bell is in perfect equilibrium at any
point of its course, so that when the valve is open
to the room air the bell will not change its posi-
tion. When one or more of the lead weights are
removed so that the bell is no longer perfectly
counterpoised it will gradually drop. For the
purpose of sampling this is a useful arrange-
ment for the weight of the spirometer serves to
drive expired air through the outlet tube, thus
washing out room air from the main tube and
the sampling connections. While the subject is
breathing into the apparatus the extra weight
of about 300 grams should be placed on the
counterpoise so as to induce a slight negative
pressure toward the spirometer. This serves
resistance which the air meets in the various
537
In the original bag method of Regnard the subject breathed through a
Denayrouse mouth-piece and a pair of valves into a rubber sack of about
200 liters capacity. At the end of an observation a sample of about 150
c.c. of air was withdrawn for analysis and the balance of the contents was
passed slowly through a series of absorbers and through a gas meter. In
the Douglas method as originally described a mica or rubber-flap valve
was used in connection with a mouth-piece and a tube of 20 mm.
diameter led to a three-way valve of large bore which was connected with
Fig. 16. Spirometer of Boothby and Sandiford as used in the. writer's laboratory.
Sampling tubes are shown on shelf above the wheels.
a wedge-shaped reservoir bag made of rubber-lined cloth (Fig.. 17). This
form of bag is more impervious than rubber and therefore "more reliable.
The shape of the bag permits it to be rolled up and emptied completely.
The expired air is measured at the end of an observation by passing it
through a meter and a sample is analyzed. By supporting the tube and
valves on a light framework upon the head and resting the bag on an-
other frame placed on the back the apparatus is made adaptable to a march-
ing experiment.
It has proved especially valuable in mountain climbing (Ilaldane,
Henderson, et al.) and other forms of open-air exercises. With violent
exercise a bag holding 60 liters will not take the air expired during one
538
JOHN R. MURLIN
minute; but Krogh has shown that experiments of even much shorter
duration are sufficient to give perfectly reliable results.
The method of Zuntz and Geppert of measuring the expired air as it is
exhaled and collecting at the same time a continuous aliquot sample for
analysis is an important one and has been very widely used in Europe.
The subject breathes through a mouth-piece attached to a tee-tube connect-
Fig. 17. Respiration apparatus of Douglas. The mouth-piece is of the Denay-
rouse type. The bag or bellows is provided with straps for carrying the apparatus
on the back.
ing two valves (made of rubber and glass as used in the Zuntz laboratory,
Magnus-Levy (&)) which separates inspired from expired air. The latter
passes at once through a moist gas-meter. The continuous sample is taken
over water by an automatic apparatus and is then immediately analyzed in
a special analyzer in which the CO2 is absorbed by potash and the oxygen
by phosphorus. In the figure (Fig. 18) the meter is shown at the left and
the special air analyzer is shown at the right. The expired air enters the
apparatus at P. The sample is drawn through the narrow tube, L, by the
lowering of the water-tube, H, which descends at a rate proportional to the
ventilation as measured by the meter. As the tube, H, descends water
NORMAL PROCESSES OF ENERGY METABOLISM 539
flows out at J and makes room for air in the two burettes (1) which fill
from L at K and K. When these burettes are filled and contents measured
the air is driven over, into the potash bulbs I, after which it is drawn back
into the two burettes (2), where it is again measured. Thence it is passed
into the phosphorus absorbers II and is finally measured for shrinkage due
to loss of oxygen in the two burettes (3). The burette (4) is a "thermo-
barometer" for recording any change in volume of the air contained in the
Fig. 18. Respiration apparatus of Zuntz and Geppert. The recording and sam-
pling apparatus is shown at the left and the air analysis apparatus at the right.
Air enters the apparatus from the lungs of the subject at P, a sample being drawn
automatically through a tube L, and being passed in duplicate successively through
the burettes numbered 1, 2 and 3. Burette 4 is for control. The part of the apparatus
labeled D, E, G is a "thermo-barometer."
burettes due to alterations of temperature and pressure during an
analysis.
The apparatus R. D. E. G. is another thermo-barometer for recording
similar changes in the volume of the total ventilation. 100 c.c. dry air
at 760 mm. pressure and 0° have been stored in two metal boxes one of
which is inserted into the entrance tube of the gas meter at P, and the other
into the exit tube. The air in these boxes communicates with the burette
E. The enclosed volume of air will be affected by the temperature of the
air entering and leaving the meter and by the atmospheric pressure, and
the volume changes can be read off on the burette when the water in G and
540
JOHN K. MUKLIN
-7
E has been brought to the same level by moving G. The burette is so
divided that, if a volume of say 107.4 is read off during an experiment,
the volume of air which has passed through the meter can be reduced to
normal conditions (0° and
760 mm. dry pressure) by mul-
tiplication with . This
arrangement is certainly not
more accurate and scarcely
more convenient than to re-
duce by means of a table after
reading the barometer and a
thermometer'placed in the exit
tube of the gas meter.
d. Air Analyzers. — With
either the spirometer method
or the bag method of collect-
ing expired air or with the
Jaquet type of chamber
an absolutely essential
part of the apparatus is a re-
liable device for determining
carbon dioxid and oxygen vol-
umetriaally. The apparatus
most used to-day is the Hal-
dane analyzer. This appara-
tus is fully described by Hal-
dane in his book entitled
"Methods of Air Analysis."
(Haldane(c).)
In a general way the
method is as follows: A
sample of air drawn into a
10 c.c. burette is accurately
measured under the atmos-
pheric pressure; the air is
then passed into a potash bulb
and back into the burette until
a constant reading is obtained; the difference is the volume of CO2
in the sample. In the same way the oxygen is absorbed in a solution of
pyrogallol in strong potash and the difference in volume obtained repre-
sents the volume of oxygen in the sample.
As used by Boothby in the Mayo clinic the apparatus is shown in Fig.
19. Full details for manipulation of the apparatus and for calibration of
Fig. 19. The Haldane air analyser as used
by Boothby. 1. Water-bath. 2. Burette. 3. Con-
trol tube. 4. Glazed glass back of water-bath.
5. Pressure tubing connecting burette and its
mercury reservoir. 6. Mercury reservoir. 7.
Ratchet and pinion. 8. Burette tap. 9. Sampling
tap. 10. Sampling connection. 14. Potash tap.
15. Level marking on potash pipette. 16. Potash
pipette. 17. Potash reservoir. 18. Control tube
tap. 19. Pyro tap. 20. Level marking on pyro
pipette. 21. Pyro pipette. 25. Level marking on
manometer tube.
NORMAL PROCESSES OF ENERGY METABOLISM 541
the burette are given in Boothby and Sandiford's book on "Basal Metabolic
Rate Determinations."
Fig. 19-a. Henderson modification of Haldane apparatus (Bailey). (1) Burette
graduated in hundredths of a c.c. ; (2) four-way stop cock at top of burette; (3) con-
trol tube same volume as burette; (4 and 5) glass tubes for circulation of air through
water jacket; (6) mercury reservoir for varying pressure in control tube; (9) mer-
cury reservoir for filling and emptying burette; (10 and 11) cord and counter-weight
for suspending mercury reservoir; (12; potash pipette; (13, 14, 15) tubing and
leveling bulb for potash pipette; (16) pyrogallol pipette; (17) leveling on pyrogallol
pipette; (18 and 19) leveling marks on potash pipette; (20) connection to sampling
bottle.
e. Analysis of Outdoor Air. — Haldane working with the portable
form of his apparatus found that outside air contains 0.03 per cent of
carbon dioxid and 20.93 per cent of oxygen. Benedict using the Sonden
apparatus found as the result of 212 analyses in the Back Bay district
542
JOHN R. MURLIN
of Boston an average value of 0.031 per cent for carbon dioxid and 20.938
per cent for oxygen. In one series of 349 analyses nearly equally divided
among 18 Haldane analyzers of the type described in Fig. 19 Boothby
and Sandiford found the average CO2 in the air taken upon the
fire escape of their laboratory in the middle of Rochester, -Minn., to be
Fig. 20. The air analyser of Krogh. This apparatus like that of Zuntz and
Geppert employs separate burettes for measurement of the air before and after
absorption of C02 and oxygen. The air is moved from one burette to another by
means of air pressure. For details of operation consult the original article.
0.037 per cent and the oxygen 20.930 per cent. In a second series of 343
analyses the average was 0.035 and 20.930 per cent. The higher percentage
of CO2 they ascribe to the fact that a large number of chimneys in the
neighborhood of the laboratory gave out smoke which often drifted toward
the laboratory.
Y. Henderson (Henderson and Morris) has devised a somewhat simpler
form of the Haldane apparatus which has been improved in certain details
by Bailey x at the N. Y. Post-Graduate Hospital. The degree of accuracy
necessary for ordinary routine analyses for the determination of the basal
metabolism in the hospital is easily attainable with this apparatus.
Krogh has recently described an apparatus which is accurate to 0.001
per cent. He finds that the sources of error which prevent the oxygen
analyses from being highly accurate in the Haldane apparatus are inti-
mately connected with the presence of water and dirt in the gas burette.
Water must of course be present to insure the saturation of the gas with
water vapor and dirt accumulates rapidly from the contact of mercury
with the rubber tubing and with oxygen. Krogh gets rid of these inter-
fering factors by employing three separate burettes (Fig. 20, 1, 2, 3) of
which one (1) is employed exclusively for moving the air to and from the
absorption pipettes, while the second (2) is of a suitable size for meas-
uring the air before and after the absorption of CO2, and the third (3)
for measuring it after absorption of O2. The water vapor necessary for
saturating the sample air, when it has become partially dried in the ab-
sorption pipettes will be supplied by the first burette and the variations in
the amount of water present has no influence upon the accuracy of the
measurements. The two other burettes (2) and (3) contain just enough
water to insure that the samples remain saturated.
A second improvement introduced by Krogh in this apparatus is that
the mercury is raised and lowered in the burettes not by raising and low-
ering a mercury reservoir but by means of air pressure, an arrangement
which obviates the use of rubber connections between the burettes and the
reservoirs and besides facilitates the manipulation considerably (Krogh
Still another apparatus employing the open circuit method is deserving
of mention. This is the apparatus of Ham'oit and Richet. By means of
air valves the inspired air and the expired air are separated, both being
measured by meters. In addition the expired air is measured again after
absorption of the carbon dioxid in potash. The first meter gives the vol-
ume of the inspired air, the second of the unchanged expired air, and the
third the volume of the expired air minus the volume of carbon dioxid.
The volume of inspired air less the final volume of expired air gives the
amount of oxygen consumed. The method as carried out by Hanriot and
Richet does not seem to be particularly accurate; but Krogh expresses
the opinion that the method has great possibilities if used with modern
gas meters of sufficient size and placed in a water bath where the volumes
measured would be subject to the same fluctuations. Krogh notes that
1 This construction of the apparatus is made by E. Machlett & Son, 153 East 84th
Street, New York City.
544 JOHN R. MUKLIN
the volume recorded by a meter is independent of the rate only within
certain limits corresponding roughly to 100 complete revolutions per hour
( Krogh (c) ) . As Benedict has shown the volumes recorded at higher rates
than this are smaller than the actual volumes, but if the high rate is constant
and the meter is calibrated at such a rate it is quite possible to record vol-
umes with no appreciable error. In such a method as that of Hanriot and
Eichet the meter employed for measuring the respiration of a man at rest
should be capable of measuring correctly not less than 12 meters per
revolution, and since in heavy muscular work the total ventilation may
be multiplied tenfold over that of the resting rate of respiration a meter
for measuring the ventilation of the lungs would need to have a capacity
of 120 meters. Krogh has recently devised a spirometer for calibrating
gas meters which should simplify this process and render the use of gas
meters much more reliable. In the paper describing this apparatus Krogh
notes that in wet meters with a constant quantity of water the volume
per revolution increases with increasing rate but can be determined with
sufficient accuracy. Dry gas meters he finds are much less accurate than
wet test meters.
2. Closed Circuit Instruments. — There are two well-known forms
of respiration apparatus used with mouth-pieces or nose-pieces and con-
structed on the closed-circuit principle. The first of these is the so-called
Universal respiration apparatus of Benedict (e?) (e) ; and the second is a
modification of the instrument constructed by Haldane and Douglas de-
vised by Krogh (a). To speak of the second form first, Krogh has so de-
vised his instrument that it may be used continuously for a considerable
period of time by a man at rest. The soda lime absorber is capable of re-
taining 1000 liters of carbon dioxid. Oxygen is admitted from a cylinder,
being passed through a meter which records electrically by closing a circuit
each time the meter revolves once and has, therefore, passed a certain vol-
ume of oxygen. A recording spirometer gives a quantitative record of
the respiratory movements. Only oxygen absorption is determined as the
apparatus is usually employed, but carbon dioxid determinations can be
made by drawing samples of inspired and expired air from certain parts
of the apparatus. So far as known to the writer this form of apparatus
has never been used in the United States.
The apparatus of Benedict en the other hand has been used quite ex-
tensively. The writer has made almost continuous use of one of these
over a period of nearly twelve years. It has been modified and improved
from time to time and is used to-day as shown in Fig. 21. Attachment
to the respiratory passages of the subject is effected .by means of the
Denayrouse mouth-piece or the rubber nose-pieces of Benedict. Quite re-
cently also the half mask of Boothby has been adapted to this use and has
given much satisfaction. It is far more comfortable than either the mouth-
piece or the nose-piece. The apparatus is constructed with three trains
NORMAL PROCESSES OF ENERGY METABOLISM 545
of absorbers. The first immediately following the rotary blower consists
of two Williams bottles containing sulphuric acid which wash out all of
the water from the expired air and water left over from the moistener
bottle. The other two are duplicate trains for absorption of carbon dioxid.
Each consists of two soda lime bottles and a Williams bottle containing
sulphuric acid. By thus reducing the size of each unit a smaller and much
less expensive balance can be employed for weighing the absorption, of
"Fig. 21. The Benedict Universal respiration apparatus as employed Toy the writer.
The spirometer and tubes leading to the face mask are carried on a separate stand
so that they may be adjusted to a subject in the reclining, sitting or standing position.
Oxygen is supplied from a pressure cylinder and is measured on its way to the
spirometer by the meter. Two sets of absorbers are used so that observations may
be made continuously in successive periods.
carbon dioxid. Oxygen is fed into the circuit from a high pressure tank
through a reduction valve and on its way is measured by a Bohr meter.
The spirometer and tubes leading to the subject are mounted on a separate
standard so that the height of the mouth-piece can be adjusted for a sub-
ject in the reclining, sitting or standing position. ' The same apparatus,
therefore, can be used for basal metabolism, for work experiments, or
for observations on the influence of food.
The technique as worked out in the writer's laboratory for operation
of this instrument is briefly as follows. Let us suppose a basal metabolism
546 JOHN R MURLIN
is to be determined. The subject comes to the laboratory early in the
morning after having taken a very light breakfast of black coffee and
toast, or no breakfast at all. For half an hour the subject is required to
lie perfectly still wearing the nose clip and breathing through the mouth-
piece into the room air or breathing through the face mask into the room
air. He thus becomes accustomed to all the sensations incident to the
experiment A slight pulsation of the air current transmitted from the
blower is felt by the patient unless special means is taken to muffle it.
Such vibrations may become very annoying to the subject.
When the absorbers have been weighed and the patient has become
sufficiently composed the blower is started and the apparatus is run idle
blowing the air round and round through the circuit for at least two min-
utes in order to make certain that any carbon dioxid left over from a
previous observation shall have been completely removed. With a small
weight placed upon the spirometer this preliminary run serves also to
test the entire circuit for tightness. If after a minute or two the spirom-
eter holds its level the entire circuit is air tight and the experiment
may proceed. The oxygen meter is read at this point.
With an intelligent subject it is our custom to let the subject turn the
valve himself, instructing him to do so just before beginning an inspira-
tion. With a .subject wholly unaccustomed to the apparatus or not suffi-
ciently intelligent to understand what is meant by "respiratory pause"
the observer quickly turns the valve at the moment of respiratory
rest intervening between the end of an expiration and the beginning of an
inspiration. In either case the second hand of a watch is read at the in-
stant the valve is thrown. If the air current is passed through a moisten-
ing bottle which follows the acid absorber in the carbon dioxid train the
air comes to the subject feeling rather soft with moisture, and also feel-
ing perhaps a little cool from the temperature of the water. These are
the only sensations which the subject should experience, when the valve
is thrown connecting him with the circuit. There should be no trace of
irritation either from the air itself or from the apparatus connecting
with his face.
With a little experience oxygen can be fed in through the meter at ap-
proximately the rate at which it is absorbed by the subject. This method
is preferable in the writer's opinion to the intermittent feeding of oxygen,
providing only that the rate of flow be kept low enough so that at the ter-
mination of the observational period the spirometer shall be lower than
it was at the moment the valve was first thrown. It is far more important
to terminate the observation correctly with reference to the phase of res-
piration when the valve is thrown than it is to terminate the observation
on the second by the watch. The observer, therefore, gives his entire at-
tention to throwing the valve and only notices the position of the second
hand after he has successfully thrown the valve. The blower is allowed
NORMAL PROCESSES OF ENERGY METABOLISM 547
to continue running for two or three minutes until the spirometer ceases
to fall and oxygen is then admitted until the spirometer comes back to the
original level. The blower continues running for a few seconds longer
to make certain that this
level will be maintained, the
oxygen now having been
stopped, whereupon the cur-
rent is turned off stopping
the blower. The oxygen
meter is now read.
If a second observation
is to follow immediately the
valves are thrown connecting
with the second set of ab-
sorbers and the blower im-
mediately started. As soon
as it is certain that the sec-
ond train of absorbers is air
tight the second period can
be started. The absorbers
of the first train can be
weighed while the second
period is running. The ba-
rometer is read and the
temperature of the water
meter measuring the oxygen
is recorded. The volume of
oxygen is then reduced to
0° and 760 mm., and the
carbon dioxid obtained in
grams is likewise reduced to
the standard conditions.
The respiratory quotient is
obtained by division of the
volume of carbon dioxid by
the volume of oxygen.
Recently several forms
of so-called portable instru-
ments constructed on the
general principle of the uni-
versal respiration machine of Benedict have made their appearance. The
best of these doubtless is the one described by Benedict and Collins. It
may be doubted, however, whether it is wise to attempt to make the deter-
mination of basal metabolism a bedside or office procedure. Special
Fig. 22. Portable respiration apparatus of
Benedict and Collins. A, mouthpiece; B, tube
conducting expired air to bell C; D, hair dryer;
E, soda-lime container; F and G, tubes convey-
ing air current to mouthpiece A ; HH, tank in
which bell C floats; J and K, cord and pulley
supporting bell C; L, counterpoise; M, pointer on
counterpoise; AT, thermometer; O and P, supports
for pulley K. a, rubber gasket; 6, rubber gasket;
c, c, tubes supporting spirometer; d, d, lower
part of frame supporting spirometer; e and /,
telescoping tubes supporting mouthpiece and
tubing ; g, g, supporting plates ; h, h, knobs fit-
ting into g, g; jk, part of support for mouthpiece
and tubing; mm, attachment to support c, c, to
tank HH; p, circular band connecting four tubes,
d, d; r, r, leveling screws; t, sliding ring; u,
knobs for support of apparatus when collapsed;
iv, 'sliding ring.
548 JOHN R. MURLIN
laboratories for this purpose in hospitals. or elsewhere will continue to
give more accurate results, as is true of x-ray and electrocardiographic
work and for the same reasons.
HI. Methods of Calculating the Heat Production
from the Respiratory Exchange
Historically four distinct methods (LeFevre(<7)) have been employed
for the calculation of the heat production from the chemical changes going
on in the body. In each case the method rests upon the fact established by
Lavoisier that the products of respiration are the -products of combustion.
1. Calculation from Heats of Combustion of Carbon and Hydrogen.—
This method possesses only historical interest to-day, yet it should be pre-
sented briefly for the sake of the underlying principle involved. Tn 1T83
Lavoisier published a celebrated work upon the respiratory metabolism and
calorimetry of the guinea pig. The chamber in which the animal was
contained was traversed by a current of air from which the carbon dioxid
was absorbed at the entrance and exit in potash bottles. The gain in
weight of the latter less the gain in weight of the former gave the carbon
dioxid produced by the animal. In ten hours a guinea pig gave off 3.33
gm. of carbon, which from previous experiments Lavoisier knew was
equivalent in heat value to 326.76 gm. of ice melted at 0°. He proved
this by placing the pig in an ice calorimeter and found 341.08 gm. melted.
In 1Y85 Lavoisier, applying his work to the human subject as well
as to the animal, established the fact that out of 100 parts of oxygen ab-
sorbed, 81 parts only reappeared as carbonic acid gas; and he concluded
that the other 19 parts were combined with hydrogen to form water (Gavar-
ret). Respiration was thus seen to be accompanied by double combustion
and Lavoisier proposed by quantitative studies of the respiration to deter-
mine the proportion in which oxygen is partitioned between carbon and
hydrogen of the materials in the blood to produce carbonic acid gas, water
and heat.
But this is not all. With Seguin, Lavoisier (Lavoisier and Seguin(&))
made a series of experiments upon the human subject and demonstrated
that carbon dicxid is produced and oxygen is absorbed in proportion to the
mechanical work effected by the organism. "By this new discovery
Lavoisier raised the theory of combustion to the level of a great generaliza-
tion and revealed for the first time the essential source of all animal
energy" ( LeFevre ( g ) ) .
A method devised by Dulong consisted siinply in measuring directly
the CO2 produced and indirectly the water by assigning to hydrogen all
the oxygen which was not recovered as CO2. Since, however, it is not cer-
tain that all of the oxygen which escapes combination with carbon serves
NOKMAL PROCESSES OF ENEKGY METABOLISM 549
only for the formation of water, Boussingault(fc) sought to establish the
exact amount of hydrogen burned by striking an exact and complete
balance of materials between the ingesta and the ejecta of the body.
The heat of combustion of carbon and hydrogen having already been
established at 8.040 and 34.46 kilo-calories per gram respectively, Helm-
holtz calculated by Dulong's method that a man of 82 kg., giving off in
the respiration in 24 hours 878.4 gm. CO2 or 239.6 gm. C produced
(239.6 X 8.04 =) 1,925 calories. The excess of oxygen going to form
water combined with 13.615 gm. H producing (13.615 X 34.46 =)
469.172 calories. The total heat production therefore was 2395.55 Cal.
Vierordt by a method entirely analogous to that of Boussingault cal-
culated the heat production from the known metabolism of food as fol-
lows: Taking the average ration of the adult at 120 gm. protein, 90 gm.
fat and 340 gm. carbohydrate and leaving out of account the hydrogen
of the carbohydrate, because it was known to be saturated with oxygen,
there were in
O -Ll!
120 gm. protein 64.18 8.60
90 " fat 70.32 10.26
340 " carbohydrate 146.80
Total 281.20 18.86
But the urine and feces contained unoxidized carbon and hydrogen de-
termined at 29.8 gm. for the former and 6.3 gm. for the latter. The net
combustion, therefore, was (281.20 — 29.8 =) 251.4 gm. C and (18.86
— 6.3 =) 12.56 gm. H, and the heat production
251.4 X 8.04 = 2031.31 Cal.
12.56 X 34.36 = 332.82 "
Total 2364.13 "
These methods of calculating the heat production upon the heats of
combustion of hydrogen and carbon contained in the food as if the hydro-
gen and carbon were free gases are now known to contain an error of at
least 11 or 12 per cent. The heat of combustion of formic acid (CO2H2),
for example, is not equal to the combustion heat value of C and H2 5 for
the heat value of H2 is 683 Cal. per gram-mol and of C is 943 Cal. per
gram-mol; whereas that of CO2H2 is only 694 Cal. per gram-mol. The
difference between the combustion heat value of CO2H2 and the sum of
the values for C and H2 is called the heat of formation.
The heat production, therefore, must be based upon the combustion
of the organic foodstuffs themselves.
2. Calculation from the Heats of Combustion of the Organic Food-
stuffs.— Berthelot and Andre determined the physiological heat value
of protein (egg albumin coagulated and dried at 100° C.) by burning in
550 JOHN R MURLIN
the calorimeter and deducting the quantity of heat represented by the
urea formed from it. The bomb value of the protein was 5.690 calories
and the urea 833, leaving a net value to the organism of 4.857 calories per
gram. The average values for eleven different food proteins was found
by them to be 5.691 Cal. and the net value after deducting the urea formed
was 4.750 Cal. per gram.
In the conclusion to their paper Berthelot and Andre state that the
influence of the intestinal excretions "cannot modify these figures very
much for the feces in man form a very small fraction of the weight of the
food." The unabsorbed residue from proteins it is now known, however,
constitute as much as 10 to 15 per cent of the food; hence they -are by no
means negligible.
The exact physiological heat values of these organic foodstuffs was
first resolved with a high degree of exactness by Rubner(rf) . He proceeded
from the known fact that in the case of proteins, urea is not the only nitro-
genous waste "product and that some of the others have very different heat
values from that of urea. Besides he saw the necessity of deducting the
heat value of the feces resulting from the food in question. An example
of the method employed by Rubner may be given as follows:
Lean meat free of connective tissue was taken and dried; it was then
macerated in alcohol to insure its complete dehydration. After drying
again and evaporation of the alcohol it was macerated once more in ether.
The albumin resulting had the appearance of papier mache and was prac-
tically free of salts. When this material was powdered and burned a
bomb heat value of 5.754 Cal. per gram was obtained.
A dog was fed for eight days with 116.8 grams of the dried and puri-
fied protein daily. The urine for the first six days was rejected, and that
for the 7th and 8th days only saved, the dried residue of which gave
a heat value of 2.706 calories per gram. The heat value of urea he found
to be only 2.523 Cal. or 7 per cent less than that of the whole urine. One
gram of the dried matter was found to contain 0.414 gm. of N, from which
it was found that 1 gm. of N" in the urine represented 6.690 calories.
The feces contained 37.8 gm. of dry matter daily. The loss by nori-
absorption therefore was 3.24 per cent. Burned in the calorimeter this
dry matter was found to contain 5.722 calories per gram. When the ash
was deducted it was found to have a heat value per gram of 6.852 calories,
and the nitrogen was found to be 7.02 per cent. The net physiological
heat value therefore could be calculated as follows :
Ingested 100 gm. dry protein of meat 575.40 Cal.
jTIrine— 109.450 Cal.
l\Feces— 18.540 "
Total - - approx. -- 128.000
Difference • 447.400 or 4.47 Cal. per gram.
NORMAL PEOCESSES OF ENERGY METABOLISM 551
Making further corrections for the heat of imbibition and of solution this
figure in the particular experiment cited was reduced to 4.42 Cal. which
was 76.8 per cent of the gross heat value of the protein as fed.
Since 100 grams of the dried albumin of meat contained 16.59 gm.
of N and its combustion gave a heat value of 4.424 Cal. per gram each
gram of N" had a heat value of 26.66 Cal.
With unwashed meat the value came out 25.98 calories per gram. In
the same research Rubner(d) calculated that the body protein of a starving
rabbit had a physiological heat value of 3.842 Cal. per gram, or 71.9
per cent of its gross heat value, or again 24.94 calories per gram of ~N.
The mean physiological heat value for a number of animal proteins —
paraglobulin (4.371), egg albumin (4.307), casein (4.404), fibrin (4.179)
—was found to be 4.21 Cal. per gram. Conglutiii was taken as a type of
vegetable protein and was found to have a value of 3.97 calories.
Since out of 100 grams of mixed protein in human food about 60
per cent is taken from animal sources and 40 per cent from vegetable, Rub-
ner calculated the mean value for food protein in general at 4.11 Cal.
per gram.
Accepting the bomb values of Stohmann for carbohydrates and con-
sidering the preponderance of starch in human dietaries Rubner estimated
the physiological heat value of carbohydrates in general (making deduc-
tion of cellulose) at 4.1 Cal. per gram. For fat he adopted the mean
value of 9.3 Cal.
These values — Proteins — 4.1 Cal.
Fat 9.3 "
C. H. — 4.1 " have become standard in the liter-
ature of metabolism and are now generally used.
Atwater and his collaborators in this country have adopted a some-
what different method of arriving at the physiological heat value of the
foodstuffs. He lays down the principle that the combustible value to the
body is found by subtracting from the heat of combustion of the utilizable
food the heat value of the urine corresponding to the food in question.
The average utilization (i. e., ingestion less feces) of the several classes
of foods he gives as follows (Atwater, Benedict, Smith and Bryant) :
Prot. Fat C. H.
Animal Foods 97% 95% 98%
Cereals 85 90 98
Legumes dry 78 90 97
Sugar and Starch . . 98
Legumes, fresh 83 90 95
Fruits 85 90 90
The fats and carbohydrates being completely burned in the body, the heat
value to the body is equal to the total calorimetric value of the portion ab-
552 JOHN R. MURLIN
sorted. The total heat value of the urine arising from the incomplete
oxidation of proteins, its heat value represents that fraction of the po-
tential energy of the proteins absorbed which the body does not utilize.
Utilization thus is used in two senses. From the standpoint of absorp-
tion it is that part of the food which exceeds the amount excreted through
the bowel. From the standpoint of energy it is that part of the absorbed
food diminished by the potential energy of the bodies excreted in the
urine. Comparing the method of Rubner with that of Atwater, it is seen
that in the former calorimetric heat value equals heat of the specific food
ingested less the heat of the feces less heat value of the urine. According
to Atwater the calorimetric heat value equals the heat value of the utiliz-
able food less heat value of the urine.
The method of Rubner is more direct and thermochemically is more
correct ; but it is impracticable in its application to man for it requires the
ingestion of a perfectly pure (salt free) foodstuff. The method of Atwater
is open to the objection that he assumes the same heat value for the pro-
teins of the feces as for the corresponding food protein. It has the ad-
vantage of simplicity, however, in that it employs a coefficient of utiliza-
tion and can be used for a mixed diet both in animals and man.
Woods made 56 determinations of the heat value of the urine in At-
water's laboratory and found an average value per gram of N of 7.9 Cal.
If this 1 gram of ~N represents 6.25 gm. of protein destroyed, for each
gram of protein absorbed and burned there is a loss of (7.9 -f- 6.25 =)
1.25 Cal.
The heat value of a food protein may then be found by the follow-
ing method. Protein of meat has (table above) a utilization of 97 per cent.
Its heat value is 5.65 Cal. The energy of the portion utilized is 5.65 X
0.97 = 5.48 Cal. per gram. But from this value must be deducted
the heat value of the urine, which according to Wood's determination
is 1.25 X 0.97 = 1.20 Cal. The physiological heat value of meat for the
human subject, therefore, is (5.48 — 1.20 Cal. =) 4.28 or in round num-
bers 4.25 Cal.
The bomb heat value of cereal protein Atwater found to be 5.8 Cal.
per gram ; its utilization was 85 per cent ; therefore, its physiological heat
value would be (5.8 X 0.85) — (1.25 X 0.85) = 3.87 Cal. per gram.
The mean physiological heat value for all animal proteins was given by
Atwater at 4.27 Cal. and that of all vegetable proteins at 3.74 Cal. or
4.05 Cal. per gram for food proteins generally.. It is now known, how-
ever, that the utilization of cereal protein such as that of bread is more
commonly 92 per cent rather than 85 per cent as found by Atwater. This
would change his figure for vegetable protein from 3.74 to 3.98 Cal. per
gram, and if the percentage of animal and vegetable proteins in the diet
be placed at 40 and 60 which more nearly accords with practice in most
NORMAL PROCESSES OF ENERGY METABOLISM 553
countries outside of the United States the mean heat value to the body
4.27 X 40 + 3.98 X 60
would be: — — -— — =4.100 Cal. which is the average
value given by Rubner.
The physiological heat values of fat and carbohydrate are found by the
Atwater method in the same manner except that no deduction is made for
the urine. The average utilization in the human subject for animal fat
being 95 per cent and for vegetable fat 90 per cent, and the bomb values
being 9.5 Cal. and 9.4 Cal. respectively, the value to the body is 9.02 and
8.46 Cal. for the two or 8.75 Cal. for food fats in general. For carbohy-
drates the factors are 4.2 CaJ. per gram bomb value, and 98 per cent utili-
zation. Therefore, the value to the body is 4.1 Cal.
Both Rubner and Atwater have justified the heat values of the several
foodstuffs to the body by direct calorimetric experiments upon the dog and
man respectively. Rubner(/) hit upon a very clever method of confirming
his heat values with the aid of his calorimeter. In one experiment he fed
a dog a large amount of protein and a small amount of fat; in another
just the reverse. The metabolism was as follows:
1st Exp. N elim. 10.09 gm.
C. of fat oxidized 9.06 "
Total Calories 379.50 Cal.
2nd Exp. N. elim. 2.95 gm.
C. of fat 19.12 "
Total Calories 311.0 Cal.
Let x be the heat value of a gram of nitrogen and y the heat value of a gram
of C from fat. Then, 10.09x + 9.06y = 379.5 Cal.
2.95x+19.12y = 311.0 "
From which x = 26.70 Cal.
y = 12.15 "
Now 1 gram of N corresponds to 6.49 grams pure protein of meat —
O A ^7 C\
hence 1 gm. = - - = 4.05 Cal. One gram C corresponds to 1.3 gm.
6.49
12 15
pure fat; hence 1 gm. =— —Cal. = 9.31 Cal.
1.3
Atwater in a series of 27 studies on human subjects, 14 of which were
carried out in the calorimeter devised by Rosa, found a difference between
the direct measurement of heat eliminated and the theoretical heat produc-
tion as calculated from his factors of less than 1 per cent, which may be
taken as satisfactory proof that these values for the human subject are
substantially correct. 2
3 The only difference of any consequence between Rubner's and Atwater's values
applies to fat. Modern authorities who have been most under the influence of the
554
JOHN R. MURLIN
The method of Alimentary Calonmetry consists then simply of finding
the average daily ingestion in terms of protein, fat and carbohydrate and
multiplying by the standard physiological heat values. Thus Gautier(&)
gives the average dietary of a middle clas's Parisian as 102 grams protein,
56 grams fat and 400 grams carbohydrate. His average energy utilization,
therefore, would be: 102 X 4.1 + 56 X 9.0 + 400 X 4.1 = 2562 Calor-
ies. If -a person on this diet were in equilibrium of nitrogen and weight,
his energy production would be equal to this sum ; otherwise not. Besides,
weight is not a satisfactory criterion of energy equilibrium and the utiliza-
tion when the diet is made up of different articles will vary considerably.
All we are justified in saying, therefore, is that an average regimen of this
sort represents such and such an energy value to the body. Some persons
would gain in weight on it ; others would lose. Another example is the fol-
lowing taken from the nutritional surveys of Army Camps in the United
States made by the Medical Department of the Army in 1918 (Murlin and
Miller).
TABLE 1
NUTRIENTS AND ENEBGT CONSUMED IN TRAINING CAMPS OF U. S. ARMY
F
ood per Man
per Day
Consumed
Nutrients
Supplied
Wasted
Consumed
Value
Averages
427 messes
Proteins gm. . .
Fat gm
131
134
9
11
122
123
14%
31%
Carbohydrate .
Fuel Value, Cal.
516
3899
31
266
485
3633
55%
100%
The "Fuel value consumed" in this and similar tables gives the energy
value to the body of the food consumed and not the amount of energy re-
leased by the body. Upon the diet of the Army Camps in 1918, the aver-
age recruit gained nearly six pounds in weight during a period of five
months training, showing that the energy content of the food was consid-
erably more than sufficient to sustain the muscular activity of hard train-
ing and to maintain body weight. 3
The actual heat production in any given case can be computed from the
physiological heat values just discussed provided the output of carbon and
nitrogen can be determined, and provided it be assumed that all of the
carbohydrate fed is burned before fat burns. This method of calculation
German school of metabolism have adopted Rubner's values of 9.3; while French au-
thorities like Gautier and LeFevre have accepted the work of Atwater as equally con-
clusive with that of Rubner and have adopted a mean value between the two authorities
of 9.0 Cal. per gram. Since the methods of calculating the actual heat production by
use of these values have been largely superseded by the method of thermal quotients
to be described in the next section, the controversy over these values has subsided.
3 Recruits fed in this way for several months have almost certainly a higher basal
metabolism (see page 607) than civilians of the same initial weight and age, and it
is not yet certain that the benefit from the standpoint of muscular efficiency is com-
mensurate with the cost in superfluous metabolism. This is a problem which Requires
careful study by the army itself.
NORMAL PEOCESSES OF ENERGY METABOLISM 555
was first applied by Eubner to the results obtained by Voit and Petten-
koffer on a fasting man (Lusk(/t) ). These observers had found that their
subject, weighing 71.09 kgm., gave off in the respiration and in the urine
207.11 gm. carbon and in the urine 11.33 gm. nitrogen. Deducting from
the total carbon the carbon (3.28 times the N) belonging to protein the re-
mainder was calculated as carbon of fat and it was learned that the man had
burned 70.81 gm. protein and 22.1 gm. fat. Rubner applied his physio-
logical heat values for a gram of N in starvation (24.98 Cal.) and for a
gram of carbon in fat (12.3 Cal.) and learned that the total energy pro-
duction of the man in twenty-four hours was :
11.33 gm. N x 24.98 = 283 Cal.
166.95 gm. C of fat x 12.3 = 2091 Cal.
Total 2374 Cal.
When the food contains only fat and protein exactly the same method
is used for calculating the heat production, except that the heat value of
nitrogen in the urine has a different value (see page 552). When the
food contains carbohydrate any gain or loss of C to the body may be esti-
mated as fat, it being assumed that the amount of glycogen in the tissues
is the same at the end of an experiment as at the beginning. It will be
seen later that Rubner, employing this method of calculation in experi-
ments on the dogs whose heat production was measured simultaneously in
a calorimeter, found perfect agreement between the heat as calculated and
as measured, thereby proving the essential correctness of the method. At-
water's method of calculation in similar experiments on human subjects
was different, but proved to be equally correct.
3. The Method of Thermal Quotients of 02 and C02. — When an or-
ganic foodstuff is burned in the animal body a definite amount of oxygen
is absorbed and a definite amount of CO2 is formed and eliminated. If the
heat formed by such a combustion is known the heat value of a gram
of oxygen absorbed or of a gram of CO2 eliminated may be expressed as
a simple quotient of heat divided by the weight of the gas. Since the
measurement of the respiratory gases by volume is an easy matter the
thermal quotient can be expressed also in relation to a liter of gas at 0° C.
and 760 mm. of pressure or at any other desired temperature.
a. Calculation of Thermal Quotients. — If we suppose that protein
burns only to the stage of urea the thermal quotient for this foodstuff
may be calculated from the following equation :
C72H112N"18SO22 + 77 O2= 63 CO2 + 37 H2O + 9 CON2H4 + H2SO4
Albumin Urea
According to this equation 1.612 gm. of protein yielding 7.810 Cal. of heat
would consume 77 molecules of O2 weighing (77 X 32 =) 2.464 gm. and
556
JOHN R. MURLIN
j
63 CO2 weighing (63 X 44 =) 2.772 gm. For oxygen the thermal quo-
ient would be (7.810-^2.464=) 3.19 Cal. per gram and for CO2
(7.810 -r- 2.772 =) 2.82 Cal. per gm. Or, on the basis of volume at
0° and 760,
4.54 Cal. per liter of O2
and 5.44 Cal. per liter of CO2
For fat the thermal quotient may be calculated from the following
equation: C57H101O6 + 80.O2 = 57 CO2 + 52 H2O
Triolein
From this it follows that 0.884 gm. of this particular fat yielding
8.423 Cal. would require 80 molecules of O2 .weighing (80 x 32 =) 2.560
gms. and 57 molecules of CO2 weighing (57x44=) 2.508 gms. One
gram of O2 therefore has a heat value of (8.423 -=- 2.560 =) 3.29 Cal.
and one gram of CO2 (8.423 -=- 2.508 =) 3.35 Cal. or, on the basis of
volume at 0°" and 760,
4.70 Cal. per liter of O2 .
and 6.58 Cal. per liter of CO2
For carbohydrate the equation is: CCH10O5 + 6 O2 = 6 CO2 +
5H2O and the thermal quotients are : 5.09 Cal. per liter of O2
and 5.09 Cal. per liter of CO2
The results may be summarized as in the table below.
TABLE 2
THERMAL QUOTIENTS ( LEFEVKE ( g ) )
Cal. pe
r Gram
Cal. pe
at 0° and
r Liter
760 mm.
at 1
3° C.
Gms. O2 Con-
sumed per
Gram of
02
C02
02
C02
02
C02
Foodstuffs
Burned
Proteins
3.19
2.82
4.54
5.44
4.261
5.104
1.524
Fats
329
3 35
4 70
6 58
4410
6.174
2.896
Carbohydrates.
3.56
2.59
5.09
5.09
4.776
4.776
1.185
To estimate the mean thermal quotient for a mixed diet the* method is a
simple one. For example, take the mean food consumption of the average
soldier in the training camps (p. 554) namely, 122 gm. protein, 123 gm.
fat and 485 gm. carbohydrate. The amount of oxygen required for the
combustion of these quantities of the several foodstuffs would be :
122 gm. Protein x 1.524 = 185.9 gm. O2
123 gm. Fat x 2.896 = 356.2 " "
485 gm. C.H. x 1.185 = 574.7 " "
Total 1116.8 " "
NOEMAL PEOCESSES OF ENEEGY METABOLISM 557
Multiplying each of these quantities of oxygen by the respective thermal
quotients (see table above) for the different foodstuffs:
185.9 gm. O2 X 3.19 = 593.1 Cal.
356.2 " " X 3.29 == 1172.0 "
574.7 " " X 3.56 = 2046.0 "
Sums 1116.8 " " = 3811.1 "
From this calculation 1 gm. O2 = 3.41 cafories.
For a liter of oxygen at 18° C. the mean thermal quotient would bo
4.601 Cal. (nearly).
Laulanie(a) conducted experiments on small animals at or near this
temperature by means of a small calorimeter and computed the oxygen ab-
sorbed by analysis of the air of the chamber after a short period of con-
finement. The average value of the thermal quotient found by him was
4.71 Cal. per liter as calculated from the metabolism and 4.75 Cal. as
measured by the calorimeter.
Atwater and Benedict (c) in a series of 12 experiments on mixed
diets found as an average a heat production for 24 hours of 2238 calories
and an oxygen absorption of 652.1 gm. The mean thermal quotient in
this series was 3.43 Cal. per gram, which agrees very well with the the-
oretical value based upon a mixed diet. At 18° C. the heat value per
liter of O2 would be 4.61 Cal.
TABLE 3
THERMAL QUOTIENT OF 02 BASED UPON EXPERIMENTS ON MAN (ATWATER AND BENEDICT)
Exp. No.
Heat Measured
Cal.
Weight of 02
Absorbed Gms.
Thermal Quotient
Cal. per Gm. 02
1
2379
708.0
3.36
2
2279
681.2
3.34
3
2085
603.2
3.45
4
2403
689.0
3.48
5
2287
664.8
3.44
6
2309
658.1
3.50
7
2151
628.5
3.42
8
2193
630.2
3.47
9
2176
659.7
3.30
10
2244
647.5
3.46
11
2272
656.0
3.46
12
2079
600.6
3.46
Mean
2238
652.1
3.43
The greatest deviation from the mean is represented by experiment
No. 9 where it is only 3.9 per cent.
In the case of a man on a lacto-vegetarian diet containing 39 gm. pro-
tein, 25 gm. fat and 265 gm. carbohydrate Atwater and Benedict found
that 1800 Cal. of heat were eliminated and that the absorption of oxygen
'The weight of a liter of oxygen at 18° C. is 1.341 gm.; that of COa is 1.804 gm.
558
JOHN K. MUKLIN
footed up 528 grams. The thermal quotient therefore was 3.41 Cal. as
against a theoretical value of 3.45 calculated from the composition of the
diet. The error involved in the use of a thermal quotient of 3.43 Cal. per
gram for vegetarian as well as mixed diet would not be in excess of 0.5
per cent.
The values thus far discussed were obtained upon the resting subject.
Would they apply equally to a subject engaged in heavy muscular work
where oxygen is utilized not merely for production of heat by combustion
but also for the transformation of the food's potential energy into mechan-
ical work? Lefevre(gr) has calculated the thermal quotients for many of
the work experiments found in Atwater's publications and has grouped
them as given in the table below. The amount of work reckoned on the
basis of 24 hours was from 120,000 to 190,000 kilogrammeters.
TABLE 4
THEBMAL- QUOTIENTS OF 02 DURING MUSCULAR WORK (ATWATEB AND BENEDICT)
Experiment
Heat Measured
Cal.
Oxygen Absorbed
Gms.
Thermal Quotient
Cal. per Gm. Oa
Mean of 3 exp. on fat-rich diet
Mean of 3 exp. on CH rich diet
Mean of 8 exp. on fat-rich diet
Mean of 8 exp. on CH rich diet
3570
3699
5128
5142
1053.5
1081.6
1512.7
1465.6
3.39
3.42
3.39
3.50
Mean .
4385
1278.5
3.425
It appears that the mechanical equivalent of oxygen when expressed
as heat is the same as the pure combustion equivalent. This is a very sig-
nificant fact for it means that the liberation of energy from combustible
substances is a constant function of the oxygen absorbed whether that en-
ergy take the form at once of free heat or pass first through the form of
mechanical work.
It is clear that if the oxygen absorption of a subject is known the
amount of energy liberated in the body (not necessarily the amount of
heat) can be found with a high degree of accuracy by simply multiplying
the number of grams of oxygen by 3.43 Cal. or the number of liters at 0°
and 760 by 4.90 Cal. or the number at 18° C. by 4.60 Cal.
b. Thermal Quotient of Carbon Dioxid. — Kesults not nearly so con-
stant are obtained when the carbon dioxid elimination is employed as the
basis of computing the heat production. For example, when tristearin is
completely oxidized the thermal quotient of CO2 is 3.35 Cal. per gram.
When glucose is completely oxidized it is only 2.59 Cal. per gram (Table
2). Besides, it is possible to have CO2 produced in large excess when glu-
cose is transformed into fat, and when the heat production is very low. Un-
der these circumstances the thermal quotient of CO2 is given by Lefevre at
0.3 Cal. per gram. Finally, if fat is ever converted to glucose in the body
559
(and the possibility of this reaction has never been disproved) the pro-
duction of carbon dioxid in proportion to the amount of heat disengaged
would be very small and the thermal quotient would be correspondingly
high. Lefevre(gr) has brought together results from Atwater and Bene-
dict's work to show that the weight of CO2 produced for each 100 Cal. of
heat eliminated from the human body is very variable. The results are
given in the table below.
TABLE 5
VABIATION IN HEAT EQUIVALENT OF CO2 (ATWATER AND BENEDICT)
Condition
Heat Measured
per 24 Hrs., Cal.
Weight of CO2 Elimi-
nated in 24 Hrs., Gm.
C02 in Gm. per 100
Cal. of Heat
Inanition
2346
698.0
29 g
Resting
2287
8235
36 0
Resting
2272
846 7
37 2
Moderate work
3420
1158.0
33 9
Severe work
5205
1657 0
31 8
Severe work
5178
1884.0
36 4
Even in experiments of long duration it is evident that the calculation
of heat production upon the basis of the carbon dioxid contains an inherent
error of as much as 25 per cent. In experiments of short duration the
error would be even greater. In fact, of the series of experiments from
which the figures given above were obtained many were performed in two
hour periods so that it is possible to follow the heat as measured and the
CO2 from period to period. In spite of a perfectly uniform heat elimina-
tion the CO2 elimination varies at times as much as 40 per cent.
c. The Respiratory Quotient and Its Significance. — Even though the
value of the oxygen absorption in terms of heat may be fairly constant,
so that for long periods the calculation of the energy production may
proceed upon this basis with involvement of very slight error, the re-
quirements of short experiments are more rigorous. For it is quite pos-
sible that an observation of, say, only 15 minutes duration made perchance
soon after a meal would coincide with maximum absorption of carbohy-
drate ; while another made some hours later might very well coincide with
the maximum absorption and combustion of fat. Two such periods could
not be concordant if the average thermal quotient for oxygen were used.
The respiratory quotient, however, enables us to know what kind of food
is being oxidized at any given time, or at least what possible combinations
of combustion there may be.
If a sample of pure food, e. g., cane sugar, be placed in a bomb with
oxygen and ignited, it is possible to learn the amount of combustion by
analyzing the gases before and after firing. In the case of pure carbo-
hydrate it would be found that just as much oxygen by weight has disap-
peared as is contained in the carbon dioxid formed. Or, since equal vol-
umes of all gases contain the same number of molecules at the same pres-
I
560 JOHN K. MUKLIN
sure and temperature, it would be found upon reduction to standard con-
ditions that the volume of CO2 produced had just replaced the volume
of O2 consumed.
The same method may be employed, in fact has been repeatedly em-
ployed, especially by the French students of respiratory metabolism, to
examine the quality of combustion in the human body. For example,
Weiss sealed a child up in a closed box containing pure air, and at the
end of an hour drew off samples for analysis. The box had a capacity
of 60 liters and in this amount of atmospheric air the child could subsist
for several hours. Comparing then the composition of the air at the end
of an hour with the composition at the beginning it was found that, in
certain instances, the carbon dioxid produced had exactly replaced the oxy-
gen utilized by the child. The observer correctly inferred that carbo-
hydrate had been the source of the energy liberated by the combustion;
for in carbohydrate there is nothing to unite with oxygen except carbon,
the hydrogen 'present being already cared for by the intramolecular oxygen.
In this instance the relation by volume of the carbon dioxid produced to
oxygen absorbed would be 1.0. This relationship in metabolism is the
respiratory quotient.
The actual chemical reactions involved in the combustion of the sev-
eral organic foodstuffs will now be given and the respiratory quotients
typical of each deduced therefrom.
Glucose, the normal sugar of the blood is oxidized thus :
C0H12OC + 6 O2 = 6 CO2 + 6 H2O
The relation of CO2 by volume to the O2 is - = 1.0, or the rela-
O vJ2
fi O
tion by weight of the O2 in CO2 to O2 absorbed is 2 = 1.0.
6 (J2
The respiratory quotient is unity. When a simple fat like palmitine,
C3H5(C16H31O2)3 is burned, conditions are as follows: The fat may be
written thus: C51H98OC and its combustion would proceed according to
the equation :
C51H98O6 + 72.5 O2 = 51 CO2 + 49 H2O
51
The relation of CO2 by volume to the O2 is ^— — = 0.703, which is
i £/«0
the respiratory quotient. With a simpler fat such as the butyrate: C3H'5
(C4H7O2)3, the relationship would be quite different, owing to the rela-
tively larger quantity of O2 already present in the molecule. Thus:
C15H20O2 + 18.5 Oj = = 15 CO2 + 13 H2O. The respiratory quotient
15
would be r =0.81. Food fats are for the most part composed of
18.5
the glycerides of palmitic, stearic, and oleic acids, an average composition
on the percentage basis being 76.5 per cent C; 11.9 per cent H; and 11.6
NORMAL PKOCESSES OF ENERGY METABOLISM 561
per cent O. One hundred grams of such fat would require 288.6 gm.
O2 in addition to that already present in the molecule for complete con-
version to CO2 and H2O. There would be produced 280.5 gm. CO2. The
relationship of — — - is ; and this divided by — -, the molecular
\J2 ^oo.o 32
weight, or multiplied by -— would give the respiratory quotient = 0.706.
A slightly simpler calculation, as noted above, is to determine the weight of
O2 necessary to form CO2 (in this case 204.0 grams) and divide this
directly by the weight of total O2 required; thus: - - = 0.706.
288.6
The respiratory quotient of all food fats is in the neighborhood of
0.71. The same is true also of body fat. Hence whether pure body fat
or pure food fat were being burned, the R. Q. would be approximately 0.71.
As a matter of fact, this quotient is probably never actually produced
under normal conditions; for there is always some protein being de-
stroyed, and, since under the conditions of high fat combustion, whether
from starvation or excessive fat ingestion this small am'ount of protein
is readily oxidized, there is a mixed quotient contributed in small part
by the oxidation of protein and in large part by the oxidation of fat. On
the assumption that the protein quotum of energy production is 15 per.
cent and the other 85 per cent is from fat, Magnus-Levy estimates that
the actual respiratory quotient should be 0.722, while if the remaining
85 per cent is produced from carbohydrate, the quotient should be 0.971.
The respiratory quotient of proteins will, of course, depend upon the
exact formula employed ; but since all proteins are made up of amino acids,
the exact relationship can best be appreciated by starting with a single
amino acid. If alanin is given to an animal, it will be oxidized after deam-
ination, as follows :
CH3 . CHNH2 . COOH + HOH == CH3 . CHOH . COOH + NH3
CH3.CHOH.COOH + 3 O2 == 3 CO2 + 3 H2O
The respiratory quotient of this reaction would be 1.0 since the volume
of O2 is just equal to the volume of CO2 produced. But the NH3 is not
yet disposed of. It cannot remain in the body as NH3 and it cannot be
eliminated as a gas, for the lungs are not permeable to NH3 even if it
could be carried in the blood as gas. Actually, the NH3 will unite with
the CO2 to form ammonium carbonate, thus :
2 KH3 + C02 + H20 = (NH4)2 CO3
Later, this is converted to urea, thus:
NH2\
CO3 — 2 H,O = CO
NH2/
562 JOHN K. MURLIN
The net result would be that for each two molecules of alanin, yielding
2 molecules of NH3, one molecule of CO2 would fail to appear in the ex-
pired air, but would be eliminated as urea or water. Hence, for 6 mole-
cules of O2 absorbed, only 5 would come back as CO2 and the true R. Q.
of alanin would be 5/6 = 0.833. If all proteins were made up of amino
acids as simply as this, the R. Q. for their combustion would be as easily
computed. The respiratory quotient of glycocoll would be 0.75; that of
leucin would be 0.73. But that of lysin containing two NH2 groups and
requiring, therefore, one molecule of CO2 for elimination of the N as
urea for each single molecule of the substance, would be only 0.71. The
more diamino acids contained in a protein, therefore, and the more leucin,
the lower would be the respiratory quotient. With gelatin, which con-
tains a high percentage of glycocoll, one might expect a somewhat higher
quotient than with casein which contains no glycocoll and a much larger
amount of leucin. Taking an example of a highly synthetized protein such
as 1-leucyl-triglycyl-l-leucyl-triglycyl-l-leucyl-octoglycyl-glycin, which was
put together by E. Fischer and whose exact chemical structure is there-
fore known, we find that 45 molecules of O2 would be necessary to produce
complete combustion ; that 9 molecules of CO2 would be needed to remove
the NH2 in the form of (NH4)2CO3 ; and that when this ammonium car-
bonate breaks down by dehydration to form urea, none of the carbon would
return to the respiration and none of the oxygen would be available for
combustion. The R. Q. therefore would be 0.81.
Taking the elementary analysis of protein of the human body and
adopting the percentages used by Magnus-Levy we get the following com-
position after making allowances for the elements which would appear
in the urine and the feces: C, 38.6 per cent; H, 4.24 per cent; O, 9.24
per cent. For the combustion of 100 grams of such protein, 127.6 gm.
O2 in addition to that already present in the molecule would be needed
and 141.5 gm. CO2 would be formed. Taking the ratio of the oxygen in
CO2 (102.9 gm.) to the total oxygen required, the quotient is 0.807 or
by the longer calculation — -^ — - — 2 X — = 0.807. The respiratory
127.6 gm. CO2 11
quotient of a complete protein such as is ordinarily used in rebuilding
the human tissues, but which, because it is not needed for this purpose, is
oxidized as completely as it is possible to oxidize protein in the body, is
thus approximately the same as that for alanin. We may think of this
amino acid as representing the type of fuel available when protein is
burned.
Laulanie(c) in 1898 gave a very simple method of calculating the
thermal quotient for oxygen from the respiratory quotient. This method
is strictly applicable however only under conditions where the metabolism
of protein is entirely negligible, or is calculated independently and suitable
NORMAL PROCESSES OF ENERGY METABOLISM 563
deduction made from the total oxygen absorbed. The method follows:
Let a be any R. Q. less than 1.0. Then Vol. CO2 = a Vol. O2. Let x
be the part of O2 used in combustion of carbohydrate, and Vol. O2 — x the
part utilized in combustion of fat. Then Vol. CO2 — x is the CO2
resulting from combustion of fat. The R. Q. of fat being 0.7 it follows
Vol. CO2 — x Vol. 02— x
that-— ^ =0.7 or, a - = 0.7. From which
Vol. O2 — x Vol. O2 — x
(0 — 0.7) Vol. O2 ,.
x == — which is the quantity of O2 utilized in combustion
O.o
of carbohydrate. The remainder, Vol. O2 — x = — - is the
O.o
part used in combustion of fat. Calling this value y we have : for carbo-
hydrate x = —-^— - and for fat y = TT^—- For example where a is
O.o O.o
2 1
0.9 x = - and y = -. The thermal quotient of oxygen at 0° and
o o
2
760 (page 556) would then be 5.09 X ~ + 4.7 = 4.96 Cal. per liter, or,
3
4.65 Cal. per liter at 18° C.
A single example of the use of the respiratory quotient for calculation
of the heat production by means of the thermal quotient for oxygen will be
given. Lefevre(/) separated the inspired air from the expired air of a
subject in complete muscular repose by means of a pair of Miiller valves
(page 533). The expired air was measured and subsequently analyzed.
In a one-hour period the amount of oxygen absorbed measured at 18° C.
was 13.73 liters. The R. Q. was 0.89, which the author states corre-
sponds to a combustion in which out of three molecules of oxygen absorbed,
two served for oxidation of carbohydrate and one for oxidation of fat.
The mean thermal quotient then would be 4.77 X 2 -J- 4.41 = 4.65 Cal.
per liter. The heat production was (13.73 X 4.65 ==) 63.8 Cal. per hour
or about 1500 Cal. in 24 hours. This minimal metabolism was confirmed
by Lefevre by direct calorimetry. It corresponds well with later determin-
ations of the basal metabolism (see page 607).
4. Calculation of Heat Production from the Respiratory Exchange
and the Urinary Nitrogen. — The method outlined above even when the
respiratory quotient is known is defective in that it does not take ac-
count of the protein metabolism which is always taking place. Apparently
the first to attempt an improvement of the method by making allowance
for the protein metabolism was Kauffmann. His paper was followed
three months later by one from Laulanie who had developed similar im-
provements quite independently.
a. The Method of Successive Thermal Quotients. — Instead of relying
upon a mean thermal quotient for oxygen which answers very well for
564 JOHN K. MURLIN
long experiments Kauffmann undertook to find an exact heat equivalent
for any particular short period by what he called successive thermal quo-
tients. This means only that he partitioned the oxygen to the several
organic foodstuffs and multiplied by their respective thermal quotients.
For example in an experiment on a dog subjected to a prolonged fast he
found that the animal had absorbed in 1 hour 5.992 liters of O2, had
given off 4.494 1. of CO2 and eliminated 0.1983 gm. N in the urine. The
R. Q. was 0.75. The nitrogen corresponded to (0.1983 X 6.25 =) 1.239
gm. protein burned, which in turn required 1,72 gm. of O2 to oxidize it to
the stage of urea (page 555). Subtracting this from the total oxygen
(5.992 1. = 8.57 gm.) there remained 6.85 gm. for combustion of fat. The
heat production was found as follows :
1.72 gm. O2 X 3.19 = 5.486 Cal.
6.85 " " X 3.29 = 22.536 "
Total 28.022 "
Applied to the human subject in good nutritive condition and sub-
sisting on a mixed diet the method would be a little more complicated.
Thus Arthus reports the metabolism of a man for 24 hours :
O2 absorbed = 496 1. or 709 gm.
CO2 eliminated = = 463 1. or 912 gm.
N" in urine 17.35 gm. == 108.44 gm. protein
The protein would require the absorption of 151 gm. O2 and elimination
of 180 gm. CO2.
709 — 151 = 558 gm. O2 or 390 1.
912 — 180 — 732 " CO2 or 371 1.
The remainder represents the metabolism of carbohydrate and fat.
Let x be the volume of O2 for combustion of fat and y the volume of
CO2 resulting. Let z represent the volume of O2 and CO2 for combus-
tion of carbohydrate.
Then y x = 0.70
x -f z = 390 1.
y + z - 371 1.
From which x = 63.33 liters O2
y= 44.33 " CO2
z = 326.33 " O2 and CO2
The weights of a liter of O2 at 760 min. Hg and 0° being 1.43 grams,
the apportionment of O2 would be as follows :
For fat (63.33 x 1.43 =) 90.56 gm.
" carbohydrate 467.12 "
" protein 151.0 "
NOEMAL PEOCESSES OF ENEEGY METABOLISM 565
The heat production then would be :
90.56 X 3.29":= 297.9 Cal.
467.12 X 3.56 = 1662.9 "
157.0 X 3.19 = 481.7 "
Total
2442.5
Kauffmann confirmed the correctness of this method of calculation by
means, of a calorimeter (p. 571) suitable for dogs. His results may be
summarized thus :
TABLE 6
Exp. No.
Heat as Calculated
Heat as Measured
I
II
III
IV
V
VI
27.4 C
30.8
43.7
39.1
37.7
40.2
al.
27.9 C
30.0
44.0
38.1
37.4
39.0
al.
«
<
i
JMl'ail
36.07 "
36.07 "
The discrepancy between the two methods is only one per cent.
b. Method of Zuntz and Schumberg (6). — In their study of the meta-
bolism of a marching soldier Zuntz and Schumberg developed a somewhat
different method of calculation based, however, upon essentially the same
principles as the method of Kauffmann. All calculations are on the basis of
one hour.
The N in the Urine (per hour) (a)X2.56 = C from protein in the res-
piration.
The CO2 output in grams per hour X 3/11 — C output in grams per hour.
The C of respiration — C of protein in respiration = C of carbohydrate
and fat in respiration (b).
N in urine X 8.45 = O2 from protein in respiration.
Total O2 absorbed — O2 from protein = O2 absorbed for carbohydrate and
fat (c).
The O2 for oxidation of one gram of fat = 3.7514 (average).
The O2 for oxidation of one gram of CH = 2.651 (average).
Let X = number of grams C from fat (1 gm. C from fat == 12.3 Cal.).
Let y = number of grams C from CH (1 gm. C. from CH = 9.5 Cal.).
x + y = b. (1 gm. N. from Prot. == 26.0 Cal.)
3.751 x + 2.651 y == c
Solving for x and y, a X 26 = Cal. from Prot.
x X 12.3 = Cal. from fat.
y X 9.5 = Cal. from CH
Total = Cal. per hour.
4 Compare the thermal quotients ( see page 556 ) .
566
JOHN R. MURLIN
5. The Non-Protein Respiratory Quotient.— It was but a step from
the method just given to a simpler calculation based upon a table giv-
ing the heat values of oxygen or carbon dioxid for the non-nitrogenous
combustion.
The respratory exchange due to protein is thus given by Lusk (A).
TABLE 7
100 gm. meat contain
Eliminated in the
Urine
52.38 gm. C.
9 406 " "
7.27 gm. H.
2.663 " "
22.68 gm.O.
14.099 " "
16.65 gm.N.
16.28 " "
1.02 gm. S.
1.02 " "
In the Feces
1.471 " "
0.212 " "
0.889 " "
0.37 " "
Leaving for respira-
tory metabolism. . .
Deducting intramo-
lecular water
41.50 " "
4.40 " "
0.961 " "
7.69 " "
7.69 " "
41.50 gm. C.
3.439 gm. H.
To oxidize these amounts of carbon and hydrogen would require 138.18 gm.
O2 and there would be produced 152.17 gm. CO2. From which it may
be deduced that for every gram of nitrogen appearing in the urine from
meat there would be absorbed from the breath (138.18 -=- 16.28 =) 8.45
grams of oxygen, and there would be produced (152.17 -4- 16.28 =) 9.35
grams of carbon dioxid. Hence by multiplying the nitrogen elimination
in the urine whether of an hour or a day by these factors and subtracting
from the total oxygen absorbed and carbon dioxid eliminated the nan*
protein respiratory quotient is obtained.
By a method entirely analogous to that of Laulanie (page 562) it is
possible to learn the heat values of oxygen for each value of this respiratory
quotient. Zuntz and Schumberg (&) prepared a table setting forth these
values which is now widely employed. As reproduced here the heat values
of both oxygen and CO2 per liter of the gas at 0° and 760 mm. Hg may
be read off for any value of the non-protein R. Q. given to two places.
It will be noted that the values for pure fat (R. Q. 0.71) and pure
carbohydrate (R. Q. 1.0) combustion differ but slightly from those of
Lefevre given in Table 2 (page 556).
The calculation of the heat production from the respiratory exchange
and the nitrogen in the urine involves then the following steps :
(1) Determination of total O2 and CO2 of respiration in grams.
(2) " " " N in the urine.
(3) Multiply N" of urine by 8.45 = O2 for protein.
(4) " N " " " 9.35 = CO2 " "
(5) Subtract these values from total O2 and CO2.
(6) Convert to volume and get Non-prot. R. Q.
NORMAL PROCESSES OF ENERGY METABOLISM 567
TABLE 8
HEAT VALUE OF OXYGEN AND CARBON DIOXID FOR DIFFERENT NON-PROTEIN RESPIRATORY
QUOTIENTS
Caloric value of 1 liter at 0° and 760 mm.
Caloric value of 1 liter at 0° and 760 mm.
R. Q.
CO,
02
R. Q.
CO,
0,
0.70
6.694
4.686
0.86
5.669
4.875
0.71
6.606
4.690
0.87
5.617
4.887
0.72
6.531
4.702
0.88
5.568
4.900
0.73
6.458
4.714
0.89
5.519
4.912
0.74
6.388
4.727
0.90
5.471
4.924
0.75
6.319
4.739
0.91
5.424
4.936
0.76
6.253
4.752
0.92
5.387
4.948
0.77
6.187
4.764
0.93
5.333
4.960
' 0.78
6.123
4.776
0.94
5.290
4.973
0.79
6.052
4.789
0.95
5.247
4.985
0.80
6.001
4.801
0.96
5.205
4.997
0.81
5.942
4^13
0.97
5.165
5.010
0.82
5.884
4.825
0.98
5.124
5.022
0.83
5.029
4.838
0.99
5.085
5.043
0.84
5.774
4.850
1.00
5.047
5.047
0.85
5.721
4.863
(7) Read off heat value of Non-Prot. R. Q. from table.
(8) Multiply by liters of Non-Prot. O2.
(9) Multiply N of Urine by its heat value (26.51 Cal. for meat diet).
(10) Add 8 and 9 for total heat production.
B. Direct Calorimetry
Without the disintegration of organic substances accompanied by a
diminution of potential energy life is impossible. One of the forms which
the liberated energy inevitably takes is heat, and in the resting organism,
i. e., not transferring energy in the form of mechanical work to other ob-
jects, all of the energy finally takes this form. The quantity of heat, there-
fore, becomes a measure of vitality.
We have seen that this measure can be applied in an indirect way by
measuring the potential energy of the foodstuffs or by assigning a heat
equivalent to a unit of oxygen absorbed. But this method is based upon
certain assumptions which are always open to debate, namely, the assump-
tion that specific chemical changes are always accompanied by the same
transformations of energy and the assumption that the law of the con-
servation of energy applies to all chemical transformations in the animal
body. Most authorities are agreed that for these reasons the direct meas-
urement of heat generated in the living organism is at least more authori-
tative even though the accomplishment of this end may be beset with great
difficulties. Krogh(c) states that "With the recent advances in calorimetric
methods due to Atwater and Benedict, Rubner and especially A. V. Hill,
568 JOHN R. MUKLIN
there is every reason to think that direct determinations of the total metab-
olism will be preferred to the indirect in many cases, and all classes of
animals, as it is undoubtedly preferable theoretically." Lefevre(<7) says,
"Aussi bien la calorimetrie physique est a la base de toute recherche de
calorimetrie biologique." And Rubner(p) points out that "Die urpriing-
liche Auffassung des Tierlebens als eine Verbrennung unter oxydativen
Abbau der Stoffe hat der allgemeine energetischen weichen miissen, denn
die letztere umf asst auch jene primativen Lebensformeln bei Bakterien und
Hefe wo Spaltungsvorgange ohne Beteiligung des Sauerstoffs die Quelle
der Energie fur die lebende Substanz bilden." Rubner also draws atten-
tion to the fact that in all organisms there are fermentative reactions not
directly related to the needs of the living substance, which nevertheless lead
to the development of heat. Such heat would represent pure loss of energy
unless, as in the higher animals which possess a specific chemical regula-
tion, it were turned to account in the maintenance of the body temperature.
The different fermentative processes therefore come within the field of
calorimetrie investigation. The production of living substance in the
growing organism on the other hand is of the nature of fermentative
changes which themselves involve no storage or liberation of energy, and
yet they are dependent upon energy changes and indeed may to a degree
be measured by the intensity of the oxidative capacity of the organism.
Calorimetry as related to living organisms has two distinct fields: (1)
the physical measurement of the energy stored in the animal tissues and
in all chemical compounds which may serve the animal as food, likewise
the energy residual in the excretory substances rejected by the cells; (2)
the measurement of the energy set free as heat during the life processes.
I. The Heat ot Combustion
The unit of heat which has been employed for nearly a century is the
Calorie of Regnault, i. e., the amount of heat necessary to raise 1 kilogram
of water from 0° to 1° C. This is the kilo-calorie written with a capital
C. The small calorie written "cal," called also the gram-calorie, is the
amount of heat necessary to raise 1 gram of water from 0° to 1° C. The
calorie more commonly used to-day is somewhat smaller than this, namely,
the amount necessary to raise a kilogram of water from 15 to 16° C or
from 19° to 20° C. In terms of the original Regnault calorie the value
of the calorie at higher temperatures is given by Longuinine as follows :
18° == 0.9995
20° =0.99925
22° = 0.99915
25° = 0.99930
NORMAL PROCESSES OF ENERGY METABOLISM 569
Berthelot (a} introduced the method of burning substances in oxygen
at high pressure, but because of the high cost of the apparatus it did not
come into general use for some years after it was described. The essential
parts of the original apparatus were a double-walled copper vessel filled
with water in which was immersed the vessel capable of holding the oxy-
Tapper-'
.'Motor
thermometer •>
,. --Release
Buiton
Release Button
Ignition Circuit-
Corrtac-ta
Ignition Switch
fuse Wire
Ignition and •
Resistance Coil
Tapper Button-^
Motor Switch
Fig. 23. The bomb calorimeter of Riche for use with Berthelot bomb. The Wein-
holdt cup which is placed inside the box and into which the pump is lowered is not
shown.
•Motor Circuit
Contnr.ts
Rheostat for
Controlling Motor speed.
Spied should be
about 300 R P.M.
(Tapper Circuit.
\Attachonc or
.(two dry cells
m
(16 Candle Power
^ Carbon Filament
\Lamp
{(Attachment Plug for
'\ Motor and Igniticn Circuit*.
i. D.C.orA.C.
gen under high pressure together with the substance to be burned. This
vessel constructed of heavy steel nickeled on the outside and lined with
platinum became known as the Berthelot bomb, and whatever the modifica-
tion from the original pattern it is still known by the inventor's name.
The outer container filled with water is the calorimeter proper. A success-
ful modem construction is that of Riche shown in Fig. 23. It consists of a
570 JOHN R. MURLIN
wooden box lined with a heavy layer of compressed cork board. Inside this
is a Weinholdt vacuum cup which serves as the receptacle for water. The
bomb is lowered into the water by a carriage attached to the top of the
box which slides upon two metal supports at the sides. The top also car-
ries a motor for operating a stirrer in the water and a Beckman ther-
mometer. The substance to be burned is placed in a nickel vessel supported
upon platinum wires inside the bomb. The bomb is then charged with
oxygen and immersed in the water. When the temperature of the water
has become constant (at about 20° C.) the combustion is started by throw-
ing a switch which connects the house circuit with a platinum or nichrome
wire inside. A standard amount of current is secured by means of a fuse
wire, which burns off with just enough current to "fire" the combustible
material. The reading at ignition is taken as the initial reading. This sub-
tracted from the final reading gives the total rise. The increase in tem-
perature multiplied by the weight of water contained in the vacuum cup
(plus the hydrothermal equivalent of the apparatus) gives the total heat
liberated. Certain corrections have to be applied for the heat caused by
the current in firing, and for any nitric acid formed from oxidation of
nitrogen. For example in burning a sample of standard cane sugar the
weight of substance taken was 1.1466 grams. Weight of water in the
cup was 2530 gm.
Hydrothermal equivalent 470 gm.
Water equivalent of apparatus 3000 gm.
Rise in temp, was 1.530°C. Ignition heat - — 60 cal.
1.530° X 3000 gm. = 4590 cal. Nitric acid 4.6 cal.
4590 — 64.6 = 4525 cal. 64.6
4525 -T- 1.1466 gm. = 3947 cal. per gm.
The table on page 571 compiled from various sources gives the heat value
of the most important organic substances concerned in metabolism of the
higher animals.
II. Animal Calorimetry
1. Forms of Calorimeters. — The various types of apparatus devised
for measuring the heat eliminated by an animal body are classified by
Lefevre(g) into four groups : (1) those which make use of latent heats; for
example, the ice calorimeter of Lavoisier and the distillation calorimeter
of D'Arsonval ; (2) those which depend upon the warming of a fixed quan-
tity of water such as the calorimeters of Dulong and Laulanie for animals
and the bath calorimeter of Lefevre for man; (3) those which employ
circulating mediums (air or water) to carry away the heat just as rapidly
as it is produced (compensation method) ; such as the respiration calorim-
NORMAL PROCESSES OF ENERGY METABOLISM 571
TABLE 9
HEAT VALUE OF ONE GRAM OF EACH SUBSTANCE IN LARGE CALORIES
Substance
Stohmann
Berthelot
Rubner
Benedict
Glycerin
4.316
Glucose
3 743
3 762
4.323
Levulose
3.755
3.739
Galactose
3.722
Cane sugar
3.955
3.962
4 001
Milk sugar
3.737
3 777
Maltose
3.722
Dextrin
4.119
Starch
4.183
4.228
Palmitic acid
Stearic acid
Oleic acid
9.265-9.369
9.429-9.549
9 511
9.745
9.745
9 ^4.
9.318
9.499
Animal fat
9.500
Butter
9.231
Vegetable oil
9 520
White of egg
5.735
ly 087
Yolk of egg
5.841
Beef (ext. free of fat)
5.721
K 798
5 778
Veal
5.663
Casein
5 850
c: «o«
Peptone from fibrin
5.942
Glycogen
4.227
Alanin
4.401
Asparagin
3.065
Aspartic acid
2.882
Creatin
4.240
Creatinin
4.988
Cystin
4.137
Glutamic acid
3.662
Giycocoll
3.110
Tvrosin
5.915
Alcohol
7.104
Lactic acid
3.615
Urea
2.537
Uric acid
2.741
eters of Atwater and Rosa, Pompilian, and Lefevre; and (4) those which
do not absorb the heat from the subject but which record only the effects
of heat in one way or another. Examples are the anemo-calorimeter or the
thermo-electric calorimeter of D'Arsonval, the siphon calorimeter of
Richet, and the second calorimeter of Rubner.
It is not necessary to describe more than two or three calorimeters.
The first method described above has never been used in studying the
metabolism of man and is now wholly obsolete. The second as a means
of following the heat production of animals has fallen more or less into
disfavor on account of the cooling correction which is necessary. Lau-
lanie(&) has overcome this to some extent by using a pair of calorimeters
of the Dulong type, running one of them, constructed in exactly the same
manner as the other, as a control of the effects of environment. With this
apparatus Laulanie confirmed the thermal quotients of oxygen (page 557)
in an apparently satisfactory manner.
572
JOHN E. MUKLIN
As a means of studying the heat production of man the second method
has been employed in the form of a bath in which the subject could be di-
rectly immersed. The first to use this method at all successfully was
Liebermeister (a), but his technique was subjected to very severe criticism
a few years later and the method fell into disfavor until rescued by Le-
fevre^.) in 1894. The chief objections to Liebermeister's method were:
(1) that he used too large a volume of water, (2) that he read its tempera-
ture on only a single thermometer and (3) did not guard against stratifica-
Fig. 24. The air calorimeter of Lefevre. 000, wall of the chamber; T, ther-
mometer for measuring the temperature of the atmosphere after it has passed over
the subject; e, e, baffle plates for distributing the air as it enters; F, G, H, baffle plates
to prevent channeling of the air as it leaves the chamber; A, the aspirator; C, covering
for the head which prevents radiation of heat to the exterior.
tion of the water. Lefevre overcame these objections and proved that the
heat production of a man could be measured with a high degree of accuracy
by this very simple method. Even the heat of vaporization of water which
ordinarily is lost through the lungs can be compensated by having the bath
at 35 °C. in which case the subject respires an atmosphere already satu-
rated with moisture.
One of the simplest types of compensation calorimeters is that of Le-
feYre(e) designed for measurement of the heat production of a man by
carrying away the heat of his body just as rapidly as produced with a cur-
rent of air. The calorimeter consists of a zinc chamber 3 meters long, nar-
row at the two ends, but broader in the middle where the subject sits 011 a
stool (Fig. 24). Air is drawn through the chamber by means of an aspira-
tor shown at A. The volume of air is recorded by means of an anemometer.
The increase in temperature is observed by continuous readings of ther-
mometers placed in the inlet and other thermometers placed in the cur-
rent after it has passed over the man's body. The heat elimination is found
by multiplying the volume of air by factors converting it to weight, by its
specific heat and by the average rise in temperature.
The two methods of Lefevre just described are well suited for a study
of the influence of environing temperature upon heat production. One has
only to vary the temperature of the bath or current of air before it strikes
the body to vary the cooling effect. Lefevre combined the water-bath meth-
od with a method for obtaining the respiratory exchange.
2. The Atwater-Rosa-Benedict Respiration Calorimeter (Atwater and
Benedict )(<i). — The fundamental principles of this apparatus which was
designed to measure accurately the heat elimination of a man, are as fol-
lows : The subject is confined in a heat-proof chamber through which a cur-
rent of cold water is kept constantly passing. The amount of water, the
flow of which is kept constant, is carefully weighed. 'The temperatures of
the water entering and leaving the chamber are read at frequent intervals
on sensitive thermometers to 0.01 of a degree. The walls of the chamber
are held at such a temperature as to prevent the loss of any heat through
them, and withdrawal of heat by the water current is so regulated by vary-
ing the temperature of the ingoing water that the heat brought away from
the calorimeter is exactly equal in amount to the heat eliminated by radia-
tion and conduction from the subject. This is accomplished by having ac-
curate knowledge of the temperature of the air inside the apparatus and
the temperature of the walls of the calorimeter. About 25 per cent of the
heat produced by the human subject is eliminated at ordinary temperatures
through vaporization of water from the lungs and the skin. This latent
heat in the water of vaporization is determined by measuring the amount
of water vaporized and passing in the ventilating current to the first sul-
phuric acid absorber. The gain in weight of this absorber is taken as the
water of vaporization.
The respiration chamber of this calorimeter has been constructed in
several different sizes. The original construction at Middletown, Conn.,
had a chamber with a cubic capacity of 5.03 cubic meters, or with the sub-
ject inside a residual air volume of 4500 liters. This apparatus was dis-
mantled at the time the Nutrition Laboratory of the Carnegie Institution
was established at Boston and in its place have been constructed a number
of different calorimeters (Benedict and Carpenter (a)) designed for dif-
ferent purposes. The first of these known as the chair calorimeter (Fig.
25) has a cubic capacity of approximately 1400 liters. A second con-
struction known as the bed calorimeter (Fig. 36) has a cubic capacity of
1347 liters. That part of the original Atwater-Rosa calorimeter which
was the property of the TJ. S. Government was shipped to Washington and
has been reconstructed into a successful calorimeter by Langworthy and
574
JOHN E. MURLIN
E' DEAD AIR
Jj F-J DEAD £AIR
1
. • AIR OUT •
L
ft
Milner. More recently calorimeters have been constructed at the Cornell
Medical College (Williams, H. B.) and at Bellevue Hospital (Riche and
Soderstrom) in New York. The operation of these calorimeters has been
under the scientific direction of Graham Lusk. The small calorimeter at
the Medical School constructed by Williams has a cubic capacity of ap-
proximately 480 liters.
This calorimeter was
.designed for the study
of metabolism in in-
fants and children as
well as of animals (Fig.
29). The large calo-
rimeter at the hospital
known as the Sage cal-
orimeter is designed for
the study of patients in
a reclining, sitting or
supine position and has
a cubic capacity of
1123 liters. Still larger
calorimeters on the
same ' principles have
been constructed by
Benedict at the Nutri-
tion Laboratory in Bos-
ton, having a capacity
large enough to accom-
modate a man doing
active muscular work,
and by Armsby at the
Pennsylvania State Col-
lege (Armsby and
Fries) designed for
measuring the heat
production of the larger
farm animals.
The wall construc-
of these calorimeters. The inner
both sides, thus permitting of
In the cross sec-
Fig. 25. Cross section of chair calorimeter of
Benedict and Carpenter. A, copper wall; B, zinc wall;
C, hair felt; F, asbestos lumber. At the upper right
hand corner of the figure is shown the ingoing and
outgoing pipes, below this at C the food aperture and
the ingoing and outgoing water pipes with their re-
spective thermometers. The chair is suspended from a
balance carried on the frame of the apparatus above
the chamber.
tion is essentially the same in all
wall consists of copper tinned on
soldering, while a second metal wall consists of zinc.
tion represented in Fig. 25, A represents the copper and B the zinc wall.
Surrounding the latter and providing air insulation is a series of panels
constructed of asbestos lumber lined with hair felt or with compressed cork.
The whole construction, therefore, is more or less of the refrigerator type
NORMAL PROCESSES OF ENERGY METABOLISM 575
permitting very little opportunity for radiation or conduction of heat from
the inside out or from the outside in. For additional security against
the radiation of heat from the calorimeters the original device of Rosa is
repeated in all of these calorimeters. This is based upon the ability to
hold the temperature of the zinc wall at the same level as that of the cop-
per wall. To this end it is necessary to know first that there is a tempera-
ture difference between the zinc and copper and second to have some method
Fig. 26. The Sage calorimeter at Bellevue Hospital, New York City. The ab-
sorber table is shown at the extreme left, the observer's table in the middle and the
respiration chamber at the right. Air is circulated by a blower, shown on the lower
shelf of the absorber table, through overhead pipes which may be seen entering the
calorimeter at the upper left hand corner. Oxygen is admitted from a cylinder shown
on the extreme right.
for controlling the temperature of the former. The temperature differences
of the two walls are recorded by means of electrical thermo-junctions, sepa-
rate series of which are arranged in the sides, in the top and in the bot-
tom of the apparatus (the ends of several thermal junctions can be seen
in Fig. 29). A current flowing through these thermal junctions is read
on a Wheatstone bridge at the observer's table and fluctuations of tempera-
ture between the two walls alters the amount of this current. To insure
a cooling effect on the zinc wall a coil of copper tubes carries a thin cur-
rent of water and to counteract this cooling effect a wire running in the
same space and between the cooling pipes is heated by sending through it
the desired amount of current. Adjustable rheostats are within reach of
576
JOHN E. MUKLIN
the observer who reads the electrical variations on the Wheatstone bridge,
so that the amount of current flowing through the several "parts" is under
accurate control. Any tendency for heat to pass outward would be indi-
cated by a deflection of the galvanometer showing that the zinc wall was
cooler than the copper. Such an indication, however, would be immediately
checked by turning additional current into the heating wire, thus restoring
the temperature of the zinc wall to that of the copper wall and thereby
preventing escape of heat.
The interior of the chamber is so arranged as to give the utmost com-
fort to the subject. It is obvious that if the heat were not carried away
Fig. 27. The wiring diagram of the observer's table with the Sage calorimeter.
In the center is the Kohlrausch bridge, to the right a tapping key with an arrange-
ment for throwing in -300 ohms resistance when needed. This key is used in reading
the thermopiles connected with the switch on the right. To the left of the bridge
is a switch for connecting either thermopiles or resistance thermometers with the
galvanometer. On the extreme left is the switch for the air, wall, rectal, ingoing and
outgoing water thermometers, each of which contains 100 ohms.
from so confined a space the temperature would very shortly become un-
bearable. The heat absorbing apparatus is installed on the ceiling of the
chamber. In the later constructions this absorber consists merely of a
continuous grid of copper pipes covering the entire ceiling. In the Cornell
and Sage calorimeters the temperature of the water as it enters is brought
to the desired level by means of a Gouy temperature regulator. This device
insures great constancy in the temperature of the water. With the speed
of the water current properly regulated and its temperature brought to
a constant level as it enters the apparatus fluctuations in the heat, pro-
duction will be manifested by fluctuations in the temperature of the water
as it leaves the chamber. Extreme variation in the former, however, re-
quires readjustment of both speed and temperature of entering water.
After circulating through the heat absorber the water is caught in a
NORMAL PROCESSES OF ENERGY METABOLISM 577
meter (can) and weighed in kilograms. An electrical device under the
control of an observer enables him to stop instantly the flow of water into
this meter upon the termination of a period by the second hand of a clock.
Fig. 28. Diagram of the Atwater, Rosa, Benedict respiration calorimeter as
prepared by DuBois for the Sage Calorimeter.
Ventilating System:
02 Oxygen introduced as consumed by
subject.
3, H2S04 to catch moisture given off by
soda lime.
2, Soda lime to remove CO2.
1, H2SO4 to remove moisture given off
by patient.
Bl, Blower to keep air in circulation.
Indirect Calorimetry:
Increase in weight of H2SO4 ( 1 ) =
water elimination of subject.
Increase in weight of soda lime (2) +
increase in weight of H2S04 (3) =
C02 elimination. Decrease in weight
of oxygen tank = oxygen consump-
tion of subject.
Heat -Absorbing System:
A, Thermometer to record temperature
of ingoing water.
B, Thermometer to record temperature
of outgoing water.
V, Vacuum jacket.
C, Tank for weighing water which has
passed through calorimeter each
hour.
W, Thermometer for measuring tem-
perature of wall.
A,, Thermometer for measuring tem-
perature of the air.
R, Rectal thermometer for measuring
temperature of subject.
Direct Calorimetry:
Average difference of A and B X liters
of water + (gm. water eliminated X
0.586) ± (change in temperature of
wall X hydrothermal equivalent of
box) ± (change of temperature of
body X hydrothermal equivalent of
body) = total calories produced.
Th. thermocouple; Cu, inner copper
wall; Cu2, outer copper wall; E, F,
dead air-spaces.
The average rise in temperature of the numerous readings which have
been taken during the period multiplied by the weight of the water gives
the amount of heat eliminated by radiation and conduction and carried
578 JOHN R. MURLIN
away by the water current. To this must be added the latent heat in the
water of vaporization and any heat stored in the body itself.
For the measurement of this latter quantity an electrical resistance
thermometer is inserted into the rectum to a depth of 10 or 12 cm. Fluc-
tuations in the body temperature can thereby be followed accurately by
readings on the Wheatstone bridge. If the body temperature rises during
the course of a period of observation the amount of'heat stored is found by
multiplying the rise in temperature by the weight of the body and by
the specific heat of the animal body (0.83). Should the body temperature
fall, heat will be given up to the calorimeter and may be deducted by a
similar calculation.
The temperature of the ingoing air must likewise be adjusted so as
to be at all times equal to the temperature of the outgoing air ; otherwise,
heat would be added to or taken away from the chamber by the air cur-
rent. Thermal junctions are so placed as to have one terminal in the
outgoing air and the other in the ingoing air immediately adjacent to
the calorimeter so that any difference in temperature of the two air cur-
rents is instantly detected by connecting the circuit with the galvanometer.
A cooling effect in the ingoing air is brought about by means of a continu-
ous current of water running at a very slow rate against which a warming
effect produced by an electric lamp is kept in action.
Finally heat may be stored in the calorimeter itself. To detect such
a change resistance thermometers are attached to the inner walls of the
calorimeter and if the temperature of these walls rises or falls between
the beginning and the end of an experiment a correction is made. With
the chair calorimeter it has been found that 19.5 Calories of heat are ab-
sorbed when the inner wall rises one degree of temperature. Conversely,
19.5 Calories are lost by the wall when the temperature falls one degree.
This quantity is known as the hydrothermal equivalent of the calorimeter.
For the bed calorimeter of Benedict the hydrothermal equivalent is 21
Calories; for the Sage calorimeter at Bellevue 19 Calories. When all of
these corrections are made the result gives the amount of heat actually
produced by the body in the period of observation.
a. Control Tests. — A calorimeter must be very carefully controlled as
regards its heat measuring capacity. What is known as a "heat check''
is run in the following manner : A current of electricity of known voltage
is run through a resistance coil placed inside the respiration chamber. To
secure uniformity in the electrical current and therefore in the amount of
heat dissipated, Williams used an accumulator battery as a source of
current. This battery was of sufficiently large capacity (about 45 ampere-
hours) to deliver the required amount of energy over periods of four or
five hours without much diminution in voltage. The current passes from
the battery through a ballast resistance, then through the heat coil and
back through a standard resistance. A precision milli-voltmeter measures
NORMAL PROCESSES OF ENERGY METABOLISM 579
the fall of potential across the terminals of the standard resistance and
serves to determine the current. From the heating coil in the chamber a pair
of wires runs out to a voltmeter. A key is provided in this circuit so
that the voltmeter may be connected momentarily to determine the fall of
potential across the terminals of the heating coil. The reading of the milli-
voltmeter is maintained constant by manipulation of the ballast resistance
Fig. 29. The small calorimeter at Cornell University Medical College shown in
process of construction. The observer's table is at the extreme left. The Gouy regu-
lator is shown as a cubical box on top the calorimeter. The arrangement of heating
and cooling elements on the outside of the zinc wall is shown at the open end of the
calorimeter. The water meter E, suspended on a balance is shown at the extreme
right. The tank supplying the heat absorber with water under constant pressure is
shown at the extreme top of the picture. Water passes from this tank through a
pipe to the Gouy regulator, thence to a reheater at the upper left hand corner of
the calorimeter, thence through the heat absorber which is a grid of pipes on the
ceiling of the inner chamber, thence back to the meter. From the waste tank, A,
water is pumped up again into the pressure tank.
and the voltmeter is read several times during each period of the experi-
ment. The heat dissipated is given by multiplying together the numbers
expressing the fall of potential across the terminals of the heating coil
(in international volts), the current in amperes and the time in seconds
and dividing by the number expressing the mechanical equivalent of heat
at the temperature of the flowing water. For example in a heat controlled
experiment performed with the small respiration calorimeter on May 6th,
1911, Williams obtained the following results: The strength of current,
580 JOHN E. MURLIN
I was 2.1 amperes. The fall of potential across the terminals of the heat-
ing coil was 5.79 volts and the time for each period was 3500 seconds.
The heat is given by the product E. I. t X 0.2393 == 10,470. This is
expressed in small calories and is equal to 10.47 large calories. The fol-
lowing is a tabulation of this experiment.
TABLE 10
Hour
Calories Calculated
Calories Found
Error in Cal.
1
10.47
10.64
0.17
2
10.47
10.55
0.08
3
10.47
10.64
0.17
The advantage of this sort of a check experiment is that the measure-
ments can be made very accurately, rapidly and in short periods. It is
customary in making such checks to place the resistance coil in the calo-
rimeter and make the connections. The current is then passed through the
coil and simultaneously the water is started flowing through the heat ab-
sorbing system and the whole calorimeter is adjusted in temperature
equilibrium. As soon as possible when the temperature of the air
and walls is constant and the thermal junction system in equilib-
rium, the exact time is noted, and the water current is deflected into the
water meter. At the end of thq first hour, the usual length of a period,
the water current is deflected from the meter, the water weighed and the
average temperature difference of the water is obtained by averaging the
results of all the temperature readings during the hour. Usually during
an experiment of this nature records of the water temperature are made
every four minutes. Occasionally, when the fluctuations are somewhat
greater than usual, records are made every two minutes. Tests with the
chair calorimeter of the Nutrition Laboratory made in January, 1909,
show between the heat developed inside the apparatus in the electric coil
and the heat as measured by the water current with corrections a discrep-
ancy of about 0.5 per cent (Benedict and Carpenter (a.))- A series of
electric checks made upon the Sage calorimeter by the same method shows
a total error for the entire series of less than 0.4 per cent (Riche and Sod-
er strom).
Another method of checking the heat measuring capacity of the calo-
rimeter is known as the "alcohol check." In this method alcohol is burned
inside the apparatus by means of a small alcohol lamp, the rate of flow
of the alcohol being made as nearly constant as possible and the amount
consumed in a period of observation being carefully recorded upon a finely
graduated burette or by weighing. In planning such a test to ascertain the
magnitude of the errors which are likely to occur in using the apparatus
with subjects of known size it is of importance to provide that the amount
of alcohol consumed per hour shall be enough to dissipate approximately
NORMAL PROCESSES OF ENERGY METABOLISM 581
the same amount of heat as the subject would be expected to eliminate in a
given time. With an experimental apparatus the error will be, assuming
a uniform technique, about constant in absolute amount so that the total
error will diminish as the total quantity measured increases.
When the rate of flow of the alcohol to the lamp has been adjusted so
that it is fed into the burette just as rapidly as consumed therefrom by
the lamp, the apparatus is sealed and after a preliminary period during
which the calorimeter is brought into equilibrium, the burette is read,
the supply bottle from which the alcohol is fed into the burette is changed
for another which has been weighed, and the experiment starts in the usual
way.
To insure complete combustion of the alcohol it is necessary to employ
a lamp so constructed that the region of the edge of the wick will always
be sufficiently hot to insure immediate ignition. Williams finds that by
using a short piece of hard glass tubing for the top of the burner and a
wick of a glass wool the difficulties attending the combustion of alcohol
are most readily overcome.
The specific gravity of the alcohol must be determined with a high de-
gree of precision after which the theoretical amounts of heat, carbon dioxid
and water which the known combustion will generate may be calculated.
Likewise, the amount of oxygen necessary to support this combustion. In
the case of the water one must make a correction for the amount of water
of dilution present in the alcohol. The heat of combustion of alcohol has
been determined a great many times. As the result of 25 observations with
the bomb calorimeter Atwater and Rosa found the heat of combustion
of pure ethyl alcohol to be 7.067 large calories per gram. This figure
is generally employed in this country. In all of the different calorimeters
of Atwater, Rosa and Benedict here described the correspondence between
the amounts of heat generated by the alcohol and the heat actually measured
has been very close. For example, in a long series of experiments of three
or four hours' duration the average error with the Sage calorimeter for the
heat of combustion was 0.9 per cent, for the oxygen absorption 1.6 per
cent, and for the carbon dioxid elimination 0.6 per cent.
3. The Emission Calorimeters. — The fourth group of calorimeters ac-
cording to the classification of Lefevre are those which do not absorb
the heat but allow it to escape into the external medium. Because of this
feature the name calorimeters deperditeurs, or emission calorimeters, was
proposed by D'Arsonval(a), who devised several different types. Some of
these calorimeters have single walls and the effect of the heat generated
within is recorded in some way. In the so-called anemo-calorimeter of
D'Arsonval the subject stands inside a tent-like cubicle which has a nar-
row chimney or ventilator at the top. In the chimney is a delicate wind-
gauge. The heat from the man's body induces a strong convection current
which is free to enter the cubicle below and which sets the wind-gauge in
582
R. MURLIN
rapid motion. By calibration of the apparatus with known sources of
heat it is possible to determine the heating effect of the live subject.
Another group of these calorimeters have double-walls, between which
is a cushion of air. The effect of heat generated within the chamber is re-
corded by expansion of this air cushion. Among those employing this prin-
ciple of registering the effect of heat are the siphon calorimeter of Richet
(6) (Fig. 30) and the second calorimeter designed by Rubner (/) (Fig.
31). Both these calorimeters have rendered extremely important service
to physiological science for 'it was by means of the former that Richet made
his contributions on the relation of heat production to body size and it was
by means of the latter that Rubner first proved with a high degree of
Fig. 30. Richet siphon calorimeter. For description see the text.
precision that the law of the conservation of energy applies to the animal
body (see page 584). The siphon calorimeter is very simple in principle.
The space between the walls of the base and cover between which the rab-
bit in the figure is placed communicate by a common tube with a pressure
bottle containing about three liters of water. A siphon from this bottle
terminates in a funnel-like vessel which catches the overflow and delivers
it into a burette. By expansion of the air water is forced into the measur-
ing limb of the siphon or over into the burette. By calibration of the ap-
paratus with known sources of heat the heat of the animal body can be
determined. It should be noted that an apparatus of this sort takes no
account of the heat of vaporization.
Rubner's apparatus is a respiration calorimeter. It is ventilated in
the same manner as the original Pettenkofer apparatus, and determines
directly only the water and carbon-clioxid. The heat-measuring device
NORMAL PROCESSES OF ENERGY METABOLISM 583
consists of a constant temperature bath of water in which the respiration
chamber is immersed. A cushion of air immediately surrounds the cham-
ber whose walls are of metal. The heat of the animal's body (dog) passes
readily through the metal and causes the air to expand. The expansion is
recorded by means of a spirometer which registers its movements graphi-
cally on a white surface (in Fig. 31 two spirometers may be seen on a shelf
Fig. 31. The second calorimeter of Rubner. Description in the text.
back of the calorimeter). As a control mechanism another spirometer
registers in the same manner the summated expansion of four vertical
air-cushions in the four corners of the water bath isolated from the first
air-cushion. Fluctuations due to variations of temperature from ex-
traneous causes or to variations of barometric pressure are thereby con-
trolled.
C. Basic Principles of Energy Metabolism
Only the most important generalizations concerning the energy metabo-
lism in normal warm-blooded animals will be attempted here. While some
of these are not yet universally accepted, sufficient evidence is at hand in
the case of all of those which will be discussed to dignify them with the
584
JOHN R. MTJRLIN
designation of "basic principles." Some indeed are so fundamental and
so universal in their application as to deserve the designation, "laws of
metabolism." But it will avoid controversy to employ the more conserva-
tive term.
I. The Principle of the Conservation of Energy
in the Animal Organism
Lavoisier, the father of metabolism, foresaw that the heat of the
animal body could be measured by two means : the computation based upon
the chemistry of combustion, and direct measurement (Gavarret), and it is
almost certain that had he been permitted to complete his researches in this
field the demonstration of complete agreement by the two methods would
have lain to his credit. Without following the historical development of the
subject or -recording the failures which intervened we may pass at once to
the work of Rubner ((7). With the calorimeter just described Rubner
studied the heat production of dogs by the two methods. He determined
.the C and N of the excreta and computed the amount of protein and fat
metabolized in fasting and after feeding with meat and lard. Multiplying
the protein and fat by the" physiological heat values of these foodstuffs re-
cently determined by him (page 551) he obtained the heat production by
and indirect method. At the same time his calorimeter recorded the actual
amount of heat eliminated. His results are given in Table 11.
TABLE 11
HEAT PRODUCTION OF DOGS BY DIRECT AND INDIRECT CALORIMETRY (Rubner)
No.
Animal
Food per Day
No. Days
Calories
Heat Prod.
Calculated
Calories
Heat Prod.
Measured
Difference
in per Cent
1
Dog I
Fasting
5
1,296.3
1,305.2
0.69
2
Dog II
Fasting
2
1,091.2
1,056.6
— 3.15
3
Dog I
390 gm. meat
1
329.9
333.9
1.20
4
Dog I
40 gm. lard
5
1,510.1
1,495.3
— 0.97
5
Dog I
80 gm. meat
12
3,985.4
3,958.4
— 0.68
30 gm. lard
6
Dog I
same
8
2,492.4
2,488.0
— 0.17
7
Dog I
350 gm. meat
6
2,249.8
2,760.9
1.20
8
Dog II
580 gm. meat
7
4,780.8
4,769.3
— 0.24
46
17,735.9
17,683.6
— 0.30
In a total of forty-six days of experimentation, with his animals Rubner
thus found a difference of only 0.3 per cent between the heat production
as calculated and the heat production as directly measured. This proves
that the energy set free by oxidation (in the absence of external work),
whatever transformations it may undergo in the body, finally leaves the
body as heat. In other words, all the available energy which entered the
body in potential form has been recovered as heat, and the applicability
NORMAL PROCESSES OF ENERGY METABOLISM 585
of tlie law of the conservation of energy to the animal body was thus
demonstrated.
Atwater and his colleagues, Rosa, Woods, Benedict, Smith and Bryant
studied this balance of energy in a series of rest and work experiments by
means of the Atwater-Rosa calorimeter (Atwater and Benedict(a, 6) ). On
four different human subjects the agreement between the direct and indi-
rect methods were almost as close as those reported by Rubner. The re-
sults may be summarized briefly as follows:
TABLE 12
HEAT PRODUCTION OF HUMAN SUBJECTS BY DIRECT AND INDIRECT CALORIMETRY
(Atwater et al.)
Heat as
Calculated
Cal.
Heat as
Measured
Cal.
Difference
per Cent
Average of 67 days rest ex-
periments
2258
2270
0 r,
Average of 76 days work ex-
periments -
4567
4554
0 3
Average of all experiments . .
3597
3577
— 0.6
The results are perfectly clear-cut. The heat-production as calculated
from the heat value of the food and from the heat value of the excreta
(for method of calculation see page 552) agrees exactly with the amount
of heat eliminated. The food in these experiments consisted of the three
classes of foodstuffs and on certain days included alcohol in small amounts.
The assumption was made (see page 554) that carbohydrate absorbed
enters into combustion before the fat. The close agreement between direct
and indirect measurement seems to justify the assumption.
All of the experiments thus far cited in support of the principle of the
conservation of energy continued for 24 hours. We now know, however,
that the principle holds for short periods as well. Thus Howland(o.) work-
ing with the Cornell calorimeter found that with young children the heat
production, expressed in calories per hour, as measured by the calorimeter
differed from the heat production as calculated from the respiratory ex-
change and the nitrogen output, on six different days, by only 2.1 per cent.
With the same calorimeter Murlin and Lusk found in a series of twenty-
two experiments in hourly periods on a dog, which was being fed large
amounts of fat alternating with fasting periods, 2244 calories5 by indirect
calorimetry as against 2230 calories by direct calorimetry, a difference of
0.6 per cent. A large part of the energy was derived from the emulsified
fat given for the most part without other food. These peculiar circum-
stances did not interfere in any way with the fundamental dynamic prin-
ciple.
'Throughout this chapter the large calorie is not capitalized unless abbreviated
as in Table 12. In human metabolism the large calorie is always understood unless
otherwise designated.
c.
586 JOHN K. MUKLIN"
Gephart and DuBois(a) in the first twenty experiments with the Sage
calorimeter upon normal subjects, some of them in the post-absorptive state
and others soon after taking foods of various kinds, reported a total heat
production of 4577.37 calories by calculation as against 4569.4 by direct
measurement, a discrepancy of only 0.17 per cent.
Instances might be multiplied further but it is unnecessary. The
potential energy of the food in so far as it is oxidized is returned by the
body without loss, in kinetic form; and even when measurable work is
done the energy can all be accounted for.
II. The Energy of Muscular Work is Definitely Related
to the Potential Energy of the Food
1. Origin in Non-Nitrogenous Food. — When Liebig had completed his
classification of the foodstuffs, and had found that all animal tissues con-
tained proteins, i. e., are nitrogenous, he suggested that the excretion of
nitrogen by the animal might be used as a measure of protein destruction
in the animal's body. Carl Voit, who had been a pupil of Liebig, was
among the first to put this suggestion to practical use. Among many
other important facts, regarding the metabolism of proteins, Voit discov-
ered that, contrary to the teaching of Liebig, the protein of the body is
not the source of the muscular energy; foT, during muscular work, no
more nitrogen is eliminated than in muscular rest. Since it had been
known from the time of Lavoisier that muscular exercise increased the heat
production, it followed, from the observations of Voit, that the non-nitro-
genous foodstuffs must be the source of the extra heat production as well
as of the energy of muscular contraction. This fact is now thoroughly
established by almost numberless experiments (Lusk(A) ). An illustration
may be taken from the work of Atwater cited above. A subject doing work
on the bicycle ergometer produced in twenty-four hours 5,100 calories of
heat, of which 434 calories came from the protein (N X 6.25 X 4.1). In
muscular rest this same individual produced 2,270 Calories, of which 400
came from protein. The day's work had increased the total heat pro-
duction 2,830 Calories, but the heat from protein had been increased only
thirty-four calories. All of the rest, 2,800 Calories (nearly), came from
non-nitrogenous food.
2. Mechanical Efficiency of Muscular Work. — Soon after the law of
the conservation of energy was enunciated by Mayer, the mechanical effi-
ciency of muscular work done by a horse was computed by Joule. He
showed that a horse could perform work equivalent to twenty-four million
foot pounds in one day, during which time the food consisted of 12 pounds
of hay and 12 pounds of corn. From original measurements of the heat
value of this food Joule inferred that one grain of food consisting of equal
587
parts of undried hay and corn could raise one pound of water 0.682° F.,
which from previous experiments he knew was equivalent to 557 foot-
pounds. From these results it appeared that one-quarter of the whole
amount of energy generated by combustion of the food could be converted
into useful mechanical work, the remaining three-quarters being required
to keep up the animal heat, etc. (Scoresby and Joule).
Since these first measurements by Joule many estimates have been made
of the mechanical efficiency of various kinds of muscular work both in ani-
mals and men. It turns out that the efficiency depends upon the type of
work performed, i. e., the particular muscles used, the training, the speed
with which the work is done, and the kind of food which sustains the
metabolism.
It is necessary at this point to distinguish between gross efficiency and
net efficiency. The former term is found by dividing the mechanical
work in terms of heat by the total metabolism of the time ; while net effi-
ciency, the more exact term from the standpoint of bio-physics, is found
by dividing the heat equivalent of the mechanical work by the extra metab-
olism' due to the work accomplished. This is found of course by subtract-
ing the basal or resting metabolism from the total work metabolism. Un-
less otherwise specified the figures used in this chapter refer to net effi-
ciency.
From data obtained by Lavoisier upon his assistant, Seguin, whose
oxygen absorption was measured during rest and while working a treddle,
Benedict and Cathcart have calculated that at most an efficiency (net)
of 7.7 per cent can be made out. This work of Lavoisier represents the
earliest collection of data from which the efficiency of human muscles can
be computed. Helmholtz presented the next in order historically when
he assembled data from the work of Edward Smith, of Dulong and of
Despretz, which according to his reckoning showed a gross efficiency of
approximately 20 per cent. Amar cites experiments by Hirn done in
1857 which, assuming that the total heat elimination was correctly meas-
ured, demonstrate an efficiency of about the same amount. Other im-
portant workers of the French school in this field are Laulanie(d) and
Chauveau(a.). The former studied especially the influence of speed upon
efficiency. He found in experiments upon himself that so long as the rate
was constant, turning a wheel with a brake attachment 5, 10 or 15 minutes
gave the same efficiency, but when the load and speed were varied the
efficiency varied from 9 to 23 per cent. The load varied from 1 to 15 kilo-
grams and the speed from 1.49 to 0.13 meter per second. The highest
efficiency was shown with a moderate load (4 kilograms) and a moderate
speed (0.61 meter per second^). This accords with everyday experience.
Chauveau's observations made upon his assistant, Tissot, were directed
especially to the question of the kind of foodstuffs which supports mus-
cular work. They will be referred to later.
588 JOHN E. MURLIN
The German laboratories which have contributed most to the literature
of mechanical efficiency in muscular work are those of N. Zuntz and of
Kronecker. Both used the method of Zuntz in determining the respiratory
exchange. Magnus-Levy (#), Durig (c), and Loewy (a), all of the Zuntz
school of workers, have given important summaries of this work up to 1911.
Durig's own experiments under Kronecker's direction, as well as those of
Zuntz, and Loewy, Muller(a), Caspari(a), Zuntz and Schumburg(a), and
L. Zuntz, show plainly the effect of training upon muscular efficiency, as
well as the influence of velocity. Much of the work was done with the tread-
mill, some with an arm ergometer and other experiments in which the res-
piratory exchange was measured by means of the Zuntz portable apparatus
was done in marching on roads or climbing mountain trails. The treadmill
showed net efficiencies as high as 37 per cent, with the average at 31 per
•cent. The arm ergometer gave the lowest efficiency, namely, 19 per cent
and the mountain climbing and marching experiments intermediate results.
In certain experiments of the latter class carried out in summer upon a
mountain trail which had an inclination of 16.4 per cent Durig's own ef-
ficiency was 31.1 per cent and that of his.three companions was 30.3, 31.7
and 30.1 per cent respectively. In bicycle riding L. Zuntz, who was the
first to make studies of the' respiratory exchange in this type of work, found
values which later were calculated to show a net efficiency of 28 per cent
(Berg, DuBois-Reymond and Zuntz, L.). Benedict and Carpenter, using
the same type of work but changing the bicycle to a stationary ergometer,
found an average of only 21.5 per cent, a figure which has been substan-
tially confirmed by a more recent *and extensive study by Benedict and
Cathcart.
The effect of training is shown in the following table from Benedict and
Cathcart exhibiting the maximum gross and net efficiencies for their six
subjects. The highest efficiency in both senses is shown by the one pro-
fessional bicycle rider (M.A.M.) of the group.
TABLE 13
MAXIMUM GROSS AND NET EFFICIENCIES WITH THE BICYCLE ERGOMETEB (Benedict and
Cathcart)
Subject
Gross, per Cent
Net, per Cent
E. P. C
19.9
23.1
J. J. C
17.8
20.4
H. L. H
18.6
21.6
J. E. F
19.8
22.7
K. H. A
18.2
20.8
M. A. M
21.2
25.2
Benedict and Cathcart have also given attention to the relation of speed
to muscular efficiency. They find that while in general the efficiency in-
creases with the load (amperage of current actuating the brake) with
NORMAL PROCESSES OF ENERGY METABOLISM 589
the heaviest loads there were definite indications of decreased efficiency.
Figure 32 exhibits the relationship of total metabolism to effective work
at varying speeds but with a constant load. In computing the net effi-
ciency the basal metabolism obtained with the subject lying quietly on
a couch was used and since this
is practically constant, the net
efficiency would be effected by
speed in the same way as the
gross efficiency (total heat out-
put). The figure shows that
in order to produce 1.565 cal-
ories of effective muscular
work at 70 revolutions per
minute it is necessary for the
subject to produce a total of
7.61 calories (gross efficiency
20.6 per cent) ; while to pro-
duce 2.425 calories of work at
130 revolutions required 15.04
calories of heat (gross effi-
ciency 16.1 per cent). "From
the upper curve it is seen that
the output of heat is constant
per 10 revolutions; on the
other hand, the increase in
effective muscular work per-
formed is not constant for each
ten revolutions, but there is a
distinct falling off. If, there-
fore, we divide the increase in
the external muscular work
between any two points on the
curve by the increase in the
total heat output correspond-
ing to the same two points, we
get an efficiency based upon
increasing speed, the load
JLO.O
15.0
14.5
14.0
13.5
13.0
12:5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
C. K.
2.50
2.40
.2.30
2.20
2.10
2.00
1.90
1.80
1.70
1.60
1.50
1 40
/
/
I
/
/
«7
c
1
/
/
A
/
v/
$
\
/
$
IF
4
v
7~
Au
1
^
1
§
I
!/
6Q 70 60 90 100 110 120 130 140
Fig. 32. Curves showing the total heat
output per minute and corresponding external
muscular work per minute, expressed in cal-
ories, for subject riding with constant load—
1.5 amperes — at varying speeds. (Benedict and
Cathcart.)
being the same. For instance,
in changing from 70 to 80 revolutions per minute, there is an increase in
the effective muscular work equivalent to 0.205 calorie. Under these con-
ditions there is an increase in the total heat output of 1.24 calories. Divid-
ing the increase in heat output due to the muscular work (0.204 calorie
by the increase in the total heat output (1.24 calories) we find an efficiency
for the increased amount of work performed of 16.53 per cent." Compu-
590
JOHN U. MURLIN
tations for the corresponding increase of ten revolutions gives from 90 to
100 revolutions 11.94 per cent, and from 120 to 130 revolutions 7.82 per
cent, with intermediate values in percentage for the intervening incre-
ments. Net efficiency showed a similar falling off with the higher rates of
speed. For example, when the effective muscular work was 1.95 calories
per minute, at a rate of 90 revolutions the net efficiency was 22.6 per cent,
while at 124 revolutions per minute it was only 15.7 per cent.
3. Relative Value of Different Foodstuffs as a Source of Energy in
Muscular Work. — From his experiments upon Tissot as subject in climb-
ing and descending stairs, Chauveau came to the conclusion from a con-
sideration of the respiratory quotients, that carbohydrate alone furnishes
the energy of muscular work and that fat can only be utilized by first
undergoing transformation to carbohydrate. Zuntz and Heinemann, how-
ever, point out that if Chauveau's hypothesis of transformations were
true, 30 per cent more energy for each unit of work performed should
be liberated when fat burns than when carbohydrate is the starting point.
Zuntz further criticizes Chauveau's experiments as being too extreme
in severity (the subject was exhausted at the end of 70 minutes) and
not of sufficient duration. -Experiments by himself and associates in
which precautions in both respects were carefully observed gave respiratory
quotients during work which were exactly the same as in muscular rest.
He cites especially the following results of Heinemann made with the
Gartner ergostat and the Zuntz respiration apparatus.
TABLE 14
"ENERGY PRODUCTION OF MUSCULAR WORK ON DIFFERENT DIETS (Heinemann)
Food
Rest
Work
Amount of
Work,
Kgm.
Per Kgm. of Work
O2per
Min.,
c.c.
R. Q.
O2per
Min.,
c.c.
R. Q.
O2 c.c.
Cal.
Fat
319
277
306
0.72
0.90
0.80
1029
1029
1127
0.72
0.90
0.80
354
346
345
2.01
2.17
2.38
9.39
10.41
11.35
Carbohydrate.
Protein . .
It appears from this comparison that there really is little difference betweei
fat and carbohydrate, and that protein likewise as the chief constituent oi
a diet occupies a place only a little less favorable as a source of muscular
energy. The respiratory quotients were the same for each foodstuff dui
ing muscular work as during rest.
This last statement seems to be true, however, only with the moderat
intensity of work which Zuntz observed. Benedict and Cathcart founc
the average respiratory quotients with their professional bicycle ridei
were as follows:
NORMAL PEOCESSES OF ENERGY METABOLISM 591
Before Work
During Work
After Work
16 days moderate work
0.84
0 84
0 77
16 days heavy work
0.85
0 90
0 78
Brezina and Kolmer likewise noted that the height of the initial respiratory
quotients during periods of muscular work varied with the intensity of
the work performed. When ^1.6 calories per minute was the rate of
metabolism the R. Q. was 0.83; but when the rate rose to 10 calories
per minute the quotient was 0.99. Lusk, who quotes this experiment, ex-
plains the higher quotients as due in part to the formation of acid with
consequent liberation of CO2 from the plasma more rapidly than it was
formed. Other factors, he states, are the increased ventilation of the
lungs and carbohydrate utilization; for acid formation accelerates the con-
version of glycogen to glucose. In very extreme work, especially in short
spurts, it is quite possible also that oxygen absorption does not quite keep
)ace with CO2 elimination from the lungs. Hence the purplish color' of
the face in muscular exhaustion as contrasted with the lighter but healthier
color of moderate exercise. After exercise when the oxygen absorption
is gaining on the CO2 elimination the tendency would be for the R. Q. to
be depressed. That there is a real and not an imaginary mobilization
of carbohydrate during work Benedict and Cathcart infer from the fact
that following carbohydrate-rich diets the quotient rises somewhat more
in work than it does following carbohydrate-poor diets.
As regards the mechanical efficiency upon different diets Zuntz was
convinced that there was nothing to choose between carbohydrate and fat.
He cites experiments performed by his students, especially Frentzel and
Reach and also of Atwater and his colleagues, which show that the absorp-
tion of oxygen is essentially the same whether carbohydrate .or fat is burned
(see Table 14). Benedict and Cathcart support this view with their
findings that the energy quotient (total calories produced per calorie of
effective work performed) was the same on days following a carbohydrate-
rich diet as on days following a diet poor in this foodstuff whether the
amount of work was large or small. Anderson and Lusk performed ex-
periments upon a 9 kilo dog while running upon a treadmill inside the
calorimeter both before and after feeding with large amounts of glucose
and noted a distinct difference in efficiency after the carbohydrate ingestion.
When the dog had been without food for 18 hours and the average re-
spiratory quotient was 0.78 it required 0.580 kilogrammeter of work to
move 1 kilo of the body weight 1 meter on the horizontal. In the first
hours after carbohydrate when the average quotient was 0.95 the same
work was done at an expenditure of 0.550 kilogrammeter, a saving of
5 per cent. Krogh and Lindhard point out that if the metabolism per
unit of work is assumed to be a straight line function of the quotient the
502
JOHN R. MURLIN
waste of energy from fat in these experiments works out as eight
per cent.
The last-named authors have carried the comparison between fat and
carbohydrate as a source of muscular work much farther. They devised
experiments upon human subjects with the bicycle ergometer of Krogh
placed inside a Jaquet-Grafe (page 520) respiratipn chamber, which would
be done, after the manner of Benedict and Cathcart's experiments, before
the first meal of the day, but following two or more days upon controlled
diets containing in turn a decided preponderance of the two non-nitro-
genous foodstuffs. The two most successful subjects were college athletes
familiar with bicycling, and, in one series, freshly trained. Both these
students and three out of five older subjects experienced great difficulty in
doing the prescribed work and suffered much fatigue thereafter following
heavy fat feeding, but did the work with ease and without fatigue follow-
ing carbohydrate. This experience accords with that of other observers.
The results of Krogh and Lindhard are summarized below.
TABLE 15
COMPARISON OF I AT AND CARBOHYDRATE AS SOURCE OF MUSCULAR ENERGY
(Krogh and Lindhard)
Subject .
Calories per Unit Work
Difference
No. of Exp.
Average Net
Efficiency
From Fat
From
Carbohy.
Cal.
Per
Cent
J. L
5.69
5.84
5.04
4.72
4.70
4.73
4.79
4.52
4.52
4.59
5.09
4.28
3.72
4.02
4.10
4.32
4.10
4.15
1.10
0.75
0.76
1.00
0.68
0.63
0.47
0.42
0.42
19.4
12.8
15.1
21.2
14.5
13.3
9.8
9.3
9.2
10
15
15
13
33
18
33
49
24
18.3
21.6
23.7
23.0
22.7
22.0
23.2
23.0
G. L
A. K
R. E
M.N. Tb. XII .
M. N. Tb. XIII .
O.H.Tb.IX ...
O.H.Tb.XVI .
O. H. Tb. XVII .
The simple average of the percentage differences, the authors state, would
be very misleading partly because of the different number of experiments
for the different subjects and partly because the several series are by no
means equally concordant. By assigning definite "weights" to each series
in proportion to the number of determinations and in inverse ratio to the
standard deviations within each series the average percentage waste of
energy from fat as compared with carbohydrate is 11.25. It follows
clearly that work is more economically performed on carbohydrate than
on fat.
From the table it may be seen that the net expenditure of energy neces-
sary to perform one calorie of mechanical work on the ergometer varies
NORMAL PROCESSES OF ENERGY METABOLISM 593
between about 5.5 and 4.0 Cal. At a constant quotient the authors find
that it varies somewhat with the subject, and for the same subject it de-
creases with training (see page 588).
The question may fairly be raised, Where does protein stand in the scale
of efficiency as a source of muscular work ? This question has been studied
in relation to the specific dynamic action of protein by Rubner(o) and more
recently by Anderson and Lusk. Both sets of observations show that there
is practically complete summation of the extra energy production due to
the specific dynamic action of meat and the energy production caused
by the muscular work. There is nothing specifically uneconomical in
doing work 011 a high protein diet except in the sense that the extra heatfof
dynamic action is added to the extra heat of muscular work and this throws
extra burdens on the organs charged with the dissipation of heat. With
cane sugar, as proved in Rubner's experiments or glucose as proved in
Lusk's, the specific dynamic effect of the food disappears, i. e., merges into,
the extra metabolism of muscular work. These facts make it clear
that the mechanism of energy release in muscular work is more nearly
akin to the mechanism by which carbohydrate raises the metabolism
(metabolism of plethora, see page 606) than it is to the mechanism of pro-
tein stimulation. The work of Fletcher and Hopkins and of A. V. Hill
on the details of muscular contraction make it appear that certain reac-
tions take place between definite substances which must be closely allied to
carbohydrates. It becomes more intelligible therefore why carbohydrate
should support muscular work more economically than fat 6 and why its
dynamic action, unlike that of protein, should not be superimposed upon
the metabolism of muscular work.
III. The Energy Metabolism is Determined in Part by
the Environing Temperature
1. How Heat is Lost from the Body. — In general, there are four main
avenues of escape for the heat which is produced in the body of a warm-
blooded animal : ( 1 ) Warming the food and air which enter the body ;
(2) Vaporization of water and setting free of CO2 in the lungs; (3)
Evaporation of water from the surface of the body; (4) Radiation and
conduction from the surface of the body.
Tigerstedt(a) gives the following calculations made by Rubner for a
man producing 2,700 calories daily :
"Krogh and Lindhard note that the standard metabolism (called basal metabolism
more commonly) is somewhat higher when the respiratory quotient is low than when
it lies in the median range. There is just a hint in this fact that the so-called waste of
energy when muscular work is supported By fat may be bound up with the specific
dynamic action of th&t foodstuff as it is in the case of protein.
594 JOHN R. MURLIN
Calories
(1) Warming food and drink to body temperature 42
(2) Warming air from 17.5° to 30° C 35
(3) Evaporation of water from lungs and skin 558
(4) Heat equivalent of external work done 51
(5) Loss of radiation from entire surface of body 1,181
(6) Loss by conduction to air from entire surface 833
Total , 2,700
Atwater, in his calorimetric studies, made the following estimations:
I. Resting man, mean of fourteen experiments comprising forty-two days:
Calories
1. Heat loss by radiation and conduction 1,683
2. Heat loss by urine and feces 31
3. Heat loss by evaporation from lungs and skin 548
Total 2,262
H. Man at work, mean of twenty experiments comprising sixty-six days:
Calories
1. Heat loss by radiation and conduction 3,340
2. Heat loss by urine and feces 46
3. Heat loss by evaporation from lungs 'and skin 859
4. Heat equivalent of -muscular work 451
total 4,676
It is evident, from these estimates, that fully eighty per cent of all the
heat produced in the body is lost through the skin.
2. The Law of Surface Area. — Closely related to this matter of the
loss of heat through the skin is the relationship of heat loss to heat pro-
duction known as the law of surface area, first enunciated over 80 years
ago by certain French writers. To quote one of the earliest communica-
tions: "As the heat loss is proportional to the extent of free surfaces and
these latter are to each other as the squares of their homologous sides, it
follows of necessity that the quantity of oxygen absorbed, or what amounts
to the same thing, the heat produced on the one hand and lost on the other,
is proportional to the square of the corresponding dimensions of the ani-
mals one is comparing (Robiquet and Thillaye)." The first experimental
evidence of relationship between skin surface and the food requirement of
animals seems to have been furnished by Miintz who in 1879 investigated
the maintenance ration of horses. Emphasizing the part played by the sur-
face he says : "A notable part of the food certainly is consumed to main-
tain the vital heat which has a tendency constantly to be lost by radiation
or conduction to the surrounding medium. Another cause of cooling is
cutaneous evaporation which is a function of the surface if it is not directly
proportional thereto. The evaporation produced by the organs of respira-
tion may equally be regarded as having a relation to the surface of the body
rather than to the weight. We are then by these considerations in position
NORMAL PROCESSES OF ENERGY METABOLISM 595
to admit the preponderating influence of surface upon the apportionment of
the maintenance ration."
This law of surface a few years later was placed upon a firmer basis
by researches of Rubner(o-) upon dogs and of Richet(c) upon rabbits.
A small animal has a greater surface, in proportion to its weight, than
has a large animal. This will be clear from the following illustration.
Suppose we have two spheres of two and four centimeters diameter. The
surface of the smaller would be 12.56 square centimeters and of the larger
50.24 square centimeters. The volume of the first would be 4.18 c.c. and
of the latter 33.49 c.c. The surface of the smaller, in proportion to its
volume, therefore, would be as 3:1, while of the larger it would be only
as 1.5 :1. Since, now, more than four-fifths of the animal's heat escapes
. through the skin, by one physical means or another, it is clear that heat
must be produced in proportion to the surface rather than in proportion
to the mass, if the body temperature is to be maintained. Hence, if two
animals, with similar coats of fur, had skin surfaces that bore to each
other the relation of these spheres, the smaller animal would produce twice
as much heat per unit of weight as the larger. Rubner found that the
average heat production per square meter of body surface for man, dog,
rabbit, guinea pig, and mouse was 1,088 calories with variations of -j- 104
calories to — 103 calories, i. e., of about ten per cent either way.
a. Measurement of the Surface Area. — Several methods have been
proposed for determining the surface area of the human subject. The first
was that of Meeh who marked out some parts of the body, which were
favorable for the purpose, in geometrical figures, covered them with trans-
parent paper and made tracings of the figures. The areas of these figures
were then calculated or determined by weighing the paper. Other parts
of the body were measured directly by wrapping with millimeter paper.
Bouchard suggested a plan which was later improved upon by DuBois and
DuBois (a), namely, of clothing the body in tights made of some thin in-
elastic material which could be weighed. D'Arsonval(e) clothed a man in
silk tights and after charging the clothing with electricity, determined the
surface relative to a metal plate of known surface by releasing the charge
as from a Ley den jar. Lissauer measured the surface of dead infants by
covering the skin with adhesive material, applying silk paper, and then
measuring the area of the paper by means of a planimeter.
The measurement was accomplished by DuBois in the following man-
ner. A light, flexible, inelastic covering was obtained by clothing the body
with a close-fitting knitted union suit, and pasting this over with ad-
hesive paper. But instead of attempting to weigh this "model" of the
body surface, it was cut up into pieces which would lie out flat and the
area of each piece determined by photographing it on sensitive paper.
The total area was then found by weighing the photographic silhouettes
and comparing with the weight of a unit area of the same sensitive paper.
596
JOHN R. MURLIN
The areas of the several members of the body as measured were then com-
pared with the areas as given by multiplying their lengths by sums of
measurements representing circumferences. For example, the area of
the arm was given by multiplying the length from the outer end of the clav-
icle to the lower border of the radius (F) by the sum of the three circum-
ferences at : upper border of axilla (G) ; largest girth of forearm (H) ;
smallest girth of wrist (I). This calculated area compared with the actual
area for several individuals gave a factor which, used with the product
first given, made up a so-called linear formula for the arm; thus: F
(G -f- H + I) 0.558. The several sub-formula3 added together could then
be employed for measuring the surface of the entire body.
This method resembles the one proposed by^Roussy in which the surface
Fig. 33. A method of calculating the surface area by treating the body as a series
of cylinders. The average is taken of 29 different circumferences (mean perimeter)
and this is multiplied by the sum of the several lengths. (Roussy. )
was given by multiplying the mean perimeter (Pm) by the mean peripheral
total height (Hm) ; thus S =Pm X Hm. The first factor was found by
taking the mean of 29 different circumferences (Fig. 33) while Hm is the
sum of 3 partial heights, (a) head, neck and shoulders; (b) trunk and
lower extremities ; (e) upper extremities.
From his measurements Meeh devised a formula based upon the well
known relationship of surfaces to masses of similar solids ; namely, that the
former varies as the % power of the latter. By employing a constant,
12.3, Meeh found that the formula S = J/(w) 2 gave results within 7
per cent of those determined by actual measurement. DuBois found an
agreement between measured and calculated values for 5 cases within
2 per cent. Later his measurements were simplified and a formula con-
taining total height, weight and certain constant factors was devised. This
is known as the weight-height formula. A = W °-425 X H °-725 X 0.,
NORMAL PEOCESSES OF ENERGY METABOLISM 597
where A is the area in sq. cm., H the height in centimeters, W the weight
in kgm., and C a constant 71.84. A chart based upon this formula for
direct reading of the surface area when height and weight in metric units
are known is given in Fig. 33-a.
b. Criticisms of the Law of Surface Area. — Various criticisms have
been leveled at the law of surface area, some of them based upon fact and
some upon interpretation. Of the criticisms based upon fact that recently
published by Harris and Benedict is perhaps the most important. They
have subjected the body surface law to a critical biometric study and have
reached the conclusion that the correlations between body surface and basal
heat production in normal adults are of about the same magnitude as
those between body weight and heat production. "These results do not,
therefore, justify the conclusion that metabolism is proportional to body
surface and not proportional to body weight." In the opinion of these
authors the closer agreement between heat production of different indi-
2
200
190
180
c/>
§170
2160
g!50
c_>
^140
— nn
0 30 40 50 60 70 80 90 100 II
0
200
190
180
170
160
150
140
130
120
110
inn
\
1.7
\
\
\
N
NO
X
N?'
X
&
X
23
v]
Q
\
\
\
\
\
N8
^
\
X
X
\
^
i
LI
V
\
\
\
\
\
V
\
\
X
X
N
X
X
^
X
^
\.
\
\
\
V
\
\
V
\
X
X
X
\
\.
^
£
\
\
\
\
s
\
N
X
X
X
s.
\
\
19
20
\
\
\
\
\
\
X
X
X
X
V^
X
•>,
Ts,
1^
\
\
\
\
\
\
X
>s
x
$*
*>
*
LjUU
120
110
inn
\
\
\
k
\
S
X
X
X
1
4
U>
p*
NS
5
\
V
X
"X
X
t:
\
*v
\
\
^
^
12
20 30 40 50 60 70 80 90 100
WEIGHT-KILOGRAMS
tlO
Fig. 33-a. Chart for determining surface area of man in square meters from
weight in kilograms (Wt.) and height in centimeters (Ht.) according to the formula:
Area (Sq. M.) = Wt-0-428 X Ht-0-'25 X 71.84 (DuBois).
viduals and their surfaces than between heat production and body weight
is not due to any causal relation between heat loss and heat production
as a mechanism for preservation of heat loss and body temperature, but
in part at least proceeds from the fact that body surface being proportional
to the % power of weight is less variable than the weight itself, and the
ratio of heat produced to body surface consequently is likewise less variable.
As a matter of fact the mathematical relationship does not stop here ;
for in many instances the constant employed in the formula, for example,
598
JOHN K. MUKLIN
of Meeh or of Lissauer by which the % power of the weight is multiplied
equalizes the proportions between surfaces and weights. This fact gives
a slightly different posture to the argument. A few illustrations will
make* this clear. Suppose, for example, we have two infants weighing 7
and 8 kilograms respectively. Expressing their weights in kilograms and
their surfaces in sq. M. by the Meeh and Lissauer formulas, we have the
proportions shown in the following table.
TABLE 16
RELATION OF BODY WEIGHTS AND SURFACES TO EACH OTHER
Meeh-Rubner
Lissauer
Weight,
kgm.
Ratio
11.9V(w)a
Ratio
10.3V (w)2
Ratio
Surface,
Surface,
sq. M.
sq. M.
7
0.4353
0.3769
8
0.88
0.4760
0.91
0.4120
0.91
20
0.8768
0.7589
21
0.95
(J.9058
0.97
0.7840
0.97 .
40
1.3920
1.205
41
0.98
1.4150
0.98
1.225
0.98
4
. 0.299
0.259
40
0.10
1.3920
0.210
1.205
0.21
3.5
0.274
0.237
70
0.05
2.021
0.135
1.750
0.136
The ratio of weights is .88 : 1 and of surfaces .91 : 1. Now it is ob-
vious that if the metabolism of these two children is proportional to their
weights it must of necessity also be nearly proportional to surface. With
two youths weighing 40 and 41 kilos the surfaces bear to each other ex-
actly the same ratio as the weights, whether the Meeh or Lissauer formula
be employed. Both, therefore, will be equally good measures of metabolism
for the two individuals.
Contrast with this the relationship between individuals weighing 4 and
40 kilograms, or still better, an infant at birth weighing 8^/0 kilograms and
a man weighing 70 kilograms. In the latter the weights are to each other
as .05 to 1, and the surfaces as .135 to 1. In other words, the weight of the
larger individual is twenty times that of the smaller, while the surface is
a little over seven times that of the smaller. In this case weight
and surface cannot possibly be of equal value as measures of the metab-
olism. One is nearly three times as good — or as bad — as the other. As a
matter of fact it is now well known that surface is about two and one-half
times as good a measure as weight between two such individuals.
Benedict and his colleagues have fallen into the error of supposing that
physiologists have" believed the basal metabolism to be absolutely propor-
tional to surface regardless of circumstances. This is quite incorrect.
Rubner for the German literature and Richet for the French are respon-
NORMAL PROCESSES OF ENERGY METABOLISM 599
sible for the first demonstrations of the applicability of the law. Rubner
worked with dogs of adult stature but widely different size, estimating their
metabolism by the indirect method. Richet worked first with rabbits
langing from 2000 to 3500 grams in weight but he determined only the
heat of radiation and conduction, neglecting, as nearly all subsequent
French observers have done, the heat given off by evaporation. Naturally
his quantities would be more nearly proportional to surface than the total.
However, in the estimation of surfaces he says, "If one supposes that
animals of different size are like spheres of different volumes, then the
respective volumes are related among themselves as the cubes of their
radii; while the respective surfaces are related among themselves as the
squares of their radii. These considerations apply to living animals, and,
since their form is so irregular compared with that of a perfect sphere,
one can only apply the geometrical facts to them approximately." Fur-
ther in summing up the factors which determine heat production Richet
notes that one of these is "the nature of the integument." In two im-
portant respects, therefore, Richet made saving clauses regarding the
application of the law of surface, one concerning the measurement of
surface and the other concerning the nature of the skin, meaning, of
course, its conducting properties. Rubner in the beginning considered
that he had demonstrated the law only for adult animals and later in
applying it to children made this very emphatic reservation : "The law
of surface area holds under all physiological conditions of life, but for its
proof it is a reasonable presumption that only organisms of similar
physiological capacities,- as regards nutrition, climatic influences, tem-
perament, and functional power, should be compared." Other students of
metabolism have made similar reservations. Thus Schlossmann says, "The
presumption is on the one hand that the environment is relatively normal,
on the other that the child has a relatively normal surface, that is, a
functioning and good conducting skin with the normal amount of sub-
cutaneous fat." Otherwise, he thinks, the law could not be expected
to apply.
The arguments against the law, so far as they rest upon facts, seem,
as we have just seen, to have been misconceived. It never was supposed
by its chief proponents that the law would apply to all physiological and
pathological conditions but only to similar physiological (normal) condi-
tions. Also, a very superficial understanding of the necessary mathematical
relations shows that the law has natural limitations which must be recog-
nized if one is to avoid compromising it with impossible conditions.
There is no doubt that Rubner, following Bergmann, has conceived
of the law as causally related to Newton's law of cooling. This dependence
as commonly accepted may be phrased in this way. Solid bodies when
warmed lose heat in proportion to the difference between the temperature
of the body and the temperature of the surrounding medium. Since this
600 JOHN R. MURLIN
heat must all pass through the surface it follows, other things equal, that
they will lose heat for any particular gradient of temperature in propor-
tion to surface. As applied to the animal body it is observed that, the body
temperature is nearly constant. Hence, if heat is lost in proportion to
surface, it must also be produced in proportion to surface. This im-
plies a causal relationship between surface loss and interior produc-
tion of heat. An elaborate biometric analysis proves nothing more re-
garding this causal relationship than is proved by the simple mathe-
matical analysis shown in Table 16. Whatever the physiological measure-
ment of surface, if it can be expressed even approximately by a formula
such as Meeh's it will follow that the ratio of body weights for certain
ranges will be the same as the ratio of body surfaces provided the weights
are not far apart, and for subjects of a continuous series in which weights
differ by small increments it will follow that surface will be only a little,
if any, better as a measure of metabolism than weight.
The question of causal relationship, stands just where it always has
stood. If the possession of a large surface in proportion to weight, as in
a mouse, is accompanied by a vastly higher heat production per unit of
weight as compared with a horse, but the heat production is found to
be proportional to the surfaces in two such animals with approximately
the same body temperature, it seems to follow that surface loss of heat
is at least a more probable cause of heat production than body mass. The
same is true as between a baby and a man.
On the basis of interpretation the objections to the law of surface run
in this way. Since the heat production of animals seems to be propor-
tional to surface area, it would seem to follow that heat is produced in
order to replace that which is lost, or to maintain body temperature. This
view, some say, denotes an all too nai've conception of nature. Blood does
not coagulate in order to prevent hemorrhage, but because certain chemical
agents are present with certain properties. The fact that it does stop
hemorrhage is quite incidental. It may have selective value, so that a
species whose blood did not -clot would have the worst of it in the struggle
for existence, but it will never do to say that thic chemical-physiological
function originated for the purpose of preventing hemorrhage; for that
would imply a mind at work in anticipation of the result. So also with
heat production. These critics, of whom Kassowitz(c) has been chief, pre-
fer to account for heat production in a perfectly causal manner. "Small
animals maintain a higher rate of oxidation, it is true, than large ones, but
this is not because they lose heat more rapidly in consequence of greater
(relative) surface, but because their alternating movements (later phases
caused reflexly by earlier phases) follow one another more rapidly on ac-
count of shorter nerve paths." Kassowitz(d) indeed finds that the higher
rate of oxidation in small, warm-blooded animals has even for them "dys-
teleological consequences ; for because of the more extensive muscular con-
NORMAL PROCESSES OF ENERGY METABOLISM 601
tractions more food and reserve substances are placed in requisition and by
this means the deposit of reserve fat in the whole body, and especially
in the subcutaneous tissues, is made more difficult, so that the protection
against cooling — which a thick layer of fat prevents — fails in part amongst
the very animals which need it most." Even Kassowitz is obliged to
admit, however, that "in warm-blooded animals which are in a position
to maintain their own body temperature under the most diverse conditions,
one can claim the appearance of some justification that their living parts
produce heat in order to protect the body against loss by radiation, etc."
Whether this is a real justification or only the appearance of one will
not trouble the practical physiologist so long as the generalization that hu-
man beings of different size produce heat in proportion to surface rather
than weight, and therefore, require food energy in proportion, helps him
to understand his feeding problems; and there is no doubt that the law
of surface area has been immensely useful in this connection. It explains
the much higher basal metabolism per unit of weight of the small individual
in comparison with the large, better than the so-called causal explanation
cited by Kassowitz. It explains also much better the need for conservation
of heat in the infant, and the role which subcutaneous fat plays in this con-
nection.
3. Heat Production as Affected by External Temperature. — a. In
Cold-blooded Animals — Varit Hoff's Law. — Increased activity in living
tissues is almost invariably accompanied by an increased evolution of heat.
Since this heat is derived from the chemical changes which proceed in the
living cells, and since all chemical processes are quickened by a rise of tem-
perature, we should expect to find that the heat, produced in the metabolic
processes of the organism would tend of itself to quicken these processes.
This is found in fact to be the case. In most chemical reactions a rise
of 10° C. would increase the velocity of the reaction from two and a half
to three times (Van't Hoff's Law), and the same law is, within the limits
of the stability of living tissues, found to apply to the process of oxidation.
For example, in the early growth of a lupine seedling it has been found
that the output of CO2 bears to the temperature the following relationship :
0° C 6 milligrams per hour
10° C 18 " " "
20° C 44 " " "
30° C 86 " " "
The same relationship has been found to obtain for the production of CO2
in the snail, the leech, and the earthworm. Perhaps the absorption of
oxygen is a still better measure of the heat production. Within the range
of 5 to 21° C. it has been observed that the f actor (Q10), which in biological
literature expresses the number of times the process is accelerated for a
rise of 10°, has, for the absorption of oxygen by the crayfish, a value of
602
JOHN K. MUKLIN
2.5 to 3.5. In the case of the leech, the same factor, between 10 and 24°,
is from 2.4 to 3.0 (Putter, A.).
In living things the range within which any such law applies is neces-
sarily very narrow as compared with its range in inorganic reactions ; and
the factor (Qi0) varies, according to the best determinations which have
yet been made, very widely. Nevertheless, it may be said that the law
that the rate of chemical change (metabolism) varies with the temperature
of the living substance is a universal law for all animals and plants. As
applied to the production of heat in living things, this law would result
in a vicious circle (the temperature increasing the oxidation and the oxida-
tion increasing the temperature) which would rapidly destroy the living
substance itself, if special mechanisms did not exist for the removal of
the heat. Where these mechanisms break down, as in fevers, the heat
must be removed by artificial means.
DuBois(fr) has recently shown that the metabolism of men in fevers in-
creases from" 30 to 60 per cent for a rise of three degrees (from 37 to 40°
C.) and the value of Q10 therefore is about 2.3. In other words the
metabolism in fevers obeys Van't Hoff's law.
b. In Warm-blooded Animals.^— In warm-blooded animals with the
development of the capacity to regulate the body temperature indepen-
dently of the surrounding medium, Van't Hoff's law is apparently re-
versed, so that the lower the external temperature becomes the greater
is the heat production. This is necessarily the case if the body tempera-
ture is to be maintained. Confirming the original observation of Lavoisier
that more heat is produced in the human subject when the external tem-
perature is low, C. Voit(e) exposed a man in light clothing in his respira-
tion apparatus to different temperatures and found that, as the temperature
fell, the metabolism increased independently of any muscular motions.
Eubner(^) carried this line of investigation much farther, using dogs and
guinea pigs, and formulated his laws of the chemical and physical regula-
tion of the body temperature. In brief, these laws are : (1) That, from
a temperature of about 30° C. downward, the body temperature is regu-
lated chiefly by varying the heat production (chemical regulation). Heat
loss is regulated, to some extent, by decreasing the amount of blood brought
to the surface. (2) From 30° C. upward the body temperature is regu-
lated chiefly by varying the amount of water evaporated from the surface
(sweating) and again by decreasing the amount of blood brought, to the
surface (physical regulation).
The conclusions of Voit and Rubner with regard to the effect of cold
as such have frequently been called in question, the contention being that
even if visible shivering and increased tonus of the muscles are avoided
no more heat is produced at low temperature. Lusk(&) found that a man
immersed for a few minutes in a cold bath at 8° C. would, immediately
thereafter, shiver enough to increase his metabolism 180 per cent above the
NORMAL PEOCESSES OF ENERGY METABOLISM 603
normal. Loewy(c) and Johansson conducted carefully controlled respira-
tion experiments by two different methods with a view to the determination
of the pure effect of cold. The former employed sixteen different subjects,
cooling the body not only by exposure to a temperature of 12 to 16° C.,
but also by evaporation of water, alcohol and ether from the«skin. The
latter performed experiments upon himself as subject after acquiring the
power to suppress all shivering or even increased tonus, when the naked
body was exposed to a room temperature of 13 to 20° C. Both observers
found that there was no increase in the elimination of carbon dioxid when
the muscular factor was really ruled out. Uncontrolled shivering in
Loewy's experiments produced an increase of 100 per cent in the metabo-
lism.
Lefevre(d) has demonstrated that the loss of heat from the skin does
not follow Newton's law of cooling exactly because of certain physiological
adjustments of which the skin and subjacent structures are capable.
Nevertheless a better estimate of the influence of the environing tempera-
ture can be obtained by measuring the cooling power of the environment
on a surface at body temperature than is given by a record of the outside
temperature alone. The recognition of this truth led Leonard Hill (6) to
invent an instrument known as the "Kata-tbermometer." This consists of
a large-bulbed spirit thermometer which is warmed up until the meniscus
rises above 1 00 °F. The rate of cooling is then determined with a stop-watch
as the meniscus falls from 100° F. to 95° F. The constants of the instru-
ment are determined, from which the cooling can be expressed in mille-
calories ( grm. calories) per sq. cm. of surface per second. The
instrument when used dry gives the rate of cooling by convection and radia-
tion and when used wet (covered with a damp muslin glove) gives the
rate of cooling by convection, radiation and evaporation. From the read-
ings of the dry instrument can be deduced the velocity of movement of the
dry air. The evaporative cooling power of the wet instrument depends
on absolute humidity and wind.
Comparisons made by Hill between the rate of cooling of the Kata-
thermometer with that of the naked pig as determined by Lefevre and
of the naked surface of the human forearm as determined by Waller, and
with the dryness or sweating of the skin of soldiers producing a known
amount of heat, suggests that the Kata-thermometer in air cools about
three to five times as quickly as the naked skin when the temperature of the
skin approximates closely to the body temperature.
Ordinary light clothes reduce the cooling power of the atmosphere
of a man as well as of the instrument to one-half its value when unclothed.
The cooling power by radiation and convection exerted on the surface
of the dry Kata-thermometer at 36.5° C. in mille-calories per sq. cm. per
second according to Hill is as follows.
604:
JOHN K. MURLIN
TABLE 17
COOLING POWEB OF Am CURRENTS AT DIFFERENT VELOCITIES (Hill)
Temp.
0 Cent.
9 M. per Sec.,
20 mi. per Hr.
4 M. per Sec.,
8.8 mi. per Hr.
1 M. per Sec.,
2.2 mi. per Hr.
1/2 M. per Sec.,
1.1 mi. per Hr.
Still Air
0
49.3 mille-cal.
36.1 mille-cal.
23.1 mille-cal.
19.0 mille-cal.
9.8
5
42.5
31.2
19.8
16.4
8.5
10
35.0
26.2
16.7
13.8
7.1
15
29.0
21.3
13.5
11.2
5.8
20
22.3
16.3
10.4
8.6
4.4-
25
15.5
11.4
7.2
6.0
3.1
• Flack and Hill made observations on the respiratory metabolism of several
students by the Doublas-bag method (p. 537) and found that the heat pro-
duction as calculated by the Zuntz-Schumberg method (p. 565) increased
in different subjects from 27 to 82 per cent when they were sitting quietly
on the roof of the laboratory, over the metabolism shown in the laboratory
in the same, clothing. For example, in one instance the heat production
was 1.57 calories per minute in the laboratory and 3.12 Cal. in a strong
cold wind on a snowy day. In another instance exposure to the inclement
cold winds of an April (1918) day increased the resting metabolism of a
young woman from 37 to 65 calories per sq. M. of body surface per
hour.
Lefevre had a subject who while lying on a bed naked, in an air cur-
rent at 5° C. and of 1-2 meter per second velocity, for 3*/£ hours, exhibited
a heat loss of 3 Cal. per minute as contrasted with 1.55 calories at 20° C.
Sitting quietly in ordinary light clothes a man gave the following records
of heat loss in air currents of 3.5 and 1 M. per second.
TABLE 18
Temperature
Weight, 65 Kg.
Surface 19,000 Sq. Cm.
Wind Velocity
3.5 M. per Sec.
Wind Velocity
1 M. per Sec.
JO
5°
10°
15°
20°
26°
Cal. per Diem.
6,654
4,704
3,690
3,144
2,754
2,270
Cal. per Diem.
5,400
4,000
3,060
2,317
1,896
IV. The Ingestion of Food Increases the Metabolism
The observation of Lavoisier that the heat production was increased
by taking food was confirmed by Pettenkofer and Voit(fr), who found that
the total metabolism of a dog was increased from 34.9 to 65 calories
per kilogram as the result of eating about two and one-half pounds of
NORMAL PEOCESSES OF EKERGY METABOLISM 605
meat. Feeding fat they observed no increase in the heat production un-
less the amount fed was far in excess of the body requirements. Feeding
carbohydrate in the form of starch, they found that 379 grams in the
food increased the metabolism 17 per cent over that of the starving animal.
More exact information concerning the influence of carbohydrate came
with the invention of methods by Zuntz and by Benedict by which the
oxygen absorption could be determined, since, without this knowledge,
it was impossible to distinguish the part taken by fat in the total heat
production from that taken by carbohydrates. Magnus-Levy, using the
Zuntz method with human subjects, came to the conclusion, substantially
in accord with those of Pettenkofer and Voit, namely, that moderate quan-
tities of fat do not increase the heat production (absorption of oxygen),
but that both carbohydrate and protein increase it considerably. Rubner,
using only the excretion of C02 as the measure of heat production, formu-
lated laws regarding the influence of different foods given to dogs, as fol-
lows : Since the different foodstuffs affect the heat production to a different
degree, we may speak of their "specific dynamic action." The proper basis
of comparison is the amount of heat produced by the fasting animal. Tak-
ing this quantity as the minimal requirement of the animal for energy
(in potential form), and feeding this quantity in the form of different
foodstuffs, the effect is for protein an increase of heat production of 30
per cent, for fat 11 per cent, for carbohydrate 5.8 per cent. In order to
keep the animal in an energy equilibrium, therefore, it is necessary to feed
him in protein 140 per cent of the requirement, in fat 114 per cent, and in
carbohydrate 106 per cent.
Lusk and his co-workers, using the small respiration calorimeter (de-
scribed on page 579), have demonstrated that the increased heat pro-
duction in dogs after ingestion of proteins is due to the amino-acids into
which the protein is broken up by digestion. It is, however, not the mere
absorption of the amino-acids themselves, nor their direct oxidation which
accelerates the metabolism, but the stimulating effect of the intermediate
oxyacids which are formed from them. Quantitatively the results of these
more modern researches confirm the conclusions of Rubner as to the speci-
fic effect of protein. These, however, relate to the dog. In man the dyna-
mic effect is ordinarily not so great. The dynamic effect of protein in
milk upon the metabolism of the infant will be discussed later (page 644).
It need only be added here that protein which becomes a part of the body
does not affect the heat production.
The dynamic effect of fat, it turns out, is not so high as Rubner found
it, if reckoned for the entire day, but for individual periods up to six hours
after feeding, may increase the metabolism as much as 30 per cent (Murlin
and Lusk), as contrasted with protein (meat) which may raise it 100 per
cent. Bloor found that the fat in the blood also increases up to six hours
after feeding.
606
JOHN R. MURLIN
Following Rubner's fundamental observation on the influence of car-
bohydrate on the respiratory metabolism of a fasting dog, Magnus-Levy,
Johansson, Durig, and DuBois, made confirmatory observations on the hu-
man subject (Lusk (h} ). One hundred grams of glucose causes an average
increase of nine per cent in the heat production of a man of 75 kilos ; and
200 grams one of 12.5 per cent during 3 to 6 hours after the ingestion. The
same dose with a smaller man produces a proportionally greater accelera-
tion of the metabolism. Lusk and his pupils have found that the period of
highest metabolism after heavy sugar feeding to dogs coincides with an
Fig. 34. After Williams, Riche and Lusk, showing the R.Q., the total metabolism
determined by indirect (heavy black line) and direct (broken line) calorimetry as
well as the nitrogen elimination (dotted line) during hourly periods after the inges-
tion of 1200 grams of meat, by a dog.
osmotic dilution of the blood caused by the rapid absorption of the sugar,
and a sudden fall in the metabolism coincides with a removal of sugar from
the circulation by the liver and a rapid elimination of water through the
kidney. Lusk believes, therefore, that the heightened metabolism follow-
ing rapid absorption of fat or carbohydrate may be called a ''metabolism of
plethora/' or, in words of one syllable, oil on the fire. Since a summation
effect is produced when carbohydrate and an amino-acid or both are added
at a time when fat is producing a maximal effect and from other considera-
tions which need not be entered into here, Lusk infers that separate mechan-
isms for oxidation of several foodstuffs exist within the body
cells.
607
V. Basal Metabolism
By way of summary of the preceding sections one may say that the
three factors which have most to do with determining the level of the
energy metabolism in the normal subject are muscular activity, external
temperature and food. A subject removed from the influence of these
three factors would be (a) completely resting; (b) at a comfortable tem-
perature; (c) and would be observed several hours after the ingestion of
food. The metabolism under these conditions would correspond to the
minimal functional activity of the body and for this reason has been
called basal metabolism after Magnus-Levy (h) (Grundumsatz). The
term "maintenance metabolism" (Erhaltungsumsatz) has also been given
by Loewy(a), and the term "standard metabolism" is preferred by
Krogh(c) who points out that even under complete suppression of mus-
cular activity the metabolism of the heart may amount to as much as 4
to 15 per cent of the total metabolism of the body, and the metabolism of
respiration to a like amount. The true basal metabolism according to
Krogh would be found by deduction of those quotas assignable to the
heart muscle and the muscles of respiration.
Whichever term is applied it should be understood that this minimal
metabolism is the line of reference for the measurement of the various
functional increases such as that due to food or to muscular work. The
term basal metabolism will be employed in this chapter as being considered
more appropriate than either of the other terms suggested. It is useless
in the writer's opinion to use as the reference line a minimal metabolism
lower than that which is attainable in the normal subject. It is, however,
a fair question whether the metabolism of sleep should be taken as the
basal metabolism in man, or, whether the condition defined by Benedict
and his co-workers as the post-absorptive condition combined with com-
plete muscular rest gives the better line of reference. F. G. Benedict has
shown that in a fast of 31 days the metabolism during deep sleep may be
as much 13.2 per cent lower than the metabolism of the same subject while
awake but lying perfectly still. In this series the increased metabolism
could not be attributed to muscular activity for a comparison of the graphic
records showed that the degree of muscular repose was even more nearly
perfect in the morning experiments while waking than in the night experi-
ments during which the subject slept in the bed calorimeter. There was
also no question of influence of food in the alimentary tract ; for during
the entire period of 31 days the subject ate absolutely no food and drank
only about 900 c.c. of distilled water daily. It is fairly certain, therefore,
that the only cause of difference was that state of the nervous system
which we recognize as sleep. Presumably the lower metabolism in this
state is due to the more complete suppression of muscular activity owing
608 JOHN R. MURLIN
to the absence of reflexes, with possibly a factor due to the suppression of
neural activity in the brain, spinal cord and peripheral nerves. In time
it may become necessary to revise the standard conditions for basal metabo-
lism and to include, in addition to complete muscular rest and complete
alimentary quiescence, neural rest. For the present sufficient data do not
exist to warrant the change in standard ; hence, the basal metabolism as
ordinarily defined will be used in this chapter to determine the influence of
age, sex, physical characteristics, etc., in the normal individual.
Even under the most uniform conditions thus far applied the basal
metabolism has been found to vary from day to day and from hour to
hour in the same individual, and even more in different individuals. For
example, Johansson found on himself an average CO2 production per
hour of 22.2 grams with an average deviation from the mean of 3.6 per
cent. Nevertheless, he found this metabolism to remain constant within
the variation given over a period of seven months. Magnus-Levy (&) ob-
served a similar degree of constancy over a period of two years. In a series
of 51 observations made during comple'te muscular rest upon an athlete
Benedict and Cathcart found a standard deviation from the mean of 4.9
per cent When different individuals are considered the variation is
much greater. The simple average percentage deviation from the mean
in 35 different subjects observed by Benedict was 13.9 per cent.
1. The Influence of Physical Characteristics. — From an exhaustive
biometric study of basal metabolism in the normal human adult including
137 men and 103 women, Harris and Benedict find that the most intimate,
correlations are obtained when correction for body size is made by express-
ing heat production in calories per square meter of body surface.7
As regards the effect of body weight upon the energy metabolism Har-
ris and Benedict find that an increase of 1 kgm. of weight in the adult man
increases the consumption of oxygen on the average 2.27 c.c. per minute
and the carbon dioxid 1.87 c.c. per minute; for women the values are 1.17
c.c. oxygen, and 1.02 c.c. carbon dioxid. A kilogram of body weight added
to the adult increases the total heat production for twenty-four hours on
the average 15.8 Cal. for men and 8.27 Cal. for women. There is also
a distinct and independent correlation between stature and- energy metab-
olism, but this is not so close as with body weight. For each 1 cm. in-
crease in stature the heat production increases about 16.6 Cal. per day in
man and 6.9 Cal. per day in women. The same authors find that there
is no very high degree of correlation between heat production and heart
activity as measured by pulse rate, unless correction is made for body
weight or body surface.
7 This admission the authors are obliged to make although they do not believe
that the closer agreement between heat production by different individuals and their
surfaces than between heat production and body weight is due to any causal relation-
ship ( see page 597 ) .
NORMAL PROCESSES OF ENERGY METABOLISM 609
Referred to body weight the metabolism even in men of nearly the
same size and weight may differ considerably. The results obtained by
Jaquet and by Caspari vary from 0.8 Cal. per kgm. and hour to 1.6 Cal. per
kgm. and hour. The latter figure was obtained by Caspari upon a trained
athlete. Benedict and Smith have also shown that athletes have in general
a higher basal metabolism than untrained individuals of the same physical
measurements. Fat persons generally have, as would be expected, a lower
metabolism per unit of weight than lean ones ; for the fat tissues are rela-
tively inactive. Other differences on the basis of weight may be accounted
for, to some extent at least, by differences in muscular tonus, and differ-
ences in "endocrine efficiency."
As a convenient reference point the average obtained by Tigerstedt
from a long series of determinations of the basal metabolism in man
(namely, 1.04 calories per kgm. and hour) should be borne in mind. The
average individual variation from this average is roughly plus or minus
10 per cent.
The physical characteristic which has proved to be most useful as a
criterion or measure of metabolism is the surface area of the body. Rub-
ner's original study on full-grown dogs is given in Table 19. Here it
. TABLE 19
INFLUENCE OF BODY SIZE ON METABOLISM (Rubner)
Weight,
Kgm.
Body Surface in
Sq. Cm.
Cal. per Kgm. and
24 Hrs.
Cal. per Sq. M. (Meeh)
and 24 Hrs.
31.20
24.00
19.80
18.20
9.61
6.50
3.19
10750
8805
7500
7662
5286
3724
,2423
35.68
40.91
45.87
46.20
65.16
66.07
88.07
1036
1112
1207
1097
1183
1153
1212
was demonstrated how much more nearly proportional to surface the
metabolism is than to body weight. While it is true that absolutely basal
conditions were not present the animals were not observed to move about
to any considerable extent. The original observations of Richet upon rab-
bits likewise are worthy of repetition here. The heat given off by radia-
tion from the animal's body caused the air enclosed within the walls of the
calorimeter to expand and to displace water in the siphon (page 582).
Heat is expressed in Table 20 as the number of c.c. of water displaced.
The number expressing the surface of the animal was found by Richet by
regarding the body as a geometric sphere. Since its weight (volume)
is equal to — and the surface by 4 it R2, the volume would be to the
2
surface as 4.2R3: 12. 6R2. Finding R from the known weight (volume)
the relative surface was obtained by multiplying the square of this number
610
JOHN R. MUELIK
TABLE 20
RELATION OF HEAT RADIATION TO SURFACE OF THE ANIMAL BODY (Richet)
Weight,
Gm.
Surface
(A Relative Number)
Heat Radiated Ex-
pressed as c.c. of Water
Displaced
Heat Radiation per
Unit of Surface
2100
2300
2500
2700
2900
3100
786
841
889
932
976
1021
119
110
115
119
125
130
129
130
129
127
128
127
by 12.6. It is evident, Eichet concludes, that the production of heat is a
function of the surface and not of the weight of the animal. More nearly
basal conditions were observed in experiments accomplished later by Slowt-
zoff(a) on dogs and by Kettner on guinea pigs. The former calculated the
surface by'Hecker's formula (S =- 12.33 X W%) and found that the
oxygen absorption per unit of surface in animals of different size (5.04
'to 38.9 kgm.) "remains fairly constant" (±10 per cent mean deviation
from the average, as against ± 12.5 per cent on the basis of weight).
Kettner found that the CO2 production per 100 gm. body weight and
hour varied from 0.108 gm. in the largest (full-grown) animals to 0.254
gm. in the smallest (and youngest), a difference of 135 per cent, while
on the basis of surface the extreme variation was only 30 per cent.
In the human subject the comparison of basal metabolism per unit
of weight with the basal per unit of surface is even more striking. The
following table from Gephart and DuBois(&) shows how much more the
metabolism of different classes of human individuals differs from the av-
erage for adult men on the basis of weight than on the basis of surface.
TABLE 21
COMPABISON OF BASAL METABOLISM PER KGM. AND PEE SQUARE METER OF SURFACE
(Gephart and DuBois)
Investigator
Subjects
a.
Cal per
Kgm. and
b.
Cal. per
Sq. M.
Per C
from
ent Variation
Average for
Men
Hr.
( Meeh ) and
Hr.
a
b
Benedict and Colla-
borators
79 men
1.08
34.7
Lusk and McCrudden
Murlin and Hoobler.
Benedict and Talbot.
Benedict and Talbot.
Dwarf wt. 23 kgm.
6 infants
Average 10 nor-
mal infants un-
der 1 month
Average 1 1 nor-
mal infants be-
tween 1 & 10 mos.
1.21
2.69 ,
1.95
2.21
32.3
36.3
25.6
35.5
12
150
81
105
— 7
5
— 26
2
NORMAL PROCESSES OF ENERGY METABOLISM 611
This table was prepared before it was appreciated how much the
metabolism varies with age and before the new method of measuring sur-
face area devised by DuBois and DuBois was completed, but it shows how
even on the old basis the metabolism was proportional to body surface
rather than to weight. DuBois and DuBois in reviewing the literature of
surface measurement found that a consistent plus error occurs in the use
of the Meeh formula which may rise in very fat individuals to as. much
as 36 per cent. By their own method (see page 596) checked with actual
linear measurements they found a total error in the case of five indi-
viduals of widely different shapes of only 1.7 per cent. On the basis of
the new method for surface area Gephart and DuBois (6) later gave the av-
erage basal metabolism of nine normal men whose surface had been accur-
ately measured as 39.7 Cal. per square meter per hour. The extremes of
variation in this series were -j- 4 per cent and — 6 per cent. Selecting
fat and thin subjects from the work of Benedict, Emmes, Roth and Smith
and that of Means the authors find that the fat and thin groups show a dif-
ference in metabolism on the basis of weight of 41 per cent while on the
basis of "linear formula" (p. 596) for surface area the difference was only
3 per cent. The law of surface therefore must be held to apply to fat and
thin subjects as well as to the so-called normal. Nevertheless a variation
of plus or minus 10 per cent must be expected even in perfectly normal
subjects; for there are variations in muscular tonus, in the specific activity
of the endocrine organs and in the conducting properties of the skin as well
as in other factors not so definitely predictable which must always pre-
clude the establishment of a fixed and rigid standard. Means found for
example an average for sixteen normal subjects of 38.8 Cal. per sq. M. by
the DuBois linear formula and that all came well within the 10 per cent
(deviation from average) zone. Harris and Benedict feeling that they
had totally discredited the law of surface as a measure of metabolism
turned their attention to the prediction of the normal basal metabolism
by means of biometric formulas based on stature, body weight, age, and sex
and claimed that by this means "results as good as or better than those
obtainable from the constant of basal metabolism per square meter of body
surface can be obtained by biometric formulas involving no assumption
concerning the derivation of surface area, but based on direct physical meas-
urements."
Boothby and Sandiford have tabulated 404 determinations of the
"basal metabolic rate," as they call it, expressed in percentages above and
below normal, using both the standard of DuBois and that of Harris and
Benedict. The average rates obtained by the biometric formula of Harris
and Benedict are 6.5 points higher than those obtained by the DuBois
method. The same authors report that they have made more than 10,000
determinations of basal metabolism on healthy people and on patients suf-
fering from disease and that "only occasionally have we found patients
612 JOHN R. MURLIN
who had metabolic rates beyond the normal limits established by DuBois
which could not be accounted for by the presence of a definite pathologic
condition."
This truly phenomenal uniformity of heat production, quite equal to the
uniformity of body temperature in normal subjects, has been explained in
various ways. Rubner following Bergman and Regnault and Reiset at-
tempted to bring the heat production into causal relationship with heat
loss as we have seen (p. 599). This attempted explanation has not been
wholly satisfactory for the reason that, as Lefevre has shown, physiological
adjustments can be made by the skin which greatly modify the applica-
tion of Newton's law of cooling. Rubner himself, therefore, is obliged to
postulate "similar physiological conditions" (page 599) and to assume that
the minimal metabolism (basal) cannot undergo rapid changes but is
adapted to the usual conditions regarding loss of heat which the animal has
to meet. V. Hoesslin(&) has subjected the hypothesis of Rubner to a se-
vere test by keeping two exactly similar- young dogs for a long time under
widely different temperatures and determining their resting metabolism at
the end. The rate of heat loss must have been continuously very different
for the coats of hair at the* beginning were the same. Later it became
thicker on one dog and thinner on the other in very obvious response to the
conditions of heat loss to which they were subjected. But the basal
metabolism was not altered.
V. Hoesslin himself considers that the metabolism of a tissue depends
upon the supply of oxygen, that the circulation (and consequently the oxy-
gen supply) must for anatomical reasons be proportional to the two-thirds
power of the weight (i. e., to surface) and that the correlation of energy
exchange with surface finds its explanation in these purely mechanical
conditions. Dreyer, Ray and Walker have given some plausibility to this
view by the discovery that in both mammals and birds the blood volume,
the sectional area of the aorta and of the trachea in animals of different
size are proportional to the two-thirds power of the weight. The trend
of this view is wholly away from the teleological view outlined at p. 602
in connection with the subject of heat loss, and probably more correctly
reflects the attitude of the modern mechanistic physiology.
Dreyer has more recently attempted the application of a more general
formula to the normal basal metabolism and has compared the results
found with those obtained by the more elaborate prediction formula of Har-
Wn
ris and Benedict. His formula is K = where W is the
^ X A
weight, n approximately 0.5, C is calories of basal metabolism, and A the
age in years. Table 22 shows that he gets a somewhat more concordant
result than is obtainable with the prediction formula.
2. Influence of Age on Basal Metabolism. — DuBois (a) first assembled
the data for the influence of time of life from birth to old age upon the
NORMAL PEOCESSES OF ENERGY METABOLISM G13
TABLE 22
Authors
No. of
Description
Average K
W°-5
%
Av. Devia-
%
Av. Devia-
tion by H
C X A0-1333
tion from K
and B. Pre-
diction form
Palmer, Means and
Gamble
8
men
0 1037
o 7
4. 4.
Carpenter, Emmes,
Hendry and Roth
Magnus-Levy and
Falk
31
10
M
u
0.1014
0 1000
5.94
5 06
5.30
K 97
<( «
Gephart and DuBois
DuBois and Aub . .
« ii
5
15
5
6
8
old men
boys
men
old men
Boy Scouts
0.1045
0.1007
0.0989
0.0993
0.0928
9.90
3.46
6.10
8.20
9.49
10.36
15.60
7.37
19.38
19.70
total heat production. His chart in terms of calories per hour per square
meter of body surface appears below. In considering the causes of the al-
tered rate of heat production, one must bear in mind first the differences
in body form which themselves affect the relationship of body surface to
body weight ; secondly, the specific influence of different organs which not
60
50
40
30
20
10
-d
:/
VL
.0
R
1^
-<
k
^
1"
«
f
"•>
a
r
.
•
a
a
0
y
•
..
a
n
/
%-
.,
"s.
•jt
=
!
A
~-\
'1
** -.
jo
$
j
»••
.
* -
4
c>
iVl
1
5
J
-
,•
1 ^
— -,
i — .
r^
r
•^
14,
S1-
^
M
-^J
fe
F1
A
f>
Vl
A
,7
M
i
s
1
i
V
/'
f
-
--
.
r
f
**
-,
..
y
T»
'
|
/
f\
*
(•
Is
\
|
\(
:
A
s
I
I
,{
)|
1
A
•\
()
^
A
I
u
i
'•'
f
T'
»i
••
Ff
--
.....
V
T"
^
3
fa
_
Is-
1
~$
I
\
a
»
1
11
V
*>
r
V
P
n
\\
f
*1
r
-)
-
V
1"
A
\\
S
51
-
(l
A
1^
h
^1
[
^
(i
(
\
|
I?
c
]
1
1
\
|-
|
YEARS a
8 10 12 14 16 18 20 22
Fig. 35. Variations of basal metabolism with age: Calories per hour per square
meter of body surface — Meeh's formula. Dash line shows average for males, dotted
line for females. After DuBois.
only bear different relations as regards size, to the body as a whole, but
probably in some instances also have quite a different coefficient of activity.
Thus, in early life the liver and thyroid, especially, both organs of high
metabolic activity, are perceptibly larger in the relative sense than in
the adult life, and may be expected to play a larger part in the total chem-
ical activity of the body. This may, to a large degree, account for the
614 JOHN K. MURLIN
heightened metabolism of the infant one year old when reckoned on the
basis of a unit of surface (Murlin and Hoobler). That the rate of growth
itself, however, may be partly responsible, is evidenced by the fact that boys
at the age of prepubescence, just when growth is accelerated, experience also
a quickening of heat production. DuBois's results indicate that this may
amount to as much as 25 per cent over the normal level for adults. Whether
the awakened activity of the internal secretory mechanism of the sex glands
acts independently or only through its effect upon growth, can only be
decided by experiments upon animals. The latest experiments of this kind
by Murlin and Bailey support the view of Loewy and Richter that in
the female at least there is an independent effect quite outside the effect
upon muscular rest. The tendency to obesity following the menopause
in women is to be explained, therefore, as due to the absence of a stimulus
which was present so long as the ovary was active. Removal of the ovary
has the same effect. The falling metabolism of old age is to be explained
in part by the tendency to reduce muscular effort of all sorts to a minimum,
this, in turn, being traceable probably to the absence of internal stimuli,
whether reflex or chemical. The deposit of calcareous material in certain
organs, which so frequently, accompanies old age, may also of itself reduce
their metabolic activity.
Statistically studied, the decrease in total heat production per 24
hours for each year of age is, according to Harris and Benedict, 7.15 Cal.
for their series of 136 adult men. For the 103 women it is 2.29 calories
for each year of adult life. Upon the basis of a unit of body surface, the
correlations with age "are of a more strongly negative character than
the correlations between age and total heat production," which means
that with each advancing year of life there is a heavier decline upon
ihe basis of a square meter of body surface than upon the basis of
total heat production. This conclusion is in accordance with DuBois's
curve, though it does not give exactly the same rate of change.
3. The Influence of Sex. — Impressive also is the difference between
the two sexes. DuBois had already drawn attention to this difference in
the first curve which he published showing the variation with age. His
curves for the two sexes ran about the same distance apart (7 per cent) as
do the newer ones here reproduced. Twenty years ago Magnus-Levy and
Falk found the difference between the two sexes both in early life and in
advanced age about five per cent, but were of the opinion that in adult life
the two sexes maintain about the same metabolism, consideration being had
to difference in size and age. Harris and Benedict have analyzed the results
of metabolism studies on the two sexes very exhaustively, .making correction
for body weight, body surface, age, and stature, and find that on every basis
the metabolism for the women is lower than that of men. Even when the
theoretical heat production of the woman is calculated by inserting their ac-
tual physical measurements in equations based on the series of men (regard-
NORMAL PROCESSES OF ENERGY METABOLISM G15
ing the woman, that is, as a man of the same size) the actual heat production
is generally lower than the theoretical. Larger women show a relatively
larger deficiency than smaller ones and the suggestion is made by the
authors that the body weight is the primary factor in determining the de-
ficiency. "The most critical test shows that when body weight, stature, and
age are taken into account, women show about 6.2 per cent lower metab-
olism than men."
D. Energy Metabolism of Growth
1. Differences between Growth and Maintenance. — The chemical proc-
esses by which the living substance is maintained are not identical with
those by which it was originally produced. For example, growth and
division of the nuclei are essential in the production of new tissues, while
the mere replenishment of cell materials, such as is taking place continu-
ally on a small scale or such as may take place in convalescence on a large
scale, may go on without division of the nuclei. Since it is known that
the nucleus is essential to processes of intracellular digestion (Verworn),
it is possible that the nucleus plays some essential role in this process of
replenishment ; but the fact that the nucleus itself does not grow and divide
under these circumstances (Loeb, J. (6)), together with the fact that its
reactions and constitution are known to be different from those of the cyto-
plasm, makes it very probable that growth involves chemical processes not
concerned in the replenishment which follows ordinary waste or that which
follows extraordinary waste in diseased conditions. Rubner(cc) has
drawn attention to the fact that the maintenance tendency is of primary
importance even in the young organism, since the "wear and tear" quota
(Abnutzungsquote) must be satisfied before growth (postembryonic) of
the organism as a whole can assert itself. If we assume that the every-
day repair concerns mainly the cytoplasm, except where cells are actually
being destroyed, Rubner's view might be interpreted to mean that the
processes in the nucleus which result in its growth and division can take
place, even in the young organism, only under certain optimum nutritive
conditions of the cytoplasm.
There is no reason for thinking that the mechanism by which energy
is liberated in young cells is different from that which performs the same
service in mature cells. The living substance of all cells (with the ex-
ception of the anaerobic forms) is dependent upon some power, call it the
"activation of oxygen," whereby oxygen becomes capable of uniting with
the elements of the soluble foodstuffs at a temperature much below the
ordinary kindling temperature.
Warburg's (a) recent observation that fertilized sea urchin eggs absorb
six to seven times as much oxygen in the same length of time as do un-
616
JOHN R MUKLIN
fertilized eggs, lends weight to the view that oxygen is in some way essen-
tial to the growth process, but his further observation that there was no
proportion between the amount of oxygen absorbed and the number of
nuclei (blastomeres) present, and that still more oxygen was absorbed
when the eggs were placed in hypertonic solutions and cell divisions had
ceased (Warburg(fr)), certainly do not favor the idea that oxygen absorp-
tion is dependent upon nuclear activity. This is in accordance with Kub-
ner's(w) view that the morphological changes in the nucleus accompanying
cell division are the expression of synthetic processes rather than of the de-
structive processes of oxidation.
Bayliss(&) explains the chemical process of oxidation in the cell as fol-
lows : "Some autoxidizable substance in the cell takes up- molecular oxy-
gen, with the formation of peroxids and activation of half the oxygen. The
other half of the oxygen serves for complete oxidation of part of the
autoxidizable substance. These peroxids are acted upon by peroxidase,
with further increase of active oxygen, which is able to bring about oxida-
tion of substances not autoxidizable and otherwise difficult of oxidation."
The structure of the cell, however, also plays a part. For example, ac-
cording to Warburg (c), in a muscle cell a much larger part of the chemical
energy appears as free energy than if the cell is disintegrated. The ar-
rangements within the cell which we call cell structure "in some way catch
the chemical energy of the oxidation processes before it has fallen to the
state of free heat." It is by such arrangements or structure that the work
of a contracting, a secreting, an absorbing cell, etc., is carried on.
Even in cells which do no external work or osmotic work, however,
structure is important for oxidation. Thus, in the unfertilized eggs of the
sea urchin, Warburg and Meyerhof have shown that the addition' of iron
salts increases oxidation very perceptibly. Salts of no other metal do this.
Iron, in other words, is a catalyst for oxidation. Now the significance of
structure (alveolar, if we please), as Warburg sees it, is just this, that it
affords surfaces for the condensation of the catalyst and thereby puts it to
work.
But why should energy be set free in cells that do no work ? Warburg's
answer to this is that the liberation of energy by oxidation preserves the
structure, or the integrity, if one will, of the living substance. If cell
constituents are to be prevented from mixing freely, diffusion surfaces
must be maintained, and the maintenance of their semi-permeable prop-
erties calls for a certain difference of electric charges which can only be
kept up by the liberation of energy from some source. Hence it is that
all living substance must respire and must liberate a certain amount of free
heat. The maintenance of a constant temperature would, on this view of
the matter, be a fundamental property for cells whose structure could be
maintained only by a certain rate of energy release (see page 602).
2. Metabolism of Embryonic Growth (Murlin(c)). — Development oe-
617
casions a more active production of carbon dioxid per unit of mass than
takes place in adult tissues. This has been demonstrated by Farkas for the
eggs of the silkworm, by Bohr for the embryo snake, by Bohr and Hassel-
balch, and by Hasselbalch alone for the developing chick, and by Bohr for
the embryo guinea pig. That this greater evolution of carbon dioxid is the
expression of a greater liberation of energy also is rendered perfectly cer-
tain by the calorimetric measurements made by Farkas of the heat of com-
bustion of unincubated and incubated silkworm esrffs and those of Tan^l
oo O
on the eggs of the cadaver fly ; by similar measurements made by Tangl and
by Tangl and Mituch on unincubated and incubated hen's eggs; and by
the direct calorimetric determinations of the heat produced in the develop-
ing hen's egg made by Bohr and Hasselbalch.
Bohr and Hasselbalch found on the fifth day of incubation of the hen's
egg a production of CO2 amounting to 2000 c.c. per kilogram of embryo
per hour as against 718 c.c. per kilogram and hour for the adult hen (Reg-
nault and Reiset). The CO2 production from the eighth to the twenty-
first day (end) of incubation was only a little greater in the embryo
than in the adult hen, but was sufficiently high for the authors to feel justi-
fied in concluding that it was "a condition for the organization of the new
nssue and not alone for the maintenance of tissues already formed." Grafe,
in reviewing this work, lays special emphasis on the fact that the highest
energy production takes place at a time when the work of differentiation
is most active. Bohr had previously supported this view with the evidence
derived from his study of embryo snakes. Increasing the temperature
from 15° C. to 27° C. increased the CO2 output of an embryo weighing
3.8 gm. about 2.8 times, while the same increase in temperature raised
the output of an embryo weighing 0.5 gm. exactly four times. The greater
increase produced in the younger embryo, Bohr believes, was due to the
greater change in the intensity of the developmental processes. That is, the
processes of new formation (differentiation) are more active in the younger
stage and it is this part of the developmental process which is responsible
for the more active metabolism.
Tangl's results on the hen's egg indicate an average heat production
for the entire incubation period of 100 calories per kilogram per day as
against 71 calories per kilogram per day (at 18°-20°) for the adult hen
found by E. Voit — an increase of 41.3 per cent. Tangl concludes that the
energy required for development (Entwickelungsarbeit) is considerably
greater than that required for mere maintenance of the adult organism
(Erhaltungsarbeit). The difference he designates as Bildungsarbeit.
Bohr's findings on the pregnant guinea pig are not so convincing. The
average production of CO2 in the embryo he found to be 509 c.c. per
kilogram and hour ; that of the mother 462 c.c. per kilogram and hour—
an increase of only 10 per cent. Granted that the conditions of heat loss
were the same in the two, which is doubtful, the amount of metabolism
618 JOHN R. MURLIN
which could be ascribed to any developmental process as opposed to the
maintenance processes would be very small.
Rubner(w) believes that the law of skin area is applicable to the em-
bryo. He calculated that the metabolism of the new-born mammal, assum-
ing its weight to be 8 per cent of that of its mother, would be nearly double
as much per kilogram and hour as that of the mother.
Because the embryo is less active in every way than the new-born its
metabolism per unit of weight should be considerably less than this, which
indeed the results of Bohr and Tangl show to be the case. Rubner ex-
plains the higher metabolism of the embryo per unit of weight, therefore,
as due not to any specific requirement for developmental energy, but en-
tirely to the greater loss of heat by the relatively greater surface. He is
obliged, however, to eliminate the first four-tenths of the embryonic life
from the operation of this law, because within that period the embryo is
of no appreciable size as compared with the mother. On the basis of the
average composition of living substance in mammals and using seven
tenths of the metabolism of the new-born as the rate for the embryo,
Rubner calculates that for the remaining six-tenths of the gestation period
the "growth quota" of the embryo in most mammals is from 38 to 40
per cent of the energy supplied, as compared with 34 per cent for extra-
uterine life. In other words, for each calorie of heat value stored in the
new-born nearly two calories of energy must be expended, while for each
calorie deposited in the embryo only one and one-half calories need be
expended (on the basis of 40 per cent). We shall see that the higher
metabolism of the embryo and fetus is continuous with that of the new-
born.
The qualitative differences in the metabolism of the embryo from that
of the adult depend on the kind of food material supplied by the mother
in the egg (oviparous development) or by the circulation (viviparous)
for the nutrition of the embryo. A hen's egg contains no carbohydrate;
hence the respiratory quotient in development of the chick can never be
greater than 0.78 (see page 560). The chemical studies of Liebermann,
the calorimetric determinations of the heat of combustion by Tangl and
the metabolism studies (using the direct and indirect methods) by Bohr
and Hasselbalch all agree in showing that the material oxidized in the
development of the chick is fat. Liebermann believed that some nitrogen
was lost, but both Hasselbalch and Tangl and Mituch have shown that
this is incorrect. The nitrogenous building material is not used as a source
of energy.
The source of energy for the silkworm embryo, according to the chem-
ical studies of Tichomiroff and the respiration experiments of Farkas;
for the blow-fly embryo according to the respiration experiments of Wein-
land ; and for the cadaver fly according to the calorimetric determination
of Tangl is likewise mainly fat. No nitrogen is lost in gaseous form dur-
NORMAL PROCESSES OF ENERGY METABOLISM 619
ing the development of any of these insects, but a portion of the energy
(according to Farkas approximately one-third) arises from the oxidation
of proteins to uric acid. Both Tichomiroff for the silkworm egg and
Weinland for the blow-fly recorded a reduction of the glycogen content
of the egg, but Weinland believes this may have been converted to chitin.
There is no evidence, he says, that glycogen' has served as a source of
energy.
Our information as to what material is the source of energy for the
mammalian embryo is extremely scanty. Cohnstein and Zuntz analyzed
the blood in the umbilical artery and vein of the sheep embryo for oxygen
and carbon dioxid, and noted a difference of 4.67 vols. per cent O2 and
4.72 vols. per cent CO2 in one case and 4..0 vols. per cent O2 and 6.5
vols. per cent CO2 in another. These figures would give respiratory quo-
tients of 1.01 and 1.6 respectively for the two embryos. It is doubtful
whether these figures are to be trusted, since on the basis of the same
analyses the authors claim a metabolism for the embryo of only one-fourth
to one-sixth as much per unit of weight as for the mother. The quotients
agree, however, with those found by Bohr on the embryo of the guinea
pig. Bohr took the difference between the total gaseous exchange of the
pregnant animal (after operation under anesthesia and immersed in a
warm bath) before and after clamping off a single umbilicus. The res-
piratory quotient indicated for the embryo was always in the neighbor-
hood of unity. Oddi and Vicarelli report also a progressive increase in
the course of pregnancy in the mouse. According to these observations,
therefore, the most diffusible of the foodstuffs, the one most readily passed
through the placenta is probably the source of energy for the mammalian
embryo. There is no satisfactory evidence as yet that proteins participate
to any considerable extent in furnishing such energy.
3. Metabolism of Post-embryonic Growth. — While metabolism is cer-
tainly more active in the youthful organism than in the adult it is by no
means proved that the growth per se calls for any expenditure of energy.
In recent times the view seems in fact to have gained rather general ac-
ceptance that the large metabolism of the young is necessary in the
interest of heat regulation. At the same time the propensity to grow,
which is the certain sign of youth in health, may be given a sort of
energy index. There is a considerable body of evidence that growth in
a given genus is proportional to the potential energy of the food consumed,
and the proportion of gain in weight to energy intake may be quite similar
in different genera.8 It would seem that the growth impulse which, in
some way not at all understood,, directs and governs developmental events
through the processes of nutrition, is geared, so to speak, at a very similar
8 This statement, in view of recent developments in the realm of the chemically
unknown accessory substances (vitamines), must be guarded by the saving proviso that
an adequacy of these several substances is assumed.
620 JOHN R. MURLIN
speed in relation to energy intake in several genera and orders of mam-
mals. A kilogram of body substance in several of them contains, accord-
ing to Rubner(cc), 30 gm. N and 1722 calories of potential energy. To
produce this unit of growth requires in the earliest period of postnatal de-
velopment approximately the same amount of food energy ; namely, 4088
calories. The human infant, however, occupies an exceptional position,
in this regard, which may be expressed as follows. Of 100 calories of en-
ergy in the form of milk there is utilized for growth in the —
Colt 33.3%
Calf 33.1%
Lamb 38.2%
Pig 40.2%
Puppy dog 34.9%
Kitten 33.0%
Young rabbit 37.7%
Average 34.3%
Human Infant , 5.2%
The average ingestion of milk in relation to the maintenance require-
.ment (this term in Rubner's usage is not synonymous with basal metabo-
lism) in the mammal is 202 per cent, while for the infant it is only 120
per cent.
The relatively long infancy period in the human family, it would seem,
is a consequence rather than a cause of this difference; for if the large
amount of time spent in sleep explained the low intake of food, and the
slow development were a consequence of this, then keeping the baby awake
and thereby increasing the demand for food ought to accelerate its growth.
Of course just the opposite is true. Owing to a growth impulse of low
speed, which in turn probably determines capacity for food (anatomical
capacity of the stomach and functional capacity of metabolism) on the
part of the infant, the human mother is called upon to supply intelligent
care and protection rather than bulk of nutrients. Interesting biological
implications are involved which space does not permit us to develop at this
time.
It is doubtful whether the growth quota of energy, i. e., the portion
left over after the maintenance factor, the activity factor, the dynamic fac-
tor and the loss by non-absorption have been covered, can ever be fixed
as a definite percentage of the maintenance metabolism for all varieties of
infants. The growth impulse, as between individuals, quite as truly as
between different orders of animals, is more a matter of heredity than
of food. Moreover, it is inherited from the father equally with the mother,
so that a small mother nursing the child »f a large father may not be able
to supply milk enough for the rate of growth which the child has inherited.
Again it is well known that growth in height often will proceed at a time
when nutrition is not sufficient to support growth in weight, and both vary
with the season of the year (Porter, Bleyer). In time we shall have in
NOKMAL PEOCESSES OF EKEKGY METABOLISM 621
addition to statistical criteria, physiological norms of growth which will
simplify the whole problem of infant feeding. At present it ia impossible
to formulate even a satisfactory physiological definition of the growth rate.
Merely to emphasize the multiplicity of factors contending for energy be-
fore growth can be wholly satisfied and to visualize what is known of their
quantitative relations, the following tabular arrangement may be presented:
Basal metabolism 60 Cal. per kgm.
Activity metabolism ( 12 to 40% of Basal) 7.2 to 24.0 " "
Loss by feces ( 10 to 15% of Basal) 6.0 to 9.0 " "
Dynamic action ( 10 to 20% of Basal) 6.0 to 12.0 " "
Growth (10 to 20% of Basal) 6.0 to 12.0 " "
Total 85.0 to 120.0 " "
This estimate is liberal in all divisions of the caloric needs. Careful
reckoning of the fate of the food energy cannot account for more than
is here allowed except in such extreme restlessness as would place the case
clearly in the pathological field.
This classification is not to be looked upon as anything fixed. The
basal requirement increases steadily up to one year of age or later. The
requirement for activity increases steadily in the absolute sense as the
child spends more and more time awake, but it is not yet certain whether
the increase is also relative to basal needs on the basis of weight or surface.
Utilization is not known to change with age, the results with very young
infants being often quite as favorable as with older ones. Dynamic action
has not been sufficiently studied to say definitely whether it is greater
or less as more and more food is ingested at a meal. There are indications
that it is greater. Finally, the requirement for growth relative to weight
increases certainly for the first three months and possibly up to six months,
after which it becomes retarded. We have yet to learn whether the
growth increment (in calories) advances more or less rapidly than the
basal requirement. Van Pirquet, who has recently invented a system of
computing food requirements, obviously based upon energy units (and
merely disguised as "nems") estimates the growth quota at one-third the
minimal or maintenance requirement. From the observations of Soxhlet
on the calf it has been estimated that this animal can utilize over 40 per
cent of the food energy for growth but an infant of 7 months was
able at best to so dispose of only 13 per cent. Mere fattening should not
of course be included in growth.
E. Energy Metabolism of Pregnancy
The energy metabolism of the fetus immediately before birth has been
determined separately only by noting the difference in respiratory ex-
change of the mother produced by clamping off the umbilical cord (see
page 619). This method, however, is open to serious objection and has
622
JOHN E. MUKLIN
not given satisfactory results. In pregnancy the extra metabolism due
to the product of conception includes the energy used by accessory struc-
tures as well as by the fetus itself. Nevertheless, it is worth while to
estimate the difference particularly with a view to determine whether any
material change in energy relations occurs at the moment of parturition.
With the dog Murlin(c) was able to show that the extra heat production
of mother and offspring just before parturition was very nearly propor-
tional to the weight of newborn pups delivered three days later. It was
impossible to record the metabolism nearer to parturition than this on ac-
count of the restlessness of the dog. Quite fortunately it happened that
the same dog gave two litters, one consisting of a single, the other of five
pups. Comparing the total metabolism on the third day before parturition
in the two pregnancies with that of the dog in sexual rest after lactation
had been stopped, it was found that the extra energy metabolism at the
culmination of pregnancy for^the one pup'was (551.3 — 505.3 =)46 cal-
ories or 164 calories per kilogram of the single newborn pup; and
(7.63.8 — 505.3*=)258.5 calories or 165 calories per kilogram for the
five new-born pups. In other words, the extra metabolism was very
nearly proportional to the weight of the newborn.
46 Cal. :' 258.5 Cal. : 280 gm. : 1560 gm.
It should be emphasized that the temperature of the cage was the same
on the several days compared, that the mother dog was trained to lie per-
fectly still, and finally that the diet was exactly the same in weight and
composition on all these days.
It is interesting to observe that the extra metabolism necessary to
maintain the embryo (and all accessory structures of the mother's body)
at a time when the pregnancy is at its highest phase is very nearly equal
to the amount which the newborn of the same weight would theoretically
produce (according to the law of skin surface), the first day after delivery,
if exposed to ordinary room temperature and if resting (Murlin(c) ).
If the law of skin surface is applicable to the embryo and the new-
born, as Eubner believes it is, we may conclude that the metabolism of
the uterus, mammae, etc., would almost 'exactly compensate for the differ-
ence between the metabolism of the newborn at room temperature and
the metabolism of the embryo at the temperature of the mother's body.
In other words, the curve of total metabolism of mother and offspring
would scarcely suffer any interruption at birth, if mother and offspring
after birth could be kept sufficiently quiet for the demonstration. If this
generalization should be true of the human mother and her offspring it
would be a matter of considerable interest and importance.
To secure proper conditions for this inquiry, the problem was taken
to the Nutrition Laboratory of the Carnegie Institution in Boston, where
a bed calorimeter had been perfected large enough to contain mother and
child (Carpenter and Murlin). Three subjects were studied. The metab-
FORMAL PROCESSES OF ENERGY METABOLISM 623
olism of the pregnant woman was determined a number of times through-
out the last two or three weeks, and similar determinations were made upon
1 Meter
Fig. 36. Cross-section of bed calorimeter (Benedict and Carpenter), with which
Studies on Pregnancy were made by Carpenter and Murlin.
the mother and child as well as upon the mother alone after parturition. A
table showing the comparative results is given below.
TABLE 23
ENERGY METABOLISM OF MOTHER AND CHILD TOGETHER BEFORE AND AFTER PARTURITION
(Carpenter and Murlin)
CASE
Mean of All Days Before and
After Delivery
Respiratory Exchange
Energy, Production, Calo-
ries per Hr.
PQ o
o> r
£uo —
2 a
£ <u
«
¥
O
O
V
FH
O W
0
tf
o
V
s
i
b — Indirect
Oj
% Ditference
Case 1.
1st, 4th, and 6th days before
delivery
36.75
36.9
36.68
36.8
36.64
37.23
21.3
20.2
22.3
21.7
23.9
23.1
18.4
18.5
19.6
20.4
20.2
20.3
.85
.80
.83
.78
.86
.81
60.0
61.2
63.6
71.1
72.2
70.8
61.3
61.2
65.9
67.5
68.7
68.6
60.7
61.2
64.7
69.3
70.6
69.7
2nd, 5th, 12th, 14th, and 17th
after delivery
+ 0.87
Case 2.
13th, 17th, 19th, 20th, and 22nd
before delivery
2nd, 5th, and llth after de-
livery
+ 7.1
Case 3.
1st, 3rd, 17th, 21st, and 24th
before delivery
4th, 8th, and llth after de-
livery
— 0.9
624: JOHN E. MUELIN
The energy production expressed in absolute figures in both cases 1 and
3 is the same after as before parturition. In case 2 there was an increase
of about 7 per cent in the postpartum over the antepartum metabolism.
This can be accounted for by the fact that the child cried lustily at times
on two out of three postpartum days and the crying disturbed the mother.
One is justified, therefore, in the conclusion that the total metabolism of
mother and child immediately after birth of the child is not greater in
absolute amount than it was immediately before delivery. The extra
metabolism of pregnancy, at its culmination, due in part to the activity
of the accessory maternal structures as well as to the fetus, as in the dog,
is just compensated by an extra metabolism set up in the new-born as it
begins an independent existence. Since the mammalian embryo has no
appreciable weight as compared with the mother until near the middle of
the gestation period, it is easily understood why several workers (Magnus-
Levy) using the Zuntz method failed to find any increase in the oxygen con-
sumption per unit of weight in pregnant as contrasted with non-pregnant
women ; or if such an increase appeared at all, it became evident only com-
paratively late in the gestation period. This was confirmed with respect
to the total energy production as computed from the output of nitrogen and
carbon by the writer in a series of experiments on a pregnant dog. The
only exception to the rule is a single case reported by Magnus-Levy in which
he observed both an absolute and a relative increase in oxygen absorption as
early as the third month of gestation.
Leo Zuntz (&) reported three cases on two of which he made observations
by means of the Zuntz-Geppert method throughout the gestation period
ynd on the third a few observations in the sixth month only. He com-
pared the results with figures previously obtained from the same subject
in sexual rest. The first two increased considerably in weight during
the gestation period, quite independently of the product of conception,
so that the amount of oxygen absorbed, when expressed per kilogram of
body weight, was even less in the ninth month (Case C) than it had been
in sexual rest, or was so little greater (Case B) that Zuntz believed the
difference was entirely due to the increased labor of respiration. In the
third case, however, the weight was less in the sixth month than it had
been previous to conception, the oxygen absorption being as a consequence
significantly larger per unit of weight in the pregnant condition. On
the basis of this experiment and that of Magnus-Levy, Zuntz concluded
that at the end of pregnancy the respiratory metabolism normally would
be considerably higher than in sexual rest and that this is not altogether
due to increased labor of respiration. Carpenter and Murlin compared
their determinations on three normal cases of pregnancy with basal de-
terminations on seven normal, non-pregnant women ranging in age from
18 to 55 years and in weight from 37 to 66 kilograms. Table 24 presents
a comparison of the energy metabolism in the ninth month of pregnancy
625
X
bo ° " >* ^
O~ i •* rj1 * 13 fl
•4
^ "^ CD S* ^
c^ cs ~*^ ^j ^* 8 3
n
PH S . ^ ^
- OH^ «>- ^ * *>
6
. 2 *J ,£3 ,B
,-H t, ~ C M CS
H
co
*^ ^ O ^j -M
^ P^ g 8 T- ^ t—* Q^
J4
CO lO
t~» c3 ^ CO "^ O^ "^
fc
h
oS
JS "* CO ^
1-1 "^ t- ,^ " S
^
S
S B ""
2 eo" oj -^ &,"oo *" ^*
0
5
O * "g S
3 r~' "^ •*-* *"* "^ 2 oo
fc
PS1
J«*H 'C§«(-iCS'*>
M
° '° 5 "S
^wg^003"^^
8
"x c S -2 -P" §""
f's-aa^fifi^
§
03 C S5r2 ^
i<i o3 -4-J ~O S <N G-i— i
o
O *OS C
02
t-i O *
H
g^bb.S
. . ..50
: : : : °.
so c o e: c-i
**J
O> "S ,
I-H C ^-
ffi 3
^
T3 CX
o
£
g
o"
•10 •* r-C 10
; co co co oo
00 CO • CO 00
*~7 °*J ! ^ *?
I
oj *"^
8
i
o
ffi
1"
1 J &&
^H ^^ ^3
os Tt< >o t>. -^
(M •»* CS CO OS
^ co eo co
o
(H
£
CD &,
H
,£j .
to
_bp bo
o o 06 n? I-H
KB IH §
22 : »^
rti U
^
CO
*" Cfl
H P?
6 '3 c
« 0
^ c" Is
. . . . to
'. '. '. '. OS
•-i IN ; eo
•-H q : q
H
•g .2 ^ 2
. . . . o
a
o> "S
to
W s §3
^
*"* FO ft.
„
H
to
tt
c
g
Q,
S .
; !>. CO CO 00
CO to crt • 3
CO CO ; GO
§
^3
(M*
M
-^>
.
PH
to
E cJ^
•M
0
HH
o
_ • b-
^
« bc.S
eo cs t-- ^ TH
os ^* 5 * to
S
Cg ^2 k> i^
eo eo eo' eo' co
CO CO V • CO*
GO
f- <J ^ i«=i
^^
13
bX> « ^
^
o
V ^^ ^J
B
/S O^
•<
CU
H
^
i-H .
M
S
tftxp
jo o co i~- co
i— 1 10 10 o co
!— H
co os ;
fcH
>. ^
!
H
to
N
u
0? ^ ^^ '
S 1 II I
I ! cs a) 1
I i fi »
Ci Os C ^ oo
M
fli "™^ ^^ r"^
^H ^H ^ ^ -rf gj
E
-2
| <"1 pqo r-,
— — ^o w
«M CO .2? —
h
V
0
o>
jn aj
oo oo «t-i fi1 «t-i
to
•8
^ S Sou
03 .03 O «t O
o
CO
02
^ ^n jto JK •
J> a o «
— ^— QJO ~ — ' ~ '•
S
aj . — .+s -t-* +J
2 ^ S 2
«!
— i^» ^-
^O Q> •>• ^^ , O
PH
a
O
u
bo S! N N cs
ctf . . •
g i4 hJh-5 O
CS CS <J ^
b d
626 JOHN R. MUKLIN"
with the metabolism of the normal, non-pregnant woman, so far as the
former has yet been studied.
It is surprising how close is the agreement between the results obtained
with the respiration calorimeter and those obtained by the Zuntz-Geppert
method. For example, Zuntz's case 3, agrees perfectly as far as the O2 ab-
eorption is concerned with Carpenter and Murlin's cases 1 and 3. The
mean oxygen absorption per kilogram and minute in the non-pregnant
woman before conception is 3.45 c.c., for the eight normal women 3.48 c.c.,
but for the three cases taken during the puerperium it is 3.65 c.c., an
increase of 5.8 per cent. The mean result for all non-pregnant women
is 3.49 c.c. O2 kilogram and minute. For the pregnant woman the result
is 3.57 c.c. or 3.5 per cent more than the amount obtained for all the cases
taken in complete sexual rest, and 2.2 per cent less than the average for
the puerperium.
For the heat production Carpenter and Murlin found 1.03 Cal. pei*
kgm. and hour for the pregnant cases as against 1.02 Cal. per kilogram and
hour for all the non-pregnant subjects. For the woman in complete sexual
rest, however, the mean result for the eight cases is 0.99 Cal. per kilo-
gram and hour, i. e., about 4 per cent less than for the pregnant woman.
The agreement between the oxygen difference and the total energy differ-
ence is very satisfactory. The conclusion which may be drawn with entire
confidence is, that the basal energy metabolism expressed per 'kilogram and
hour, of the pregnant woman in the last month of her pregnancy, is but little
larger (4 per cent) than for the woman in complete sexual rest.
While we have but little data as to the depth of respiration or as to
the increased labor of respiration in pregnancy, one may be inclined to
think that so slight a difference might be attributable entirely to such a
cause, instead of only partly so, as L. Zuntz believed. In fact, according
to Zuntz's own estimate of the increased labor of respiration in his Case
B the difference in oxygen absorption between the pregnant and the non-
pregnant condition is exactly accounted for in this way. This conclusion
would mean, very clearly, that the metabolism of the fetus, together with
all accessory structures, is the same as so much maternal tissue. If the
metabolism of the fetus itself were slightly higher in the human, as it
seems, from Bohr's experiments, to be in the guinea pig, this factor would
be counterbalanced by the fact that the liquor amnii (and possibly the
membranes) takes no part in the metabolism.
On the other hand, the heat production in the puerperium is dis-
tinctly higher than that for complete sexual rest or for the pregnant con-
dition— the average for Carpenter and Murlin's three cases being 1.10 cal-
ories per kilogram and hour, or 11 per cent higher than the average for
the former and 7 per cent higher than the average for the latter.
What is the explanation of this higher energy production of the puer-
perient mother ? That it was not fever is apparent from the very accurate
NORMAL PROCESSES OF ENERGY METABOLISM 627
temperature measurements made by rectal thermometer. It is conceivable
that the processes of involution, which were not yet entirely complete
at the time of the above observations were made, set free decomposition
products which stimulate tlie general heat production in a manner anal-
ogous to the stimulation of the mammary glands by fetal products. If
so, the processes by which heat is lost from the body (evaporation of water,
radiation and conduction) must be equally stimulated, for there is no
accumulation of heat. A state of hyperactivity of the sweat-glands, es-
pecially during the early days of the puerperium, is a phenomenon well
known to obstetricians and it is possible that this activity is a primary
cause of the increased heat production — a cooling of the body surface
generally resulting in a reflex stimulation of the heat-producing tissues.
The writer believes, however, that the most important factors are the
activity of the mammary glands and the specific dynamic action of the
foodstuffs burning — especially the increased protein combustion due to
involution of the uterus. The lower respiratory quotient found in the
puerperium is to be ascribed to the restricted diet very commonly imposed
immediately after delivery, and is a sign that the patient has used up her
store of glycogen during labor and is thrown back on her reserve of fat, and
on the protein resorbed from the uterus for her supply of energy. The
dynamic action of the latter would considerably increase the heat pro-
duction.
F. Energy Metabolism of the Newborn
Infant
1. The Respiratory Quotient of the Newborn. — In the observations
of Mensi, Scherer, and Babak, the respiratory quotient of the newborn
child was found to be extremely low, so much so that it was inferred that
oxygen must be utilized in the infant's body for some other purpose than
that of combustion. More recent observations have discredited this inter-
pretation, for it has been rendered very probable that the technique of
the early observers was seriously at fault. Hasselbalch points out that
Scherer's oxygen must have contained a much larger percentage of nitro-
gen than he assumed, from an old analysis, to be present ; also that there
was an admitted error of 6 per cent on the carbon dioxid.
Hasselbalch (a) himself obtained quotients which were much higher.
Since his technique seems to have been carefully controlled, it is probable
that his results are much more reliable. In fact, Hasselbalch lays stress
on the fact that the R. Q. of the newborn infant before it begins to take
food is often much higher than that of an adult in a similar state of inani-
tion, and he thinks it is fair to infer that in such cases, which in his tables
include both the well-nourished infants born at term and infants prema-
628 JOHN R. MURLIN
turely born, there is a plentiful amount of glycogen available at birth and
it is the requisition upon this reserve carbohydrate which produces the
high quotients.
Hasselbalch infers much from the single experiment of Bohr on the
pregnant guinea pig (quoted at page 619) showing that the respiratory
quotient of the embryo is 1.0. It is quite possible that this is true, but
the single experiment of Bohr can hardly be accepted as proving the case
beyond doubt. Recent analyses of the blood of the mother and of the um-
bilical vein taken simultaneously at parturition show clearly that other
materials than glucose can pass the placenta very readily, and while one
may be prepared to believe that the main reliance of the embryo for energy
is the most diffusible of the foodstuffs, it must not be inferred that no
other substance is available for combustion in the fetus. Were carbo-
hydrate the only fuel available during antenatal life, it might be argued
that the enzymes are not yet ready for liberation of energy from fat (which
certainly is present), even if a large store of glycogen could not be demon-
strated ; and we might expect to find the quotients rather higher immedi-
ately after birth than a little later. Hasselbalch himself admits that the
facts are not quite so easily explained. Referring to Table 25 it is seen
that the highest quotients do not always come at the earliest hour. When
the same subject was used in two successive experiments, however, this
was found to be true.
So convinced was Hasselbalch that the quotient was higher the bet-
ter the state of nutrition of the newborn that he thought he could tell
when the quotient was lower than 0.9 by signs of hunger in the infant.
The occurrence of high quotients within the first seven or eight hours
after birth was observed independently also by Bailey and Murlin. They
drew attention to the particular interest which the quotient at this time
presents, as indicating the kind of material available for combustion as
the child breaks connection with the maternal circulation. They were
on their guard, however, against inferring, without further information
regarding the absorption of oxygen at this age, that the high quotient
necessarily proves a predominantly carbohydrate combustion. "Assum-
ing that oxygen absorption is normal at this age," they say, "the quo-
tients obtained would indicate the combustion of a considerable amount
of carbohydrate (glycogen)." Since Morris has published his sugar an-
alyses in maternal and umbilical bloods and has shown that the level of
the blood sugar is raised in both by a severe labor or by the use of an anes-
thetic, another explanation of the high quotients which are met with in the
early hours of postnatal life has been presented. Henceforth it will be
necessary to know something of the severity of labor and whether the
mother was given an anesthetic, before a plentiful supply of glycogen in
the liver of the newborn all ready for combustion the moment the cord is
tied, can be inferred. However, it is possible that the severe labor would
NORMAL PROCESSES OF ENERGY METABOLISM 629
d1
p QO <N
!""• ^O CO
35 2 O
•
QO QO
• O Ci
O
1-1
J* *| g
co S * "^ *• *~
1^0
O'-S P~°
QJ
tc
O
a,
Oi
«
!H
J5
i
*: i 22 — *- -a
"3 .a "3 go g B
43 SJ3 .C_0 rt
in ^ bn >
S rH fe 0 3^
-£ O p g O
•g bc.n =5 2. s
,5 C ^O 43
S* -2"« .g _jo so
.s'* -^
&« is
^M g.S5
« BC -G >i
s
GQ QQ ^3
X r^ .„
§
-^ c — g S "*
* * * |2
T3
cS
S BJT3 03 «
O S *n S
bo .5 § o S .5 s
!|J||
TJ
O ^"e C C* *
SJ> <fH *3 S
O
^ ^"5 -^ H ?^
P SH
O
43 § »\ ^
O ••* ^^ tUD
fa
•** — -g £ o t.
C B -S m .S
0
QJ4j'73cO 3."^^
•3 c cs "S ^ fe "tj
If-Nl
00
9 ^ >pi ^ *"
c c S ^ 2
J*
• »\»S "" S, r«. S § •*•
(-4 . «x QJ . », -*3
h
aj
Q O O "Q 2 *J> C Q
" o 9 o ^^
1
o B'^ g«*H £ 'E o
0 «2 S "^ ° §
a)
PH
^•sinmsj?
S ° "c ^ ° **
.5
kO 0 o 0
§
T* CO CO CO
• •
bo
W
: - ^ ^
* M
43 •
'So
uj m «5 ie>
^H 0
w »o
to
jTIN
O 0 0 0
in o o o
0 S
1C O
«£
co" co" co" •^
CO* CO*
X
tn ^ fe fa fa ^
a
. » . 2 . -
a*
H
W
630 JOHN R. MURLIN
mobilize glycogen from the maternal tissues and that ether administered
would mobilize it from both the maternal and fetal tissues, so that the um-
bilical vein would get a contribution from both directions. Hasselbalch's
insistence upon a relationship to general nutritive condition is not neces-
sarily discredited, for it is well-known that in the majority of instances
a large, well-formed infant produces a more difficult labor which itself,
without the assistance of an anesthetic, would in all probability call out
enough carbohydrate into the circulation to raise the quotient several
points. Premature infants also produce an easy labor, and this fact with
absence of a hyperglycemia may explain the impression of Hasselbalch
that in the prematurely born infant "the store of carbohydrate is very
quickly spent."
Benedict and Talbot(a) (6) did not observe especially high quotients
immediately after birth ; for the technique of their experiments was not cal-
culated to separate the respiratory quotients into individual periods. The
authors state, however, that when the quotients above and below 0.80 are
compared, it is found "that up to the eighth hour the greater number
lie above 0.80, while subsequent to the tenth hour the larger proportion
lie below this value."
All the modern observations agree in showing a rapid fall in the
respiratory quotient toward the end of the first day. Hasselbalch did not
repeat his observations on the same infant except in immediately succeed-
ing periods ; but even these second periods show in four out of five cases
a noticeable fall. Bailey and Murlin made observations on two infants
born three hours apart on the same day and placed in the respiration in-
cubator at six hours of age. The observations were repeated on the sec-
ond, fourth, fifth, and sixth days with one child, and on the second, fourth,
fifth, and eighth with the other. The quotients fell to 0.67 in both cases
on the second day. While distrusting the exact figures obtained, the au-
thors point out the extreme significance of the indication, confirmed on
a third newborn at the twenty-seventh hour, that all available carbohydrate
has been utilized by this time, and the importance of supplying artificially,
if need be, some materials to protect the body substances. Mother's milk
was available in small amount for both infants on the third day, but the
quotients did not reach the level usually obtained after breast feeding of
older babies until the sixth day in one instance and the eighth in the
other. These observations were confirmed by Benedict and Talbot in
their long series, the values shown in Table 26 having been obtained as
averages of several short periods for each infant.
a. The Influence of Food on the Respiratory Quotient. — Milk appears
in the mother's breast usually by the fourth day, and by the fifth day the
infant receives enough to prevent further loss in weight. The course
of the average respiratory quotient from the first to the eighth
days reflects the adequacy of the food intake. Unless artificial feeding
NORMAL PEOCESSES OF ENERGY METABOLISM 631
TABLE 26
RESPIRATORY QUOTIENTS THE FIRST EIGHT DAYS (Benedict and Talbot)
DAY
1
2
3
4
5
6
7
8
Respiratory Quotient
0.80
0.74
0.73
0.75
0 79
0 82
0 81
0 80
Number of Cases
74
64*
62
51
41
22
15
9
i '
is resorted to, the modern infant is doomed to almost complete starvation
for the first three days, although it is clear, even from the average R. Q.
in the observations made at Boston, that glycogen is present in sufficient
quantity to prevent starvation acidosis the first day. When milk comes
in sufficient quantity on the fourth day, the average respiratory quotient
responds noticeably and on the fifth and sixth days mounts to a level
which indicates a satisfactory state of nutrition.
The question has often arisen whether the newboni infant is capable
at once of digesting and metabolizing a sufficient quantity of breast milk
even if it were present, to prevent loss of weight. The answer to this
question must be sought by means of the respiration apparatus. The mat-
ter will be discussed in its quantitative aspects at greater length beyond.
Meantime, it may be noted that Hasselbalch has tested the capacity of
the newborn to absorb and metabolize grape and milk sugar and that per-
fectly satisfactory evidence was obtained from the respiratory quotient
that this capacity is developed by the end of the second day.
Infants born prematurely may have a high R. Q. within the first few
hours after birth but by the fifteenth hour the supply of glycogen, or the
hyperglycsemia due to labor or anesthesia or both, has been considerably
reduced and the child may be already on a nearly pure fat metabolism.
When an adult mammal already well nourished is giver even a small quan-
tity of an easily absorbed sugar, the effect upon the R. Q. may be seen
within the first half hour. When, on the other hand, fat is given in large
amount, the effect upon the quotient may not be seen until the third to
sixth hour. We may expect then that in feeding an infant with milk,
whether mother's or cow's milk, it is the sugar of milk which is burned
first and the fat will only be absorbed in sufficient quantity to affect the
R. Q. after several hours.
The work of Hasselbalch demonstrates these points very clearly. After
feeding infants 2 and 4 days of age with breast milk, he found the high-
est quotient (.92 and .93) l1/^ hours after the meal. In one case he was
able to show that an experiment begun 2 hours after a feeding gave a
quotient 4 points lower than an immediately succeeding period begun only
one hour after a similar -feeding. Apparently in Hasselbalch's experi-
ments, as in those of Bailey and Murlin, it is much easier to secure this
rise of quotient with infants five days or more of age than it is with
those of 2 days or less. The explanation clearly is that unless artificial
632 JOHN R MUKLIN
nourishment has been resorted to, the infant's tissues are depleted of
glycogen at 2 days just as are those of an adult after several days of
fasting, and anything less than a large feeding of carbohydrate is held
up by the tissues to satisfy their craving for storage glycogen.
2. Basal Metabolism in the Newborn. — Carpenter and Murlin found
the metabolism of the newborn taken per unit of weight to be two and a
half times that of the mother lying in bed beside the child. Later observa-
tions by Benedict and Talbot (6) and by Bailey and Murlin make the figure
for newborns less than a week old 1.75 and 1.87 calories respectively per
kilogram and hour as against 1.0 calory per kilogram and hour for the
normal adult. The figure given by Benedict and Talbot is the average of
observations on nearly one hundred subjects which ranged from two and a
half hours to seven days of age, and had an average age of two days.
That given by Bailey and Murlin is the average of twelve hourly periods
on four infants less than one week of age, during which the infant slept
all or substantially all of the time. On the basis of twenty-four hours
at the same rate, the metabolism would be 42 calories per kilogram
according to Benedict and Talbot, or 45 calories per kilogram and
twenty-four according to Bailey and Murlin. It should be noted, however,
that the periods selected for this average represented the periods of unusual
muscular repose, and that no infant would ever actually maintain a
metabolism so low for an entire twenty-four hour period. It avoids con-
fusion, therefore, to report all results of metabolism experiments done in
short periods on the hourly basis ; for it is obvious that when a child sleeps
quietly for the entire period, as it did in most instances in the two series
of experiments referred to, the metabolism obtained does not represent
an average condition for the entire twenty-four hours. In fact, it would
be next to impossible to find a short period or to arrange conditions for
one which could be said to represent average conditions for twenty-four
hours. Moreover, a child does not metabolize materials in periods of
twenty-four hours as an adult may be said on certain grounds to do. If
there is any cycle of metabolism in the newborn, it corresponds to the
feeding period.
The influence of weight on the metabolism per unit of weight is well
illustrated by the table on page 633 from Bailey and Murlin. The
metabolism is noticeably higher for a light-weight baby (W, birth-weight
6 Ibs.) than for a heavy baby (B, birth-weight 10 Ibs. 3 oz.). From
considerations which will be presented in discussion of metabolism of older
infants, it is practically certain that the principal factor responsible for
such a difference is the insulating effect of subcutaneous fat or of the
effect of fat to reduce the effective radiating surface.
The average heat production of all of the infants over 4.00 kilos
body weight and over one day of age in Benedict and Talbot's(&) Table 12
(loc. cit. p. 95) is 1.75 calories per kilogram and hour, while the average
NOEMAL PEOCESSES OF ENEEGY METABOLISM 633
TABLE 27
Weight, Kgm.
Age, Hours
Cal. per Hour
Cal. per Kgm.
and Hour
Cal. per Sq.
Meter and Hr.
(Meeh)
w
2.9
6
5.649
1 94
2367
B
4.6
6
6.724
1 46
20 43
W
2.82
31
6.255
2 22
26 54
B
4.49
31
9.704
1 94
26.87
W
2.75
80
5.972
2 18
25.57
B
4.27
80
7.101
1.66
22.67
W
2.75
104
5.252
1 83
21.85
B
4.27
104
7.500
1.77
23.47
W
Average
5.782
204
24.43
B
Average
7514
1 70
23.36
of all those between 2.70 and 3.00 kilos in weight and within the same
range of ages is 2.00 calories per kilogram and hour. The observations of
Benedict and Talbot are thus in substantial agreement with those of
Bailey and Murlin. One cannot say, however, that every individual case
in these groups as compared with every other shows a metabolism which is
inversely proportional to weight. The influence of body weight (fat) can
be shown best by contrasting the extremes.
Within the age of one week the metabolism is by no means constant.
The average of 31 cases less than 12 hours of age is, according to the re-
sults of Benedict and Talbot, 1.59 calories per kilogram and hour, while
for their ten infants from 12 to 22 hours of age it is 1.87 calories. Be-
yond the first day there is but little fluctuation in the average. Thus for
fourteen infants two days old the average is 1.86 calories per kilogram
and hour and for thirteen infants four, four and a half, and five days of
age, the average is 1.85 calories. It is evident from these calculations
that the lower value noted above for Benedict and Talbot's longer series
is due to the large number of infants less than 12 hours of age included
in their observations. Summing up all the modern results, it may be
stated categorically that the metabolism per unit of weight for the first
twelve hours is approximately 15 per cent lower than it is the rest of the
first week.
3. Metabolism of the Newborn Infant per Unit of Body Surface.—
When the metabolism per unit of surface area of the newborn is compared
with that of the adult, account must once more be taken of the actual age.
The average for the first two weeks may be illustrated by the following
table from Carpenter and Murlin slightly modified by Lusk(&). Here it
is seen that the metabolism of the pregnant mother with an average weight
for the three subjects of 63 kilograms was 33.4 calories per square meter
of body surface (Meeh's formula). After parturition the average weight
was 53 kilograms and the heat production 33.2 calories per square meter.
634
JOHN R. MURLIN
TABLE 28
METABOLISM BEFORE AND AFTER PARTURITION. THE METABOLISM OF THE CHILD WAS
DETERMINED BY DIFFERENCE
Weight
in Kg.
Calories
per Hour
Calories
per Sq. M.
(Meeh)
Calories
per Kg. per
Hour
Case I:
Before parturition
63.0
60.7
31.4
0.96
After parturition
51.4
53.9
31.7
1.05
Difference
11.6
6.8
Child
2.7
7.3
30.5
2.70
Case II:
Before parturition . . .'
58.0
64.7
35.1
1.11
After parturition
48.5
59.0
36.2
1.21*
Difference
9.5
5.7
Child
3.4
9.8
34.9
2.88
Case III:
Before parturition
69.1
• 70.6
34.0
1.02
After parturition
60.1
60.4
31.9
1.00
Difference
9.0
10.2
Child
3.2
9.3
34.8
2.90
Average :
Before parturition .
63.4
65.3
33.4
1.03
After parturition
53.3
57.8
33.2
1.09
* Child cried during experiments.
The average heat production for women between 20 and 50 years, according
to Benedict and Emmes, is 32.3 calories per square meter. Now the still
more remarkable fact is that the metabolism of the child (determined by
difference between the metabolism of mother and child taken together and
mother alone) with an average body weight of 3.10 kilos is 33.4 calories
per square meter of body surface — exactly the same as that of the mother
whether before or after parturition. A more striking agreement in ac-
cordance with the law of surface area would indeed be difficult to find.
A woman heavy with child, the same woman immediately after delivery,
the child itself, and normal non-pregnant women differing enormously in
weight and showing a metabolism per unit of weight differing two and a
half times have the same metabolism when this is reckoned on the basis of
surface. The agreement, in fact, is too close to represent the exact truth,
except for the circumstances presented by chance in these particular ex-
periments. We now know from the further work of Murlin and Hoobler
as well as that of Benedict and Talbot that the exact age makes a measur-
able difference in both the newborn and older infants. Nevertheless it
holds as a substantial statement of the facts that the metabolism of the
young infant (two weeks to two months of age) on the basis of surface
area is the same as that of the adult. It is now known that the level of
metabolism of the newborn less than one week of age is considerably lower
than that of the adult. This discovery was made simultaneously by Bene-
dict and Talbot, and Bailey and Murlin, though it was emphasized first
NORMAI PKOCESSES OF ENERGY METABOLISM 635
by the latter authors. According to Meeh's formula the basal heat pro-
duction of the newborn was 23.7 calories per square meter per hour.
Benedict and Talbot interpret their results on all their infants be-
tween birth and one week of age as showing no relation between body
surface and metabolism. Yet when two extreme groups like those men-
tioned on pages 632 and 633 are selected from their results, it is found
that the average metabolism per unit of weight differs 12.5 per cent, while
on the basis of surface area (Meeh's formula), the same groups show a
difference of less than 3 per cent, namely 24.1 and 23.4 calories per square
meter per hour.
The basal metabolism of the newborn above 12 hours of age while,
sleeping quietly at a comfortable temperature is in the neighborhood of
23 or 24 calories per square meter of surface, in contrast with that of the
adult which is in the neighborhood of 32 or 33 calories. In other words,
the metabolism of the newborn is nearly one-third less than that of the
adult. On the same basis, the basal metabolism of the 31 newborn babies
less than 12 hours of age in Benedict and Talbot's series is about 20
calories per square meter per hour or quite 40 per cent less than that of
the adult. Singularly enough this same level of metabolism may be
reached by the adult after twenty days of fasting.
4. Influence of Sex on Basal Metabolism of Infants. — From the sec-
tions immediately preceding, it is already evident that sex at this early age
exercises little, if any, specific influence. Further examination confirms
this impression. Thus the group of 31 infants under 12 hours of age in the
Boston series includes 17 males and 14 females. The average weight of
the males is 3.76 kilos and they have an average metabolism per kilo and
hour of 1.53 calories. The average weight of the females is 3.29 kilos and
they have an average metabolism per kilo and hour of 1.61 calories. The
metabolism of the larger body is slightly less as before. The two groups,
however, have exactly the same metabolism per unit of surface.
Carrying the comparison to older groups, we find the same is true of
all infants two days of age. There are seven boys and seven girls of this
age in the Boston series. The average metabolism of the boys is 1.85
calories per kilogram and hour, while that of the girls is 1.87 calories.
The average metabolism per unit of surface (Meeh) is 23.5 calories for
the boys and 23.2 calories for the girls. Using the DuBois height-weight
formula and calculating the surface, the average for the boys is 30.7 calories
and for the girls 30.4 calories. The mean percentage deviation from the
average is slightly less for both groups on the basis of the Meeh formula
than it is on the basis of weight or on the basis of the surface as estimated
by the DuBois formula (Table 29).
Going on to infants 4 to 5 days of age, in the same series, we find the
average weight of the boys is 3.34 kilos, that of the girls 3.83. The basal
heat production per kilo and hour of the former is 1.88; that of the latter
636
JOHN K. MUKLIN
l£
*g
<M m m m us <M co
•*
> s
32
T(< -^4 CO Tf CD CO r-H
•*
TJ^* .
o^; t,
:-. —
P-i cy1'"'"'
O 1— 1 1— CO t— t- <N
b-
•s50^
g tH C
B 8,*
(M (M CO O5 oq O5 O
co co <N IM n <N <n
0
CO
fct
•«*<5
.23
OO O Tj< O5 <N TH «5
O ""f O »™< QO ""^ rH
(N <M (M (M rH (M <N
t-.
0
<N
»2ffl c
^Q
OOOOOC°
O
s*s
0 5^
£ a
CO «5 00 00 i-l ^-1 i-l
r-t
> g
fiS
co m « co 10 <N ca
•^ '
|SC
Pk ,j,B
•* 00 5O O5 t^ O CD
m
-^•g
OS >- g
<D HI TO
a *
T)H TjJ CJ rH TJH CO CO
(M (M (N IN (M (M (M
CO
<N
4) .—
•sll
CO i-l IO CO O I— CO
i-- t— CO OO Tj< t- OO
(M <N (M (M <M (M <M
1— 1
1--
(M
S<JS
OQ ^
0000000
O
Srf
0 5s*
<N IN b- O O <N (M
O5
K- C<J
> fll
Si
CO CO (M t- (N CO CO
f— (
•*
1||
i-H ^H O (M t- OS O5
O5 O5 00 t~ O t- t-
m
00
gfeg
B ^
73 oo
O t<
£W
^^
-U (VI
O <M •* •* CO CO CO
CO CO -^ 1O ^< 1C US
CO
in
03 'r
m >H
W&
o o 0*0 m o o
o
wg
i— I (N r-i (N 1— i— I <N
m in us 10 •* o m
i— i
m
-4lJ ^
oo m co co b- co co
TJ< -^ co t— GO m co
CO
•^
^w
CO CO CO CO CQ CO CO
CO
d
S5
CO O O ri CO O •*
i— i co in w t- 1-
Average . . .
O <N O5 O5 (M OJ r-l
CO
o co •* o t>. co •*
Tt<
•* TJ< os r-i <M m 1-1
Tjl
O CO OO O CO (M OJ
CO CO (M CO (M «5 (M
O
CO
O (M O5 OO 00 (M <M
O3 (M Oi CO O5 i— l 00
•-I (M i-H I-H i-H (M l-l
CO
o
0000000
o
I-H o 1-1 •* TJ< in oo
co
m CD m o o in o
CO
o co o co ^ m co
(M
oj •*' oi co' co •*' co
<N (N CM <N (M <M (M
CO
<M
(M ^H ^H CO (M O CO
CO O CO •*!•<*< 00 C4
<N CO (M Ol (M <M (M
0
m
(M
0000000
o
o o co b- os co m
•*
oo <N m co <M 1-1 1^.
•*
IM CO t~ Tfi (M O 1-1
t— 00 t— O O5 O5 O
t^
00
i— i
os oo oo co •* in »—
CO 1^ CO CO CO CO (M
w
T*
m o o o m o o
>n
CO I-H O O O O OJ
•^ in in in m in •*
o>
•«*•
oo •* m <M o (M co
(M O (M O5 C5 CO CO
CO
(M
CO Tl< CO CQ (M CO <N
eo
•* os co ~« Tf co in
-< oa co •* co
Average . . .
NORMAL PROCESSES OF ENERGY METABOLISM 637
1.83 calories. On the basis of the Meeh formula the basal metabolism of
the boys per square meter of surface is 23.5 calories and that of the girls
23.2. On the basis of the DuBois formula the metabolism is 30.5 and 31.0
calories per square meter per hour respectively. The mean deviation from
the average is again less for the Meeh formula.
In the statistical analysis of the basal metabolism of the entire Bos-
ton series, Harris and Benedict carried the comparison somewhat further.
They predicted the metabolism of girl infants from constants based on
the boys, and determined the sign and magnitude of the difference be-
tween observed and calculated values. Equations employed were those show-
ing regression of basal metabolism on stature (body length), on weight,
and on body surface in the male infants. Subdividing the entire seriea
of female infants into stature groups, it was found that out of six groups
three showed a higher metabolism and three a lower metabolism than
that predicted on the assumption that all were boys of like height. Clas-
sifying for surface area, out of seven groups four showed a higher metab-
olism and three a lower than predicted on the assumption that they were
boys with the surface area of the girls. The comparison for body weight
turned out the same. The authors conclude: "As far as our data go, they
indicate that on the average there is no sensible difference between the
heat production of the two sexes in the first week of life."
5. Influence of Crying. — Since the newborn child is scarcely able to
influence metabolism by any other form of muscular effort than crying,
the activity factor may be discussed under this heading. Bailey and Mur-
lin cited among their results the case of a child ten days of age who pro-
duced 8.14 calories per hour while sleeping quietly throughout the period
of observation. The next day, while crying "most of the time," i. e., one
hour, she produced 10.73 calories, an increase of 31 per cent. Howland
with Lusk's calorimeter observed an increase of 39 per cent in an infant
7 months of age for a one-hour period of "struggling and crying." Bene-
dict and Talbot have contrasted in one of their tables minimal with maxi-
mal periods of activity (including crying) for 93 infants, and deduce an
average difference of 65 per cent, the individual differences ranging from
4 to 211 per cent ! Unfortunately 65 out of the 93 maximal periods are
"calculated from the carbon dioxid produced during a preliminary period
for which the respiratory quotient was not determined." Since even those
periods for which oxygen as well as carbon dioxid was determined often-
times gave "defective respiratory quotients due to excessive carbon dioxid
excretion . . . or to a defect in the measurement of the oxygen, particu-
larly the residual oxygen," it is impossible to compare Benedict and Tal-
bot's results with those of Howland or Bailey and Murlin whose "crying"
periods like their basal periods, were controlled by residual analyses.
From a practical point of view, however, namely the effect of crying upon
the energy requirement of the newborn, the several authors are in sub-
638 JOHN E. MUKLIN
stantial agreement. For an infant who cries no more than the average nor-
mal infant probably 30 per cent increase above the basal would more than
cover the energy requirement for maintenance ; while for an infant who
cries "most of the time" (admitting considerable latitude in the use of
the expression), probably 40 per cent above the basal would be more than
adequate ; for it is certain that, no newborn infant can continue to cry at a
rate sufficient to increase the metabolism 40 per cent for more than a
few hours out of the twenty-four.
6. Influence of Food and External Temperature. — Very few observa-
tions have been made indicating that the food of the newborn has any
dynamic effect. Hasselbalch (a) reports two observations on premature in-
fants in which he surmises that the increase of some 15 per cent in
metabolism the second period is due to the "work of digestion." "At
any rate," he asserts, "it was impossible to recognize a difference in the
muscular activity of the infant." Since the first effect of hunger is to
induce muscular activity in the form of crying, it is very difficult to secure
.complete muscular repose on empty stomach so as to have a basis of com-
parison with periods following the ingestion of food. In Hasselbalch's
comparison just cited both periods follow the feeding and the more
active work of digestion in the second period is inferred from the
higher respiratory quotient. Coupled with the difficulty just mentioned
is the natural reluctance of the physician to give the newborn a large
feeding. In fact, it is quite possible that the stomach of the child at
this time cannot contain enough food at a single filling to raise the metab*
olism sensibly.
We are equally without convincing evidence that external temperature
acting independently can influence metabolism in the newborn. Scherer
reported a difference of 23 per cent in oxygen absorption by the infant
between what he called summer temperature (16 to 26.8° C.) and winter
temperature (9.5 to 16.2° C.). But there was no control of muscular ac-
tivity, or even notes regarding crying. Hasselbalch conducted his ex-
periments at an average temperature of about 33° C. ; Bailey and Murlin
maintained a temperature of 27° to 29° C. ; while Benedict and.Talbot
kept their chamber air at approximately 20° C. Hasselbalch is deeply im-
pressed with the fact that his newborn infants (most of them only a few
hours from birth) produced only 270 c.c. of carbon dioxid per kilogram and
hour and that "this is not essentially higher than the corresponding figure
for a grown individual in absolute repose." From the connection in which
the author alludes to this comparison one might infer that the low metab-
olism which he mentions was due to the absence of all "chemical regula-
tion" since the temperature was "so regulated that the question of the
feeble heat regulation of the infant is eliminated as far as possible." Re-
sults even lower than this, however, may be seen in several instances
amongst the data reported in the more recent publications, notwithstand-
639
ing the lower temperatures employed. A careful scrutiny of the several
tables has failed to reveal any relationship between external temperature
and the metabolism recorded. Doubtless the infants in the several series
of observations were wrapped in different quantities of clothing and bed-
ding necessary to maintain an environmental temperature high enough
to induce quiet sleep which was always the aim. Since the notes with
reference to this precaution are not very complete, it will be necessary
to give special attention to clothing before any final judgment as to the
influence of external temperature can be rendered.
In conclusion of this discussion of the factors which may influence
heat production in the newborn, emphasis should be placed once more upon
the fact attested by several observers that crying is the only normal form
of activity which can materially raise the metabolism above the basal level.
In the words of our Danish colleague, "as regards the amount of tho
metabolism, ... it seems impossible for me to conclude anything else
from the tables than that the activity of the infant is the chief determining
factor." Hasselbalch goes on to say that even the influence of age has not
been demonstrated (in the newborn). While sanction cannot be given
to this statement since the publication of Benedict and Talbot's results
(see page 635), emphatic assent can be given to his estimate of the mus-
cular factor. The newborn does not shiver. He responds, however, to a
drop in external temperature, as he does to hunger, very promptly, by cry-
ing, and since this form of exercise is almost his only resort, it serves at
once the double purpose of restoring the heat production to an equality
with heat loss and of calling the attention of his nurse to his unhappy
plight. The importance of conserving the energy resources of the new-
born infant by keeping him warm, especially before his natural food is
forthcoming, is obvious.
7. Total Energy Requirement of the Newborn. — Thus far we have
considered the basal metabolism — i. e., the metabolism of the sleeping
infant — and have learned that body weight is nearly, if not quite, as
good a measure as body surface, and that length of body (stature) com-
bined with surface (or weight) gives possibly the best measure now avail-
able. The newborn up to one week of age requires for maintenance while
asleep 1.87 calories per kilogram and hour or about 25 calories per
square meter of body surface (Meeh). On the 24 hour basis this becomes
45 calories per kilogram or 600 calories per square meter of body surface.
The formula of Benedict and Talbot(6)(L X 12.65 X 10.3 \/(w)2), i. e.,
length in centimeters times a constant times the body surface, as given by
Lissauer's formula, is a slightly closer approximation to the average needs.
There is a normal variation from this standard of 6 per cent, due to fac-
tors (possibly endocrine index) not yet understood.
For the time during which the infant is awake and crying, the require-
ment, as nearly as it can be estimated to-day, is from 30 to 40 per cent
640 JOHN E. MUKLIN
higher. Since, however, the period of crying continues for the normal
newborn rarely more than a few hours at most, the additional allowance
of food energy should not be computed on a 24-hour basis, but an attempt
should be made to estimate the total period of crying.
The energy allowance for growth cannot yet be estimated with any
accuracy. In general it may be stated only that any energy left over
after the basal and activity metabolism are provided for will be available
for growth, since, so far as we can see at present, no allowance is necessary
for dynamic action or for fluctuations of external temperature.
It would appear from the foregoing that an energy supply of 2.5 cal-
ories per kilogram per hour or 60 calories per kilogram and 24 hours,
will amply cover the maintenance requirement of newborn infants who
are not more than normally active. Any intake beyond this amount may,
it is presumed, be counted upon to furnish materials for growth. Further
study of the ."growth quota" in infants of this age, however, is very much
needed.
G. Energy Metabolism from Two Weeks
to One Year of Age
The energy metabolism of infants over two weeks of age has been
much more extensively studied. Beginning with the fragmentary ob-
servations of Forster in 1877 down to and including 1920, not less than
a score of important researches have been published on the normal child.
(Birk and Edelstein, Howland(6), Rubner and Heubner(a, b, c,\
Schlossmann and Murschauser (a,li,c,d}, Bahrdt and Edelstein, Frank
and Wolff, Murlin and Hoobler, Niemann(o, c), Bonniot, Saint-Albin,
Variot and Lavialle, Hoobler(&)). These fall into two groups according
to the method of observation adopted. The earlier researches by the in-
direct method were made for the most part upon a few individuals, but
these were studied very exhaustively with a view to account for all of the
food ingested. The later researches by the indirect method and all the ob-
servations upon normal infants by the direct method have sought rather to
establish standards of metabolism with which abnormal or pathological
cases could be compared. Consequently a considerable number of sub-
jects have usually been employed. Several of the investigators have se-
lected from their own cases those whom they consider normal. In the
case of some others it has been necessary to select from the published tables
whom the authors describe as of normal weight for age.
1. Respiratory Quotient. — Very little need be added to what was said
under this heading for the newborn. Carbohydrate is the food which in-
fluences the quotient most. Soon after a feeding of milk, whether breast
or cow's milk, the quotient will be found higher than just before, provided
the feedings are, two hours or more apart, and if easily assimilable sugars
are added to the milk the quotient will be even higher. For example, an
infant four months of age was given a dextri maltose formula and the
respiration experiments were begun on different days at successively longer
intervals from feeding with the following results:
Time After Feeding
18 minutes
1 hour 30 minutes
n go
'
From this point the quotient usually falls progressively (see page
631). Benedict and Talbot's (a, b] data show many cases like the fol-
lowing :
Case
Time After Feeding
R. Q.
F. B
6 to 7V> hours
(\ on
R. E
20 to 22
25 to 27
6 to 8 '
0.78
0.73
n R?
18y2 to 21 '
24 to 26i/2 «
u.74
0.72
Schlossmann and Murschauser ( d) , however, often found quotients as high
as 0.84 and 0.85 as much as 18 to 20 hours after last food. No details re-
garding the composition of the food taken at the last feeding are given.
The fact that the respiratory quotient is higher soon after a meal
(and progressively falls from a point which may be placed at 1 to 2l/2
hours thereafter depending on the formula) does not denote accelerated heat
production, for it will be remembered that carbon dioxid has a lower heat
value when the quotient is high than when it is low (see page 567).
Another reason why an ordinary feeding of milk does not raise the
heat production in an infant is the interesting fact first recognized by
Rubner that protein retained for growth does not raise the heat produc-
tion. In truth one can say that any foodstuff retained for growth does
not raise the heat production. It is only when a surplussage of digestive
products enter the circulation that oxidation of them is accelerated by
adding more fuel to the fire or by stimulating the intracellular processes.
In the infant or any other stage of active growth (pregnancy or convales-
cence) the materials entering the circulation are retained with greater
avidity by the cells and therefore are not exposed to the destructive oxida-
tions to the same extent as in the normal adult. Hoobler(&) has made
this point as regards protein an object of special study in an infant, with
the following results :
Protein In-
gested, Gms.
Protein De-
stroyed, Gms.
Protein Added
to Body, Gms.
Calories of
Metabolism
Period I
33.1
18.0
15.1
363
Period II
43.3
18.9
24.4
363
642 JOHN R MUELIN
2. Basal Metabolism. — Three different observers have attempted to
secure the metabolism of the infant while fasting. Rubner and Heubner
compared the metabolism of a breast-fed infant 5^ months old and
weighing nearly ten kilos while on a full diet four days with his metabol-
ism on the fifth day when he received only tea instead of the breast
milk. The metabolism on the day of starvation was even higher than the
average of four days on food.
Two objections may be urged against this experiment: First, that
no graphic record was obtained to prove that the infant was just as quiet on
the starvation as on the food days. It is almost unbelievable that such
should be the case. The second objection is that caffein is known to in-
crease metabolism and there is every reason to believe that the closely
related thein might have a similar effect especially upon an unhabituated
infant. Howland(&) tried an experiment in fasting in much the same way
with an infant three months of age, and weighing 4.65 kgm., giving tea
and saccharin instead of ^ milk and 5 per cent milk sugar which had
been the regular food. The result was the same : namely, that the metabo-
lism was not quite as low even when the child was known to be asleep as
while sleeping after a feeding. The first objection urged against Rubner
and Huebner's experiment would not, therefore, seem to apply, although a
graphic record giving proof that sleep while fasting was just as peaceful
as after feeding would be required to make the matter wholly convincing.
The second objection has not been removed. Schlossmann and Mur-
schauser(a) kept careful and continuous notation of the repose of their in-
fants, and determined the metabolism repeatedly on the three different
female infants from 87 to 180 days of age 18 hours after last food. All
received tea and saccharin which the authors used habitually to soothe
their subjects to sleep. The average minimal metabolism of the three
was 12.22 gm. CO2 and 11.02 gin. O2 per square meter (Meeh) of body
surface per hour, or 859 calories per square meter and 24 hours.
It will be apparent from this recital that the whole question of basal
metabolism is complicated on the one hand by the difficulty of securing
perfect repose without any immediately preceding meal and on the other
hand by the question of age. None of the researches yet reported have
fulfilled in a wholly convincing manner the conditions now recognized as
necessary to secure the absolute basal metabolism of infants. We must
be content for the present, therefore, to speak of the lowest metabolism
obtainable under the various circumstances as the "minimal metabolism."
As landmarks of progress in this direction, the brief table on page 643 may
be borne in mind.
It is somewhat hazardous to compare the results of different authors
obtained on different subjects by methods which are not strictly alike; but
the results suggest, if they do not prove, that the stage of digestion as well
as the age of the infant is a factor which must be reckoned with in at-
NORMAL PROCESSES OF ENERGY METABOLISM 643
tempting to arrive at truly basal conditions. The environing temperature
was different in the groups of cases cited, but the fact that quiet sleep was
TABLE 30
AVERAGE MINIMAL METABOLISM OF NORMAL INFANTS
(All sleeping or nearly quiet)
Authors
Condition
Cases
Averaged
Age, Months
Calories per
3q. M. (Meeh)
ind 24 Hours
Schlossmann and Mur-
schauser ( a )
Fasting 18
hrs
3 (S, P, L)
3-6
859
Benedict and Talbot(a) ....
Post-*
Absorptive ( ? )
6 (E.F., E.R.,
A.S., R.A.,
N.D., B.F.)
2-3
809
Murlin and Hoobler
V> to 3 hra.
4 (A.S., W.I.,
2-3
843
after feeding
E.H., E.N.)
Benedict and Talbot (a) ....
Post-
Absorptive
2 (E.G., P.S.)
10 and 12
983
Murlin and Hoobler
Vi to 5 hrs.
2 (C.M., W.S.)
l01/> and 12
1104
after feeding
* No details given by authors for three of these infants.
/
induced may be accepted as proof that the clothing was properly adapted
to the temperature of the chamber.
We pass now to a consideration of the two factors just mentioned:
namely, (1) the dynamic action of food, and (2) the influence of age upon
the metabolism.
3. Dynamic Action of Foods in Infants. — It will be seen later that
the average energy metabolism of the sleeping infant from two months
to one year of age is about 2^ times that of the adult on the basis of
weight. This means that the alimentary tract of the infant must be at
least two and one-half times as active as that of the adult in order to
supply to the circulation the materials necessary for combustion. Added
to this is the requirement for growth. It might be expected a priori, there-
fore, that the proportionately more rapid streaming of materials into
the blood (see page G05) would sot up a greater dynamic effect in the in-
fant than in the adult. The evidence to date, however, is that the reverse
is true.
Rubner and Heubner(6) were of the opinion that they had demon-
strated a dynamic effect of cow's milk when they found in their second
study a higher heat production in an artificially-fed infant of T1/^ months
than in their first breast-fed infant of nine weeks. Using the latter as a
basal experiment, they calculated that a diet of cow's milk containing 44
per cent more than the maintenance requirement of energy had raised the
metabolism in the former 9.7 per cent The difference in the ages of
the two infants together with the absence of certainty that the second
644
JOHN E. MUKLIN
infant was not more active than the first wholly invalidates their con-
clusions.
The dynamic effect of protein in the metabolism of an infant was first
proved by Rowland (&). Adding 4 grams of nutrose (containing 14.25
per cent nitrogen) to each of three previous feedings increased the metab-
olism of his first subject, three months of age, 10 per cent. Adding 30
grams to the food of his second child of 7 months raised the metabolism
26 per cent
TABLE 31
DYNAMIC EFFECT OF PROTEIN (Howland)
Date
Weight
Food
Calories per Hour
1911
Feb 23
4.32
% Cow's Milk, 5% Milk
15.35 Sleeping entire time
Feb. 25
4.32
Sugar
Same, + 30 gm. Nutrose
19.31 " " "
Difference
3.96 Cal. or 26%
Murlin and Hoobler saw a similar effect from changing to a richer protein
formula the diet of an atrophic infant three months of age. The
nitrogen in the urine rose in response to the greater intake of protein
and the heat production was increased more than two calories per hour.
The child slept throughout, but made more frequent readjustment move-
ments after the high protein feeding. Hoobler (&) followed up this sub-
ject independently and demonstrated a much higher metabolism by feed-
ing progressively higher and higher protein formulas. The following
comparison of the periods on low and on high protein diets summarizes
his results on a single subject.
TABLE 32
DYNAMIC EFFECT OF PROTEIN (Hoobler)
No. of
Hrs.
Food
Degree of
Repose
Distribution of
Calories
Calories Produced
Increast
Per Ceni
25.4
Per Hr.
Per Sq. M.
24 Hrs.
5
10
Low Prot.
High Prot.
Sleeping
Sleeping
P, 12.2%; F,
26.4%; CH,
61.4%
P, 40.2%; F,
18.1%; CH,
41.1%
10.78
12.74
893
1120
The highest dynamic effect of milk protein ever recorded was obtained
on this child on the twelfth day of the special feedings when the amount of
protein (in the form of albumin-milk) in the 24 hours food was 43.3 grams
compared with 9.9 grams in the basal diet. The dynamic effect in ab-
solute terms was 108 calories for the 24 hours, or 42.4 per cent!
The dynamic action of fat seems to be proved by the following obser-
vations made by Xiemann(a) on a normal, though at the time underweight,
NORMAL PROCESSES OF ENERGY METABOLISM 645
child four weeks of age. In one period of four days when the food con-
tained 127 calories from protein, 105 from fat, and 168 from carbohy-
drate, or 400 calories in all, the average daily metabolism was 521 cal-
ories or 1337 calories per square meter of body surface (Meeh). In the
following period of five days the food contained 145 calories from pro-
tein, 368 from fat and 177 from carbohydrate or 629 calories in all. The
heat production averaged 569 calories per day or 1443 calories per square
meter. An increase of 70 per cent in the energy intake (largely fat) in-
creased the metabolism 10 per cent. Niemann observed a similar effect of
increasing the fat in
the food of an atrophic
infant 22 weeks old.
H e 1 1 e s o n(6) deter- •
mined the resting me-
tabolism of a normal
infant five months old
and found that when
a part of the carbo-
hydrate of the diet
was replaced by an
isodynamic amount of
fat the heat produc-
tion was increased 8.3
per cent. Schloss-
mann made a similar
substitution in kind
though not in amount
and observed an in-
crease in the metab-
olism of fifteen per
cent.
The writer is not
Kgs.
Q
O
O
u_
Z
0
2
10
9
^
^
8
^
^
I
j5c(
6
<*
&
B
,
Gals.
'9004
8003
700
600
500
400
300
200
100
0
C
Fig.
/
'
/I
^0**
W
*z
*
^s
<?
S
0*
.^r".
r\
s*
--"
//
'
'*
OS
..
5
SJct
***•'
/<
t
-'wl\>&
i\>
I — **
£tf
fr
.X
j^-'
^
C
^
U
w
rs
'^
1^"
V5
^
oxl 2 3 4 5 6 7 8 9 10 II 12
37. Metabolism During First Year of Life
(Talbot).
of
any
aware
ment establishing
experi-
the dynamic action of carbohydrate in infants.
The evidence of dynamic action thus far applies only to surplus food.
There is no satisfactory evidence that an ordinary feeding given at the
time when the infant is naturally ready for it raises the metabolism at
all. In the first place the difficulty of securing perfect repose when the
infant is hungry has thus far foiled all efforts to get a clean-cut contrast
before and after an ordinary feeding. Although Schlossman states in one
place that the effect of a meal may be discerned as long as 18 hours after-
ward, yet as already noted (page 642) neither Schlossman and Mur-
schauser nor Rubner and Heubner nor Rowland were able to demonstrate
a lower metabolism in fasting. Benedict and Talbot likewise assert that
646
JOHN E. MUELIN
in some instances the heat production (based on carbon dioxid) in their
subjects twenty-one hours after food was slightly "greater even in periods
of complete muscular repose" than immediately after food.
4. Influence of Age on Basal Metabolism. — Basal metabolism is the
term used to describe the fundamental requirements of the body for energy
when it is resting, fasting, and kept comfortably warm. It is the lowest
normal metabolism. With the infant this lowest metabolism will always
occur during sleep and at that distance from feeding time just preceding
the point where hunger becomes so acute as to induce crying or some other
form of activity.
In connection with the dynamic action of food we have chosen to
speak of the lowest metabolism yet attained as the minimal rather than the
basal metabolism ; for we have yet to learn of the details of this subject.
However, the minimal metabolism ordinarily seen in the infant, i. e., the
sleeping metabolism of the recently fed infant, cannot be much greater than
the basal metabolism if food really exercises so small an influence on total
heat production as it seems to. We shall not go far wrong then in speak-
ing of the minimal metabolism observed in infants of different ages as
the true basal.
Benedict and Talbot first demonstrated the influence of age on the
basal metabolism per unit of area, although not recognizing the fact, in
the following table:
TABLE 33
HEAT-PRODUCTION PER SQUARE METER OF BODY-SURFACE (Meeh Formula) FOR NORMAL
INFANTS
Body-
Heat per Sq.
Subject
Weight
Without
Clothing,
Height,
Cm.
Age .
Experi-
mental Days
Periods
Meter of
Body-Sur-
face (Meeh)
Kg.
Cals.
M. D
3.99
17 davs
2
4
656
L. L
5.13
57
21/> mos.
10
13
759
B. D
4.90
58
2 mos.
2
4
802
M. C
6.17
63
4 mos.
3
7
837
L. R. B. ...
5.99
64
4 mos.
4
11
844
E. G
9.37
74
10 mos.
3
5
907
R. L
7.58
71
S^A mos.
5
8
991
P. W
7.11
64
7 mos.
2
5
998
The next year Murlin and Hoobler brought together their own data
from normal infants and those of Benedict and Talbot published in their
second paper and conclusively showed that both on the basis of surface
area and weight the metabolism of infants above six months of age is sig-
nificantly higher than that of infants four months and less. The results
are condensed in the following table :
NORMAL PROCESSES OF ENERGY METABOLISM 647
TABLE 34
BASAL HEAT PRODUCTION- FROM Two MONTHS TO ONE YEAR OF AGE
Months
2
3
4
6
7
9
ion
10
Cal. per Sq. M. and Hr. (Meeh)
Cal. per Kgm. per Hr
34.7
2.43
33.2
2.29
36.0
24
40.2
2 56
41.6
2 57
41.7
2 36
41.8
o 94.
46.4
9 ftl
H. Energy Metabolism of Children
up to Puberty
Logically, as we now see very clearly, everything starts from the mini-
mal or mere maintenance requirement, although historically the order
has been quite different. The latest and in many respects the most com-
plete researches have been made upon the basal metabolism. It is proper,
however, to see how much had been learned regarding the basal needs
from earlier investigations.
The Zuntz school headed by the late N. Zuntz of Berlin had long
emphasized the necessity of eliminating the influence of muscular activity
and of food if results upon subjects of different size or age were to be com-
pared. Magnus-Levy and Falk, followers of Zuntz, employing the well-
known method of Zuntz and Geppert with which important results had been
obtained on the influence of muscular work in mountain climbing, in
marching, and in the treadmill, on the influence of altitude and on the
influence of digestion, undertook in 1899 an investigation on the influ-
ence of age on the basal metabolism. The subjects ranged from 2^>
years to old age, including eleven boys and nine girls under fourteen
years of age. At the time of observation the subjects were all in the
niichtern condition, which is Zuntz's term for the absence of digestion, i. e.,
at least twelve hours since taking food, or, what has been called by others,
the "post-absorptive state." The subject lay upon a couch and suppressed
all muscular contractions. The Zuntz method as described on page 539
permits of the determination of oxygen absorbed as well as of C02 elimi-
nated.
The results upon the group of children mentioned above are presented
in Table 35. The respiratory quotient characteristic of the nurhtern
condition in children is well illustrated in this table. The average is
0.82 for boys and 0.84 for girls. With adults the quotient is quite
commonly several points higher for the reason that adults do not consume
their store of glycogen quite so rapidly. This is in accord with the well
known fact that fasting is much more exhausting for children than for
adults. The capacity to handle carbohydrates in the diet is the basis
of the craving for sweets among children. The arrangement in Table
35, following that of the authors themselves, is according to weight rather
than age. It is apparent at once that the metabolism in both sex groups
648
JOHN R. MTJRLIN
TABLE 35
THE GASEOUS EXCHANGE OF CHILDREN* (Magnus-Levy and Falk)
Age,
Y?s.
Weight,
Kgm.
Height,
Cm.
02 Consumed
R. Q.
Cal. per Sq.
M. and Hr.
Per Kgm.
and Hr.,
c.c.
Per Sq. M.
and Hr.
(Meeh) liters
2l/2
11.5
|
585
10.74
0.83
51.9
6
14.5
110.0
552
10.92
0.80
52.4
6
18.4
110.0
457
9.78
0.80
46.9
7
19.2
112.0
476
10.32
0.85
50.2
7
20.8
110.0
478
10.68
0.83
51.6
9
21.8
115.0
407
9.24
0.85
44.9
11
26.5
129.0
374
8.22
0.80
39.4
10
30.6 .
131.0
377
8.52
0.84
41.3
14
36.1
142.0
313
8.40
0.84
40.7
14
36.8
141.5
301
8.10
0.84
39.3
14
43.0
149.0
308
8.76
0.81
42.1
GIRLS
7
15.3
107.0
490
9.90
0.81
47.6
6%
18.2
?
445
9.48
0.81
45.6
12
24.0
129,0
338
7.92
0.92
39.2
12
25.2
128.0
322
7.68
0.84
37.2
13
31.0
138.0
332
8.46
0.89
41.6
14
35.5
143.0
317
8.46
0.82
40.8
12
40.2
?
295
8.22
0.78
39.2
11
42.0
149.0
301
8.52
0.81
41.0
* This table is reconstructed in part from a table given by Tigerstedt in NagePs
"Handbuch der Physiologic," 1909, I, p. 475, and in part from a table in Magnus-Levy's
"Physiology of Metabolism," Van Noorden's Handbuch, English ed., Vol. I, p. 268.
decreases as age and weight increase, whether it is estimated on the
basis of a unit of weight or a unit of surface. Comparing the basal
metabolism of a boy and a girl, on the basis of the oxygen absorption,
with adults of middle age, and of old age having approximately the same
body weight the following result was obtained.
TABLE 36
GASEOUS EXCHANGE AT DIFFERENT AGES (Magnus-Levy and Falk)
Absolute
Relative
Amount of
Age
Weight,
Kg.
Height,
Cm.
Amount
of O2
Per Kg.
oa
per Kilo.
O2 per
Sq. M. Sur-
face
Girl
13
31.0
138
171.7
5.54
112
111
Woman
49
31.6
134
156.6
4.96
100
100
Old Woman . .
Bov .
75
15
30.3 circ
437
i 140(?)
152
128.6
216 6
4.25
4 97
86
110
84
100
Man
24
432
148
195.8
4.53
100
100
Old Man
71
47 8
164
1632
3 42
75
78
Cals
1100
950
87554
80048
Cals
670
K9!
610180
550165
430 13 5
370 12.0
310
PULSE
100
50
490 150
OE/
9.0
4.5
T
r
s
-No145(F.)-
CALORI S PER SO
M./\
\
CALORIES P R KILO.
^ "STOTAL CALORIES
NOEMAL PEOCESSES OF ENEEGY METABOLISM 649
They conclude that children produce more heat not merely for the
reason that their superficial area is greater in relation to their weight
but more also on account of the increased vital energy characteristic of
youth.
Sonden and Tigerstedt in the course of an extensive investigation on
the metabolism of children sitting quietly as in school, which will be prev
sented later, obtained results on two boys 11.2 and 12 years of age re-
spectively while sleeping. They found the CO2 elimination on the basis of
surface area (Meeh) 52
per cent higher than that
of adults in sleep. While
the conditions of these
experiments did not ex-
clude the influence of
food altogether, they ap-
proached the true basal
conditions very closely
and furnished early evi-
dence of a variation di-
rectly caused by a differ-
ence in age. The con-
clusion of these authors
agrees with that of Mag-
nus-Levy and Falk that
the youthful body in and
of itself independently of
its smaller size possesses
a more active metab-
olism.
1. Basal Metabolism
of Children up to Pu-
berty.— Among the sub-
jects studied at intervals
over a long period of time
by Benedict and Talbot(c) was a girl, designated in their series as No.
145, whose record extends from the age of five months to the age of three
years and five months. In all she was placed in the respiration chamber
on thirty-one different days and the observational periods of approximately
30 minutes each numbered 4 to 5 daily. The minimal metabolism is
given for 25 different days and the accompanying chart represents 19
distinct points in the course of the three years (Fig. 38).
The most rapid growth (as would be expected) is seen in the first half
of the time, namely from the 5th to the 21st month. During this time the
basal metabolism, calculated to 24 hours (called "total calories" in the
BODY WEIGHT
Mos.3 6 9 12 15 18 21 24 27 30 33 36 39 42
Fig. 38. Body-weight, pulse-rate and basal metab-
olism per 24 hours of a girl from 5 months to 41
months of age (Benedict and Talbot).
650
JOHN K. MURLIN
chart) rises nearly parallel with the growth in weight, after which the
metabolism rises less rapidly than the weight. It is evident from the curve
representing metabolism per unit of weight, however, that the parallelism
is only apparent and arises from the fact that metabolism and weight are
plotted to ordinates which are not strictly proportional; for the metab-
olism per kilogram falls from the beginning instead of running hori-
zontally. The level at five months is 60 calories per kilogram and at 24
months it has dropped to 38 calories. From this point onward the
curve is horizontal indicating that the progress in growth is equal to the
progress in basal heat production. Charted on the basis of a unit of body
TOTAL CALORIES REFERRED TO WEIGHT.
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
SOJ
Kf
^—
^
•**~~
>"
•^
^
*•"
;x
,s~
^<
XT
^
•••;
S
; /
/.
;••/
/•'
• /
jt«
/
/
20 22 24 26 28 30 32 34 36 38 40 42
Fig. 39. Basal heat production of boys from birth to puberty. Total calories per 24
hours referred to weight (Benedict and Talbot).
surface (DuBois' linear formula) the general trend again is downward —
from 1086 calories at 5 months to 841 at 24 months from which time it
rises to nearly 900 calories per square meter at 41 months. Figure 39
gives the progress of the basal metabolism in relation to weight for boys and
Fig. 40 the same for girls for the entire series of children studied. The
continuous line represents the average ; dots individual cases. In the
first of these charts it may be seen that the basal metabolism in boys as
determined by the most recent observations runs from a little less than 100
calories daily at 2 kilos body weight to 1325 calories at 42 kilos or
from about 45 to about 31 calories per kilogram. With girls the curve
starts at a slightly lower level at 2 kilos and rises to 1100 calories
daily at 32 kilos, or from about 40 to about 34 calories per kilo-
gram. The values obtained by Benedict and Talbot are lower than
those obtained by any previous observers except Olin. Curves of the same
Cats.
1500
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
TOTAL CALORIES REFERRED TO WEIGHT. GIRLS.
•
ff.-*f
_...
.--•"
'^
^
^
s*
^>
^
^
>r-
•
tv
'.•
• /
X"
•
./
/•
•
•/
{;
,
/:
/'
2 >g». 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Fig. 40. Basal heat production of girls from birth to puberty. Total calories per 24
hours referred to body weight (Benedict and Talbot).
Cals
1700
ieoo
1500
1400
1300
1200
1100
1000
900
bOO
700
600
500
400
300
200
100
0
.2
TOTAL CALORIES REFERRED TO SURFACE. BOYS
0
0
•
0
J
/
[
/
" >
X,
/
•/
S
/
'
•y
y •
V
z
o-DL
BOU
BOli
(191f
>(191
)
X
^.
o-Dl
3)
/'
_
sqm.
3 .4 .5 -(
\ .7 .8 9 1.0 11 1.2 1-3 14 i.O r.c
Fig. 41. Basal heat production of boys from birth to puberty. Total calories per 24
hours referred to surface area (Benedict and Talbot).
651
652
JOHN R. MURLIN
Cals. TOTAL CALORIES REFERRED TO SURFACE. GIRLS.
general character are obtained when the total basal heat production cal-
culated to 24 hours is referred to the body surface (Figs. 41 and 42).
The surface area in these observations was calculated from numerous ac-
tual measurements according to DuBois linear formula, and a revision
of the formula of Lissauer is proposed by derivation of the con-
stant, with which the two-thirds power of the weight should be
affected, from the surface as measured. The authors find a slightly closer
agreement upon this basis
than upon the basis of
weight, but persist in their
belief that there is no causal
relationship between body
surface and heat production.
This topic has been suffi-
ciently discussed at p. 598
and it may only be reiterated
here, that the vastly better
agreement between basal heat
production and body surface
than between this physio-
logical character and body
weight, as between individ-
uals of the same species but
of widely different size, re-
mains as a challenge to dis-
believers. The factor of age
must be taken into account
as now is definitely estab-
lished by the work of the
several authors described
above.
Benedict and Talbot(c)
find wide variations from their mean curves — from 20 to 64 calories per
kilogram and 24 hours for boys and an even wider range for girls ; from
650 to 1275 calories per square meter (DuBois linear formula and
Lissauer formula modified) per 24 hours for boys, and from 600 to 1350
for girls. The widest variation on both bases for any single age falls in
the latter half of the first year, being over 60 per cent for boys and over
65 per cent for girls on the basis of weight ; and in the neighborhood of
50 per cent for both sexes on the basis of surface. The variability upon,
the basis of surface is noticeably less than upon the basis of weight for
other ages also.
2. Influence of Sex on Basal Metabolism. — Signs of sex difference in
metabolism appear in the very early work of Andral and Gavarret and
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
3.
.
/
/
f
"/
/
\/'
/ *
S
^
'/•
•
•
• /
X:
* «
1. ''/
7'
. •
'/
•
£
i
-/.
£
sq. m..3 .4 .5 .6 .7 .8 .9 1.0 11 12 U
Fig. 42. Basal heat production of girls
from birth to puberty, total calories per 24
hours referred to surface area (Benedict and
Talbot).
NORMAL PROCESSES OF ENERGY METABOLISM 653
of Scharling; but it is not until the classic investigation of Sonden and
Tigerstedt that definite proof is furnished. While the conditions of ex-
perimentation were not those recognized to-day as essential to demon-
strate a basal difference, the authors are very positive in their opinion that
under like conditions in the young the CO2 output both per kilogram of
weight and per square meter of surface (Meeh) is considerably greater in
males than in females (see page 656). The average difference for their
age series (see below, Table 38) is as 140 : 100, "This difference appears
to vanish gradually with increasing age until in old age it disappears
completely."
DuBois(a) first drew attention to a probable difference of actual basal
Cats.
1500
J300
1100
900
700
500
300
.100
TOTAL CALORIES REFERRED TO WEIGHT.
^
-^
>^"
***
''/
^
/£
,,'*,,
^
/
s
JS
^
BO
ys
A
V
GIF
LS
/
2kgs. 6
10
14
18
22
26 30 34 38 42
Fig. 43. Comparison of basal heat production of boys and girls per 24 hours referred
to body-weight (Benedict and Talbot).
metabolism between the sexes in children (Fig. 35, p. 613) upon the basis
of the observations of Magnus-Levy and Falk, who did not themselves rec-
ognize such a difference. Its demonstration, however, is due to Benedict
and Talbot (c). They find that the absence of a sexual difference for the
very young infant (p. 635), "persists until about the weight of 11 kgm.,
but that frequently there is a tendency for the boys to have a somewhat
higher metabolism (average) than girls of the same weight" (Fig. 43).
On the basis of surface they find that the two sexes remain at, essentially
the same metabolism (average) until the surface reaches 0.48 sq. M.
(DuBois). "From this point the line for the boys rises above that for
girls and there is no evidence of a tendency for the two lines to cross
later."
654 JOHN R. MURKEST
a. Influence of Puberty. — Andral and Gavarret maintained that with
boys the carbon dioxid output suddenly increased at the age of puberty,
while with girls it just as suddenly ceased to increase at this critical point.
Sonden and Tigerstedt give the following comparison of the total CO2
output for different age .groups using that of a man 57 years of age as 100.
9-12 years 98
13-19 " 126
22-25 " Ill
34-44 " 105
The combustion in the body of male individuals from 13 to 19 years
of age is therefore greater than that of younger or older individuals of
the same sex. This coincides with the period of most rapid growth in
length (15th year) and the most rapid growth in weight (16th year).
In a remarkable series of observations on 200 boys ranging from 9
to 19 years of age Olin(a) thought she had found, in agreement with
Sonden and Tigerstedt, that the CO2 output whether as total elimination
or on the basis of body surface shows a distinct elevation for the age of
puberty (14-16) above the general trend of the metabolism for the entire
group. Her table given on p. 655, however, does not appear to bear out
this conclusion.
The first work carried out on the same youths just before and just after
the attainment of sexual maturity was that of Olmstead, Barr and DuBois.
Eight normal boys were studied in the respiration calorimeter when they
were twelve and thirteen years of age and again two years later when they
fourteen and fifteen years of age. On both occasions the boys were placed
in the respiration chamber four or five hours after a very light breakfast,
which has been shown with adults to leave the basal metabolism unaffected,
and were observed for two or three consecutive hourly periods while lying
quietly, but for the most part awake. In the first series of observations
the basal metabolism was found to be 25 per cent higher than the adult
level per unit of surface (linear formula), while in the second after
puberty had been definitely established in four of the eight subjects the
metabolism was on the average only 11 per cent higher than the adult level.
Benedict and Talbot very properly criticise these observations as failing
to establish definitely by a sufficient number of observations the true basal,
and point out that if the quieter periods of the first series be selected the
metabolism is very close to that found in the second series. It might be
urged further that there were at the time of DuBois' observations scarcely
a sufficient number of basal experiments in the literature at ages preceding
and following the ages of his subjects to warrant the inference of a distinct
rise in metabolism of the prepubescent age above that of adjacent ages.
Benedict and Talbot in a few scattered observations on boys and girls of
prepubescent age find no such increase but they admit that their experi-
ments are not yet sufficient in number to warrant a definite conclusion.
3. The Influence of Muscular Activity in Children. — The extensive
FORMAL PEOCESSES OF ENERGY METABOLISM 655
observations of Sonden and Tigerstedt at Stockholm, of Rubner(^) at Ber-
lin and of v. Willebrand at Helsingfors in contrast with the very low if not
actually minimal values obtained by Magnus-Levy and Falk at Berlin, by
lin at Helsingfors and by the Boston workers, furnish some very interest-
ng, though as yet very incomplete, data on the effects of moderate mus-
sular activity.
The resting and post-absorptive rate established by Magnus-Levy and
k have been discussed above and while the average line established by
em lies considerably above that of Benedict and Talbot, their results lie
rithin the range of variability given by the latter authors. So also do
those of Olin, notwithstanding that her subjects were studied in the sit-
ting position. They were placed in the apparatus individually, usually
in the morning after a light breakfast. The results are summarized in
the following table.
TABLE 37
METABOLISM OF BOYS SITTING VEEY STILL (Olin)
No. of
Subjects
Average Age
Average
Height
Bodj Surface
(Meeh)
sq. M.
C02 per
Kgm. and Hr.
Heat Produc-
tion per Sq.
M. and Hr.*
4
9
35.9
1.299
0.425
34.1 Cal.
15
10
31.4
1.217
0.505
37.9
14
11
36.1
1.327
0.492
39.3
27
12
38.1
1.396
0.372
37.5
26
13
43.1
1.573
0.452
35.7
22
14
49.6
1.726
0.425
35.3
19
15
52.9
1.805
0.412
35.3
18
16
59.2
1.948
0.399
35.0
9
17
55.4
1.864
0.385
33.5
M
18
65.6
2.086
0.359
32.8 '
* Assuming a R. Q. of 0.85 i. e., Heat-value of C02 of 5.721 Cal. per liter.
In calculating the surface area by Meeh's formula the constant 12.205
was used by Olin for boys under 13 and 12.847 for boys over that age.
The heat production in relation to surface area calculated by the writer
upon the assumption of a R. Q. of 0.85 are very close to those ordinarily
obtained upon adult subjects under the conditions usually accepted as
basal (see page 610). It has recently been shown that a person propped
up in a semi-reclining position may have a metabolism even lower than
when lying flat in bed. These results by Olin seem to signify that young
persons may be induced to sit quietly enough to exhibit a metabolism even
lower ( ?) than when lying down. It would seem that Olin's subjects
must have been supported in such a position as to require no muscular
tension and that, as in the semi-reclining position in a steamer chair, the
diminished pressure of the abdominal organs upon the diaphragm may
have lessened the muscular effort of breathing. The results should prob-
ably be regarded as representing truly basal conditions.
656
JOHN K. MUELIN
In strong contrast with these are the figures obtained by Sonden and
Tigerstedt upon groups of 6 boys and girls of approximately the same age.
The authors state that their purpose was to obtain data which would be
of value in determining the ventilation requirements of public assembly
halls and especially school rooms. Their subjects were required to sit as
still as they would in school, but were permitted to handle and read books
and at times to nibble candies and fruits. Their results follow :
TABLE 38
METABOLISM OF CHILDREN SITTING AS IN SCHOOL (Sonden and Tigerstedt)
Average Age
Average Weight
COj per Kgm.
and Hour
Calories per Sq.
M. (Meen) and
Hr.*
Years
Months
BOYS
7
10
20.1
1.149
73.1
9
7
27.5
1.207
83.1
10
6
30.2
1.106
78.6
11
5
31.6
1.063
76.7
12
6
34.1
0.997
72.1
13
10
44.5
1.000
75.0
14
6 '
45.3
0.960
74.2
GIRLS
7
10
21.8
1.133
74.1
9
11
26.6
0.850
57.8
11
2
31.0
0.845
60.6
12
2
36.2
0.743
56.1
13
4
39.5
0.696
51.4
14
0
44.3
0.661
50.7
15
2
48.6
0.562
44.5
* In view of the fact that the children of this series were permitted to eat candy
and fruit at times while in the respiration chamber a R. Q. of 0.90 is assumed,
i.e., the CO., is given a heat value of 5.471 Cals. per liter.
The heat production here is calculated upon the assumption of a R. Q.
of 0.90 employing the values for CO2 given by the authors upon the basis
of a square meter of surface. The results are nearly double those obtained
by Olin. Benedict and Talbot have calculated the heat production per
kilo and 24 hours of these subjects on the assumption of a R. Q. of 0.90
and these values are shown for comparison upon a chart (Fig. 44) pre-
pared by them to exhibit the basal metabolism according to several authors.
The average distance of the individual points designated as the "active
subjects of Sonden and Tigerstedt" above the continuous line representing
the average basal may be taken as approximating the activity metabolism
occasioned by sitting at a desk reading a book and making such minor
movements as a well-behaved child in school would make during study
periods. This amounts to fully 30 calories per kilogram and 24 hours.
Table 38 shows a very marked difference between boys and girls which is
NORMAL PROCESSES OF ENERGY METABOLISM 657
even greater than the difference in basal metabolism between boys and
girls (Fig. 43) of the same age. This is due to the greater degree of
composure readily induced in girls of the adolescent age.
Cals
68
64
60
56
52
48
44
40
36
32
28
24
\
CALORIES PER KILO. REFERRED TO AGE. BOYS.
*
P
K
*
1.
^
ft
*
7
\
'*
\
N
X.
.•
^^"
*--*
•^
0
^
\
^^
•
•
. '
-
-^
*->*,
4
a- SCHARLING
x- SONDEN AND T
GERJ
kND 1
TED'
•ALK
'
o - DU BOIS (1916)
o - DU BOIS (1918)
OBLE
""V.
• - 1
MGI<
US-L
EVY t
&- 1
/IURL
NAN
DHO
R
0
n. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Fig. 44. Basal heat production of boys from birth to puberty (continuous line
according to Benedict and Talbot I . x x x x Active cases of Sonden and Tigerstedt.
Total Calories per kilogram referred to age.
Sonden and Tigerstedt give the following values for two of their boys
during sleep :
Boy of 11 yrs. 3 mos. — 14.09 gm. CO2 per sq. M (Meeh) and hour.
" " 12 " —13.78 " " " " "
From which we may derive the following heat production on the assump-
tion of a R. Q. of 0.88:
Boy of 11 yrs. 3 mos. — 35.1 cal. per Sq. M. and Hr.
<< « 12 a _343 « « « « « «
Boys of the same age in school showed a heat production of fully twice as
much (Table 38).
Von Willebrand's observations were made upon boys from 9 to 14
years of age in the apparatus used by Olin. They were confined for the
entire 24 hours, taking all three meals in the apparatus. They went to
bed at 8 to 9 P. M. and rose in the morning about 6 o'clock. In some
instances the subjects slept for a short time during the day. The differ-
ence between waking and sleeping metabolism for four individuals is
shown in the following table somewhat modified from one given by
Benedict and Talbot (c).
658
JOHN R MUKLIN
TABLE 39
METABOLISM OF BOYS AWAKE AND SLEEPING (Von Willebrand)
Name
Age, Years
Body Weight,
"Kgm.
Cal. per Sq. ]
Awake
H.7 and hour
Asleep
Veikko
9
25.9
57.8
27.3
Viktor
10
30.8
49.0
22.0
Julius
13
34.1
47.6
249
Silo
14
36.5
38.9
20 4
7 Meeh's formula using 12.205 for 'the first two boys and 12.847 for the second two.
Heat is calculated from the CO2 assuming an R. Q. of 0.83.
Rubner's experiments were made upon two brothers, one fat and one
thin, the sons of parents of slender means and therefore not likely to be
overfed. They were confined for about 22 out of the 24 hours in the
respiration -chamber, ate and slept there and during waking hours were
permitted to move about, even walking some. The following summary of
the results are given by Lusk(Tt).
TABLE 40
METABOLISM OF A FAT AND THIN BOY (Rubner, after Lusk)
Age,
Years
Weight,
Kgm.
Heat Production
Per Sq. M.
24 Hrs.
(Meeh)
per Hr.
Total for
24 Hrs.
Total Kgm.
and 24 Hrs.
Fat boy
Thin boy
10
11
41
26
1786.1
1352.1
43.6
52.0
1321
1290
55.0
53.7
The last column may be compared with the results of v. Willebrand
(Table 39) and those of Souden and Tigerstedt (Table 38).
A most interesting phase of the activity metabolism in children, name-
ly, the muscular efficiency as compared with adults, has never been studied.
Nor has any attempt been made to estimate the actual energy expenditure
of an active child for the entire 24 hours. How much the values just given
for boys who were permitted to move about, to a limited extent in the
respiration chamber falls short of the actual daily requirements with its
large quota for growth may be gained from the following chart taken
fromLusk(/) (Fig. 45).
I. Energy Metabolism of Old Age
In modern times the energy metabolism of old age has been studied by
three sets of observers. Magnus-Levy and Falk studied by means of the
Zuntz-Geppert method five old men and seven old women. One of
their tables has been reproduced 011 page 648 where comparison is made
between the metabolism of a boy and a girl and of middle aged subjects
NORMAL PROCESSES OF ENERGY METABOLISM 659
of approximately the same body weight with two of their aged subjects.
Aub and DuBois determined the basal metabolism of six old men
between the ages of 75 and 85 years. The authors describe their subjects
as "in good condition and fairly well nourished, though 011 plain and some-
what scanty diets. Considering their ages, they were in good health,
though most of them suffered from arteriosclerosis, chronic interstitial
nephritis and emphysema, which 'normally' accompany advanced years."
5.0
347395 12 145 16 19 205 22 25 27 30 33 35 40 45 50 KG
82B 891 961 106 112 117 12? 127 133 137 142 148 155 160 CM.
CALS.
4.500
4,000
3,500
3.000
2,500
2.000
1,500
500
2 34 5 6 7 8 9 10 II \i 13 14 IJYRS.
2'95" 2'M" 32" 3' 6" 3'8' 3'IO" 4 4*2" 4'4" 4'6" 4'8 4'lO" 5'l" 5'3'fT.I.IN
751621 27 32 36 41 45 495545 60 67 72 80 88 99 III LBS.
Fig. 45. Metabolism in calories per day of boys from birth to 15 years of age.
(After Lusk.)
The average basal heat production was 35.1 calories per square meter
(linear formula) per hour, which is 12 per cent below the average for
men between the ages of 20 and 50. The respiratory quotients lay be-
tween 77 and 86, the average being 81. Since these subjects had been
on rather meager fare and were kept in the metabolism ward of BelleyuQ
Hospital for several days before the tests were made, the low metabolism
and rather low quotients are in part accounted for by these factors. How-
ever, since these conditions accord with the usual routine of life for sub-
jects of very advanced age the metabolism findings are such as would ordi-
narily obtain.
660
JOHN E. MURLIN
From the Nutrition Laboratory at Boston are available a few scat-
tered data on the basal metabolism of old people. For example, Benedict
(/) in a discussion of the factors affecting basal metabolism includes in
one of his tables one man 63 and one woman 74 years of age and notes
that a person "of advanced years has a still lower metabolism than the
person in middle life."
Magnus-Levy observes in explanation of the low metabolism of old age
that "the cells of the body lose their thermodynamic powers with old
age" and cites the older observations of Andral and Gavarret, Son-
den and Tigerstedt and his own work with Falk in support of
the view that an old man utilizes less food, not only because his output
of work is less, but also because his cells generate less heat during rest.
Whatever special causes may underlie the onset of senility physiological
old age can only be said to exist when the involution of the various organs
takes place gradually and at a proportional rate. In such changes is found
sufficient cause for the decreasing metabolism. How low the hour-glass
must run before the processes of oxidation must cease or what level
of heat production marks the ultra-minimum for the support of respira-
tion and circulation has not yet been disclosed. "And his days were
ended and he died, for he was old and weary of life."
SECTION VI
Bacterial Metabolism, Normal and Abnormal, Within
the Body Arthur Isaac Kendall
Introduction — The Significance of Bacterial Metabolism — Bacterial Metab-
olism—General Eelations Between Surface and Volume of Bacteria and
the General Energy Requirements of Bacteria — The Influence of Sap-
rophytism, and Pathogenism upon Bacterial Metabolism — Chemical Re-
quirements for Bacterial Development — The General Nature of the Prod-
ucts of Bacterial Gro.wth, Arising from the Utilization of Proteins and
of Carbohydrates for Energy — Toxin, Indol and Enzyme Formation —
The Specificity of Action of Pathogenic Bacteria and Its Relation to
Proteins and Carbohydrates — Quantitative Measures of Bacterial Metab-
olism, the Effects of Utilizable Carbohydrates upon General Metabolism,
and the Elementary Composition of the Bacterial Cell — The Chemistry of
Bacterial Metabolism— General Reactions: The Formation of Phenols,
Indol and Indican, Amins — Reactions Illustrative of the Decomposition
of Proteins by Bacteria— The Effects of Utilizable Carbohydrate upon
the Formation of Phenols, Indol and Amins — The Physiological Action
of the Aromatic Amins — Summary — Intestinal Bacteriology — General
History and Development — The Intestinal Bacteria of Normal Nurslings
—Adolescent and Adult Intestinal Bacteriology — Sour Milk Therapy and
Bacterial Metabolism — Exogenous Intestinal Infections — Summary and
Conclusions.
Bacterial Metabolism, Normal and
Abnormal, Within the Body
ARTHUR ISAAC KENDALL
A. Introduction: The Significance of
Bacterial Metabolism
That remarkable chapter in the history of the development of the
Science of Medicine which treats of the relations of microorganisms to
the causation of specific disease in man has exposed an entirely new and
extraordinarily fertile field for study and for speculation.
The first two decades of this era were greatly enriched by the isolation
and identification of microbes which were shown to be etiological agents
in some of the most formidable infections of mankind. The second decade
of this period also witnessed the beginnings of specific bacterial therapy.
The brilliant investigations of Von Behring, Kitasato, Roux, Yersin,
Smith and others, upon the soluble toxins of diphtheria and tetanus
bacilli, and the preparation of their specific antitoxins, seemed to prepare
the way for a universal antitoxic therapy which should be efficacious in all
disorders of microbic causation.1
Time has shown, however, that antitoxic therapy is limited to a very
few specific . diseases. The development of the field of Immunology by
Ehrlich, Metchnikoff, Bordet and their followers, and the elucidation of
the nature of the complex reciprocal relationships between host and para-
site, which comprise the phenomena of infection and of resistance to infec-
tion have shown the basis for antitoxic therapy very clearly, and the
limitations which surround it. These studies also indicate very definitely
that entirely new procedures must be established to combat those micro-
organisms for whose pernicious activities no antitoxins can be prepared.
The third decade of medical bacteriology has been endowed with
greatly improved methods of culture. These have led to the discovery of
many incitants of infection that had eluded the earlier attempts at isola-
tion. The rapid development of the Science of Serology, and the defini-
1Von Behring: Die Blutserum-therapie, Leipzig, 1892.
663
664 ARTHUR ISAAC KENDALL
tion of the limits surrounding the uses of vaccines for therapeutic pur-
poses, are also significant events of this decade. The preparation of
specific serums, begun in this period, represents as yet an immature phase
of bacteriotherapy, but it is a most promising field for further study.
Progress up to the present time in medical bacteriology, therefore, has
been chiefly along diagnostic lines, both with reference to the isolation and
identification of the etiological agents of specific microbic diseases, and
with reference to the recognition of serological reactions in infected indi-
viduals. Indeed, with the exception of those few bacteria to whose soluble
toxins specific antitoxins have been prepared, the advances in the ameli-
orative and curative aspects of medical bacteriology have been disappoint-
ingly limited. Yet this is the most important field of all.
It is quite apparent that a shifting of the point of attack must precede
further advances. Diagnostic, or morphologic, bacteriology must give
place to dynamic or chemical bacteriology. "It is what bacteria do rather
than what bacteria are that commands our attention, since our interest
centers in the host rather than the parasite," as Theobald Smith has so
aptly said. The application of biochemical methods to the elucidation of
conditions which surround the preparation of soluble toxins, and which,
therefore, permit of the generation of potent antitoxins is a striking
example of the correctness of this dynamic principle: Those same phe-
nomena which influence the formation of toxin in cultures of diphtheria
bacilli play a very important part in determining the nature of the
significant products formed by other pathogenic bacteria.
It is not without significance that those very procedures which Escher-
ich and the long list of bacteriologists following him have found useful,
and even essential for the identification of microbes have their origin and
explanation in these bacteriochemical studies of the mode of action of
bacteria. In this regard, bacteriology merges imperceptibly into the fields
of protein and carbohydrate chemistry.
Also, the explanation for the striking alternations of bacterial types
in the alimentary canal in response to dietary stimuli, and for the con-
ditions which surround the production of endogenous, physiologically ac-
tive bacterial putrefaction products, depends upon the same biochemical
principle of bacterial metabolism. The amelioration, or even the rectifica-
tion, of exogenous and endogenous disturbances or infections of microbic
causation in the alimentary canal can be accomplished through the simple
and direct application of the same metabolic principle. A new science, that
of baeteriochemistry, is gradually forging into prominence. A new field
in medical bacteriology is developing. In this new field, certain funda-
mental principles underlying the metabolism of bacteria, are being ex-
ploited in the direct interest of the host. The nature of these principles,
their limitations, their relation to bacteria, and to bacterial infections of
man, are discussed in the following pages.
BACTERIAL METABOLISM WITHIX THE BODY 665
B. Bacterial Metabolism
1. General Relations Between Surface and Volume
of Bacteria and the General Energy
Requirements of Bacteria
Bacteria in common with all living things exhibit two distinct phases
in their life history — the anabolic or structural phase, and the katabolic or
energy phase. Of these, while no absolutely sharp line of demarcation
can always be determined, the manifestations and significance of the latter
phase are by far the more conspicuous, inasmuch as the amount of material
transformed into energy and heat far exceeds that entering into the body
of the organism and the replacements of structural wear and tear, and
losses incidental to the formation of enzymes and other essential nitrogen-
ous secretions and excretions.
The bacteria differ quantitatively from the great majority of plants
and animals in their disproportionately large ratio between surface and
volume. An ordinary typhoid bacillus, for example, has a volume of
approximately 0.000000002 cubic millimeter. The surface area of a
bacterium of this size is nearly 0.00001 square millimeter. Inasmuch
as the energy requirement of organisms in general varies with the surface
area rather than with the volume (Du Bois), it is not surprising to find
that bacteria bring about transformations of nutritive material for meta-
bolic requirements considerably greater than their minute size would
appear to permit of at first sight.2
Bacterial cells exhibit no morphologically definable nucleus,3 and the
complex phenomena attending nuclear division, so characteristic of more
highly organized cellular structures, is not a feature of bacterial multi-
plication. Hence, reproduction among bacteria is mechanically an ap-
parently simple process. It takes place by direct transverse fission, the
resulting parent and daughter cells being of approximately equal size.
The rate of increase among bacteria is a geometrical progression which
in favorable mediums is theoretically maintained until the accumulation
of waste products and other environmental factors imposes a restraint
upon the process.
Among the more rapidly growing organisms, as for example the cholera
vibrio, successive generations may appear at intervals as frequent as
*A man of average figure, 200 cm. long and weighing 100 kg., would have a surface
area of about 2.36 square meters. It will be seen that the ratio between weight [or
volume] and surface in this instance is much more nearly equal than that of the
bacteria.
'Bacterial cells are, however, rich in nuclear material. The chemical basis for
nuclei probably is quite uniformly distributed throughout the entire cell.
666 ARTHUR ISAAC KENDALL
every fifteen minutes. The theoretical descendants of a single microbe
after four hours of unrestrained growth would number almost thirty-three
thousand. Their combined volumes would be approximately 0.000066
cubic millimeter,4 but their united surface areas would be nearly 0.33
square millimeter. It is obvious that the amount of structural substance
essential for the thirty-three thousand cholera vibrios would be little in-
deed; the quantity of material necessary to provide the requisite energy
for these organisms is relatively very large.
The rapidity of reproduction among bacteria, therefore, furnishes an
additional explanation of the magnitude of transformation of nutritive
material, which is such a conspicuous feature of bacterial growth. From
this viewpoint, the activities of bacteria appear to lie within the realm of
colloidal chemistry — the chemistry of surface relations.
The relations between surface and volume of bacterial cells as an
explanation of the magnitude of bacterial metabolism cannot be empha-
sized to the exclusion of the specific activities of individual species or
types of bacteria, however. Bacillus proteus and Bacillus typhosus, for
example, are of nearly equal dimensions and multiply at nearly the same
rate. Nevertheless, the former is far more energetic, under apparently
parallel conditions, in its chemical transformations to obtain the elements
requisite for energy than the latter.5 The fact remains, however, that in
general, bacteria effect changes in their chemical environment, both in
time and amount, greatly exceeding that to be expected from such minute
organisms, and the significant aspect of this activity is that associated with
the energy phase rather than the structural phase of their metabolism.
2. The Influence of Saprophytism, Parasitism, and
Pathogenism upon Bacterial Metabolism
From the viewpoint of mankind, bacteria may be classed for con-
venience as of three principal groups (Smith, Kendall (a)) : First, sapro-
phytic bacteria, living upon dead organic material, and usually without
significance in a pathogenic way. Their function in Nature is to bring
about deep-seated changes in dead organic matter, returning the essential
elements, as nitrogen, to the vegetable kingdom as fully mineralized com-
pounds ready for resynthesis into proteins and other necessary organic
compounds, by chlorophyll-bearing plants. Secondly, parasitic bacteria,
which live upon the body of the host* or in channels or cavities in free
communication with the exterior of the body of the host. Usually such
organisms are endowed with the power of multiplying within the tissues,
*The cholera vibrio is approximately equal in size to the typhoid bacillus.
5 In general, it may be stated that non-pathogenic bacteria are more active
chemically than pathogenic bacteria.
BACTERIAL METABOLISM WITHIN THE BODY 667
in the presence of opposition from the various "bactericidal forces of the
host, but they lack the power of independent invasiveness. They are "op-
portunists" with respect to pathogenicity and they are usually secondary
invaders because they require some break in the continuity of the skin or
mucous membranes to permit of their entrance to underlying tissues. Such
an organism is the Streptococcus. Parasitic bacteria do not ordinarily
incite epidemics, -because they have not perfected a mechanism for escape
from the tissues, and as a general rule their excursion into the tissues
results in relatively non-specific inflammatory processes, rather than well-
defined anatomical lesions.6 Recovery from an invasion of organisms of
the opportunist type does not ordinarily appear to result in a well-defined
specific immunity, thus again affording a contrast to bacteria of the pro-
gressively pathogenic type.
Finally, the members of a small but formidable group of bacteria are
progressively pathogenic, that is to say, they appear to possess the power
of independent invasiveness of the body, if they reach a suitable portal of
entry in sufficient numbers. After invasion they multiply for a period of
time within the tissues of the body in the presence of the opposition offered
by the various non-specific lines of defense. They have individually per-
fected, finally, well-defined mechanisms of escape from the tissues to
channels in communication with the outside world, thus providing for
escape to other, susceptible hosts, and the perpetuation of the species.
The typhoid bacillus may be cited as illustrative : The organism must
reach the small intestine of a susceptible individual, penetrate the mucosa,
and enter the circulation. It grows in the tissues and, after a period of
time, reenters the intestines from the gall bladder from which it escapes
to the environment in increased numbers, or it escapes from the urinary
bladder to the outside world.
Thus, it is possible to distinguish a "cycle of parasitism" and a "cycle
of pathogenism." The essential factors of the former are — first, for the
parasitic microbe to reach the surface of a suitable host, or to reach chan-
nels or cavities in free communication with the outside world ; secondly,
for the microbe to multiply there, and, thirdly, to escape to other, suitable
hosts, thus insuring the perpetuation of the species. Penetration of the
tissues and growth therein is not a part of this cycle — the microbe cannot
escape to the outside, as a general rule, and perishes, although it may
overwhelm the host in so doing. Parasitic organisms, therefore, are not
progressively pathogenic. The pathogenic cycle is somewhat more com-
plex. The organism must reach a suitable portal of entry to the under-
lying tissues of the host, actually penetrate into the underlying tissues and
grow therein in the face of non-specific and specific opposition. Finally,
•Thus, the lesions caused by progressively pathogenic bacteria, as the tubercle,
typhoid, or syphilis microbes, are fairly distinctive and characteristic in structure and
distribution, contrasting sharply in this respect with the non-specific inflammations in-
duced by streptococci or other pyogenic microbes.
668 AKTHUE ISAAC KEXDALL
the organism must escape from the tissues in significant numbers to chan-
nels in communication with the outside world, and eventually reach other,
suitable hosts. Such organisms incite specific epidemics. They are pro-
gressively pathogenic from host to host.
It is a striking fact that the evolution of bacteria from saprophytic
types through parasitic to pathogenic types has been attended by a marked
decrease in the chemical activities of the microbes. For example, the con-
trast in chemical activity between the powerfully proteolytic members
of the saprophytic hay bacillus group, which are without virulence,
through the ordinary skin Staphylococcus to the exquisitely fastidious
Meningococcus is only equaled by the increased pathogenicity of these
latter organisms. Generally speaking, intense chemical activity appears
to be incompatible with pathogenicity (Kendall).
The facts adduced thus far relate to general properties of bacteria;
they furnish little or no information relative to the specificity of bacteria
and of bacterial action. Bacteria, in the last analysis, are "living chem-
ical reagents," as Professor Folin once characterized them, and the
specificity of bacterial action is largely, if not almost wholly, a problem
of the chemistry of their interchange with their environment.
The ultimate chemistry of bacterial action, particularly that relating
to the pathogenic organisms, is as yet unsolved. The formulae for diph-
theria and tetanus toxins, the nature of the poisons of the typhoid and
dysentery bacilli, are problems for the bacteriological chemists of the
future to solve. Nevertheless, all bacteria of interest or of importance to
man exhibit certain rather general relationships with respect to their
energy requirements, which are of interest and of increasing importance
in the solution of certain problems of medicine. A discussion of these re-
lationships will necessitate a survey of the general phenomena of bacterial
nutrition.
3. Chemical Requirements for Bacterial Development:
a — For Structure. b — For Energy.
The cytoplasm of bacteria contains nitrogen, carbon, hydrogen and
oxygen, together with other elements in lesser amounts, in about the same
proportions as those found in other living cells. The phosphoric acid
content is higher than that found in the cells of a majority of higher
plants or animals, however.7 It is obvious that the growth of bacteria in
the abstract depends upon the availability of these elements, together with
those of lesser occurrence, in proper amounts and in proper combinations.
For purposes of discussion, attention will be directed specifically toward
* Thus, the ash of Bacillus xerosis contains 34 per cent of phosphorus calculated
as phosphoric acid, the tubercle bacillus 55 per cent, the cholera vibrio about 45 per cent.
BACTERIAL METABOLISM WITHIN THE BODY 669
nitrogen, as an element of great structural significance, and carbon, of
peculiar importance as the basis of the energy phase of bacterial
metabolism.
a. Structural Chemical Requirements. — Bacteria can not multiply
in non-nitrogenous media, and the organisms of interest and significance
to man derive their nitrogen requirements from nitrogen in combination
with carbon, hydrogen and oxygen of the amino-acid complexes — poly-
peptids, peptones, or proteins. The more fastidious organisms, as the
Gonococeus and Meningococcus, require, or at least develop best in, media
containing protein but little altered from the state in which it exists in
the human or animal body. Others grow very well indeed in media con-
taining less highly organized nitrogen, as for example that of peptone.
None will grow in the absence of this element ; hence, it may be regarded
as an essential structural element, Nitrogen has no energy value, however,
for parasitic or pathogenic microbes.
b. Energy Chemical Requirements. — Bacteria derive their energy
from the oxidization of carbon, in the last analysis, and the state of com-
bination of this element with others — particularly oxygen and hydrogen
[as well as nitrogen in proteins and protein derivatives] — determines to a
very considerable degree the nature of the products of specific bacterial
metabolism. The influence of associative elements upon bacterial metab-
olism and even the specificity of bacterial action, from the viewpoint of
energy, is shown in the following well authenticated series of illustrations :
4. The General Nature of the Products of Bacterial
Growth, Arising from the Utilization of Proteins
and of Carbohydrates for Energy — Toxin,
Indol and Enzyme Formation.
Diphtheria Toxin. — It is well known that the soluble or exotoxin of
the diphtheria bacillus is the specific product which makes this organism
formidable to man. Diphtheria toxin is also excreted incidentally to the
growth of the microbe in plain nutritive broth, which consists essentially
of a neutral mixture of peptone, meat extractives, salts and water. In
such a medium, the diphtheria bacillus develops rapidly and within a
week or ten days the filtrate of this culture medium, freed from all bacteria
or other particulate matter, is extremely toxic for guinea pigs. Indeed,
0.025 cubic centimeter of such bacteria-free broth frequently kills 250
gram guinea pigs within four days with very definite specific symptoms
and lesions.
Contrast this highly toxic broth with that resulting from the growth
of the same organism under precisely the same conditions in the same
670 AETHUE ISAAC KENDALL
medium to which has been added merely a minimum of 0.5 per cent of
glucose. Here the broth is acid in reaction in place of slightly alkaline,
but otherwise it appears to be the same (Van Turenhout, Smith, Kendall).
Injected into guinea pigs, however, the glucose broth is found to be wholly
without toxicity. The simple addition of a small amount of glucose has
completely changed the character of the products formed as the result of
the growth of the diphtheria bacillus. Lactic and other acids are formed
under these conditions, but no soluble toxin.
Indol Formation. — The amount of indican excreted in the urine has
long been regarded by some observers (Combe, Bahr) as an index of the
intensity of that obscure clinical condition spoken of as "auto-intoxica-
tion." Irrespective of the clinical significance of urinary indican, how-
ever, the parent substance is indol (Kendall), an aromatic residue of the
amino acid tryptophan. In man, indol is produced from tryptophan in
the intestinal tract by the action of Bacillus coli, Bacillus proteus, and to a
lesser extent by other facultative proteolytic organisms, acting in the
absence of utilizable carbohydrates. The absorption of indol from the ali-
mentary canal, its oxidization in the liver, and its excretion and sig-
nificance are discussed later.
The production of indol from tryptophan by cultures of B. coli, Bacil-
lus proteus, the cholera vibrio or other bacteria can be observed readily
in the test tube; the conditions favoring or preventing its formation are
easily controlled. Indol appears within twenty-four to forty-eight hours in
ordinary sugar-free nutrient broth containing tryptophan, such as that in
which the diphtheria bacillus produces toxin. Precisely as the addition of
glucose to plain nutrient broth prevented the formation of diphtheria toxin
by the diphtheria bacillus, so that addition of glucose to such broth pre-
vents the formation of indol by the colon bacillus, Bacillus proteus and the
cholera vibrio. In place of indol and other products of putrefaction, which
appear in sugar-free media of the kind described, the addition of glucose
so changes the products of metabolism of these organisms that only organic
acids — as lactic and acetic — are formed, together with carbon dioxid and
hydrogen ; in other words, the substitution of utilizable carbohydrate for
protein as a source of energy alters completely the nature of the products
formed.
The Formation of Protein-Liquefying Enzymes. — Bacillus proteus,
the cholera vibrio, and several other parasitic and, less commonly, patho-
genic bacteria, form soluble enzymes, much like trypsin in their protein-
digestive power, in sugar-free media. These enzymes may be obtained in a
reactive state, quite free from bacteria, by filtering the latter away (Fuhr-
mann). The germ-free filtrate is strongly proteolytic for a variety of
proteins, including gelatin, breaking the complex molecule into amino
acids and po-lypeptids.
The addition of glucose to cultures of the cholera vibrio or Bacillus
BACTERIAL METABOLISM WITHIN THE BODY 671
proteus prior to inoculation [to the extent of 0.5 per cent or more] will,
so alter the products of growth that the soluble proteolytic enzyme and all
other evidences of proteolytic and putrefactive activity are no longer
detectable in the culture medium (Kendall and Walker). On the con-
trary, lactic and other acids indicative of the fermentation of carbo-
hydrates are formed. Here again the addition of glucose in a minimal
amount of 0.5 per cent has completely altered the products of growth. In
other words, from the illustrations cited, small amounts of glucose pre-
vented the formation of toxin in cultures of the diphtheria bacillus, of
indol in cultures of Bacillus coli and Bacillus proteus, and of a soluble
proteolytic enzyme in cultures of the cholera vibrio and Bacillus proteus.
If space permitted, examples of the sparing action of utilizable carbo-
hydrate for protein as sources of energy might be cited from all fields of
bacterial activity, but those herewith presented are illustrative. Ad-
ditional observations of specific interest are discussed . in appropriate
sections.
It is worthy of note that a minimum of 0.5 per cent of glucose was
specified in each instance. Experience has shown that the diphtheria
bacillus can utilize from 0.1 to 0.3 per cent of glucose without producing
enough fermentation acid and other products of the cleavage of glucose to
inhibit its further growth (Theobald Smith). Under these conditions
no toxin is demonstrable until the sugar [glucose] has disappeared. Then
toxin begins to form.
Bacillus coli and Bacillus proteus do not form indol in culture media
until the utilizable sugar is used up. If the amount of sugar is somewhat
less than 0.5 per cent, the products of fermentation incidental to the
utilization of it for energy do not inhibit the subsequent development of
the colon or proteus bacilli, and the formation of indol proceeds after
the glucose is fermented.
Similarly, relatively small amounts of glucose or other utilizable car-
bohydrate, somewhat less than 0.5 per cent — the limit of tolerance varies
somewhat with the strain of the organism — prevent the formation of pro-
teolytic enzymes by cholera, proteus and other bacilli. When the carbo-
hydrate is used up, however, provided the conditions due indirectly to the
accumulation of products of fermentation are not too unfavorable, the
organisms attack the protein constituents of the medium for their energy,
and the proteolytic enzyme makes a belated appearance. It should be
emphasized that the presence of glucose, or other utilizable carbohydrate
in cultures of cholera, proteus, or other bacteria, which form a soluble
proteolytic enzyme, prevents the formation of the enzyme in the reactive
state. Neither glucose nor any other carbohydrate prevents the action of
the mature, reactive proteolytic enzyme when it has been elaborated (Ken-
dall and Walker (&)). In other words, when the enzyme is formed in an
active state, as for example in sugar-free media, this bacteria-free enzyme
672 ARTHUR ISAAC KEXDALL
.will act quite as readily upon protein media containing glucose as upon
protein media from which glucose is absent.
The foregoing illustrations typify a very general property of bacteria,
and of other living things for that matter, with respect to metabolism.
It has long been a physiological dictum that i 'carbohydrate spares body
protein" (Howell(a) ), meaning by that that an animal requires a definite,
if minimal, amount of dietary protein to maintain the nitrogen equilibrium
of the adult organism. This minimal amount of nitrogen is indispensable
for the repair of structural wear and tear, and for the replacement of
nitrogenous losses in secretions, enzymes and other nitrogen-containing sub-
stances, which are of necessity constantly lost to the body. The fuel or
energy requirement of the organism, on the contrary, amounting to many
times the minimal nitrogen requirement, can be met by the feeding of
non-nitrogenous food, as carbohydrate and, to a lesser degree, organic
acids or fat.
Bacterial nutrition presents the same fundamental phenomena of
structural and energy requirements. The former absolutely requires
nitrogen as one element in its make-up, whereas the latter may be satisfied
by non-nitrogenous organic substances. Of these, the carbohydrates as a
class are of paramount importance, although of varying degrees according
to specific characteristics of the organisms under investigation. Precisely
as saprophytic bacteria were found to be more energetic cleavers of protein
than parasitic and pathogenic bacteria, so the saprophytic types are some-
what more energetic cleavers, both in kind and amount, of carbohydrate
than the pathogenic types. Hence, a majority of the progressively patho-
genic bacteria, as typhoid, dysentery, diphtheria and many others, utilize
the hexoses [especially glucose], but fail to utilize the bioses, as lactose and
saccharose. The pathogenic bacteria produce less deep seated changes
even in the hexoses than do the saprophytic types. In general, the
changes induced by the former result in the formation of lactic and acetic
acids, whereas the latter frequently oxidize a not inconsiderable portion of
the hexose to carbon dioxid and hydrogen.
Returning to the conditions prevailing in cultures of diphtheria, colon
and cholera organisms referred to above, it will be found that plain or
sugar-free media offer to bacteria protein and protein derivatives [pep-
tone, polypeptids and amino acids] , as the sole source of structure and of
energy. The glucose media offer precisely the same protein and protein
derivatives for structure — non-nitrogenous substances are not suitable for
structure, generally speaking — and, in addition, a choice between this
protein or protein derivative and carbohydrate for energy. To sum-
marize :
The marked difference discernible between the significant products
formed by bacteria in non-saccharine media, where both structure and
energy requirements are of necessity obtained from the nitrogenous protein
BACTERIAL METABOLISM WITHIN THE BODY 673
derivatives, and the absence of such significant products [toxin, indol or
enxyme] in the glucose-nitrogenous media indicates the importance of the
source of energy as a determining factor in directing the type of action1
of the microbe.
5. The Specificity of Action of Pathogenic Bacteria
and Its Relation to Proteins and Carbohydrates
From what has been stated previously, it would appear that pathogenic
and parasitic bacteria produce significant or specific nitrogenous waste
products incidental to their utilization of protein or protein derivatives
for energy. Thus, diphtheria, typhoid, dysentery, cholera, paratyphoid;
glanders, colon, proteus, and many other pathogenic microbes produce
specific toxins or other characteristic nitrogenous products in protein en-
vironments from which utilizable carbohydrates are excluded.
On the contrary, when in addition to protein utilizable carbohydrates
are also available as sources of energy, these same organisms act upon the
latter instead of the former, and produce therefrom acidic products, chiefly
lactic and, to a lesser extent, acetic acid.
In other words, the simple addition of glucose to cultures of patho-
genic bacteria, other conditions remaining the same, brings about a strik-
ing alteration of the nature of their metabolic products. In place of toxins,
phenols, «katol, and other protein derivatives, specific or characteristic
of each individual microbe, all produce innocuous lactic and acetic acids.
These formidable incitants of disease in man have become potentially
lactic acid bacteria. Grown in glucose media, therefore, the diphtheria,
typhoid, cholera and other pathogenic bacteria become the qualitative
equivalents of the Bulgarian lactic acid bacillus.8
Stated differently, it may be said that the specificity of action of the
vast majority of bacteria pathogenic for man is dependent upon their
utilization of protein for energy (Kendall).
Fats play a very minor part in the metabolism of pathogenic bacteria,
other than those of the acid-fast group, which includes the tubercle and
leprosy bacilli. The effects of utilizable fats are comparable to the carbo-
hydrates rather than the proteins, however, so far as their energy rela-
tionships are concerned.
The toxicity of the cellular substance of bacteria is not considered in
this connection, nor is it relevant, Available evidence indicates that the
cytoplasm of non-pathogenic bacteria, as for example Bacillus prodigiosus,
may be many fold more deadly to animals than that of such formidable
8 It is obvious that a continuous supply of utilizable carbohydrate must be avail-
able; when the sugar is used up, provided the organisms are not killed by the products
resulting from fermentation, they will at once attack the protein again and generate
their specific protein decomposition products.
674 ARTHUR ISAAC KENDALL
incitants of. disease as diphtheria, anthrax, or typhoid bacilli (Vaughan).
The effects of carbohydrates and proteins upon the composition of the
cytoplasm of bacteria is discussed in the following section.
6. Quantitative Measures of Bacterial Metabolism, the
Effects of Utilizable Carbohydrates upon General
Metabolism, and the Elementary Composition
of the Bacterial Cell.
' It is very evident that there are far-reaching theoretical and practical
applications of the theory that the "specificity of action of the vast
majority of bacteria depends upon their utilization of protein or protein
derivatives for energy." The application of the theory to the domain of
medicine is closely associated with the corollary thereof, namely, that the
"great majority of pathogenic bacteria become potentially lactic acid
bacteria when they are growing in an environment containing carbo-
hydrates or other non-nitrogenous compounds from which they can obtain
their energy."
So sweeping an assertion would appear to require more than qualitative
evidence for its consideration or acceptance. Fortunately, such evidence
is available from several sources.
The chemical basis for the proof of the theory of the sparing action of
utilizable carbohydrate awaited the development of methods for the study
of metabolism which were applicable to bacterial cultures. Qualitative
evidence has long been known, even though it was not appreciated for its
full significance.
The very exact micro methods of urine analysis, developed and per-
fected by Folin and his associates (Folin(d)), have been found applicable
to the study of nitrogenous metabolism in cultures of bacteria (Kendall
and Farmer). The analytical data obtained are as precise as any obtain-
able for corresponding metabolic studies upon man or animals. Indeed,
in some respects they are of greater precision, inasmuch as the total nitro-
genous changes induced by various bacteria under varying cultural con-
ditions are always reproducible, since there is neither gain nor loss of
nitrogen during the experiment.
The quantitative studies of bacterial metabolism were carried out in
precisely the same manner as a corresponding metabolic study upon man
or upon an experimental animal. Broadly speaking, the significance of
the results is the same for bacteria in either case. The results of these
quantitative metabolic studies appear to be very clear cut and definite;
they bear out exactly what has been indicated by qualitative observations,
namely, that utilizable carbohydrate added to protein culture media does
675
shield the nitrogenous constituents from utilization for energy. These ex-
periments also demonstrate the very considerable amounts of acid — chiefly
lactic and acetic — which appear concomitantly with the utilization of the
carbohydrate for energy. In this respect, the sugar-protein cultures con-
trast strikingly with the purely protein cultures, which become more or
less alkaline, due to the gradual accumulation of basic, nitrogenous waste
products arising from the combustion of the nitrogenous constituents of
the non-saccharine media. The nitrogenous waste products arising from
the utilization of protein for structural requirements and structural re-
placements, although relatively small in amount, were also clearly indi-
cated in these quantitative analytical studies.
A word of explanation of the analogy between the metabolic waste
products of man and of bacteria will be required to indicate the parallelism
between human [multicellular] nitrogenous metabolism and bacterial
[unicellular] metabolism.
It will be remembered that the principal end product of the physio-
logical metabolism of the proteins of the food and the tissues in man is
excreted through the kidneys into the urine as urea. Urea is derived, in
the last analysis, largely or chiefly from the deamination of amino acids :
the ammonia liberated is changed, principally in the liver, to urea.
Ammonia has no energy value and whenever amino acids [protein or
protein derivatives] are used in the body for energy, for transformation
into glucose, or glycerin, or for storage as glycogen or fats, the ammonia
is discarded and changed to urea, unless a deficit of alkali leads to its
combination with acids that must be excreted through the kidneys* The
excretion of urea is markedly increased when a purely protein diet is
provided, and it is greatly reduced when the energy requirements of the
body are provided for by a carbohydrate regimen, supplying, however,
sufficient protein for structural and replacement needs.
This urea may be regarded, therefore, as of exogenous and of en-
dogenous origin (Folin), the former being influenced largely by an
excess of protein above the structural requirements, the latter more spe-
cifically associated with structural changes in the tissues and organs. The
exogenous urea is greatly influenced by the nature of the diet, being in-
creased when the energy requirement of the body is obtained chiefly by
the oxidization of proteins and reduced when the energy needs are de-
rived largely from dietary carbohydrate and fat. The endogenous urea
is less variable under proper dietary conditions.
Similarly, bacteria deaminize amino acids prior to their utilization
of the remainder of the amino acid molecule for energy. Also, a small
amount of ammonia is apparently produced from the utilization of some
nitrogenqus substance for the structural needs of the bacterial cell. Bac-
teria have no livers; therefore, so far as is known, they do not excrete
urea (Kendall and Walker). Ammonia, which has an analogous origin
676 ARTHUR ISAAC KENDALL
in man and in bacteria, is "bacterial urea," and as such it is the best
available measure of nitrogenous metabolism.
The "endogenous" ammonia is recognizable when bacteria derive their
energy solely from carbohydrates, in a protein-carbohydrate medium. It
is of course masked in a purely protein medium where deamination of
protein occurs prior to the combustion of the protein for energy, as well
as from the structural nitrogenous changes.
The following analytical data are illustrative of the nitrogenous metab-
olism of several saprophytic, parasitic, and pathogenic bacteria, under
parallel conditions:
Briefly, the conditions of experiment are as follows: Plain, nutrient,
sugar-free broth, and glucose broth respectively, which differ only in
that the latter is reenforced with one per cent of glucose, are inocu-
lated with the same organism under exactly similar conditions, incubated
side by side, and examined at the same time for changes in titratable
acidity and nitrogenous changes, particularly ammonia formation. Am-
monia formation is an index of deamination, associated chiefly with the
utilization of the non-nitrogenous residue of the amino acid complex for
energy. In media containing glucose in addition to the protein derivatives,
the energy requirement is obtained largely at the expense of the non-
nitrogenous carbohydrate, which of course does not undergo deamination
prior to its energy transformation. Under these conditions the sparing
action of glucose [carbohydrate] for protein is obviously manifested by
a greater or lesser reduction in the amount of ammonia formed [deamina-
tion] in contrast to the amount observed in the corresponding glucose-
free medium.
The table on following page also shows the relatively lesser nitrogen
change in media induced by pathogenic bacteria than that characteristic of
the saprophytic types — as, for example, between Bacillus dysenteriae and
Bacillus mesentericus. This is in harmony with the observation cited
above that pathogenic organisms, generally speaking, are less active chemi-
cally than the ordinary saprophytic types (Kendall, Sears).
Explanation : In general, it will be seen that all the bacteria studied
become alkaline in reaction and form considerable amounts of ammonia
in sugar-free broth. Among the products formed, but not indicated in
the table, are diphtheria toxin by the diphtheria bacillus, indol by
Bacillus proteus and Bacillus coli, a soluble proteolytic enzyme by Bacillus
mesentericus, Bacillus proteus and Staphylococcus aureus, and a soluble
hemolysin by Streptococcus hemolyticus.
In the glucose medium, all the bacteria produce a relatively strong
acid reaction [chiefly lactic and acetic acids] and relatively slight amounts
of ammonia, indicating that the major reaction is upon the glucose in
place of the protein. Neither toxin, enzyme, hemolysin nor indol is
to be found among the products produced from glucose by the organisms.
BACTERIAL METABOLISM WITHIN THE BODY 677
Ten-Day Observations
Organism :
Sugar-Free Broth
Glucose Broth
Reaction :
Ammonia:
Reaction :
Ammonia :
B dysenterise Shiga
— 0.30
— 0.25
— 0.50
— 0.45
— 0.20
— 0.60
— 1.00
— 2.00
— 0.70
+ 0.70
— 0.75
-I- 4.20
+ 4.50
+ 3.10
+ 5.40
+ 6.30
+ 7.50
+ 24.40
+ 58.40
+ 38.50
+ 1.40
+ 38.70
+ 2.80
+ 2.45
+ 2.80
+ 3.10
+ 3.40
+ 3.75
+ 4.90
+ 3.55
+ 1.50
+ 3.50
+ 3.75
+ 0.70
+ 0.70
+ 1.05
+ 0.60
+ 1.20
+ 1.40
+ 1.05
+ 1.40
+ 2.80
+ 0.70
+ 0.70
15 dysenteriae Flexner
B diphtheria;
B typhosus
B paratvphosus alpha
B paratvpliosus beta
B coli
B proteus
B mesentericus
Streptococcus hemolyticus
Staphvlococcus aureus
Legend :
Reaction, — indicates the amount of alkalinity developed in terms of normal
alkalai per 100 cubic centimeters of culture.
+ indicates the amount of acidity developed, in terms of normal acid
per 100 cubic centimeters of culture, compared with suitable controls.
Ammonia, The figures indicate the number of milligrams of nitrogen as ammonia
developed in 100 cubic centimeters of media, compared with suitable
controls.
These qualitative and quantitative observations, illustrative of the
sparing action of utilizable carbohydrate for protein as a source of en-
ergy, together with the significance of this sparing action in terms of
important products arising from the use of protein, and their replace-
ment by innocuous compounds when carbohydrate is available, leads
logically to the generalization that "the significance of the action of
pathogenic bacteria, so far as is known, depends upon their utilization of
protein for energy." When carbohydrate is used for energy, the organisms
are potentially lactic acid bacteria in terms of their reaction products
(Kendall).
The endotoxins, so-called, of bacteria are not considered in this dis-
cussion, which deals with the products of growth. It appears to be a
fact, however, that carbohydrate influences the composition of bacteria in
a striking manner. Thus, Cramer has analyzed the dried substance of
bacteria grown upon ordinary nutrient agar, and upon glucose agar of
otherwise the same composition, with the following results, expressed
in percentages:
ORGANISM:
Sugar-Free Agar
Glucose Agar
Nitrogen
Alcohol-
ether ex-
tractives
Ash
Nitrogen
Alcohol
ether ex-
tractives
Ash
Pfeiffer bacillus
66.6
73.1
71.7
68.4
17.7
16.!)
10.3
11.1
12.56
11.42
13.94
13.45
53.7
50.0
63.3
62.1
24.0
18.4
22.7
20.0
9.13
9.20
7.88
9.44
Bacillus H-28
Pneumobacillus
Rhinoscleroma bacillus
678 ARTHTJE ISAAC KENDALL
It will be seen that bacteria grown on glucose agar contain nearly
twenty per cent less nitrogen, and materially more extractives than those
grown on media with the same nitrogenous constituents but without the
glucose. The significance of this difference is yet to be determined.
Inasmuch as the immunizing processes are apparently inseparable from
nitrogenous substances, however, there may be some relationship between
a maximum nitrogen content of bacteria and their antigenic potency,
which may play a part in the large field of bacterial vaccines. In this
connection, the reciprocal variation of nitrogen and lipoids, clearly sug-
gested in the table, may also be of significance inasmuch as solubility
and anti-complementary properties of bacteria appear to be related to
the lipoidal content of bacterial bodies (Warden). Whatever the sig-
nificance of the composition of bacteria may be, it may be stated con-
fidently that the entire series of phenomena outlined above — relating to
the sparing action of utilizable carbohydrates for protein in the energy
manifestations of bacteria and their effects upon the composition of bac-
teria even — is of material importance in determining the nature and
extent of bacterial action.
C. The Chemistry of Bacterial Metabolism
1. General Statements
The chemistry of bacterial metabolism naturally is divided into two
rather distinct phases — the anabolic, or structural, phase, which in point
of time occurs first, and the katabolic, or energy phase, which follows the
maturation of the bacterial cell.9 The latter exceeds the former, both
with respect to the amount of material transformed and in respect to
the significance of the products resulting from the utilization of the
various substances for energy.
Generally speaking, the structural or anabolic phase consists of a
series of hydrogenic condensations whereby simpler nitrogenous sub-
stances, as amino acids or polypeptids, are built into specific proteins;
where glycerin and fatty acids are synthesized to fats, and, in association
with phosphorus, into nucleins; and where glycogen-like bodies are ap-
parently synthesized from glucose.10 This phase of bacterial development
* It is almost certain that a certain amount of interchange referable to the anabolic
phase must take place throughout the period of vegetative activity of the cell. The
losses associated with the formation of enzymes and other essential excretions belong
in this group.
10 Considerable evidence has accumulated indicating the possibility of a mutual
transformation of glycerin, alanin and glucose through pyruvic acid into the three
great types of proteins, carbohydrates, and fats.
BACTERIAL METABOLISM WITHIN THE BODY 679
is quite similar to that of all living cells. The amount of material re-
quired to meet the structural requirements of bacteria, and to replace
losses incidental to the formation of soluble enzymes and other elements,
is very little. Usually, also, the structural waste incidental to the elabora-
tion of the bacterial substance is inconspicuous in amount and reactivity.
The cytoplasm of the bacterial cell is always more or less poisonous
when it is liberated within the tissues of an animal or man, that of the
saprophytic types of bacteria being quite as reactive on the whole in this
regard as that of the very virulent organisms, as Bacillus diphtherias
(Vaughan). The significance of bacterial infection, however, is asso-
ciated primarily with the growth of bacteria in the tissues, or with the
absorption into the tissues of products incidental to their growth. In
other words, the energy phase of bacterial metabolism is in all probability
of the greatest importance from the viewpoint of microbic infection and
microbic intoxication.
The products arising from the transformation of nutritive substances
into energy by bacteria are of two principal types — nitrogen-containing,
or derivatives thereof, and non-nitrogenous. The former arise from pro-
teins or protein derivatives, the latter from carbohydrates, less commonly
from fats.11
The composition of the highly complex nitrogenous bacterial toxins, as,
for example, that of the diphtheria bacillus, is unknown, although it may
be separated from solution by protein precipitants, and it appears to
have some points of resemblance to that group of the proteins known as
the globulins. From the viewpoint of the present discussion, diphtheria
toxin, and the soluble bacterial toxins in general, may be defined as soluble
products of unknown but complex composition, containing nitrogen, aris-
ing from the utilization of proteins or protein derivatives for energy by
specific bacteria.
In general, the measurable changes induced in the nitrogenous con-
stituents of culture media by the great majority of pathogenic microbes,
as deamination, or changes in amino nitrogen, are quantitatively the
same. (See table page 677.) The nitrogenous metabolism of bacteria
which produce soluble toxins, as the diphtheria, tetanus, and Shiga bacilli,
is comparable in magnitude and general characteristics to that of such
pathogenic bacteria as the typhoid bacillus, in whose cultures soluble,
specific toxins have not been detected.
The qualitative changes induced by these same organisms upon ni-
trogenous [protein] substances are, on the contrary, quite unknown. The
elucidation of the chemical structure of toxins and other harmful nitro-
gen-containing products of the transformation of protein, or protein de-
rivatives, is a problem for the bacterio-chemist of the future to solve.
"There is some evidence that lecithin and similar phosphatids may be decom-
posed by bacterial action with the liberation of physiologically active substances.
080 ARTHUR ISAAC KENDALL
As knowledge of bacteriology has increased, attention has been di-
rected to the method of formation and mode of physiological action of
bacterial products, derived from protein, from polypeptids, or even amiiio
acids, other than soluble toxins. Some of these substances, as indol, are
regarded by certain observers to be indicative of that condition spoken of
as auto-intoxication (Combe, Bahr). Others, as betaimidazole ethylamine,
possess physiological activity even in minute amounts, which may have
pathological significance. Between these two general groups of substances
in all probability lie the specific products of the typhoid bacillus, glanders,
paratyphoid, and many others, which are perhaps neither as highly or-
ganized chemically as the soluble toxins of the diphtheria or tetanus
bacilli, nor as simple as the ainins derived from the aromatic ammo
acids.
2. General Reactions: The Formation of Phenols,
Indol and Indican, Amins
The types of reactions through which proteins are transformed by
bacteria into simpler compounds incidental to their utilization for energy
are fairly well established, and inasmuch as certain substances of clinical
importance are formed in this manner, they have a real importance in
any discussion of bacterial action. It is to be remembered that each
kind of organism utilizes protein or protein derivatives somewhat dif-
ferently and characteristically, but in general one or more of the fol-
lowing reactions are involved, either successively or simultaneously in
the katabolism of proteins:
1. R.CH2.CHKH2.COOH -f H:2 = R.CH2.CH2.COOH + NH3.
Reductive deamination of an amino acid to a fatty acid with
the same number of .carbon atoms.
2. R.CH2.CHNH2.COOH + H2O = R.CH2.CHOILCOOH 4- NH8.
Hydrolytic deamination of amino acid to an oxyacid with the
same number of carbon atoms. Lactic acid may be formed
from alanin by this process.
3. R.CH2.CHNH2.COOH + O = R.CH2.CO.COOH -f NH,.
Deamination and simultaneous formation of an alpha ketonic
acid. [Pyruvic acid transformation.]
4. R.CH2.CHNH2.COOH -f O2 = = R.CH2.COOH + CO2 + NH3.
Deamination of amino acid and simultaneous oxidization, re-
sulting in a fatty acid with one less carbon atom.
5. R.CH2.CH2.COOH - --> R.CH2.CH, -f CO,.
Carboxylic decomposition of fatty acid with the formation
of a fatty acid containing one less carbon atom.
BACTERIAL METABOLISM WITHIN THE BODY 681
Ga. R.CH2.CHNH2.COOH - -» R.CH2. Cir,2NH2 + CO2.
Carboxylic decomposition of ammo acid with the formation
of an arnin,
or
6b. R.CH2.CHNH,.COOH + H2 == R.CH2CH2NH2 + H.COOH
Decarboxylation with the formation of formic acid, and an
amin.
H.COOH = CO2 + H2
Formic acid, under the action of formiase, may be decom-
posed into carbon dioxid and hydrogen.
3. Reactions Illustrative of the Decomposition of
Proteins by Bacteria
a. The Decomposition of Tyrosin. — Organisms like Bacillus pro-
teus act upon proteins in solution, first by an extracellular cleavage of
the protein to polypeptids, and probably peptones by the soluble pro-
teolytic enzymes they secrete, then decomposing the polypeptids intra-
cellularly, according to the reactions indicated. [In the alimentary canal
of man, it is probable that the digestive enzymes are largely responsible
for the initial cleavage of the protein molecule. The subsequent steps,
giving rise to products not formed by the activity of gastro-intestinal
enzymes, as indol, are the result of intracellular digestion of the protein
fragments by bacteria.12]
The following steps in the decomposition of tyrosin to paracresol and
phenol indicate the theoretical progress of the decomposition of this amino
acid to compounds, as paracresol and phenol, which have no available
energy for the organism. In this state they are eliminated from the
bacterial cell and appear in the culture medium, or in the alimentary
canal.
Tyrosin Paraoxyphenyl propionic acid
OH OH
t
1.
OH2CHNH2COOH + Ho CH9CHoCOOH + NH
u The formation of protein-liquefying enzymes and the production of indol do not
take place in cultures of Bacillus proteus containing utilizablo carbohydrate.
682
ARTHUR ISAAC KENDALL
Paraoxyphenyl acetic acid
OH
2.
CH2CH2COOH +30= CH2COOH + H2O + CO2
OH
Paracresol
OH
3.
CH9COOH
OH
CH,
00
Paraoxybenzoic acid
OH
30 =
COOH
Phenol
OH
C02
b. Tryptophan Decomposition. — Similarly, tryptophan undergoes de-
composition through a variety of intermediary products, some of which, as
indol acetic acid, claimed by Herter to be the urinary pigment urorosein,
skatol, and indol, are of some physiological and possibly pathological sig-
nificance. Bacillus coli and Bacillus proteus are the common producers of
indol in the intestinal tract. [It may be repeated here that utilizable
carbohydrate will prevent the formation of indol and skatol.]
1.
/VCH2CHNH2COOH
Indol propionic acid
A CH2CH2COOH +
N
BACTERIAL METABOLISM WITHIN THE BODY 683
Betaethyl indol
cH2CH2COOH > A-,CH2CH3 + C02
Indol acetic acid (urorosein)
A CH2CH3 + 30 A_ CH2COOH + H2O
yj
v K
Skatol
,CH3 + CO2
Betaindol formic acid
CH3 + 30 = /V COOH + H2O
COOH
Indol is formed in the greatest amounts in those cases where intestinal
putrefaction is actively taking place. Obstruction of the small intestine
is a very potent factor in promoting excessive amounts (Combe). Slug-
gish peristalsis with the attendant relatively slow absorption of the
products of protein digestion provides conditions favoring an overgrowth
of Bacillus coli and other indol-forming bacteria.
Gelatin, which is deficient in tryptophan [and other aromatic amino
acids] does not play a part in indicanuria. The toxicity of indol ap-
pears to be slight, and it is lessened when indol is oxidized and is paired
with sulphuric acid (Herter). Amounts administered by mouth to 0.2
gram, however, appear to cause headache, malaise and lassitude.
Defective oxidization in the liver may lead to a low grade indol
toxemia. Herter and Wakeman found that surviving liver acts upon
indol in such a manner that it cannot be recovered by distillation of the
organ. The kidney and muscle are unable to fix indol in this manner.
684 ARTHUR ISAAC KENDALL
The daily excretion of indican varies greatly, both in the period of life
and with the individual. Nurslings practically never excrete indican
(Soldin). Adults secrete up to 10-12 milligrams daily without symp-
toms (Folin and Denis).
Indol acetic acid, resulting from an oxidative deamination of tryp-
tophan, is said by Herter to be the mother substance of the urinary pig-
ment, urorosein. Indol is absorbed from the intestinal tract and oxidized
in the body, chiefly apparently in the liver, to indoxyl:
OH
and excreted as the sodium or potassium salt, indoxyl sodium [potas-
sium], sulphonate, or indican. It is also excreted under certain conditions
paired with glycuronic acid.
ONa ONa
/
OH + H — OS = O = O.S = O + H2O
O
Indoxyl sodium sulphonate
Phenyl alanin undergoes decomposition similar to tyrosin, finally
being absorbed from the alimentary canal and paired with glycuronic acid
or with sulphuric acid. In the latter event, it becomes, together with
indican, phenol and paracresol, the principal ethereal sulphates of the
urine. Phenol,13 and paracresol, resulting from the bacterial degradation
of phenyl alanin and tyrosin, are excreted in considerable amounts as
ethereal sulphates. Folin and Denis state that as much as 0.2 to 0.3
gram of phenol may be excreted through the urine daily by apparently
normal adults. None of the substances excreted as ethereal sulphates
appear to be very toxic, although long continued formation of them in
the alimentary canal may be associated with severe disturbances. At the
present time it may be stated that the formation of the mother substances
of the urinary ethereal sulphates is an indication of bacterial decompo-
sition of the products of gastro-intestinal digestion of proteins. This
13 It is worthy of note that the body rids itself of phenol, cresol, and indol [products
arising from the bacterial putrefaction of protein] together with sulphuric acid, which
arises from the oxidization of the sulphur of protein, as non-poisonous ethereal sul-
phates. This combination of noxious products of protein degradation, with a minimal
withdrawal of sodium or potassium would appear to be a not unimportant method of
elimination of a fixed acid (sulphuric acid), without impairing to any marked degree
the alkalai reserve of the body.
BACTERIAL METABOLISM WITlilX THE BODY 685
takes place chiefly in the small intestine. A change of diet, restricting
protein and furnishing a large part of the caloric requirement above that
associated with a reasonable level of nitrogen equilibrium, by carbohy-
drate and fat, usually will lead to a reduction of protein putrefaction
through the sparing action of utilizable carbohydrate for protein in the
metabolism of the intestinal bacteria.
4. The Effects of Utilizable Carbohydrate upon the
Formation of Phenols, Indol and Amins
Simple decarboxylization of aromatic amino acids gives rise to amins,
some of which are of significance from their physiological action. Thus,
ornithin, NH2.CH2.CH2.CH2.CHNH2.COOH, is changed by mixtures oi
bacteria acting upon protein into putrescin or tetramethylenediamin,
NH2.CH2.CH2.CH.2CHNH2COOH ->
CH2CH2CH2CH2 -f CO2
and lysin similarly is decarboxylized to cadaverin :
NH2CH2.CH2.CH2.CH2.CHNH2.COOH^
CH2CH2CH2CII2Cir2 + C02,
or pentamethylenediamin.
Putrescin and cadaverin were about the first of the group of sub-
stances, frequently called ptomains, to be isolated and identified. It is
probable that sepsiii (Fraenkel) also belongs to this class of diamins.
The clinical significance of cadaverin and putrescin is not clear. These
substances have been frequently detected and occasionally isolated from
cases of cystinurea (Spiegel). The information available at present is
insufficient to explain the relationship, however, — if, indeed, any exists.
Sepsin is said by some to be a capillary poison (Barger).
Tyrosin is changed by the loss of the carboxyl group to tyramin
or paraoxyphenyl ethylamin.
OH OH
CH2.CHNH,.COOH + H,
686 ARTHUR ISAAC KENDALL
•
Barger and Walpole have detected tyramin in meat that has been
allowed to putrefy spontaneously. It appears to be a physiologically active
substance that is formed in small quantities when ordinary putrefactive
organisms are allowed to act upon protein in the absence of utilizable
carbohydrates. Such a condition appears to be present in the alimentary
tract of man not infrequently. When tyramin ^s injected intravenously in
small amounts into dogs, it raises the blood pressure rapidly and decidedly.
The same authors have shown that this substance is also an important
pressor constituent in some ergot preparations.
Phenylethylamin, derived very probably from phenyl alanin, as
paraoxyphenyl ethylamin is derived from tyrosin, is perhaps a pressor
base, although convincing data upon this point is wanting.
Similarly, histidin, through the loss of the carboxyl group, becomes the
powerfully reactive histamin, or beta imidazole ethylamin.
H H
/ /
H — C — N H — C — N
^C-.H-» \C-H + C02
C — N C — N
I I
CH2 . CHNH, . COOH CH2 . CH2KE2
Ackermann has detected histamin among the products resulting from
the decomposition of histidin by bacterial action. Somewhat later, Ber-
thelot and Bertrand described their Bacillus aminophilus intestinalis, an
intestinal parasite belonging to the Mucosus capsulatus group, which they
believed to be the causative agent in the production of histamin in the
alimentary canal. About the same time, Mellanby and Twort isolated an
organism, apparently closely related to, if not identical with, Bacillus
coli, which effects the same transformation. The year before, Barger and
Dale had isolated histamin from the intestinal wall. Koessler and
Hanke have shown recently that Bacillus coli will produce histamin from
histidin in cultures of this organism.
It is significant that both Berthelot and Bertrand and Mellanby and
Twort have found that the amin is not produced in acid solutions. A
survey of the experiments suggests strongly that the acid which is present
in such cases is derived from the fermentation of glucose. Histamin
is best isolated from "putrefying" mixtures. In this connection, the ob-
servation of Garcia that glucose added to putrefying horseflesh reduces
the yield of diamins very materially is significant. It would appear
that utilizable carbohydrates interfere with the utilization of the protein
or protein derivatives for energy, precisely as is the case with other putre-
faction products described above.
BACTERIAL METABOLISM WITHIN THE BODY 687
Histamin is a very reactive compound. According to Vaughan, one-
half milligram injected into a guinea pig will cause death very soon. The
symptoms elicited suggest in a striking manner those characteristic of
anaphylactic shock. There is a strong contracture of smooth muscle fiber,
including that of the bronchial musculature. The latter narrows the
lumen of the bronchi to a very small opening, which in connection with
the somewhat tortuous course of the respiratory tract, leads to asphyxia-
tion. There is also noticed a rapid fall of body temperature. According
to the observations of Dale and Laidlaw, however, the coagulability of
the blood in such cases is practically unaltered, which is a point of dif-
ference between this syndrome and that of anaphylaxis induced in a
sensitized animal with the homologous protein.
It would appear from available evidence that the formation of the
aromatic amins, phenyl ethylamin, paraoxyphenyl ethylamin, beta indol
ethylamin, and beta imidazole ethylamin, under ordinary intestinal con-
ditions, is chiefly the result of the activities of the colon-proteus-mucosus
capsulatus group of bacilli. It is probable that these amins do not form
in detectable quantities when the proportion of carbohydrate to protein of
the food is sufficient, with existing alimentary conditions of absorption, to
provide at least a minimal amount of sugar at the intestinal levels where
these organisms ordinarily are found. A sour milk diet is supposed to
restrict or prevent the formation of amins, and of other putrefactive prod-
ucts as well. It should be remembered that a sour milk diet is one re-
stricted in protein, which of course reduces the amount of protein from
which the parent amino acids are derived.14 The carbohydrate content of a
typical sour milk diet is decidedly increased in proportion to the protein.
This furnishes a readily utilizable source of energy for the bacteria of the
alimentary canal, and thereby switches their metabolism1 from the protein
constituents. Under these conditions, lactic and acetic acids are produced
largely, in place of the amins and other putrefactive products.
5. The Physiological Action of the Aromatic Amins
Generally speaking, the amins containing the benzene nucleus, phenyl
ethylamin, paraoxyphenyl ethylamin, and indol ethylamin cause an in-
crease of blood pressure upon injection, paraoxyphenylamin being the
most powerful of this group. There is some theoretical ground for asso-
ciating the symptoms induced in experimental animals with a direct
stimulating action of the sympathetic system. Barger and Dale, in study-
ing this relationship, have made use of the term "sympathomimetic,"
which seems to be appropriate.
"Gelatin contains much less of the aromatic amino acids than the true proteins.
It can not replace protein in the diet, but may be of some value for temporary dietary
reduction in these compounds.
688
ARTHUR ISAAC KENDALL
Beta imidazole ethylamin depresses the blood pressure upon injec-
tion, thus differing from the amins with benzene nuclei.
Continued formation of these aromatic amins is probably taking
place within the alimentary canal in those whose diet is rich in protein,
or whose peristalsis is sluggish, and in whom therefore there must be a
protein residuum at levels where the colon and proteus organisms can
grow. Such individuals would appear to have the bacterio-chemical basis
for increased blood pressure and other symptoms indicative of the phar-
macological action of these drugs. Usually such is not the case.
When the liver is functioning well, it appears to possess the ability
of changing the aromatic amins, which are brought to it from the intes-
tinal vessels, through a process of direct, oxidative deamination to cor-
responding fatty acid derivatives.
Thus, tyramin is changed to paraoxyphenyl acetic acid :
OH
OH
CH2CH,NH2
Tyramin
CH2.COOH
Paraoxyphenyl acetic acid.
and indol ethylamin is changed to indol acetic acid, thus:
CH9CH9NH9 A CH2COOH
Indol ethylamin
Indol acetic acid (urorosein)
Erwins and Laidlaw have actually shown by perfusiou experiments
that indol ethylamin and tyramin are changed respectively to indol acetic
acid and to paraoxyphenyl acetic acid. This suggests that the normal
condition is one in which the amounts of aromatic amins absorbed from
the intestinal contents and carried with the portal blood to the liver, are
oxidized, and thus rendered adynamic in that organ.15 Defective oxida-
tion powers, or a flood of aromatic amins too great for the liver to
handle, would lead to the escape of the unaltered amins into the general
circulation, where they might well lead to increased blood pressure and
associated symptoms.
The preliminary studies of Woolley and Newburgh upon the effects
15 Folin and Denis have apparently found that the oxidization and subsequent pair-
ing of phenols is less quantitative than had been supposed.
BACTERIAL METABOLISM WITHIN THE BODY 689
of injecting1 indol into the circulation of animals suggest that the escape
of unoxidizcd putrefactive products, such as indol or aromatic ainin.s,
from the live;1 to the general circulation is more frequently a causative
factor in the production of symptoms than a mere overproduction and
absorption of these substances from the alimentary canal, when the liver
is functioning normally.
It is conceivable, although evidence upon this point is not available,
that the epithelial or underlying cells of the intestinal tract may possess
to a degree the power of oxidizing or altering these aromatic amines and
other putrefaction products.
Attention is directed at this point to the important studies of Si-
nionds upon the effects of carbohydrate in liver poisoning. He says,
"The administration of sugar will prove to be an important therapeutic
measure in phosphorus and chloroform poisoning, — in human beings, in
acute yellow atrophy and possibly in eclampsia." It would appear from
his experiments and observations that inasmuch as liver enzymic activ-
ity is strengthened, even when specific poisoning has taken place, that a
similar procedure would be of material benefit when the liver is permit-
ting the escape of unoxidized putrefactive products into the general cir-
culation. The administration of carbohydrate, it seems, is at once good
physiology, good biochemistry, and good bacteriology.
Summary
Evidence has been presented that the bacterial decomposition of pro-
teins or protein derivatives for energy may result in the production of
specific, soluble toxins, aromatic, physiologically active amins, putrefac-
tive products, such as indol or skatol, and of unknown products which are
harmful in varying degrees to man. In a majority of instances, these
various products, which are specific for the specific organisms, do not form
in the presence of utilizable carbohydrates. In the latter event, practi-
cally all these bacteria are potentially sour milk bacteria so far as their
products of growth are concerned, forming lactic and acetic acids in place
of specific products of protein degradation.
Many of these protein products of bacterial formation are, or may be,
found in the alimentary canal. It is obvious that a correlation may exist
between alimentation, intestinal bacteria, health, and chronic or acute
disease. Furthermore, the close connection between the nature of the
food and the character of the products produced in the test tube may
have a corresponding relationship in the human alimentary canal, inas-
much as the two reacting agents — food and microbes — are fundamentally
the same in both instances. The striking parallelism between diet and
bacteria is shown in the changes in intestinal bacteria which follow ma-
terial changes in diet.
690 ARTHUK ISAAC KENDALL
D. Intestinal Bacteriology
General History and Development
The earliest convincing studies of the bacteria of the alimentary canal
were those of Theodore Escherich upon the intestinal flora of nurslings.
This talented observer isolated and described many of the more common
and important normal microbes of the intestinal tract, inventing methods
for their recognition which are in use in modified form to-day. He tried
to correlate their physiological processes with normal and abnormal intes-
tinal conditions, as well. This work is of special merit, not only for its
detailed information, but also for the broad viewpoint from which the
work was conducted.
Comparatively little attention was paid to the work of Escherich for
several years after its publication. The discovery of the cholera vibrio
by Koch, in 1883, followed by that of the typhoid bacillus by Gaffky in
1884, focussed attention upon the disease-producing intestinal bacteria to
the virtual exclusion of the normal organisms and their relations. What-
ever progress was made in the study of the non-pathogenic types was
directly associated with methods for their detection and differentiation
from the pathogenic microbes. Intestinal bacteriology, in common with
the entire field of microbiology, became a purely diagnostic science. This
extensive interest in diagnostic intestinal bacteriology has been extremely
fruitful, however. The microbes which are causative agents in practically
all the acute intestinal infections of exogenous origin are now well known,
and the domain of preventive medicine has profited greatly through the ac-
cumulated information relating to the cycles of infection of these
bacteria.
Escherich was unable to isolate the predominating organisms of the
normal nursling feces, although he recognized them morphologically and
realized that he was unsuccessful in this direction. It remained for
Tissier to accomplish this difficult task, and with his studies of Bacillus
bifidus communis, the way was cleared for satisfactory studies of the in-
testinal bacteria from birth to adult life.
The discovery of paratyphoid bacilli by Salmon and Smith, Gartner,
and Brion and Kayser, and their significance by Achard and Bensaude,
and of the dysentery bacilli by Shiga and Flexner, practically com-
pleted the list of bacilli which induce extensive epidemic intestinal disease
in man.
Attention was then of necessity directed to the endogenous intestinal
organisms. Advances were made in two principal directions — the isolation
of bacteria from the normal intestinal contents and their identification,
and, secondly, the study of intestinal microbes at different periods of
BACTERIAL METABOLISM WITHIN THE BODY 691
life. The former studies, which culminated in the comprehensive mono-
graph by Ford, showed quite clearly that the normal organisms were
quite closely related to the coli, proteus and mesentericus groups. This
is suggestive in that the normal bacilli of the alimentary canal which
exhibit chemical characteristics common to the colon-proteus-mesentericus
types remain dominant throughout adult life.16 Observations by the au-
thor upon the residual intestinal flora of a man who starved for thirty-one
days supports this view.
The other line of study considered more specifically the relations which
exist between the normal or abnormal chemical peculiarities of intestinal
processes of microbic causation, and the activities of specific bacteria.
The comprehensive monograph of Herter, summarizing his extensive con-
tributions to the field of excessive bacterial activity in the alimentary
canal, epitomizes the information upon this phase of the subject. Herter
also clearly recognized that the injection of lactic acid bacilli into the small
intestine of dogs reduced the excretion of ethereal sulphates in the urine,
while Bacillus coli and Bacillus proteus appeared to increase intestinal
putrefaction, thus foreshadowing the "lactic acid therapy" which Metch-
nikoff so forcefully presented in his work upon the prolongation of
life. About this time Sittler studied and summarized the corresponding
information with respect to the nursling.
During this period of approximately twenty-five years there was an
ever-increasing precision of methods, both chemical and bacteriological,
and the last decade has witnessed the application of these procedures to
the study of bacterial metabolism under various conditions. As a result
of the application of these more refined methods to the study of bac-
teriological activities, a new viewpoint has presented itself. Many of
the conflicting statements and observations which had embarrassed earlier
investigators have been reconciled, and a fairly definite unification of
the phenomena underlying bacterial chemistry has led to renewed interest
in the highly important field of bacteriotherapy.
Some of the more important relations of bacteriochemistry to bac-
terial metabolism in the alimentary canal follow.
1. The Intestinal Bacteria of Normal Nurslings
The Relation Between Diet and Microbic Response. — The entire ali-
mentary canal of the newly born babe is sterile under normal conditions,
and the first bacteria appear in the intestinal tract several hours after birth
(Escherich). This earliest infection of the alimentary canal is by ad-
ventitious organisms derived from the environment of the infant. The
kinds of microbes found at this time are those which have gained en-
16 This applies only to adults. The flora of nurslings is quite different and distinct
with reference to the type of bacteria and their characteristics.
692 ARTHUR ISAAC KEXDALL
trance through the mouth to the alimentary canal from various sources,
and their numbers — up to the third day of life — are determined chiefly
by their ability to grow in the fetal intestinal detritus, and the cholostrum.
In temperate zones, the initial microbic growth is usually more luxuriant
in summer than in winter.
On or about the third day after birth, the nature and appearance of
the alimentary microbic flora undergoes a clearly discernible change
(Tissier). The variety of forms and dissimilarity of staining reactions
which characterize the postfetal flora give way to the dominance of a
rather long, slender bacillus with slightly tapered ends which rapidly
supplants the adventitious types. This is Bacillus bifidus (Tissier), a
lactic-acid-producing bacterium, characteristic of the intestinal and fecal
floras of a great majority of normal nurslings. It is worthy of comment
that Bacillus bifidus becomes prominent synchronously with the full flow
of the breast milk. Breast milk, it will be remembered, contains more
than six per cent of lactose, and scarcely one and a half per cent of
protein. In addition to Bacillus bifidus, other bacteria in much smaller
numbers are found normally, — Micrococcus ovalis, Bacillus acidophilus,
and even fewer members of the colon and lactis aerogenes groups [the
feces stained by Gram's at this time are strongly positive]. The author
has found that these organisms without exception can grow extremely
well in mediums rich in lactose, and they all produce considerable amounts
of lactic acid. The combined acidity arising from the utilization of
lactose for energy by these bacteria is the principal source of the acid
reaction characteristic of the normal intestinal contents and feces of the
nursling. Lactic acid, in the concentration normally present -in the
intestinal tract, restrains the growth of endogenous proteolytic bacteria,
and it also restricts the development of exogenous, pathogenic microl
which gain entrance to the tissues through the alimentary canal.17
• When, for any cause, as for example decreased peristalsis, the lactose
is absorbed in the higher levels of the tract, a purely protein residuum
is left in the lower levels of the small intestine, and in the large intestine.
Under these conditions, the habitat of the obligate acidogenic bacteria
is restricted, and they are greatly reduced in number and in activity.
This follows through their inability to grow well in a residuum in which
protein derivatives are their only source of energy.
The immediate effect is a greater or lesser reduction in the amount
of lactic acid 18 formed in the intestines, and in consequence of this
"In this connection, the observations of the Medical Research Committee that
dysentery bacilli may be isolated from dejections having a neutral or slightly alkaline
reaction, for days after they are excreted, are of interest. It was found that "dysentery
bacilli could not be isolated from the same stools having an artificially induced acid
reaction ( lactic acid ) , approximately that of the normal nursling movement, even after
a few hours.
"All the lactic acid bacilli appear to produce some acetic and formic acid together
with minute amounts of similar volatile decomposition products of the fermentation of
BACTERIAL METABOLISM WITHIN THE BODY 693
reduction the principal obstruction to the development of endogenous pro-
teolytic bacteria, as Bacillus proteus -and Bacillus mesentericus, is re-
moved, or at least greatly reduced. Also, the absence of lactose and other
utilizable carbohydrate at the level of the tract where Bacillus coli and
related forms are ino.it numerous forces these organisms to become pro-
teolytic in place of fermentative. The net result is an immediate increase
in proteolytic activity, and a decided extension of the proteolytic zone.
Indol and other decomposition products resulting from the utilization
of protein for energy are formed in increasing amounts from the in-
testinal contents, and these may be absorbed from the tract and excreted
as aromatic sulphates or glycuronates into the urine. Peristalsis may
be, and frequently is, further reduced by this process, which tends to
become therefore of the magnitude of a vicious cycle.
The biological basis for successful invasion of the intestinal tissues
by exogenous microbes is probably created or at least augmented hereby,
because available evidence indicates that intestinal invasion is more read-
ily accomplished when the proteolytic activities of bacteria exceed, or
replace, the normal fermentative processes.19
Bacteriologically considered, therefore, the normal nursling intestinal
flora reacts with breast milk in the alimentary canal in a manner analogous
to the natural souring of milk outside the body. Both are essentially
preservative processes. Milk soured by lactic acid bacilli does not readily
undergo putrefactive changes which render it unfit for human consump-
tion. Similarly* the normal intestinal contents of the normal nursling
do not appear to undergo putrefaction.
The lactic acid, representing seme decomposition of lactose, has fuel
value for the body ; hence, it is not an entire loss in terms of the original
caloric value of the milk. In this respect, it is in sharp contrast with
the products arising from the degradation of proteins of milk by bac-
teria which do not ferment lactose. Such putrefactive products as are
known are either useless, or more or less harmful to the human body
when absorbed from the alimentary canal.
It would appear therefore that a natural relationship exists between
the nature of the diet of the nursling and the character of the products
formed in the intestinal tract which are qualitatively those formed in the
natural or artificially induced souring of milk outside of the body. The
bacteria concerned are chemically, but not specifically, the same. Intes-
tinal conditions are unlike those outside of the body. This is true not
the lactose, and to a much lesser degree from fats: — for convenience, the lactic acid
will be mentioned as the principal product, and indicative of the entire group of
acidic compounds.
18 The theoretical advantage of preparing patients for surgical operations, especially
those upon the large intestines, by the induction of a suitable fermentative flora in place
of a putrefactive flora is suggested. Of course this applies to operations which are
not omergency cases, since time is required to effect this change.
694 ARTHUR ISAAC KENDALL
only with respect to temperature [that of the body being 37.5° C., and
that of the outside world varying with climate and season], but also
in association with those purely intestinal factors of secretions, includ-
ing bile, enzymes and products of enzyme activity. These ancillary fac-
tors exercise a not immaterial influence upon prospective intestinal ten-
ants. It is -significant, however, that notwithstanding these environmental
differences, the intestinal souring of milk is the qualitative equivalent
of the spontaneous souring outside of the human body. The significant
factor is the continuous availability of lactose in both processes,
Experimental Evidence of the Effects of Sugars upon the Intestinal
Flora. — Many studies upon experimental animals have shown the effects
of utilizable carbohydrates, as lactose, glucose, and other bioses, and
polysaccharids, upon the establishment of an intestinal flora in adult
animals and man. When such substances are added to the diet in suffi-
cient amounts to permeate the entire absorptive length of the alimentary
canal, the flora induced is the chemical replica of that of the normal
nursling. When the carbohydrates are reduced or eliminated from the
regimen, proteolytic bacteria rapidly gain the ascendency.
Escherich appears to have been the first observer actually to per-
form dietary experiments upon animals. Dogs were selected. A four
weeks' old puppy was fed first upon milk, then upon meat. The changes
in the character of the excreta and of the bacteria in the excreta were
observed in each instance. A milk diet led to the evacuation of bright
yellowish dejecta, the consistency and odor of which were reminiscent
of those characteristic of the normal nursling. The organisms detectable
were very similar to those of a normal nursling.20 Gelatin-liquefying
bacteria were few in numbers, but coccal forms became more numerous.
The substitution of meat for milk induced a striking change in the
appearance of the feces, and in the character of the fecal bacteria. The
former lost their golden yellow color and became dark in color, smaller
in bulk, and possessed of a fecal odor, suggesting in this respect that
of a normal adult. Gelatin-liquefying bacteria increased very decidedly
in numbers and in activity. Coccal forms were relatively diminished.
Spores of proteolytic organisms, presumably of the mesentericus group,
became prominent in stained smears from the meat-diet feces, and the
entire picture, bacterial and chemical, so far as determinations were
possible, suggested that the entire intestinal condition induced was simi-
lar to that of normal adults.
Following this monumental work of Escherich, which was so care-
fully carried out but unfortunately limited because of the meager fund
of bacterial knowledge and the lack of adequate chemical methods avail-
**It should be remembered that the dominant organism of the typical nursling's
feces — Bacillus bifidus — was not known in Escherich's time. It was isolated nearly
fifteen years later (Tissier).
BACTERIAL METABOLISM WITHIN THE BODY 695
able at that time [1886], a series of investigations appeared which
added many detached facts to the problem of intestinal bacteriology.
The discovery of the dysentery bacillus in 1898, and of Bacillus
bifidus in 1900, marks the close of the older period of the study of in-
testinal bacteria. The greatly improved cultural methods, both aerobic
and anaerobic, which resulted in the isolation and identification of closely
related types of organisms, as the several types of dysentery bacilli,
focused attention upon the value of carbohydrates, or derivatives of
carbohydrates, for diagnostic purposes in bacteriology. The decade be-
tween 1895 and 1905 was particularly noteworthy for the numbers of
new types and kinds of bacteria, both aerobic and anaerobic, which were
detected by this procedure.
The problem of the intestinal bacteria was restudied, by the author,
with the great advantage of reasonably accurate methods of bacterial and
chemical procedures in 1909. The relationship between diet and intestinal
flora was observed, and the general phenomena relating to the alterna-
tions in dominance of fermentative and putrefactive intestinal floras in
response to carbohydrate and protein regimens were elucidated at this
time. The first observations were made upon cats and monkeys. It was
found that both carnivorous and omnivorous animals responded to the
same dietary changes in a similar manner.
The striking features were the dominance of an acidogenic intestinal
flora, similar to that of a nursling, upon a carbohydrate diet [glucose
added to milk], and the dominance of proteolytic bacteria in the ali-
mentary canal upon a purely protein diet. The urinary changes also
were significant. Upon a carbohydrate regimen the urinary products of
putrefaction, as indican and phenols, were greatly diminished, or absent.
This corresponded to the chemical activities of the nursling bacteria cul-
tivated outside the body. Such organisms do not form indol or phenol
in culture media. The return to a protein diet was followed very soon
by the appearance, or great increase, of the indolic and phenolic sub-
stances of the urine. The fecal bacteria from such diets were predomi-
nantly proteolytic and reproduced in culture medias under proper condi-
tions the antecedent substances from which indican and the ethereal
sulphates are derived.
It would appear from these observations that there was a very definite
and controllable relationship between certain diets, the bacterial types of
intestinal flora, and the presence or absence of urinary putrefactive
products. These experiments were repeated, greatly amplified, and con-
firmed in a later series (Herter and Kendall).
The following observers, Bahrdt and Beifeld, Sittler, Eettger and
Ilorton, Torrey, Hartje and Klotz, have since corroborated the principle of
the alternation of bacterial types in the alimentary canal in response to
definite dietary stimuli, and have extended the field by indicating the
696 ARTHUR ISAAC KENDALL
selective effects of various carbohydrates upon the types of lactic acid pro-
ducing microbes which become dominant in the intestinal tract as one or
another sugar is added to the diet.
A more recent series of observations by Torrey has not only amplified
this particular aspect of the subject and confirmed anew the principle
of the bacterial response to dietary alternations, it has also shown that
fats play a very minor, or entirely negligible, part in this process.
In general, therefore, it may be stated that the normal nursling in-
testinal flora is essentially fermentative in character. It represents the
natural bacterial response to a definite nutritive condition created within
the alimentary canal by the continuous passage of milk sugar — lactose —
throughout the absorptive area. Furthermore, it is possible to reproduce
essentially the same chemical activities and bacterial types in the in-
testinal tracts of experimental animals, both carnivora and omnivora, by
the administration of the diet of the normal nursling.
2. Adolescent and Adult Intestinal Bacteriology
Adolescents and adults, unlike nurslings, are normally omnivorous.
The proportions of proteins and carbohydrates [principally starches and
dextrins] in the average adolescent and adult diet are more nearly equal
than is the case with nurslings or milk-fed children. The large intestine,
from the cecum to the rectum, therefore, becomes more and more a
receptaculum of the products of protein digestion, and of protein deriva-
tives altered by bacterial digestion. The tendency is for putrefactive
processes to predominate, due to the more or less periodic intervals of
carbohydrate disappearance. These periods of carbohydrate presence and
absence exercise a very decided influence upon the types of bacteria
which can thrive under these intervals of carbohydrate and protein offer-
ings for energy. The obligate lactic acid flora, either Bacillus bifidus
or Bacillus acidophilus, according to Moro, Finkelstein, and the author,
dies out and the succeeding bacteria are of the colon type, which, as has
been stated before, can utilize protein for energy nearly as well as
carbohydrates.
Organisms of the Bacillus coli type, in fact, are the dominant bacteria
of the intestinal and fecal flora in normal adolescents and adult life,
when the ordinary mixed diet is that of the dweller of the temperate
zone. Under such conditions some indol is formed in the alimentary tract
and in many individuals at least — more frequently those who are heavy
protein eaters — it will be found as indican in moderate amounts in the
urine.
The conditions under which indol is formed are also favorable to
the formation of aromatic amins, as histamin, indol ethylamin, or even
BACTERIAL METABOLISM WITHIN THE BODY 697
tyramin. The bacteria which can form amins by the decarboxylization
of the aromatic amins are not thoroughly studied. Berthelot and Ber-
trand have described Bacillus aminophilus, a member of the Mucosus
cap^ulatus group, but according to Koessler and Hanke, Harai, Yoshimura,
Guggenheim, Einis, and Berthelot, it is probable that a number of in-
testinal bacteria can decarboxylize these compounds.
The amounts of the putrefactive derivatives of the aromatic amino
acids found in the urine of normal adults under normal dietary conditions
arc not large in proportion to the amount of protein ingested. The
figures for indican and phenolic bodies, chiefly phenol and paracresol,
are the best known because these substances give color reactions which
are quantitative, or approximately so; consequently, fairly accurate
measurements are possible. About 10 milligrams of indican and about
0.3 gram phenolic bodies are usually found (Folin and Denis). The
fecal content of indol and phenols under these conditions is unknown,
although a variable amount of each must escape absorption.
At times, particularly in purulent infections incited by Staphylococci,
and to a lesser extent by Bacillus coli and Bacillus proteus, some indican
may properly be of parenteral origin, it being well known that these or-
ganisms form indol and phenols from the degradation of tissue and blood
proteins. This is not the usual source of the urinary putrefaction prod-
ucts, however; as a rule they are derived solely from bacterial activity
in the intestinal tract.
Obstruction of the lower levels of the small intestine, intestinal stasis,
and, in general, any factor which leads to an upward extension of the
habitat of Bacillus coli and related forms, is a potent factor for in-
creased protein putrefaction.
It should be noted that the relative desiccation of the intestinal con-
tents at the lower levels of the large intestine, together with the accumu-
lation of products of bacterial proliferation carried down from higher
levels, restricts materially the intensity of growth and activity of the
intestinal flora from the transverse colon to the rectum. On the other
hand, the relative emptiness of the upper small intestine, particularly the
duodenum, in interdigestive periods, has been emphasized by Escherich,
Tissier, and the author and is correlated with a periodic diminution of bac-
teria, most of which are carried downward mechanically with the food.
The net result is a large fluctuation in the numbers of bacteria in the
duodenum, corresponding approximately with the ebb and flow of the
duodenal content of food, and a gradual increase in numbers and decrease
in fluctuation, as the ileum is reached, where an intestinal residuum is
almost constantly present.
At the rectum, the number of living microbes is very greatly reduced,
although the corpses of bacteria [which appear to be insoluble in the
digestive juices] are present in enormous numbers. It has been estimated
698 ARTHUR ISAAC KENDALL
that fully eighty per cent of the bacteria seen in the feces are dead or
so weakened in vitality that they can no longer bp cultivated in artificial
mediums. In other words, the most intense bacterial proliferation is in
the lower ileum, the cecum, and the ascending colon.
The types of bacteria vary at the different levels. In the duodenum
and jejunum, where the carbohydrates are ordinarily abundant during
digestive .periods, the amylolytic bacteria — those which thrive best where
starches are present — are found in dominating numbers.21 At the lower
levels, facultative bacteria, as Bacillus coli — which can grow well upon
a carbohydrate or upon a protein diet — are found to be the principal
types. The carbohydrophilic bacteria are carried to these levels with the
downward passage of the intestinal contents, but gradually decrease in
numbers as well as activity with the diminution of the sugar content of
the intestinal medium.
In the cecum a considerable number of types of bacteria are found,
chiefly those which thrive upon a protein regimen. Starches appear
to play a minor part in determining bacterial types, especially in the
lower levels of the alimentary canal; the products of hydrolysis of the
ordinary starches are glucose, and polymers of glucose. These are not
liberated in considerable amounts at any one time, and the soluble products
of hydrolysis are usually absorbed relatively rapidly. Under these con-
ditions the effect of starches upon intestinal bacterial metabolism, par-
ticularly with reference to their sparing action for protein, is not great.
The observation of Torrey is that fats do not apparently play a prominent
part in the nutrition of intestinal microbes.
It is not difficult to advance an explanation of the sudden rise in
indican when an intestinal obstruction is created. In such cases, car-
bohydrate is removed more rapidly from the intestinal contents than the
protein, leaving a nitrogenous pabulum for the bacteria. The gradual
filling of the intestines to the higher levels encourages a corresponding
extension upward of the habitat of the indol-forming bacteria of the
colon type and the periodic emptying of the duodenum no longer is a
factor in sweeping down the organisms which are resident there. The
net result is an upward extension of the putrefactive flora, and an aug-
21 Surgical operations involving the small intestine are said to be less frequently
complicated by bacterial infection than those of the large intestine. The suggestion
is offered that the microbes of the upper small intestine are not only fewer in numbers
but are also lactic acid producing, and therefore fermentative rather than toxicogenic
in their activities. Whatever of carbohydrate (starch or sugar) there may be h
the food is absorbed chiefly from the intestines — not from the stomach (Howell)-
and therefore the upper levels are periodically or even constantly bathed in this grouj
of non-nitrogenous substances. In the interdigestive periods the food passes downward
carrying a majority of the bacteria with it. This appears to be an explanation of the
prominence of acidogenic bacteria in the duodenum.
At the lower levels, the normal adult intestinal flora is facultative with referen(
to proteolysis; such organisms are more commonly found to be incitants of infectic
than the more strictly or obligately acidogenic forms.
BACTERIAL METABOLISM WITHIN THE BODY 699
mentation of its activity beyond normal. Indol and other substances are
formed in increased amounts and, for a time at least, appear to be ab-
sorbed from the intestinal contents [which are not desiccated at these
levels] into the blood stream. Very shortly thereafter the normal capacity
of the liver to oxidize the indol to indoxyl, and to pair the latter with
sulphuric acid [or, more accurately, with the monopotassium salt of sul-
phuric acid] is exceeded, and there is an overflow of indol into the general
circulation.
Normally, the indol and phenols, and other products arising from the
bacterial decomposition of aromatic amino acids, are oxidized in the liver,
as indicated in a preceding article, before they enter the general circu-
lation. They are excreted from the circulation chiefly as aromatic sul-
phates, but whenever the available sulphate is decreased in amount, the
body produces glycuronic acid, and pairs these aromatic nuclei with that
substance prior to elimination through the kidneys into the urine. By
this process the body is rid of these somewhat toxic putrefactive sub-
stances, their toxicity being reduced materially by the dual process of
oxidization and pairing with sulphuric or glycuronic acid.
The phenomena of intoxication ordinarily ascribed to indol, and
probably participated in by other aromatic residues of amino acids, are
frequently associated with one or more of three factors; first, the con-
tinued production of unusual amounts of indol formed in the alimentary
canal as the result of an unsuitable amount of protein in the diet, or
persistent intestinal stasis, or both. This may lead to the absorption of
amounts of the aromatic nucleus beyond the normal capacity of the liver,
and the excess of indol then may appear as such in the general circulation.
Secondly, defective oxidative power of the liver, leading again to the sys-
temic flooding with indol; or, finally, an impaired power of combining
the oxidized indol with sulphuric or glycuronic acid.
Any of these processes, imperfectly carried out, may result in the
slow, cumulative effects which eventually are recognized clinically by
lassitude, malaise, headache, and dizziness, and other symptoms spoken
of as "auto-intoxication."
It is quite as possible for an individual to suffer from an excessive
production of lactic acid of intestinal origin as it is to be injured by an
overproduction of indol or other bacterial derivatives of the aromatic
amino acids. Such conditions have been described by Escherich, Finkel-
stein and Salge. The few cases on record occurred in young children,
once in almost epidemic proportions, in a hospital in Gratz.
The causative factor appears to be an upward extension of the normal
zone of growth of Bacillus acidophilus, or a closely related organism, into
the small intestine. The most prominent symptom is a profuse, watery
diarrhea. The dejections are yellowish and have a very sour smell. The
acidity in the few cases studied was found to be four to eight or even
700 ARTHUR ISAAC KENDALL
ten times that characteristic of the normal acidophilic stool. In spite of
the great prostration, there was little evidence of a toxemia of ali-
mentary origin. The removal of all carbohydrate from the diet appeared
to reduce the excessive acidity quite promptly. Excessive lactic acid pro-
duction in the digestive tract is uncommon.
3. Sour Milk Therapy and Bacterial Metabolism
For more than two decades, evidence relating to possible correlations
between products of protein putrefaction in the alimentary canal and those
somewhat general symptoms designated by many observers "auto-intoxica-
tion," has been collecting. Metchnikoff, following a suggestion by Herter,
wove the various observations and facts upon this subject into a coherent
theory covering the salient features and advanced his sour milk therapy
as a remedial procedure to combat these conditions.
Briefly, the Metchnikoff hypothesis is as follows: .In advanced adult
life, or earlier, the intestines become populated with bacteria, chiefly an-
aerobic, which produce, indol and other putrefactive products in unusual
or intolerable amounts. The antecedent cause is a protein-rich diet. The
absorption of these substances for variable periods of time leads to arterial
hardening and that series of structural changes which is frequently spoken
of as premature senility. The site of trouble, says Metchnikoff, is chiefly
the large intestine. In support of this view, two cr three instances are
cited in his book in which patients suffering from so-called intestinal
toxemia were benefited by the shortening or removal of the large intestine
by surgical operation. By so doing, the offending bacteria and their en-
vironment were simultaneously eliminated.
In contrast to this possibility, that longevity and the normal approach
to uncomplicated old age are interfered with to a degree by excessive
bacterial putrefaction in the cecal cesspool, attention was directed to the
unusual span of life enjoyed by some of the Biblical patriarchs (Piffard).
Metchnikoff also found that longevity is, or was, a noteworthy char
acteristic of those inhabitants of southeastern Europe who drink mil
soured by lactic acid bacteria as a principal article of food.22
The suggested relationships between soured milk,23 sour milk bacteria,
longevity, on the one hand, and mixed diets, intestinal putrefaction and
auto-intoxication, with premature senility on the other hand, have led
Metchnikoff to conceive of the possibility of replacing the putrefactive
intestinal flora by the lactic acid bacilli of Bulgaria. Replacing malig-
23 Souring is induced by adding to the freshly drawn milk lumps of coagulated
casein containing impure cultures of lactic acid bacilli, known variously as Kephir
granules, Lebenraib, Maadzoun, Yoghourt. and by other names.
23 The souring of milk is the only method of preservation in warm countries where
refrigeration can not be practiced.
BACTERIAL METABOLISM WITHIN THE BODY 701
nant microbes by beneficent bacilli, and encouraging the latter to colonize
in the large intestines as a safeguard against future endogenous poisoning,
is the essence of the Metchnikoff hypothesis.
The method of administration of the Bulgarian sour milk bacillus was
through milk which first was to be sterilized, then inoculated with a
pure culture of the organism, and set aside to ferment to a high degree
of acidity. Milk thus soured and populated with enormous numbers of
Bulgarian bacilli was to be drunk in large amounts daily. It will be seen
that the objective to be attained was to introduce naturally preserved milk
[soured milk] containing preformed lactic acid, into the alimentary canal,
in the expectation that it would not undergo putrefaction there. Also,
that the Bulgarian bacillus would become resident, and supplant the naj
tive putrefactive microbes.
The results have, on the whole, been disappointing from the clinical
point of view, although sour milk has unquestionably become a popular
beverage. It is unfortunate that the emphasis was laid upon the accli-
matization of the bacilli of Bulgarian kephir granules in the alimentary
tract of man. Available evidence through the work of Herter and Ken-
dall, and Rahe, indicates they do not grow in the alimentary tract in com-
petition with the normal intestinal flora. From a priori considerations
there is little justification for the belief that they would grow there. Ob-
servations upon the alimentary flora of normal or milk-fed nurslings have
never revealed the presence of Bulgarian bacilli. It might confidently
be expected that lactic acid producing bacteria, parasitic in milk, would
grow if they could endure the intestinal environment. On the contrary,
the human intestinal lactic acid bacilli which thrive on a milk diet are
Bacillus bifidus in the normal nursling, and Bacillus acidophilus in arti-
ficially fed babies.
One of the important details of the Metchnikoff sour milk therapy
procedure is a restriction of the protein in the diet of the patient. It is
quite clear that rigorous attention to this factor is of unqualified benefit.
To make up the requisite caloric [energy] content of the food, some sort
of carbohydrate is recommended. It was surmised that the carbohydrate
might also help establish the Bulgarian bacillus as an intestinal inhabit-
ant
It may be stated that the chief value of the sour milk therapy as out-
lined above was to introduce considerable amounts of preformed lactic
acid. There appears to be little doubt that this lactic acid of exogenous
origin is an important restrictor of certain types of intestinal fermenta-
tion, especially that in which the "gas bacillus" is either a causative factor
or at least an indicator through its unusual luxuriance of growth (Kendall
and Smith, Hewes and Kendall, and Simonds).
There is no very definite proof that anaerobic bacteria are important
factors in intestinal putrefaction. Indeed, the evidence points to Bacillus
702 ARTHUR ISAAC KENDALL
coli and related forms as the more common organisms which produce
indol in the alimentary canal.
From what has been stated above, the increase in carbohydrate and
a restriction of the protein in the diet tend of themselves to change the na-
ture of the products formed by colon and other bacilli from the indolic to
the lactic type. If enough carbohydrate can be ingested to maintain a car-
bohydrate content throughout that portion cf the tract where bacterial pro-
teolysis is dominant, the substitution of lactic acid for products of' protein
putrefaction through the shifting of the metabolism of the facultative
bacteria, as Bacillus coli, naturally follows. The success of the dietary
change will depend in no small degree upon the extent to which carbo-
hydrate may be kept continuously in the alimentary canal. In general,
therefore, it may be stated that the chief beneficial results observed
in cases of so-called intestinal auto-intoxication which have been dieted
upon Bulgarian lactic acid milk are to be ascribed largely to the restriction
of the protein, and to an increase in the carbohydrate.
This leads to a diminution of the protein residuum in the intestine, to
the shifting of the metabolism of the intestinal putrefactive bacteria, and to
lactic acid production in- place of indologenesis. The increase of peristal-
sis, and partial or complete relief from constipation, which not infre-
quently follows the change from a basic to an acidic reaction in the middle
segment of the alimentary tract, may also be a factor in the beneficial
process.
Since the publication of Metchnikoff's work, many attempts have been
made to secure cultures of lactic acid bacilli for purposes of lactic acid
implantation. None of these to date are selected with a view to their
fitness for intestinal acclimatization. The efforts have been to seek for
milk parasites, which will produce a smooth, palatable and very acid
sour milk outside the human body. Some cultures have even been dis-
pensed as tablets or lozenges. The bacteria in such preparations are
dried, much like commercial yeast cakes, and are to be taken in this form.
Frequently, the directions for using these dried cultures of bacteria fail
to indicate that sugar be taken with the bacterial tablets. It must be
obvious that these bacteria, or almost any other bacteria, cannot be ex-
pected to produce therapeutic amounts of lactic acid unless they are pro-
vided with a source of energy from which lactic acid may be formed.
If, therefore, intestinal implantation of normal lactic acid bacilli is
to be practiced, it would appear logical to select normal intestinal lactic
acid bacilli for inoculation into milk, intended for therapeutic purposes,
or for ingestion as pure cultures, and to maintain these cultures under
conditions which shall guarantee they have not lost their intestinal para-
sitism in favor of parasitism upon artificial media outside the body (Rotch
and Kendall). It is not improbable that frequent passage of such cul-
tures through the alimentary canal will be found essential to maintain
BACTERIAL METABOLISM WITHIN THE BODY 703
their intestinal parasitism, quite as frequent passages of pneurnococci
through experimental animals are required to maintain their virulence.
To summarize: there appears to be an abnormal state or condition,
more common in adults of middle age or older, in which available evidence
points to putrefactive products, the results of bacterial decomposition of
protein residues in the alimentary tract, as the underlying cause. This
state or condition is referred to by many as "auto-intoxication."
If such be the case, the cure, or at least the arrest, of the morbid
process, naturally would be a restriction or prevention of the putrefactive
bacterial processes within the alimentary canal. The bacteria which are
known to produce indol, aromatic amins, and other similar putrefaction
products associated with the phenomena of auto-intoxication are for the
most part microbes of the colon-proteus-mesentericus groups. These bac-
teria produce the putrefaction products when they utilize protein or
protein derivatives for energy. When they utilize carbohydrate for
energy, these same bacteria produce lactic and other acids. If periods of
ebb and flow of carbohydrate occur in the alimentary canal, where these
organisms are abundant, there will be corresponding alternate periods of
putrefaction and fermentation.
It follows that a continuous supply of the proper kind of carbohydrate
will result in a continuous production of lactic acid. Implantation with
normal intestinal lactic acid bacilli, as Bacillus acidophilus, with a con-
tinuous supply of carbohydrate, will tend theoretically at least to dimm-
ish the numbers of colon-proteus-mesentericus types, and restrict their
activities. Such a procedure probably will be found to be feasible in
a proportion of appropriate cases.24
Lactic acid or sour milk therapy has not yet reached its final develop-
ment. The brilliant conception of its possibilities as a contribution to
gastro-intestinal therapy is a monument to Metchnikoff's genius and con-
structive imagination.
The discussion of intestinal bacteriology thus far has revealed two
distinct but related types of response to dietary alternations: First, a
change in the type of bacteria, as, for example, the dominance of Bacillus
bifidus in the normal breast-fed infant, and, secondly, the change in
metabolism as protein or carbohydrate is available for the energy require-
ments of the bacteria. The dominance of types is usually met with when
the diet is monotonous, and with a preponderance of one or another type
of energy-producing substance. In the case of milk in the normal nursling,
the seven per cent of lactose is the determining factor. On the other
hand, when the energy producing substance changes from time to time,
as for example in the lower levels of the small intestine of adults, where
periods of carbohydrate ebb and flow are superimposed upon a protein
"Certain ill effects of unrestricted feeding of carbohydrate are discussed under
Endogenous Intestinal Infections, ride infra.
704
residuum, bacteria which are accommodative to alternations in metabolisi
are confidently to be looked for. Such happens in the adult alimentary
canal, and facultative bacteria, as Bacillus coli, which can accommodate
their metabolism to protein or carbohydrate energy, become the dominant
organisms.
The nature and extent of bacterial acclimatization in the intestinal
tract is not a matter of indifference to the host; the character of tl
normal resident flora is of equal or greater importance.
It is conservatively estimated that a normal, healthy adult, enjoying
an average mixed diet, excretes daily in the feces from one hundred to
thirty hundred billion of bacteria (Schmidt and Strasburger, McNeal,
Latzer and Kerr, and Cammidge): The dried weight of this bacterial
mass would exceed five grams, and the nitrogen in it alone would weigh
nearly seven-tenths of a gram. It is apparent that the ingested food
does not contain this prodigious number of bacteria, and, furthermore,
the kinds of organisms isolatable from the excreta do not coincide in
type or proportion with those of the regimen. Indeed, many of the latter
do not appear to endure intestinal conditions and the bacterial antagonisms
therein. It must be conceded, therefore, that the alimentary canal is a
singularly efficient incubator and culture medium from the bacterial point
of view; an environment in which bacterial growth along rather definite
lines exceeds in intensity and selectiveness that of any known natural
process.
The range of reaction and the composition of nutritive substances
at different levels are such that theoretically a great variety of organisms,
capable of growing at body temperature, might find conditions favorable
for their development. Notwithstanding the nutritive possibilities
throughout the alimentary canal, from starches to glucose and fermenta-
tion acids, from practically unaltered protein to amino acids and extrac-
tives, and from fats to fatty acids and glycerin, the number of types
of bacteria which occur normally and in significant numbers in this in-
cubator-culture medium is surprisingly small. They are also fairly well
known.25
The underlying principles of normal intestinal bacteriology, in the
light of available information, may be summarized from the clinical view-
point as follows:
1. The constant temperature, variety of food, and range of reac-
tion in the alimentary canal create conditions favorable to bacterial
growth.
2. The bacterial response to these conditions is enormous, viewed
25 A distinction is made between the resident bacterial types which persist under
normal dietary conditions for considerable periods of time, and those transient forms
which successfully run the intestinal gauntlet, and which may be encountered in any
massive bacterial process. Exogenous pathogenic bacteria, which will be discussed
below, are specifically excluded from the present discussion.
BACTERIAL METABOLISM WITHIN THE BODY 705
from the standpoint of numbers — a normal adult eliminates daily several
hundreds of billions of microorganisms in the feces.
3. The opportunities for bacteria of the most varied kinds to enter
the mouth and to pass to the intestinal tract are almost unlimited. At
one time or another virtually all bacteria from the outside world may
thus become prospective tenants. Notwithstanding this possibility of a
most varied immigrant flora, the predominant and, presumably therefore,
the normal intestinal flora is composed of strikingly few types. The
daily proliferation of these few types is responsible for the bulk of bacteria
excreted in the feces.
4. Starvation reduces the number of bacteria materially, but the
types found in the intestinal flora under such a condition are of the
normal kinds.
5. A monotonous diet, in which carbohydrate continuously permeates
the intestinal tract, leads to a simplification of the intestinal flora. In
normal nurslings, obligately acidogenic bacteria of the bifidus type be-
come dominant. In dextrin-starch mediums, members of the Bacillus acid-
ophilus type predominate.
6. The products characteristic of the activity of the obligate fer-
mentative flora are normally innocuous and in a measure protective, in that
the lactic acid generated is a deterrent to the growth of non-fermentative
[putrefactive] organisms. A similar phenomenon is observed in milk
soured outside the body. It does not ordinarily putrefy.
7. It is sometimes observed that an overgrowth of acidogenic bac-
teria, as Bacillus acidophilus, may lead to intestinal disturbances, par-
ticularly in young children. An overgrowth of the gas bacillus [Bacillus
welchii] may also lead to, or be associated with, severe intestinal dis-
turbances which may become serious.
8. Upon a diet in which the proportion of carbohydrate to protein is
nearly equal, leading to periods of ebb and flow of carbohydrate in the
lower levels of the intestinal tract, the facultative organisms, members of
the colon-proteus-mesentericus groups, become the principal kinds met
with. Such a flora is more varied because a greater number of bacteria
capable of deriving their energy from carbohydrate or protein can thrive
in the intestinal environment than appears to be possible with the more
or less obligately fermentative, lactic acid types.
9. The facultative flora, in which periods of carbohydrate ebb and
flow is the dietary determinator, partakes of the acidogenic and amino-
tienic types respectively. At a given level of the tract, during these periods
in which ample carbohydrate is present, the acidogenic activities of the
flora are stimulated. During intervals of carbohydrate deficiency, the
proteolytic activities are resumed.
10. A continuous, relative deficit of carbohydrate in proportion to
the protein in the diet leads to the establishment of a proteolytic flora,
706 ARTHUR ISAAC KENDALL
in which protein-liquefying organisms of the mesentericus and proteus
types, together with smaller numbers of other similar organisms, are
the prominent varieties met with.
11. The putrefactive products formed by the facultative and purely
proteolytic types of intestinal bacteria comprise, in addition to unknown
substances, aromatic amins, fatty acids, and aromatic nuclei of amino
acids. Of these, histamin, tyramin and indol ethylamin are physio-
logically active even in minute amounts. Also, indol, phenol, paracresols,
and skatol are formed in recognizable amounts. The subsequent fate
of these substances within the body has already been discussed.
4. Exogenous Intestinal Infections
Bromatherapy. — Thus far, emphasis has been placed upon the prin-
ciples underlying the general phenomena of bacterial metabolism, and
applications of these principles to the elucidation of the mutual and re-
ciprocal relations between diet and microbic response in the normal, or
nearly normal, digestive tract.
An obvious extension of these principles to the therapeutics of ex-
ogenous and endogenous infections of the intestinal tract clearly presents
itself. The need for specific therapy in intestinal infections is very
great. The treatment of typhoid, cholera, dysentery, and other enteric
diseases is expectant and supportive. There are no serums or antitoxins
of proven value available, and chemotherapy is thus far unsuccessful.
There is clearly an important place in clinical medicine for procedures
of specific intervention which are in favor of the host, and antagonistic to
the microbe, once infection is established. The prevention of infection
does not of course enter into the discussion at this point,
A theoretical basis for specific intervention in intestinal bacterial in-
fection resides in the relation of carbohydrate and protein sources of
energy to the production of benign or noxious products of metabolism by
pathogenic and parasitic bacteria. It will be remembered that diphtheria,
dysentery, cholera, typhoid, paratyphoid, colon, proteus, and many other
organisms form benign lactic acid from utilizable carbohydrate. They
are potentially buttermilk bacilli so far as the chemical products of their
growth are concerned, upon a suitable sugar diet. The removal of the
carbohydrate, however, is immediately followed by the formation of
nitrogenous, noxious products, many of which are poisonous.
Available evidence indicates that the same metabolic phenomena are
involved in the intestinal culture in vivo and in the artificial culture
in vitro. The underlying principles are identical. "Utilizable - carl
hydrate protects protein from bacterial decomposition."
This principle of the protective action of utilizable carbohydrate fc
BACTERIAL METABOLISM WITHIN THE BODY
protein has been deliberately applied by the author in the treatment of
bacillary dysentery. This is a severe infection of the intestinal mucosa
incited by Bacillus dysenteric, of the Shiga, Flexner, or Flexner variant
types. The effects are particularly severe in young children. The in-
fective agent is restricted chiefly to the large intestine, and the organisms
do not usually penetrate tissues deeper than the mesenteric lymph nodes.
The essential specific feature of this treatment was to feed the patient
lactose solution by mouth ; glucose was injected subcutaneously for reasons
to be detailed later.
Lactose was fed to permeate the entire digestive tract of the patient.
By so doing the metabolism of the dysentery bacilli, and of the resident
intestinal population as well, was shifted from protein to carbohydrate.26
Two distinctly specific but related beneficial results were expected: To
reduce the formation of toxins by the dysentery bacilli and to prevent
the formation of indol and other putrefactive products by Bacillus coli
and other intestinal organisms. The other beneficial effect hoped for
would come from the acidification of the intestinal tract, due to the com-
bined lactic acid generation of the entire intestinal flora, both pathogenic
and parasitic. One of the significant results of lactose feeding was a
reappearance of the normal nursling lactic acid bacilli ; especially Bacillus
bifidus and Bacillus acidophilus. In favorably progressing cases, these or-
ganisms rather rapidly became prominent. Their energetic lactic acid
generating powers were of undoubted significance in rendering intestinal
conditions intolerable for the acidophobic dysentery bacilli.27' 28
In addition to the oral feeding of lactose solutions, two other pro-
cedures for the administration of carbohydrate were practiced. One of
these was an attempt to give glucose-lactose irrigations per rectum in
the hope that some of the sugar would pass the sigmoid and enter the
absorptive areas of the large intestine. This was soon abandoned. It
proved to be annoying to the young patients without a proportionate gain.
The ether procedure was to infuse glucose solutions subcutaneously
28 The generally accepted treatment for bacillary dysentery in young children at
this time was starvation, upon the assumption apparently that the dysentery bacilli
would gradually exhaust themselves. Water alone was given. It was obvious that
all the intestinal microbes of necessity became proteolytic. The dysentery bacilli
formed toxin, the colon bacilli indol, and the entire burden of detoxicating whatever
of these nitrogenous products were absorbed from the intestinal tract fell upon the
liver. The intestinal secretions and tissues furnished the requisite protein for the
formation of these harmful products.
27 The antagonistic effects of lactic acid production upon the viability of dysentery
bacilli in the intestinal tract and dejecta have recently received unexpected substantia-
tion in the Report of the Medical Research Committee.
28 It is probable that lactic acid produced by microbic action within the alimentary
canal and immediately in the presence of acidophobic bacteria is more effective in its
action than an equal quantity would be brought from a distance. The neutralizing
effect of salts and alkaline secretions would certainly change considerable amounts
of the acid to the lactate, which is far less effective in its inhibition of microbic
activity.
708 ARTHUR ISAAC KENDALL
(Heilner, Allen).29 It was found that young children could not retail
even water by mouth when the dysenteric infection was severe. The dehy-
dration of the tissues following the profuse diarrhea left the patients in a
serious condition. The addition of glucose (Allen) to the saline infusion
was devised to provide the tissues with an immediately utilizable source oi
energy as well as restore body fluid. It was also hoped that some
this glucose would be carried to the mesenterlc lymph nodes or other
tissues where bacteria might be growing within the body, and thus aid ii
a reformation of their metabolic products. This would mean, if it were
realized, that the dysentery bacilli within the tissues would produce lactic
acid in place of toxin so long as the glucose was available. In other
words, these dysentery bacilli would become potentially lactic acid microbes.
An unexpected beneficial effect of lactose feeding was noticed. Chil-
dren that constantly regurgitated water appeared to retain the lactose
solution without difficulty. No explanation presented itself to account
for this peculiar result.
At first sight, the selection of lactose as the carbohydrate for oral
administration might be criticized on the ground that dysentery bacilli
do not ferment this sugar* It should be emphasized, however, that lactose
is more slowly absorbed from the digestive tract than any other sugar.
This fact alone would increase manyfold the chances of permeating the
entire intestinal canal with sugar.30 Lactose is fermented by a majority
of the normal intestinal bacteria and it will be remembered that -one
objective of the specific dietary treatment of toxic intestinal infection
is to reduce intestinal bacterial prcteolysis and augment lactic acid pro-
duction. Acidogenesis should extend the entire length of the tract to be
effective.
Lactose is apparently hydrolyzed in the intestinal mucosa by the
enzyme lactase (Morse and Talbot). The products of hydrolysis are the
hexoses, glucose and galactose, both of which are readily utilized for en-
ergy by dysentery bacilli. Inasmuch as the dysentery bacilli are grow-
ing in the intestinal mucosa, the advantages of liberating fermentable
sugars there are obvious.
There is of course the possibility that the intestinal mucosa and im-
mediately underlying tissues might be so injured by the poisons of the
dysentery bacilli that the cleavage of lactose might be interfered with.
It is not possible to disprove this contingency, but it may be stated that
repeated examinations of urines from a series of cases treated in this
manner were invariably negative with reference to the presence of re-
29 These infusions were sterilized solutions of normal saline containing 2.5 per
cent of Kahlbaum's chemically pure, anhydrous glucose. From two to four ounces were
injected very slowly each d,ay by the subcutaneous route for several days.
hepeated, relatively small, feedings of lactose were prescribed rather than fewer,
larger amounts. This was to insure the continuous presence of sugar throughout the
intestinal tract.
BACTERIAL METABOLISM \VITHIX THE BODY 709
ducing sugars. This would suggest that unaltered lactose failed to enter
the tissues and blood stream in significant amounts.
It was soon realized that prolonged feeding of carbohydrate alone
became harmful. This might confidently have been expected. Subse-
quent feeding with lactose-protein solutions were very well tolerated, no
evil results attributable to the protein being observed so long as the car-
bohydrate was fed in amounts sufficient to insure a continuous flow to
the lowest levels of the alimentary canal. Protein solutions without car-
bohydrate were found to be distinctly harmful.
The earlier cases of bacillary dysentery treated with the protein-lac-
tose diet as indicated showed neither signs nor symptoms suggestive of
harm arising from the liberal use of lactose. Somewhat later in the
season, however, a striking instance of apparent harm attributable to
lactose feeding presented itself. Inasmuch as this case presents details
of importance in connection with the therapeutic application of dietary
procedures to bacterial infections, the salient features will be briefly
related.
A young child was convalescent from a severe attack of bacillary
dysentery. It had passed successfully through the febrile and diarrheal
stages of the disease upon the lactose-protein diet, and was apparently
in such good condition that a more liberal regimen was indicated. Sud-
denly, without warning, the diarrhea reappeared together with the san-
guineous, mucopurulent intestinal discharges previously observed. The
clinical picture at first sight was one of a severe relapse. It was per-
fectly clear at this stage of the case that the lactose-protein feedings were
distinctly harmful. They aggravated the patient's condition beyond rea-
sonable doubt. It was observed that there was a slight difference in
the constitutional symptomatology of this new attack. The patient was
weakened very greatly, but the mental signs of profound toxemia were
disproportionately slight as compared with those of the initial infection.
Repeated attempts to isolate dysentery bacilli from the feces and
blood-stained mucus were unsuccessful at this time, although no trouble
had been experienced in cultivating the organisms during the earlier
diarrheal period. Gas bacilli [Bacillus aerogenes capsulatus or Bacillus
welchii], however, were found in abundance. This had not been en-
countered in the dysenteric period of this case, nor had they been de-
tected in other dysentery cases previously studied.
It is well known that gas bacilli are intolerant of preformed lactic
acid, and with this in view well-soured buttermilk was administered in
considerable amounts in place of the lactose-protein solution. 3* The symp-
toms, including the diarrhea, promptly abated, and the patient made an
31 The use of well soured milk in cases of overgrowth of gas bacilli in the intestinal
tract is an important example of the value of lactic acid milk in intestinal therapy.
(Kendall and Smith, Hewes and Kendall.)
710 ARTHUR ISAAC KENDALL
uneventful recovery. Subsequent examination of some of the lactose
itself revealed an extensive contamination with the spores of the gas
hacillus. Even so small an amount as ten milligrams sufficed to produce
the well-known stormy fermentation of milk, and the development of
the rancid odor characteristic of butyric acid. The injection of some of
this milk into rabbits produced the characteristic distention, foamy liver
and other signs of the Welch-Nuttall test, thus affording ample con-
firmation of the diagnosis.
The origin of the second attack of profuse diarrhea and the obvious
relationship between the lactose and the aggravation of the symptoms in
this case is very clear. The contaminated lactose was responsible for a
direct implantation of spores of the gas bacilli in the digestive tract
of this child.32 These spores vegetated, and the gas bacilli multiplied
rapidly. Inasmuch as Bacillus welchii is a most energetic fermenter
of carbohydrates (Simonds, Blake), producing therefrom considerable
amounts of butyric acid, it was in all probability the irritant effect of
this acid upon the intestinal mucosa which caused the diarrhea. The
absence of symptoms of toxemia is probably associated with the fact
that butyric acid is not a toxin.
Two other patients, out of a number of dysentery cases undergoing
the lactose-protein treatment, also developed gas bacillus diarrhea before
the condition and its remedy were recognized. The administration of
buttermilk was as effective in arresting the process in these cases as it was
in the first instance. It should be mentioned in passing that gas bacillus
diarrhea was so prevalent two years later among patients coming to the
same hospital,33 that it might be said to have existed in epidemic pro-
portions (Kendall and Smith). It was not transmitted through lactose
at this time, however, inasmuch as the infection existed prior to their
admission to the clinic. Buttermilk proved to be as efficacious in the
treatment of this group as it had been in the single cases just men-
tioned.34
To summarize: these dysentery cases and the gas bacillus infections
arising from them are of interest from two viewpoints: First, because
underlying principles of bacterial metabolism observed in culture and in
the normal digestive tract have a direct bearing upon the specific dietary
treatment of intestinal infections. Indeed, these principles are applicable
to any infection where the anatomical relations to the host are such that
full advantage may be taken of procedures which shall alter directly
the metabolism of the microbe in favor of the host. These conditions
w All lactose solutions were subsequently sterilized in the autoclave, and all trouble
from this source was at an end.
83 Fifty-three out of a total of one hundred and thirty-five cases of severe diarrhea
studied. (Kendall.)
"Similar cases have been seen in adults; also subacute and chronic types are
occasionally met with. They are usually unrecognized, however. (Hewes and Kendall.)
BACTERIAL METABOLISM WITHIN THE BODY 711
usually may be predicted. Secondly, apparent exceptions to the practical
working out of these principles may be caused by the abrupt development
of latent, unrecognized organisms whose activities are favored by the
regimen which controls those of the primary infective agent.
Such instances are not indicative of a failure of the principle; in
fact, they are supplementary evidence of the correctness of the principle.
They do suggest the necessity of a complete survey of the residual intestinal
flora as a basis for the formulation of a correct dietotherapy. The
gradual, or rapid, reestablishment of a normal lactic acid flora, antago-
nistic to the development of the dysentery bacilli was readily determined
by direct examination of the fecal flora, by cultural methods, and by
chemical determinations of lactic acid. TJie shifting of the metabolism
of intestinal organisms of the colon type was rendered probable. The
shifting of the metabolism of the dysentery bacilli from toxicogenic to
acidogenic was surmised. It could not be definitely proven.
The clinical results were, generally speaking, favorable. In no in-
stance was any harm to the patient discernible. If it were possible to
determine the initial damage to the patient by the dysenteric infection
before specific food therapy was started, much more accurate statements
could be made with reference to the probable beneficial effects of dietary
treatment as a means of preventing subsequent poisoning. It may be
stated without reservation that whatever was accomplished by direct
dietary interference with the antagonistic activities of the dysentery
bacilli was entirely in the interest of the host.
It is unfortunate that accurate chemical studies of the metabolism of
at least a few of the cases so treated could not have been made. It
was apparent that the dysenteric intoxication produced a deep-seated and
unfavorable effect upon the metabolic processes of these patients.
The only available evidence is qualitative, not quantitative. The re-
duction of signs and symptoms of toxemia, the general suggestion of an
amelioration of the severity of the infection, improvement of intestinal
conditions with respect to digestion, and a tendency toward a relatively
early recovery from loss of weight suggested that those same dietary
factors which would theoretically restrict the pernicious activities of the
invading microbe were favorable to the return of the host to a normal
state.
Although metabolic studies upon dysentery cases fed with the lactose-
protein diet are not available, the effects of the Shaffer-Coleman high
calorie diet in typhoid fever offer a somewhat parallel condition. It
has long been known that there is a "toxic destruction of body protein"
in infectious febrile diseases, as typhoid, which is probably due in part
to simple pyrexia, and in part attributable to the toxins originating with
the organisms causing the morbid condition. The loss of tissue nitrogen
and of body weight may be very considerable in typhoid fever, particu-
712 ARTHUR ISAAC KENDALL
larly if the partial starvation diet principle be adhered to. Shaffer and
Coleman sought to prevent this large loss of body nitrogen. They were
led to prescribe a diet moderately rich in protein dnd fat, and extremely
rich in carbohydrate, through a consideration of the well-established physi-
ological dictum that carbohydrate spares body protein. They were able
to keep several typhoid patients in approximate nitrogen equilibrium,
but little below the normal, upon such a high calorie diet, and this form
of dietary treatment has been rather generally adopted since the appear-
ance of their studies.
The sparing action of the carbohydrate for body protein was mani-
fested by the relatively slight losses in weight experienced by their pa-
tients. Another, and perhaps unexpected, result was observed. The
toxic appearance, the "typhoid facies" of older days and accompanying
symptoms of toxemia were noticeably reduced in those patients who were
obviously benefited by the carbohydrate-rich diet. Among their conclu-
sions, they state: "The 'toxic' destruction of body protein, as well as
the destruction due to simple pyrexia in this disease [typhoid] may be
either prevented or compensated for." "If, as seems probable from our
results, the 'toxic' destruction of body protein may be prevented by a
large carbohydrate intake, the mechanism of this 'toxic' destruction can-
not be a direct [poisonous] injury to body cells and protein."
Bacteriologically, typhoid fever exhibits several similarities to bacil-
lary dysentery. Both are initially intestinal infections. The dysentery
bacillus rarely penetrates beyond the mesenteric lymph nodes, but typhoid
bacilli usually invade the blood stream and may enter all the tissues.
From the viewpoint of bacterial metabolism, a carbohydrate rich diet
would be quite as much indicated to induce a reestablishment of the
intestinal flora, and a reformation of the metabolism of the typhoid
bacillus in typhoid fever as is the case correspondingly in bacillary
dysentery. The careful study of Torrey upon the intestinal flora of
typhoid patients receiving the high calorie diet indicates that there is
a clearly discernible change of the intestinal bacteria very similar to that
observed in bacillary dysentery cases fed upon a lactose-protein diet.
Torrey says, "On a diet consisting of a daily average of 50-100 grm. of
protein, 75-100 grm. of fat, and 250-300 grm. of carbohydrate, including
lactose, the intestinal flora tended to become converted into a fermenta-
tive type in which the dominant organism was Bacillus acidophilus.
Patients exhibiting an initial fermentative flora of the aciduric type
adapted themselves more readily to the high calorie diet of Coleman
—in such patients the disease showed a marked tendency to run a mild
course."
In addition to the changes noted in the types and metabolism of the
bacteria of the intestinal tract, there is the additional possibility that
a reformation of the metabolism of typhoid bacilli in the blood stream,
BACTERIAL METABOLISM WITHIN THE BODY 713
and possibly even in the tissues, may take place. Feeding a diet rich
in carbohydrate certainly tends to keep the glycogen reservoir in the
liver, muscles and elsewhere at a high level. The normal blood sugar,
nearly 0.1 per cent in man, would likewise tend to be kept at or near its
maximal level, through continuous repletion from the glycogen deposits
and additions from the intestinal tract. One-tenth of one per cent of
glucose continuously present in the general circulation would abundantly
supply the minute requirements of the typhoid bacilli therein present.
Under such conditions it is difficult to conceive of the failure of the
organisms to utilize such a readily assimilable source of energy.35 The
living typhoid bacilli in the circulation would become potentially lactic
acid bacilli. Furthermore, inasmuch as glucose appears to exist in simple
solution in the plasma, it would diffuse readily into the tissues. It is
possible, even probable, that the outside of necrotic foci containing the
organisms in the spleen, liver and other organs would receive glucose.
Whether this glucose would penetrate to the depths of such foci cannot
be stated. A large carbohydrate intake stands in some very direct rela-
tion to the favorable progress of the disease. Sugar can not neutralize
toxins, however, although they do prevent the formation of toxins in
many well known instances.
The diminution in signs of toxemia and the "prevention of or com-
pensation for toxic destruction of protein and body cells," noticed by
Shaffer and Coleman, has significance in the light of the effect of utiliz-
able carbohydrate upon the metabolism of the typhoid bacillus. It must
be recognized that the "toxic" action observed in typhoid fever rests
ultimately with the growth of the organisms, because they alone incite
the disease, typhoid fever. An amelioration of the signs and symptoms
of toxemia suggests direct interference with the formation of the toxic
agent, whatever it may be. Looking at this reduction of toxic phenomena
from the viewpoint of the shifting of the metabolism of the typhoid
bacillus from proteolytic [toxicogenic] to fermentative, it will be seen
that the continuous supply of glucose, furnished by the Shaffer-Coleman
high calorie diet, provides exactly the chemical basis for its accomplish-
ment.
Attention is redirected again at this point to the general theory, attested
to by physiologists, that "utilizable carbohydrate spares body protein" and
the essential agreement of the physiological and bacteriological response
under parallel conditions.
85 Metabolic studies of typhoid bacilli in sterile, defibrinated blood, and in sterile
blood serum (containing the normal percentage of blood sugar) have shown that the
protein constituents are left practically intact until the glucose is fermented. In this
connection, the observations of McGuigan and von Hess that glucose may be obtained
from the circulating blood in animals by dialysis through collodion memuranes is of
significance. They conclude: "Dialysis of normal circulating blood shows the blood
sugar to be entirely free and to exist in simple solution in the water of the plasma."
Sugar in this state is available for energy in the blood stream by typhoid, or in fact
any other, bacteria which can utilize it.
714 AKTHUK ISAAC KENDALL
Summary and Conclusions
Other infectious diseases of the digestive tract of the toxicogenic type,
as paratyphoid fever, Asiatic cholera, coli colitis, and invasion by the
meat poisoning bacteria, are equally available for carbohydrate therapy.
The general principle involved is the same. The objectives to be attained
are:
1. The establishment of a lactic acid [fermentative] intestinal
flora in which Bacillus acidophilus or Bacillus bifidus, or
both, become dominant.
2. The shifting of the metabolism of the normal, facultatively
proteolytic organisms to the fermentative side.
3. The shifting of the metabolism of the invading organism from
the toxicogenic [proteolytic] to the fermentative side.
4. To be certain that organisms productive of abnormal fermen-
tative products, as gas bacilli, are not resident in the
intestinal tract in numbers sufficient to become offensive
when the carbohydrate regimen is established.
5. To administer carbohydrate in amounts and at intervals suf-
ficient to keep the entire digestive tract, and particularly
the lower levels, continuously permeated with the requisite
amount and kind of sugar.
Properly carried out, this bromatherapeutic method of specifically
influencing infection will result in several important contributions to the
welfare of the patient.
The reestablishment of a normal acidogenic flora will create intestinal
conditions unfavorable to the development of those invaders which are in
the alimentary canal.
The fermentative shifting of the metabolism of the members of the
facultative group will prevent the formation of indol and other bacterial
decomposition products of the amino acids. This will lessen materially the
work of the liver.
The fermentative shifting of the metabolism of the invading organism
will make it potentially a lactic acid bacillus in place of a toxicogenic
organism. The abundant supply of carbohydrate will tend to reduce the
loss of body protein to a minimum, thus conserving the strength of the
patient. It will be seen that this procedure of bromatherapy is equally
indicated from the physiological, bacteriological, and biochemical view-
points. It is specifically in the interest of the host and equally directly
in opposition to the baneful activities of the parasite. It must be realized
that bromatherapy, as outlined above, is subject to the same general
limitations as any other form of therapy. Damage already accomplished
BACTERIAL METABOLISM WITHIN THE BODY 715
before dietary procedures are begun can not be rectified, nor can the influ-
ence of this damage upon the subsequent progress of the disease be deter-
mined with precision.
Perforations, hemorrhage, or other complications, can not be influ-
enced to any extent, nor can they be prevented, in all probability, by such
measures. Some time the specific poison or poisons of the cholera-typhoid-
dysentery group, as well as those of other intestinal invaders, may be dis-
covered, and more specific antidotes discovered for them than are now
available. In the meantime, the possibility of reforming, but not of
annihilating, these microbes appears to be the most direct method of re-
stricting their activities. The dietary route, both in the interest of the
metabolism of the patient and the reformation of the metabolism of the
microbe, is the procedure which thus far has had experimental justification
and practical application.
SECTION VII
Actions of Drugs and Therapeutic
Measures
The Effects of Certain Drugs and Poisons upon the
Metabolism Henry C. Barbour
Water and Salts — Deficiency of Water — "Mineral Waters"— Salts — Saline
Cathartics — Other Cathartic Drugs — Sodium Chlorid — Potassium, Lith-
ium and Other Salts — Bromids — lodin and lodids — Salts of Organic
Acids — The Alkaline Earths — Calcium Deprivation — Calcium in Leprosy
— Calcium in Tetan-y — Other Effects of Calcium, etc. — Aluminium —
Acids and Alkalies — Neutrality Eegulation — Acids — C.C. of CO Bound
by 100 C.C. of Plasma — Total Metabolism — Purin Metabolism — Boracic
Acid and Borax — Oxygen and Asphyxiants — Oxygen Deficiency — Carbon
Dioxid— Carbon Monoxid — Other Blood Poisons — Cyanids — C.C. CO in
100 C.C. Blood — Phosphorus, Arsenic, Heavy Metals, etc. — Organic Phos-
phorus— Cod Liver Oil — Arsenic and Antimony — Mercury — Chromates —
Lead, Platinum, Copper, Zinc — Radium — Narcotics — General Anesthet-
ics: Chloroform and Ether — Hypnotics — Alcohol — Opiates — Antipyretics
— Quinin and Its Congeners — Ethylhydrocuprein — Cirichophen (Ato-
phan ) — Ammonia, Amins, Alkaloids, Purins, etc. — Ammonia — Hy drazin —
Ethylenediamin — Iso-amylamin, Phenylethylamin, and Tryamin — Beta-
tetrahydroiiaphthylamin — The Amino Acids — Atropin Pilocarpin, etc. —
Strychnin — Some Other Convulsants — Camphor — Santonin — Curare —
Cocain — Purins — Endocrine Drugs — Epinephrin — Thyroid Gland Sub-
stance— Pituitary Substance — Anterior Pituitary Lobe — Other Gland
Products— Thymus Gland— Parathyroid Gland— Spleen— Prostate Gland
— Testis— Pineal Gland.
The Effects of Certain Drugs and
Poisons upon the Metabolism
HENRY G. BARBOUR
McGILL UNIVERSITY, MONTBEAL
I. Water and Salts
Water taken in excess of demand is promptly eliminated from the
body, but its removal may alter the mineral balance or disturb the relative
proportions of the ions. The metabolic changes may include a temporary
increase in the urinary nitrogen, due apparently not only to "flushing,"
but also to some extra protein breakdown (Hawk).
The effects of water in moderate amounts upon the total metabolism
were first investigated by Bidder and Schmidt (1852), who reported them
negligible, and F. G. Benedict employing highly perfected technique has
recently shown that normal adults may ingest 500 c.c. of water at room
temperature without altering the basal metabolism. Larger amounts may
prove stimulating, but 200 c.c. of water given per os did not alter the
metabolism of Lusk's 9.3 kilo dog.
Such water ingestion in health does not affect the body temperature.
Large amounts of water taken with proteins and fats do not influence
the absorption of the latter from the alimentary canal (Edsall).
Deficiency of Water. — Water deprivation as well as excess results
in an increased protein destruction; the excess metabolites do not, how-
ever, appear in the urine until its checked flow has been restored by re-
newed intake of fluid. (Straub.)
An adequate water content of the blood is so essential to the various
processes of heat elimination that any considerable dehydration of the
body (because of the diminished blood volume) results in fever. Salt
fever (see below) has been thus explained by Balcar, Sansum, and Wood-
yatt, who themselves produced extraordinary temperature elevations in
dogs by dextrose dehydration (in one case 125° F. was observed!). Con-
versely water often serves as an antipyretic agent. The fever of the new-
born, formerly accepted as physiological, can be prevented entirely by an
occasional spoonful of water.
The effects of water deficiency are further discussed in connection
with salt action.
717
718 HENRY G. BAKBOUR
"Mineral Waters." — Natural spring waters have been so long and
extensively exploited that the tendency to ascribe to them some occult
therapeutic value still lingers. No evidence exists, however, that their
employment (most successful at their source) is associated with effects
beyond those attributable to the individual mineral ingredients (see below)
or to psychic, climatic and hygienic factors.
Salts. — The effects of salts upon the metabolism fall into two categories,
namely, those due to (1) "salt action" (chiefly osmotic processes) and
(2) the action of individual ions. Pertaining chiefly to the first group
are the effects of the
Saline Cathartics. — Poorly absorbable salts, of which the sulphates
of sodium and of magnesium are-, noted examples, act as dehydrating
agents, their systemic effects being therefore essentially those of water
deficiency. This applies as well to parenteral administration, where
diuretic instead of cathartic action results.
Body Temperature. — In connection with the therapeutic employment
of saline cathartics significant temperature changes are not seen. Hay
was unable to substantiate the reputed "cooling effect" in fevers. On
the contrary, where the dehydrating effect becomes pronounced, some
increase in temperature may be anticipated (salt fever).
Total Metabolism. — It was claimed by Loewy(6) that saline cathartics
augment the total metabolism, this effect being attributed to increased
peristalsis. Others, on the basis of Hay's theory considered that the alleged
increase in the total metabolism was due to the work involved in the active
"secretion" of water into the intestine. However, after Wallace and
Cushny showed that osmotic factors alone will account adequately for the
passage of fluid into the bowel, it was not surprising that Brodie, Cull is
and Halliburton should find that hypertonic magnesium sulphate causes
no increase in the oxygen consumption of the intestine itself. Ultimately
F. G. Benedict demonstrated that oral therapeutic doses of the saline
cathartics do not measurably increase the total metabolism of healthy
individuals.
An instance of increased oxygen consumption in a single organ is,
however, seen in the results of Bainbridge and Evans, who, in a contribu-
tion to the secretory theory of diuretic action, describe an increase in the
gas consumption of kidneys subjected to the action of sodium sulphate.
Protein Metabolism. — The protein catabolism may be increased by
saline cathartics when exhibited in amounts sufficient to deplenish the
body's stock of water.
Fat Metabolism. — The habitual use of salines is frequently efficient in
reducing the weight in obesity. Many of the natural mineral waters have
acquired a reputation in such cases. Their action appears to be due in
part to their hindering the absorption of proteins and fats (Hay), in part
to a depletion of the body fluids by the salt action. Saline cathartics ai
EFFECTS OF CERTAIN DRUGS AND POISONS 719
said to increase the percentage of butter fat in cow's milk, but this is
not a dependable result (McCandlish).
Carbohydrate Metabolism. — Franck attributed "salt glycosuria" (dis-
cussed below) to polyuria, but other explanations are better supported
by the evidence.
Mineral Metabolism. — Chiari has suggested that since all cathartic
ions are antagonistic to calcium the action of the saline cathartics may be
explained by assuming that the calcium normally present keeps the intes-
tinal cells in a state of low permeability.
The specific systemic effects of neither the magnesium ion of Epsom
salts nor the tartrate ion of Rochelle salts are seen after oral administra-
tion. For a discussion of these see under "Alkaline Earths" and "Salts
of Organic Acids," respectively.
Other Cathartic Drugs. — The effects upon the metabolism of those
cathartic drugs which act primarily by stimulation of peristalsis have never
been adequately investigated.
Aloin. — This drug was administered to mammals and birds by Berrar,
who observed a marked increase in the energy exchange accompanied by
a rise in temperature. The nitrogen excretion (especially urea in mammals
and uric acid in birds) was also augmented.
Sodium Chlorid. — Because of the high normal sodium chlorid con-
tent of the body (150-300 grams according to Magnus-Levy) and the
fairly delicate chlorid-regulating mechanism, a considerable salt intake
is required before effects upon the metabolism are noted. In general the
effects of sodium chlorid upon the metabolism are probably due rather to
osmosis than to specific ion actions.
Mineral Metabolism. — The skin acts as the chief of several chlorid
depots, storing or releasing salt according to need.
Rosemann(e) found the entire chlorid content increased by 100 per
cent when dogs were given highly salted food. The chlorid threshold of the
plasma is said to be 5.62 grams per liter. According to MacLean if the
concentration falls below this level no chlorid is excreted; if it exceeds
it the excretion varies as the square of the excess.
Holt, Courtney and Fales(c) have investigated in children the effects
upon the mineral metabolism of 200 c.c. injections, by hypodermoclysis, of
physiological saline. Salt and water are retained for several days. The
effects are most marked in conditions where salt and water, deficiency exist,
as in acute diarrhea, marasmus and protracted vomiting. The retention
is accompanied by much symptomatic improvement. The changes in
magnesium, calcium, phosphorus, and potassium metabolism were also
followed by Holt and his collaborators, but no uniformity could be de-
tected. A "balanced" salt solution (potassium and calcium chlorids being
added) gave results not differing from those of the sodium chlorid solu-
tion alone.
720 HENKY G. BARBOUR
Water Metabolism. — The urine is increased in amount by sodium
chlorid, as by other solids which the kidney eliminates. All salts readily
absorbable from the alimentary tract act therefore as diuretics. It is
well known that salts, especially sodium chlorid, play an important role
in the movement of fluids everywhere in the body, as in secretions, effusions
and edemas.
Body Temperature. — The phenomenon known as salt fever came tc
light through observations of pediatricians, notably Finkelstein am
Schaps, who observed a rise in the body temperature of infants sub-
sequent to oral or subcutaneous administration of saline solutions. In
adults Bingel obtained less constant results from one liter injections of
0.0 per cent sodium chlorid; the maximum temperature changes varied
all the way from — 0.3° to +2.5° C., the fevers greatly predominating,
however. When a solution containing NaCl 1.8, CaCl2 0.24, KC1 0.42 and
XaHCO3"0.2 gm. in one liter was given the temperature increases were
also frequent and pronounced.
To account for salt fever a specific sodium ion effect has been claimed
by many ; Burnett and Martin, for example, were able to prevent its ap-
pearance by antagonizing the sodium with proper amounts of calcium.
While the above-mentioned results of Bingel in no wise disprove the
sodium ion theory, some observers, as Holly and Christ] ansen, find hyper-
tonic (3 per cent) saline more effective than isotonic. indicating that salt
action is at least an important factor.
Heubner(&) studied the effects of intravenous saline injections in rab-
bits and states that while 0.1-0.3 milligram were pyretic, doses of twenty
times this magnitude gave a prompt temperature decrease. This latter ef-
fect was possibly associated with protracted dilution of the blood. Having
obtained negative effects with his Ringer solution injections Heubner
favors the sodium ion theory.
Extensive work upon salt fever has been reported by Freund, who
pointed out a parallelism between sodium chlorid and epinephrin effects;
under similar conditions he produced both fever and glycosuria by in-
jecting either of the two agents intravenously. From these and like
results he concluded that "the disposition to sodium chlorid fever" is
equivalent to a state of hyperirritability of the sympathetic nervous
system.1
Freund also obtained sodium chlorid fever by oral administrator
in rabbits, 1.5-2 grams giving the best results; 3 grams frequently, and
grams always, reduced the temperature (as was the case with Heubner's
larger injections). He pointed oat that the oral experiments dispose
effectively of a rather widespread contention that salt fever might be
attributed entirely to the "water infection" which intravenous injections
Epinephrin, salt and sugar fevers lend themselves to a single interpretation:
loss of water from the blood.
EFFECTS OF CERTAIN DRUGS AND POISONS 721
of stale distilled water sometimes produce. He also failed to obtain salt
fever with intravenous Ringer solution.
In the hands of the present author 20 c.c. per kilo of dextrose-free
Locke solution made with water freshly redistilled from glass gave the
same results as physiological sodium chlorid solution, — a temperature
rise of over 1° C. when either was injected into the ear veins of normal
rabbits. (In both cases a fall of 0.2° C. during the first twenty minutes
was obtained.) Furthermore Barbour and Howard with 8 c.c. per kilo
of a similar Locke's solution intravenously injected were able after an
interval of fifteen minutes to superimpose a steep salt fever rise upon the
plateau of the "eoli fever" curve in dogs.
It certainly appears probable that salt fever is due chiefly to a loss of
water from the blood, whether the water be drawn chiefly to the kidneys,
to the site of salt administration or, on account of disturbed capillary
permeability (for which complex ion interchanges might be responsible),
to other tissues.
Hashimoto has shown that salt fever is less readily produced during
artificial warming of the "heat centers" in rabbits. The contention that
salt fever results from irritation of the "heat centers" by products of the
interaction of sodium with the tissues has not, however, been substantiated.
The salt fever riddle has important bearings upon infectious fevers, in
many of which disturbances of the water and chlorid metabolism are well
recognized.
Total Metabolism. — Sodium chlorid increases oxidations slightly
whether given per os or subcutaneously. Freund and Grafe found that
the heat production was augmented 8 per cent as against 22 and 28
per cent increases after Ringer and dextrose solutions, respectively.
Raeder found in the case of subcutaneously injected saline solutions
that hypertonicity favors the increase in oxidations. This may be merely
the result of a higher body temperature or it may be due in part directly
to osmotic action.
Tangl found the oxidations increased by sodium chlorid given per os
to curarized animals without kidneys. This would tend to relegate both
central nervous and diuretic factors to a position of secondary importance
in salt fever questions. Apparently dehydration into the stomach would
account for Tangl's results.
Nitrogen Metabolism* — In salt fever Freund and Grafe found 20 to
45 per cent increases in the excretion of urinary nitrogen (&). (Compare
the effects of water drinking described by Hawk.) Straub(fc), however,
states that sodium chlorid in non-dehydrating>concentrations exerts a slight
sparing effect upon the nitrogen metabolism ; similar results have been ob-
tained with the nitrate, acetate, carbonate, sulphate or phosphate of sodium
(Loewi).
722 HENRY G. BARBOUR
Salt Glycosuria. — This phenomenon, which has been investigated
chiefly in rabbits, bears an undoubted relation to salt fever. It was dis-
covered in 1871 by Bock and Hoffmann as the result of injecting into
the arterial circulation of rabbits large amounts of 1 per cent sodium
chlorid. Others have added to the list of glycosuria-producing salts the
acetate, bicarbonate, phosphate, succinate, valerianate and sulphate of
sodium. Kleiner and Meltzer(&) have shown that the last mentioned pro-
duces no hyperglycemia, thus differing from magnesium sulphate (see
below).
A number of authors have considered the possibility that salt acting
through the central nervous system may exert a stimulating influence upon
the adrenal glands. This would accord with Freund's parallelism between
the glycosurias and fevers caused respectively by salt, sugar and epineph-
rin. Furthermore, Waterman and Smit found an increased epinephrin
content in "the blood in salt glycosuria, while Stewart and Rogoff(a) have
recently shown that concentrated sodium carbonate solutions increase the
epinephrin output from the adrenals. Mobilization of glycogen by salt
through the agency of these glands would thus seem to be strongly
suggested.
However, MacGuigan's demonstration that epinephrectomy in cats is
without influence upon salt glycosuria (although in dogs the operation
does make the glycosuria more difficult of accomplishment) seems to
exclude the adrenals as the prime causative factor.
Fischer (a) found that the intravenous injection of sodium chlorid (one-
sixth molecular_or stronger) causes glycosuria in rabbits after a certain
latent period. Weaker solutions exert less effect or none at all. The
addition of calcium chlorid prevents or puts an end to the appearance of
sugar; the latter reappears, however, after returning to pure sodium
chlorid. Fischer was inclined to exclude osmosis as a factor because urea,
glycerin and alcohol all failed to produce glycosuria. Since salt injec-
tions into arteries leading directly to the brain caused quicker and more
profound results the theory of a central action was favored.
The blood sugar in salt glycosuria was investigated by Underbill and
Closson, who found it diminished. Underbill and Kleiner (6) were able to
inhibit the hypoglycemia and glycosuria as well as the accompanying
polyuria by calcium chlorid whence they concluded that the latter restores
the retaining power of the kidney for glucose which sodium chlorid appar-
ently impairs. The calcium injection even made the kidneys unusually
impermeable to injected glucose which affords a counterpart to Pavy
and Godden's experiment in which sodium chlorid was shown to reduce
the tolerance of rabbits towards injected sugar. Salt glycosuria was there-
fore attributed by Underbill and his co-workers to increased renal perme-
ability; dyspnea was invoked as an additional factor, for in the case of
arterial injections hyperglycemia and glycosuria without polyuria were
EFFECTS OF CERTAIN DRUGS AND POISONS 723
noted. Recently McDanell and Underbill have accomplished further work,
M M
showing that — - — — sodium chlorid produces glycosuria with neither
2i o
relative nor absolute hyperglycemia.
Hyperglycemia has also been found by others, but only when concen-
trated saline solutions were injected. According to Wilenko intravenous
injection of 20 per cent saline produces by stimulation of the central
nervous system a hyperglycemia in which the muscles and probably the
liver lose glycogen. . He concluded that the nervous stimulation is a sodium
ion effect and that owing to osmotic factors the permeability of the kidney
is first increased and then decreased. Hhsch also obtained hyperglycemia
from concentrated (10 per cent) sodium chlorid; 2.5 per cent or more
dilute solutions did not increase the blood sugar nor did sodium car-
bonate, sodium acetate or calcium chlorid. He favored the central nerv
ous system theory, which, however, fails to account for the non-appearance
of hyperglycemia with the dilute injections.
Burnett has demonstrated the inhibiting effect of potassium salts upon
the glycosuria produced by sodium salts, thus adding weight to the im-
portance of the ions wherever the action may be exerted.
That the point of action of the ion antagonism in salt glycosuria is
renal seems difficult to doubt in the light of the recent experiments of
Hamburger, Brinkmann and their co-workers (a) (&). These investigators
have studied the permeability of the glomerular membrane in the frog (the
tubules being anatomically separated therefrom in this animal). They
have demonstrated clearly the power of the glomeruli to retain free
dextrose, but have also shown that this power depends upon the main-
tenance of a very delicate ion balance in the perfusion fluid. While Ham-
burger's attention was confined more to the calcium-potassium relations
and the bicarbonate requirement, it is obvious that conditions which alter
the sodium-ion concentration are likely to disturb seriously the entire ion
balance. This applies to ion physiology in general, as shown by Loeb, and
to the instance of salt glycosuria in particular, as shown by the calcium
antagonism of Fischer and of Underbill and the potassium antagonism
of Burnett.
An interesting practical deduction which Hamburger makes is that
the oatmeal treatment in diabetes mellitus may owe its value to bolstering
up the retaining power of a glucose-surfeited glomerular membrane by
the excess of potassium ions contained in that food. Hamburger's (6) work
should lead to a new understanding of the various types of renal glycosuria,
of which sodium chlorid glycosuria appears to be a notable example.
Salt Starvation. — A deficient salt intake leads to emaciation, the oc-
currence of acetone in urine and breath and other untoward symptoms. A
generally lowered mineral excretion results. The nitrogen balance ap-
pears to be but little affected (Rosemann (<?)).
724 HENRY G. BAEBOUR
Potassium, Lithium and Other Salts. — Outside of the importance of
the potassium ion in preserving the retaining power of the glomeruli for
dextrose practically no metabolic eifects peculiar to potassium salts have
heen demonstrated. They are, however, said to antagonize the beneficial
effects of calcium in parathyroid tetany (MacCallum and Voegtlin).
These ion relations in tetany appear, however, to concern rather the
irritability of muscle than the metabolism (Zybell, cited by Gamble).
Salts of lithium, rubidium, cesium, etc., are more toxic than the corre-
sponding sodium or potassium salts. Specific metabolic effects have not
been shown. Lithium does not form soluble urates in the presence of
sodium or potassium, which fact disposes of its formerly alleged value
in gout
Bromids. — Chlorids and bromids mutually increase the elimination
of one another. The theory of Wyss, however, that the therapeutic action
of bromids is due to chlorid-deprivation is not sound, for simple dechlora-
tion exerts no antispasmodic effect. Furthermore, Janusche has shown
that bromid depression can be neither efficiently antagonized by sodium
chlorid administration nor reenforced by chlorid-poor food.
Bromids appear to 'reduce the edema of uranium poisoning, stimu-
lating the retarded water and chlorid excretion (Laeva).
Boenniger claimed that bromid administration may save animals
from chlorid starvation and replace completely the chlorid of the serum,
but Bernoulli finds that, the replacement by bromid of more than 40 per
cent of the blood chlorid is generally fatal.
The protein metabolism remains uninfluenced even by large doses of
bromids; for example, Chittenden and Culbert found it unchanged dur-
ing ten days in which 46 grams of potassium bromid were given. In
experiments upon himself Schultze observed an average reduction of 19
per cent in the phosphate excretion following 10 gram doses of potassium
bromid ; the excretion of nitrogen and sulphur, however, remained un-
affected. Japelli(a) in more recent investigations found little or no effect
upon the total nitrogen or phosphorus excretion, but observed a diminution
in the uric acid accompanied by an increase in the purin bases.
Schabelitz has studied chronic bromism, which leads to emaciation.
The administration of chlorid, in addition to stopping the drug, was
found to hasten the disappearance of the symptoms.
lodin and lodids. — In very exact experiments Magnus-Levy was
unable to detect any influence of potassium iodid or of iodin upon the
total metabolism of either healthy or obese persons; 3-10 grams of potas-
sium iodid or 4-10 .drops of tincture of iodin were given daily over a
period of weeks. Magnus-Levy further found iodin inactive in a case of
myxedema in which the metabolism had been notably stimulated by
iodothyrin. The only case in which he observed any increase in the total
oxidations under iodids was that of an emphysematous patient in whom
EFFECTS OF CERTAIN DEUGS AND POISONS 725
the drug aroused a febrile reaction towards the close of each day. Magnus-
Levy's negative results have been confirmed.
According to Christoni iodids may increase the excretion of urea,
total nitrogen, uric acid, purin bases and chlorids.
Hunt and Seidell have shown that thyroid preparations are efficient
in treatment in proportion to their iodin content.
Recent investigations upon the catabolic effect of various thyroid prep-
arations appear to indicate that the increase in nitrogen elimination is
proportional to their iodin content (Courvoisier, Peillon, Lanz).
Swingle maintains that iodin is the specific agent by which amphibian
metamorphosis is accelerated when thyroid substance is fed.
Treatment and Prevention of Goiter. — Iodin becomes rapidly fixed
in the thyroid; Marine and Rogoff(&) ascertained that the fixation end-
point is reached five minutes after the intravenous injection into dogs of
50 milligrams of potassium iodid.
The careful administration of iodids causes a regression of active
thyroid hyperplasia into the relatively harmless colloid type of goiter.
For this purpose Marine (a) advocates syrup of ferrous iodid in doses grad-
ually increasing from 0.3 -to 1.2 c.c. per day.
The prevention of goiter by iodid has been definitely achieved by
Kimball and Marine. They fed 2-4 grams sodium iodid (in ten equal
doses) to school girls in Akron, Ohio, none of whom became goiterous.
Twenty-six per cent of the control series of girls (according to expecta-
tion in that locality) showed definitely enlarged thyroid glands. Hun- .
ziker suggests the use of iodin-rich manures in regions where goiter is
endemic and vegetation lacks the standard proportion of iodin. He
further suggests the admixture of iodin with table salt.
Toxic effects are often seen in goiterous (especially Basedow) patients
if the large doses of iodids commonly employed in other diseases are ad-
ministered. The symptoms, which include emaciation and fever, are
detailed by Oswald ( b ) . Acute untoward effects of intravenous or subcutan-
eous injections of iodids include pulmonary exudation and edema besides
pericardial effusion. According to Chiari and Janusche these may be pre-
vented by calcium injections.
The destructive effect of iodids upon pathological growths, particu-
larly gummata, has never been completely explained. Jobling and Peter-
son believe that they restrain the antitryptic activity of serum and tissues,
thus permitting autolytic digestion to proceed. Full doses of iodid in
man greatly lower the anti-ferment index of the serum.
Salts of Organic Acids — Oxalates. — Salts of oxalic acid possess no
known therapeutic value. Many of their effects are doubtless due to
calcium deprivation. Sarvonat and Roubier found that sodium oxalate
diminishes the calcium content of the soft tissues before affecting the
bones.
726 HENRY G. BARBOUR
Corley maintains that the total metabolism is much depressed in
oxalate poisoning and that there is a lowering of the respiratory quotient.
Wichern has described anuria followed by polyuria. Asphyxia, pyrexia
and glycosuria may also occur.
Tartrates. — Intravenous injection of tartrates (Rochelle salts), in
rabbits inhibits markedly the excretion of urea, but chlorid excretion
remains unaltered. Underbill, Wells and Goldschmidt showed that this
is due to a specific effect upon the renal tubules.
To be similarly accounted for is the fact that tartrates diminish the
intensity of various glycosurias, e. g., phlorhizin (Baer and Blum),
epinephrin and dextrose glycosurias (Starkenstein).
Benzoates. — These are of importance in view of their use for the
preservation of food. Chittenden, Long and Herter in an exhaustive
study could demonstrate no effects upon healthy individuals if the in-
gestion of one-half gram per day was continued for weeks. Even four-
gram doses were rarely injurious. The body weight did not diminish,
the digestion and utilization of fat and protein as well as the nitrogen-
balance and partition and the quantitative composition of the urine all
remained normal.
In man benzoic acid ingested in doses up to ten grams per day is
excreted almost quantitatively as hippuric acid (Dakin).
Large doses of benzoates (eight grams per day in man) increase the
urinary urates at the expense of the blood (Denis (d)). During the period
of maximum hippurate excretion, however, Lewis and Carr observed a
marked decrease in uric acid excretion. This was seen after seven to
eight grams of benzoate, but could not be produced by the direct adminis-
tration of hippuric acid.
Creatinin metabolism is not affected by benzoates.
Acetates and Citrates. — Acetates and citrates are converted into
bicarbonates in the tissues, then acting as alkaline diuretics. (See Chap-
ter III.)
II. The Alkaline Earths
Calcium, Magnesium, etc.
Mineral Metabolism. — That calcium administration in man may in-
crease the calcium store of the tissues and blood was shown by Voor-
hoeve(c). Heubner and Rona state that intravenous injections of calcium
salts in cats will double or triple the calcium content of the blood ; this, how-
ever, returns to normal within two hours.
Givens(a) (&) has shown that calcium lactate in man increases the
calcium excretion in the urine, but not to the same extent as milk does. On
the other hand, magnesium citrate does not, increase the magnesium excre-
tion.
I
EFFECTS OF CERTAIN DRUGS AND POISONS 727
The calcium content of the serum in tuberculosis was investigated by
Halverson, who found that it is not increased by a milk diet.
Magnesium, as shown by Malcolm, lessens lime deposition in young
animals. In accord with this fact Mendel and Benedict found that it in-
creases the urinary calcium. The presence of phosphates, however, in-
hibits the increase by magnesium of calcium excretion in the urine (Steen-
bock and Hart).
Strontium administration to young animals disturbs bone formation.
Lehnerdt showed that the osteogenetic tissue is stimulated, but the bones
become imperfectly calcified, the calcium being deficient and the strontium
incompletely deposited.
In the magnesium narcosis of Meltzer and Auer (which can be an-
tagonized by calcium chlorid injections) Stronsky has studied the plasma
and has shown an increase in the magnesium content while the calcium
content is diminished.
C. Mayer maintains that the chlorids of the alkaline earths tend to
increase urinary acidity. This is contradictory to the usual holding since
part of the phosphate is deflected by calcium, for example, to the intestines.
Calcium Deprivation. — In young animals fed on a calcium-poor diet
the bones may contain a normal percentage of calcium, but what little new
bone is formed is thin, pliable, deformed and fragile (E. Voit). It con-
tains more water, sodium and potassium, while the magnesium is not
materially increased. The percentages vary in different parts of the
skeleton. Weiser describes the animals as undersized, with poor appetite
and defective nutrition. Luithlen has increased or decreased the calcium
content of the bones in rabbits by feeding, respectively, a green or an oat
diet. ( See also Oxalates. )
In studies of multiple exostosis Underbill, Honeij, and Bogert found
evidence suggesting that a restriction of the calcium and magnesium in-
take during the stage of proliferative cartilage changes would be bene-
ficial.
Calcium in Diseases of Bone Deficiency. — Rickets, being due not to
deficient calcium income, but to derangement of the processes of assimila-
tion, the therapeutic inefficiency of calcium in this disease has been gen-
erally upheld (Klotz (&)). This does not mean, however, that none of the
administered calcium1 is retained. Schloss(&), for example, reports in a
series of eighty experiments upon rachitic children the following results:
Retention of CaO
gram per day.
Fore period 0.032
With calcium administration 0.297
With cod liver oil 0.167
With cod liver oil and calcium 0.354
728
HENRY G. BARBOUR
In respect to enhancement of the cod liver oil effect calcium appeared
superior to phosphorus, which, when given with the oil, did not exhibit
any influence upon the calcium retention.
Triacalcium phosphate Schloss found slightly better than calcium
acetate and equal in retention value to some other organic calcium prep-
arations.
In the florid stages of rickets a high magnesium retention was noted.
This fell rapidly as the calcium retention increased, presumably owing to
medication.
Gamble cites the following figures relative to calcium retention in
osteogenesis imperfecta :
Author Age of patient Medication
Bamburg &
Huldschinsky
Bookman
Orgler
3 months
3 months
3 months
Schabad
MO
years
inone
cod liver oil -4- phosphorus
none
calcium lactate with food
none
rnone
cod liver oil -f- phosphorus
cod liver oil -4- phosphorus
-4- calcium lactate
cod liver oil -f- phosphorus
-f- calcium lactate
thyroid substance
Herbst
Retention of CaO
gram per day
0.042
0.089
0.054
0.402
0.130-0.210
0.176
0.340
0.338
Fowler's solution
Fowler's solution
(neg. balance)
(low or nega-
tive)
0.403
0.382
0.418
Schabad (c) prefers arsenic to other medication in this condition, but
his results and those of others suggest that wide variations in calcium reten-
tion occur independently of medication.
The conditions which govern calcium retention and assimilation n
pathological states are practically unknown.
Calcium in Leprosy.' — Recent investigations of Underbill, Honeij and
Bogert suggest that in leprosy administration of calcium may be of benefit
in retarding or arresting the progress of the characteristic bone chan£
Calcium in Tetany. — Parathyroidectomy is followed by clonic con-
vulsions with fever. MacCallum during such an attack in a dog observec
the temperature increase from 39° to 43.2° C. The administration oi
calcium acetate stopped the convulsions in a few minutes and within oiu
half hour the temperature fell to 38.9°. MacCallum and Voegtlin als
reported success with calcium injections in a number of cases of human
tetany.
The precise relationship of the calcium metabolism to parathyroid
tetany has, however, not yet been demonstrated. Wilson, Stearns, Thur-
low and Janney as well as McCann and others have shown that removal
of the parathyroid is followed by a condition of alkalosis. This is neu-
tralized by the acid production incident to tetany, or the tetany may be
M
prevented by — - HC1 intravenously injected. Now calcium salts have been
found to lower the oxygen-combining power of the hemoglobin as well as
the alveolar carbon dioxid tension, both of which effects may also be
induced by acids. Calcium is, therefore, in some respects adapted to
reduce a condition of alkalosis.
Howland and Marriott (&) have contributed to the question of the cal-
cium metabolism in infantile tetany by demonstrating that in this condition
the calcium content of the blood is approximately halved. Their average
figure for eighteen cases was 5.6 milligrams in 100 c.c., the lowest being
3.5 milligrams. The corresponding normal figure was found to be 10-11
milligrams. They do not wholly accept the alkalosis theory. Calcium
chlorid per os was found effective in increasing the serum calcium coin-
cidently with cessation of the symptoms, although in most cases the normal
calcium content was not attained.
Brown, MacLachlan and Simpson have recently found that intravenous
injections of 1.25 grams calcium lactate may keep the signs of tetany
in abeyance for from seven to ten hours. They state, however, that no
permanent effects are obtained unless the treatment includes cod liver oil
and phosphorus. The value of these last as regards rapid reduction of
the symptoms is. enhanced by the addition of the calcium. Cod liver oil
and phosphorus produce within about two weeks an increase in the calcium
content of the blood.
Uhlenhuth(a) has succeeded in suppressing with the lactate of calcium
or magnesium as well as with a weak milk solution the tetany exhibited
by thymus-fed salamander larvaB. The development of permanent
paralyses and contractures is not, however, prevented. This form of
tetany (which Uhlenhuth believes to be a true parathyreoprival tetany)
is therefore shown to be due to a specific toxic substance not perfectly
antagonized by calcium, magnesium or milk.
Marine (&) has shown that parathyroid hyperplasia of the fowl (which
is produced by feeding maize or wheat) can be retarded by feeding calcium.
When the prevention or treatment of the dysparathyroidisms shall
have been perfected, one feels justified in believing that a prominent role
therein will be played by calcium.
730 HENRY G. BARBOUR
OTHER EFFECTS OF CALCIUM, ETC.
Water Metabolism. — The effects of the calcium ion upon water
exchanges in the organism are very imperfectly understood.
Many of them may be ascribed to diminished permeability of the
kidneys. Diminution in urine flow, for example, was described by Forges
and Pribram. Davis has observed antagonism of sodium chlorid
diuresis by calcium in dogs. Besides this the elimination of injected saline
fluids has, by Fleisher, Hoyt and Leo Loeb, been decreased by the intra-
venous injection of calcium chlorid.
The last named authors find, however, that calcium injection increases
the tendency to peritoneal and pulmonary transudation. Augmented
rather than reduced permeability would be indicated in such a case, unless
one assumes that the calcium acts rather by hindering some normal re-
absorptive process than by facilitating the escape of fluid into the affected
cavities.
On the other hand, prevention of various experimental inflammatory
edemas was accomplished by calcium injections in the hands of Chiari
and Janusche.
In view of the present state of our knowledge it is not surprising that
clinical applications of calcium in the treatment of effusions, coryza, etc..
have been rather disappointing. The success attained by Choksy and
others with magnesium sulphate in the reduction of the swellings of
erysipelas and other inflammations is probably due largely to salt action.
Excess of calcium did not retard recovery from saline hydremia in
the rabbits of Bogert, Mendel and Underbill, although a positive result
might have been anticipated.
Body Temperature. — The effects of calcium upon the heat regulation
have not been sufficiently investigated.
MacCallum, as mentioned above, describes an antipyretic effect from
calcium in tetany and Hill has obtained a similar result in normal rabbits
when small doses were administered intravenously. Five to eight c.c.
of a five per cent solution of calcium lactate thus given cause an initial
temperature fall of from 0.4° to 0.6° C. The higher of these doses pro-
duces toxic symptoms accompanying this temperature fall ; a rise of from
1.5° to 2.5° C. then ensues, with disappearance of the other symptoms
of poisoning.
Gum arabic (consisting largely of the calcium and magnesium salt
of arabinic acid) when given in 1 to 20 per cent solution acts, temporarily
at least, as an antipyretic agent in fevered rabbits and dogs, but not ii
healthy animals. In normal dogs, moreover, a considerable rise of tem-
perature results. (Barbour and Baretz.)
Magnesium salts are stated by Schuetz(&) to reduce the body tempera-
ture even if the narcosis is prevented by calcium (as accomplished
EFFECTS OF CERTAIN DRUGS AND POISONS 731
Melteer and Auer). The latter fact might tend to exclude a centrally
induced antipyretic action.
The prevention of sodium chlorid fever by proper concentrations of
calcium salts (balanced solutions) has already been discussed.
In infants, Bosworth and Bowditch maintain that an excess of ingested
calcium causes an accumulation of insoluble derivatives in the tissues.
High temperature with toxic symptoms results and calcium lactate appears
in the urine. The untoward effects are preventable by the administration
of sufficient chlorid or phosphate to keep the calcium in soluble form.
Carbohydrate Metabolism. — The inhibitory effect of calcium upon
sodium chlorid glycosuria has been discussed.
The effects of calcium upon blood and urine sugar in rabbits have been
extensively investigated by Underbill (ft). He maintains that calcium salts
play a noteworthy role in the regulation of the blood sugar content; al-
though lacking marked effect in normal animals they distinctly alter the
character of the curve of epinephrin hyperglycemia, often augmenting
the glycosuria. Furthermore, withdrawal of calcium (by administration
of sodium phosphate or oxalate) produces %poglycemia, curtailing the
hyperglycemia and often the glycosuria produced by epinephrin. Under-
bill and Blatherwick showed that while thyreoparathyroidectomy results
in hypoglycemia as well as in tetany, calcium lactate will temporarily re-
store the blood sugar to its normal level. These facts accord with the
conception of tetany as an alkalosis.
After subcutaneous injections of magnesium sulphate Underbill (/) ob-
served hyperglycemia and slight glycosuria when general anesthesia de-
veloped. With subanesthetic doses only a slight hyperglycemia, without
glycosuria, was seen. Calcium antagonizes not only the magnesium
anesthesia, but also the hyperglycemia. This would appear to classify
the latter as of asphyxia! origin, but Kleiner and Meltzer(6) have shown
that it occurs under adequate artificial respiration.
Diabetics, according to Kahn and Kahn, exhibit a negative calcium
balance. Following cautious injections of one-eighth molecular calcium
chlorid into a vein these authors observed decreases in glycosuria, glycemia
and polyuria. Relief of symptoms and prevention of acidosis were also
attributed to the procedure. The renal factor appears to be largely re-
sponsible here and calcium therapy is unlikely to offer permanent relief,
for with its employment no improvement in the capacity of the organism
to oxidize dextrose has been demonstrated.
Brinkmann(&) has shown in frogs that an optimum calcium concentra-
tion is necessary to prevent the escape of glucose through the glomeruli.
Jacoby and Rosenfeld's demonstration of the inhibitory effects of calcium
upon phlorhizin diabetes 2 also indicates the significance of the renal
factor.
. 'Retention of nitrogen and of acetone were also noted.
732 HENKY G. BAKBOUE
According to Salant and Wise calcium does not protect against zinc
glycosuria in rabbits.
Upon the permeability of the kidneys for sugar, there appears to be no
question of the inhibitory influence of the alkaline earths, but their1
excessive occurrence occasionally favors glycosuria, probably asphyxial in
nature.
Purin Metabolism. — Abl maintains that calcium prevents cinchophen
(atophan) from increasing the excretion of uric acid. But Gudzent,
Maase and Zondek state that calcium, like cinchophen, increases the uric
acid of the urine at the expense of the blood.
Pohl found that two grams of calcium chlorid per os decreased allan-
toin excretion from 0.397 to 0.104 gram. It did not alter the effect
of epinephrin which was to increase both allantoin and uric acid excre-
tion. / .
Strontium is stated by Lehnerdt to increase uric acid excretion.
Growth and Reproduction. — Emmerich and Loew found that the
administration of calcium salts to female mice, guinea pigs and rabbits
was followed by an increase in the number-of pregnancies and of offspring.
Pearl (a) has observed that such salts accelerate growth in female (but not
in male) chicks and that this effect can be inhibited by corpus luteum
extract. According to Cramer the growth in vitro of cells of mouse
carcinoma is inhibited, with loss of water, by calcium chlorid. Sodium
ions antagonize this effect.
Aluminium. — Schmidt and Hoagland maintain that aluminium, like
calcium and magnesium, deflects phosphates from the intermediary metab-
olism in man. In special cases a low phosphate intake may be excreted
entirely in the feces, in combination with aluminium.
HI. Acids and Alkalies
Neutrality Regulation. — The mechanism which regulates the con-
centration of free hydrogen ions in the blood and tissues is very delicate.
In sixty miscellaneous medical cases Levy, Eowntree and Marriott found
the reaction of the serum normal (Pn = 7.6-7.8) ; the whole blood was
also nearly unchanged (Pn= 7.1-7.3). Even when symptoms of acidosis
are present the alkalinity is but little decreased (serum Ph = 7.2-7.5) ;
alkali therapy combats this decrease. In diabetic coma Masel found
Ph = 7.11 just before death.
The addition of hydrochloric acid to acidosis blood was found by Van
Slyke to raise its H-ion concentration relatively more than when added
to normal blood; thus the essential change in acidosis is loss of reserve
alkali. VanSlyke defines acidosis as "a condition in which the concen-
tration of bicarbonate in the blood is reduced below the normal level."
EFFECTS OF CERTAIN DRUGS AND POISONS 733
TT
If the normal ,T * f ^- ratio (=Tff) remains undisturbed the condi-
tion is one of compensated acidosis, but should the respiratory center fail
to remove the relatively excessive carbon dioxid present when bicarbonate
has been lost the acidosis is said to be uncompensated.
Since excess of carbon dioxid gas in the blood may occasionally in-
crease the numerator of the ratio without disturbing the denominator a
true acidosis without change in the bicarbonate level is possible.
Next to carbonic acid and sodium bicarbonate the acid and alkaline
phosphates of the corpuscles and tissues assist in maintaining the neutrality
NaH PO
of the blood. The normal =^- ratio in the blood plasma is given as
-rr by Michaelis and Garmendia.
5.1 *
Besides these defenses and the ammonia regulation (see "Acids"), a
factor of possible significance in maintaining the neutrality is lactic acid.
MacLeod and Knapp observed that this acid may appear in the urine,
after alkali injections in animals, in amounts sufficient to account for
five or six per cent of the alkali given.
Acids. — Walter in 1877 appears first to have shown that acids dimin-
ish the carbon dioxid content of the blood by displacing the "weaker"
acid, H2CO3. Kraus and many others showed later that acids diminish
the total or titratable alkalinity. Walter pointed out the differences be-
tween herbivora and carnivora with respect to their manner of regulating
against acids. While the former to accomplish this must surrender their
fixed alkali from the tissues,3 the carnivora are able to deflect ammonia
from the protein metabolism (at the expense of urea formation) for pur-
poses of neutralization. Recently Loeffler has shown that acids inhibit
somewhat the formation of urea by the perfusion of the liver in vitro with
ammonium salts.
NH
Thus an augmented 3 ratio in the urine has become a significant
guide to acidosis.
The term "acidosis" may be understood in its broadest sense to in-
clude all those disturbances of the acid-base equilibrium in which there
occurs either an actual increase in the Ph (i. e. in the * f - ratio) of
the blood, or, as is far more frequent, a decrease in the alkali reserve, or
both. The appearance of the acetone bodies, as in diabetes, merely indi-
cates one form of acidosis, sometimes designated as "ketosis."
L. J. Henderson and Palmer (6), as well as Hanzlik and Collins, have
shown that acid sodium phosphate increases the urine acidity, although
* But Hart and Nelson have found a certain degree of ammonia regulation in cattle.
734
HENRY G. BARBOUR
scarcely to an abnormal extent. The highest acidity figures in the two
investigations were, respectively, Ph - 5.3 and 4.85.
Marriott and Rowland (&) have found an interesting difference in the
reaction of dogs to hydrochloric acid on the one hand and acid phosphate
on the other. While the former increased the urinary ammonia parallel
to the acidity, corresponding amounts of the latter gave, in spite of a
great acidity increase, no change in the ammonia excretion. The authors
attribute this to a difference in "strength" of the respective acids, "weak"
acid being apparently unable to arouse the ammonia metabolism.
Alkalies. Treatment of Acidosis. — Walter established the efficiency
of sodium carbonate injections in combating the acidosis produced by
giving hydrochloric acid by mouth, even in the last stages. Using the
alkali as a preventive a triple fatal dose of the acid could be withstood
without increase in the ammonia excretion or the appearance of other
symptoms.
In acid poisoning Salkowski and Munk and others have reduced the
ammonia excretion to normal by giving fixed alkali.
In diabetes Stadelman(o-) founded the, theory of acid poisoning as the
cause of coma and increased ammonia excretion, and instituted the alka-
line treatment. Subsequently Magnus-Levy developed the use of alkalies by
injection and per os, both in preventing and meeting the diabetic acidosis.
The bicarbonate is now generally employed, its potential alkalinity being
high in proportion to its actual (locally irritating) alkalinity. Even the
subcutaneous injection, which may result in serious sloughing, may be
accomplished with but slight irritation if the solution be first freed from
all traces of the carbonate (Na2CO3) by saturating with carbon dioxid
(Magnus-Levy) .
The bicarbonate treatment should be instituted with the appearance
of acetone substances in the urine ; after the onset of coma it may be too
late. The initial dose by mouth may be 30 to 40 grams in divided doses,
freely diluted,' given between meals. In coma oral administration may
be supplemented by drop enemata (4 per cent), or, for a more prompt
result, 1,000 c.c. of 4-6 per cent solution by vein.
In the acidosis of anesthesia: Palmer and VanSlyke demonstrated
depletion of the alkali reserve of the blood and suggested prophylactic in-
jections of bicarbonate. Morriss employed this measure in gynecological
cases (under chloroform or ether) and summarizes his results as follows :
C.C. OF C02 BOUND BY 100 C.C. OF PLASMA
Without bicarbonate
With bicarbonate
Before After
anesthesia anesthesia
50.7 41.7
54.7 49.0
Differ- No. oj
ence cases
9.0 10
5.7 10
EFFECTS OF CERTAIN DRUGS AND POISONS 735
In studies of anesthesia Killian found the acidosis, increased diastatic
activity and sugar content of the blood all controllable by alkali (e. g., 20-
30 grams of bicarbonate per os). The blood acetone bodies in operative
anesthesia Reimann and Bloom found increased sufficiently to account
for from 20 to 100 per cent of the bicarbonate depletion. They endorse
the recommendation that in cases where the carbon dioxid capacity is
less than 58 c.c. the bicarbonate be used prophylactically.
The alkali depletion resulting from the overventilation usually accom-
panying light ether anesthesia can, as Henderson and Haggard have shown,
be prevented by administration of a suitable carbon dioxid mixture with
the anesthetic. Reimann and Hartman prefer the bicarbonate to the gas,
believing it advisable to introduce more alkali into the body to combat the
production of acid metabolites.
Uranium nephritis is associated, as MacNider(a) (&) has shown, with
ketosis and depletion of the plasma bicarbonate. He finds that alkali injec-
tions protect against the toxic effects of uranium as well as against the un-
favorable action which anesthetics exert upon the kidneys whether uranium-
poisoned or "naturally nephropathic." Furthermore, the action of
diuretics in these conditions is enhanced by sodium carbonate.
In the acute experimental nephritides of cantharadin, arsenic, diph-
theria toxin and chromate poisoning Goto(a) (6) has reduced the acidosis
with oral bicarbonate injections.
In the "retention acidosis" of nephritis Denis and Minot(&) find that
small intermittent oral doses of bicarbonate keep the urine free of
ammonia.
In infants a type of acidosis occurs during attacks of severe diarrhea;
dyspnea is present but no cyanosis, and Czerny states that mineral acid
poisoning in rabbits is simulated. Howland and Marriott (c) were the first
to attempt the rescue of such children by the alkaline treatment. The
blood was found free of acetone bodies in this condition. In one of their
cases treated with bicarbonate the alveolar carbon dioxid tension (in
millimeters) was on five successive days: 21, 42 ,54, 55, 41. The normal
tension for infants is 36-45 millimeters. On the third day therefore the
treatment was stopped.
Blood studies of such children have shown not only a depleted alkali
reserve, but also a reduction from Ph =7.4 to Ph =7.2. Anuria is fre-
quent and the acidosis is attributable to a retention of acid phosphate in
the organism.
Schloss and Stetson have in similar cases reported, besides the de-
creased carbon dioxid in alveolar air and blood, a high ammonia co-
efficient and an increased "bicarbonate tolerance." 1.25-3.25 grams of
sodium bicarbonate rendered the urine alkaline in normal infants, while
5.5-7.0 grams was required to accomplish this in cases of acidosis. Such
736 HENRY G. BARBOUR
doses increased the carbon dioxid of the blood from 19.6-26 to 40-5
volumes per cent.
Water Metabolism. — Either acids or alkalies may act efficiently as
diuretics. However, if the blood volume of rabbits has already been
doubled by the intravenous injection of saline the addition of 0.4 per cent
sodium carbonate does not hasten its return to normal. (Bogert, Mendel
and Underbill)
Alkalies enjoy considerable repute as obesity cures, Stadelman(fr) and
others having noted a marked reduction in weight during their prolonged
use. Much of this may be attributed to water loss. (Digestive disturb-
ances may, however, play a role.)
Bicarbonate edema sometimes occurs during the treatment of diabetes
and other conditions with this alkali. Fitz associates it with a retention
of sodium chlorid.
Body Temperature. — The relations existing between the acid-base
equilibrium and the regulation of body temperature are not yet understood.
Mineral Metabolism. — A retention of intravenously injected chlorids
(as well as of lactose) was observed by Herz and Goldberg after the ad-
ministration of alkali. ' This was ascribed to renal action, and is con-
firmed by the observations of Fitz (a). On the other hand, Bunge and
others have consistently observed an increased chlorid excretion after alka-
lies.
That acid administration per os increases the urinary calcium has
been noted by Secchi as well as Givens(a) (6), in animals on a calcium-
rich diet. Gi vens, however, found the calcium balance unaffected, and
noted no appreciable increase in the magnesium excretion, in which two
respects Secchi's work lacks confirmation. The latter found the sodium
and potassium output after hydrochloric acid augmented for but a brief
time, in contrast to the persistent ammonia excretion.
Stehle(a) found an increased calcium and magnesium excretion in dogs
given hydrochloric acid by mouth. Sodium and potassium excretion were
augmented to a lesser extent. He suggests a connection between calcium
loss and diabetic acidosis.
Sawyer, Baumann and Stevens studied the mineral loss in children
during acidosis and found both calcium and phosphates largely excreted.
The loss of these ions varied with the severity of the acidosis.
Fitz, Alsberg and Henderson found that the administration of acids
first increases the excretion of phosphates, but later this becomes dimin-
ished owing to exhaustion of the supply.
In experimental acute nephritis Goto(&) succeeded in diminishing the
chlorid retention by oral administration of bicarbonate.
Total Metabolism. — While the effects of acid or alkali upon the tot
oxidations are not marked, there is some evidence that the former ten<
to diminish and the latter to augment the respiratory exchange. Chvostek
EFFECTS OF CERTAIN DRUGS AND POISONS 737
gave rabbits orally 0.9 gram (per kilo) doses of hydrochloric acid in 0.2
to 0.3 per cent solution. In four experiments both carbon dioxid out-
put and oxygen absorption were reduced by about one-fourth, although
decreased muscular activity was not noted. Lehmann obtained similar
results under artificial respiration, noting also an increase in oxidations
when alkali was administered.
Lactic acid causes a slight increase in the basal metabolism, as shown
by Atkinson and Lusk.
Carbohydrate Metabolism. — The first evidence of a relation of the
acid-base equilibrium to the carbohydrate metabolism was furnished by
Pavy's discovery that phosphoric acid, orally or intravenously given, pro-
duces glycosuria in dogs.
Elias found that hyperglycemia accompanies acid glycosuria in dogs
and rabbits. He and Kolb also showed that in the "hunger diabetes" of
young dogs there is a diminution of the carbon dioxid of alveolar air
and blood.
The inhibitory influence of alkali upon the glycosuria of ether and
chloroform was discovered by Pavy and Godden, who abolished the sugar
by the intravenous injection of sodium carbonate. In like manner Elias
and Kolb inhibited "hunger diabetes."
Murlin and Kramer showed further that sodium carbonate intro-
duced into the blood stream of a depancreatized dog lessens the sugar
excretion. Bicarbonate was later found less effective. No compensatory
increase of sugar was found in the blood and no evidence that the retained
sugar is deposited as glycogen. The inference that alkali increases the
combustion of sugar was only partially substantiated in such cases for,
while in partially depancreatized dogs both mono- and disodium carbonate
increased the respiratory quotient, the latter was found ineffective in cases
where the entire pancreas had been removed.
Attempts were made by Murlin and Graver to treat human diabetes
by the administration of alkalies through a duodenal tube. Sodium car-
bonate thus given reduced the glycosuria, but the bicarbonate curiously
gave opposite results.
Underbill (i) showed that intravenous sodium carbonate usually induces
a marked though transient fall in the blood sugar content of rabbits. He
first suggested that the acid-base equilibrium is a factor in blood sugar
regulation and showed further that both the hyperglycemia and glycosuria
provoked by epinephrin can be prevented partially by sodium carbonate.
He further pointed out the association between hypoglycemia and alka-
losis in tetany and in hydrazin poisoning.
Applying the acid-base theory to therapeutics Underbill was able to
maintain a diabetic individual in a state of comparatively good health
and vigor over a period of years by giving large doses of sodium bicar-
bonate; as much as 120 grams was once given in a single day. The carbo-
738
HENRY G. BARBOIJR
hydrate tolerance in this case could be varied at will by appropriate
changes in the dosage. (See figure 1.) On the other hand. Beard has
been unable to control the sugar tolerance in this fashion. Fitz warns,
in this connection, that the possibility of bicarbonate edema should be
kept in mind.
The hyperglycemia resulting from etherization and operative pro-
cedure in sugar-fed dogs was reduced by MacLeod and Fulk by injecting
ISO
too
50
ft±
A -H AAA - iAA^>
tSQ
too
50
Fig. 1. Influence of sodium carbonate ingestion on the glycosuria of a diabetic:
solid line, sugar; broken line, intake of sodium bicarbonate. (F. P. Underbill, J.
Am. M. Assn., 1917, LXVIII.)
intravenously enough sodium carbonate to lower the Ph of the blood.
(Compare Killian's results, mentioned above.) These investigators lay
emphasis upon increased storage of glycogen in liver and muscles, under
the influence of alkali.
The influence of alkali upon renal permeability for sugar was sho\
by the researches of Hamburger (b) upon the frog glomeruli. When the
perfusion fluid contained NaCl, 0.6 per cent; CaCl2, 0.0075 per cent;
KC1, 0.01 per cent; NaHCO3, 0.02 per cent and 0.1 per cent of glucc
a "urine" containing 0.07 per cent of the latter was excreted, indicating
a retention of 0.03 per cent. When, however, the bicarbonate content of
the perfusion fluid was increased to 0.285 per cent, the equivalent of the
normal frog serum content, a sugar-free "urine" was obtained.
EFFECTS OF CERTAIN DRUGS AND POISONS Y30
While the exact effects upon either the combustion or the, storage of
glucose are not as clear as the influence of alkali upon renal permeability
it may safely be affirmed that acids and alkalies tend, within certain limits,
to increase and decrease, respectively, the excretion of sugar.
Protein Metabolism. — The augmented excretion of various protein
metabolites, following administration of dilute mineral acids, described
by some observers, is probably chiefly a diuretic effect. Alkalies have not
been shown to affect appreciably the protein catabolism. Jawein found
that 20-40 grams of sodium carbonate or citrate produced in man either
inconstant changes or none at all. The neutral sulphur of the urine, how-
ever, appeared to be increased at the expense of the acid sulphates.
The retention both of non-protein and of urea nitrogen in the acute
nephritis of metal poisoning, etc., was overcome in Goto's experiments
by alkali 'administration.
The excretion of creatin in rabbits may be initiated or augmented by
acids or diminished or abolished by alkalies, as shown by Underbill (fc).
Denis(Z) and Minot(c?) failed to establish such a relationship in a few
human cases.
Purin Metabolism. — The alkalies have been extensively used in gout,
partly on the theory that the supposed combustion increase would destroy
more uric acid and partly in an attempt, by neutralizing this acid, to pro-
mote its excretion. We have seen, however, that increased oxidation has
not been established and Ritter has shown that no direct solvent action of
alkalies upon urate tophi can occur in the body. MacLeod and Haskins
maintain that citrates by their alkalinity increase the elimination of
endogenous uric acid and purins, but this may be due to intestinal
derangement.
The "alkaline cures" for gout probably owe their beneficial effects
merely to the considerable quantity of fluid ingested. In spite of the
greater solubility of urates in alkaline form, alkalies do not remove gouty
calculi from kidney or bladder; furthermore, alkalinity of the urine is
likely to promote the deposition of phosphates.
Tetany. — Wilson and his associates found intravenous injections of
hydrochloric acid effective in preventing the tetany which follows thyreo-
parathyroidectomy. They describe tetany as a condition of alkalosis.
McCann found a lowered carbon dioxid capacity of the plasma in this
condition and states that tetany may sometimes depend upon derange-
ments in the acid-base relations of the alimentary secretions.
Harrop(a) has described a case of tetany resulting from the intravenous
infusion of sodium carbonate in an adult suffering from mercuric bi-
chlorid poisoning and totally anuric. He emphasizes the danger of
the use of bicarbonate in cases of marked renal impairment. Tetany has
occasionally been observed in young children given sodium bicarbonate for
acidosis.
740 HENRY G. BARBOUR
Boracic Acid and Borax. — Boracic acid and borax are respectively
weakly acid and alkaline in reaction. Moderate doses of either do not
effect the metabolism, but Chittenden and Gies(6) found that large quanti-
ties (5 to 10 grams per day for dogs) increase the urinary nitrogen; a
dose of 4 to 8 grams in man retards the absorption of proteins and fats.
Tinder borax the body weight often falls, which has been attributed
to augmented fat destruction by Rost and by Rubner(i), who found a cor-
responding increase in the carbon dioxid elimination. Boracic acid is said
to be the least harmful of the food preservatives.
IV. Oxygen and Asphyxiants
Breathi-ng undiluted oxygen produces no very significant effects, but
when the supply of oxygen has been deficient asphyxial symptoms are
promptly removed by inhalation. Lavoisier and Seguin in 1789 estab-
lished the fact that pure oxygen under ordinary conditions does not affect
the metabolism. Long continued exposure -to atmospheres rich in oxygen
produces pneumonia. (Karsner.)
Oxygen Deficiency. — Haldane has described the acute effects of
atmospheres low in oxygen. Chronic oxygen-lack as seen in anemias, etc.,
causes considerable tissue destruction (Frankel), fatty degeneration and
acidosis, often with increased ammonia excretion. A. Loewy found amino-
acids in the urine. Mansfeld attributes the increased protein metabolism
to thyroid influence, for it fails to occur in the partial asphyxia of thyroi-
dectomized dogs. In anemias with the hemoglobin as low as 20 per cent,
Dubois has observed a marked augmentation of the total metabolism.
Exposure to rarified air, as first shown by Viault, increases the hemo-
globin content. This is preceded by a relative hemoglobinemia (Dallwig,
Kolls and Loevenhart). This blood concentration probably induces the
fever of "mountain sickness" in which the temperature, according to
Caspari and Loewy, sometimes attains 42° C. Such a temperature favors
the free dissociation of oxygen, tiding over the period of preparation of
better oxygen-transporting facilities. Douglas, Haldane, Henderson and
Schneider at an elevation of 4,290 meters, found the hemoglobin some-
times increased to 150 per cent, Some evidence of "secretion" of oxygen
into the pulmonary capillaries was found.
The total metabolism, in similar investigations by Wendt and by
Diirig and Ziinz was found increased, while there were evidences of a
diminished protein catabolism.
Asphyxial Glycosuria. — Araki(d) and others have shown that simple
asphyxia and other conditions associated with oxygen-lack cause an excre-
tion in the urine of both glucose and lactic acid, the latter being regarded
as a result of imperfect combustion. The glycosuria, like those produced
EFFECTS OF CERTAIN DRUGS AND POISONS 741
by piqure and the emotions, appears to be of central origin. It cannot
occur when the liver glycogen is exhausted. MacLeod has shown that,
although it can still be produced with the liver denervated, it is prevent-
able by double splanchnotomy, or excision of both adrenals. The effect
is apparently due to increased hydrogen ion concentration of the blood
(compare the acid glycosuria of Pavy) acting through the nervous centers,
but involving often the cooperation of the adrenals.
Kellaway(a) (&) produced asphyxia by causing animals to breathe gas
mixtures low in oxygen or high in carbon dioxid. Accelerated secretion of
epinephrin and hyperglycemia were observed, both being due mainly to
lack of oxygen, rather than to carbon dioxid excess. The hyperglycemia
was only in part caused by acceleration of the epinephrin output. In
anoxemia the ordinary mechanism of action is central, the splanchnics pro-
viding the path of the impulses.
F. M. Allen enumerates a list of poisons to which the production of
asphyxial glycosuria has been attributed. Many of them will be discussed.
Blood Alkalinity. — Galleotti found in himself and several others as
a result of several days' residence upon Monte Rosa (4,560 meters) a re-
duction of 40 per cent in the blood alkalinity.
Lactic Acid. — Araki's(a) finding of increased lactic acid excretion in
conditions of oxygen-lack has been amply confirmed and so much stress
was at one time laid upon this feature that, as Lusk points out, it was
wrongly taken as pathognomonic of an asphyxial condition.
Terray found that when the oxygen percentage in the inspired air
was reduced to 10.5 an increased respiratory activity commenced. With
half of this concentration there was every indication of oxygen-lack, and
the elimination of lactic acid became pronounced. The lactic acid elimi-
nated as a result of breathing 3 per cent oxygen varied in eight observa-
tions from 1.206 to 3.686 grams in twenty-four hours.
Carbon Dioxid. — Carbon dioxid acts as a weak acid, serving as the
respiratory regulating hormone. The central nervous system, especially
the medulla, is so sensitive to its stimulating effect that it may become
an important factor in the asphyxial phenomena just described. In high
concentrations, however, the gas evokes the symptoms of oxygen-lack in the
same way as when an indifferent gas such as hydrogen or nitrogen is in-
haled ; Loevenhart therefore refers its effects to interference with oxygena-
tion. Westenryk showed that carbon dioxid inhalation reduces the tem-
perature, Magyary-Kossa finding this effect more marked in fever than
in health, and associated with reduced oxidations. To produce glycosuria
10 to 15 per cent of carbon dioxid (enough to narcotize) is required
(Edie, Moore and Roaf).
Acapnia. — Excess of carbon dioxid is rapidly blown off by the respira-
tory mechanism and overcompensation often occurs, resulting in a lowered
carbon dioxid content of the blood (Y. Henderson). Since this carbon
742 HENKY G. BAKBOUR
dioxid content runs essentially parallel to carbon dioxid capacity (i. e.,
varies with the alkali reserve of the blood), acapnia is a variety of acidosis.
Y. Henderson and Underbill showed that a lowered carbon dioxid
content of the blood was associated after piqure, pancreatectomy, light
etherization, excessive artificial respiration and in other conditions with
hyperglycemia and glycosuria.
Carbon Monoxid. — Clearly an asphyxial poison, carbon monoxid
forms a firm combination with hemoglobin for which it has two hundred
times the affinity of oxygen. When an atmosphere containing 0.05 per
cent carbon monoxid is inhaled oxygen transportation is seriously ham-
pered; 0.2 per cent is generally fatal, the hemoglobin then being about
60 per cent saturated with the poison (Haldane(fr)). Carbon monoxid
acts only by displacing oxygen, for when oxygen is breathed under two
atmospheres pressure (which renders an animal independent of its hemo-
globin) the addition of carbon monoxid in any amount produces no
symptoms. Furthermore, in gas poisoning cases, oxygen if administered
soon enough, which is rarely feasible, rapidly dispels the symptoms.
Hemoglobin-free animals, for example, insects, exhibit no deleterious
effects in the presence of carbon monoxid.
Blood Gases. — Saiki and Wakayama in carbon monoxid poisoning
in rabbits found the carbon dioxid of the blood reduced from 30 to 5.21
volumes per cent; in dogs from 30-40 to 3.22 volumes per cent The
blood oxygen in the two species was reduced respectively from 12.64 to
7.62 per cent and from 20 to 2.01 per cent. .
The low carbon dioxid content is not due to lessened carbon dioxid
production, for, as Hans Meyer has shown, the latter must be very mark-
edly reduced to produce even a slight diminution of the blood carbon
dioxid content; it indicates rather a reduced alkalinity of the blood.
Araki confirmed this by tritration and Saito and Katsuyama showed
further an increase in the blood lactic acid in hens from 0.0269 to 0.1227
per cent. The fact that in dogs the blood carbon dioxid content is dimin-
ished so much more profoundly after carbon monoxid than after acid
administration does not militate against acid production being the cause
of this acapnia, for Loewy reminds us that acid feeding by mouth is one
thing and acid formation in the tissues another ; in the latter case, as, for
example, in carbon monoxid poisoning, the fixed alkali becomes attacked
before the ammonia regulation comes into play. Spiro, in fact, has demon-
strated a marked acapnia as a result of the injection of acids intraven-
ously (the ammonia regulation being thus more or less evaded). The
occurrence of acidosis may satisfactorily be'attributed to oxygen deficiency.
Total Metabolism. — Bock found in a dog subjected to an atmosphere
of 0.2 per cent carbon monoxid (leaving less than half the hemoglobin
saturated with oxygen) that the oxygen intake remained practically un-
changed, while there was a considerable rise in the carbon dioxid excre-
EFFECTS OF CERTAIN DRUGS AND POISONS 743
tion. This result is often seen in oxygen-lack. Profound carbon monoxid
poisoning leads, of course, to a diminished oxygen intake (Desplats), but
in the grade induced by Bock it appears that the total metabolism re-
mains unaltered. The high carbon dioxid output is attributable to dis-
placement of the gas from the blood, first by the carbon monoxid itself;
secondly by the decreased alkalinity as the condition progresses, and
thirdly, probably temporarily by deeper ventilation.
Protein Metabolism. — An increase in the protein catabolism in man
occurs, persisting for two or three days. Miinzer and Palma found an in-
crease in the phosphate excretion parallel to the nitrogen increase. In
fasted dogs the nitrogen excretion is greater. Jeannert found 4.6 grams
urea excreted in the 6^ hours following carbon monoxid poisoning as
against 2.5 to 2.9 grams on control days. The increased catabolism is
attributable to oxygen-lack.
The nitrogen partition, as has been observed, need not be altered in
this type of acidosis; Miinzer and Palma in man and Araki in animals
noted only slight increases in ammonia excretion. Occasionally a very
high uric acid excretion has been noted on the first day (Noel Paton).
Frankel failed to find amino-acids in the urine. Katsuyama and others
find the synthesis of hippurates and of ethereal sulphates inhibited in
carbon monoxid poisoning.
Mineral Metabolism. — Phosphate and sulphate excretion are prob-
ably increased, as in oxygen-lack. Kast found in carbon monoxid poison-
ing a decreased chlorid output in animals whose tissues were well sup-
plied with this ion. In chlorid-poor animals, however, the output was
increased. This apparent paradox is explainable upon the supposition
that in the latter case an inherent tendency to lose chlorids is enhanced
by the condition of oxygen-lack. The alkali-depleting mechanism is doubt-
less involved.
Lactic Acid. — Urinary lactic acid was found in carbon monoxid
poisoning by Miinzer and Palma and by Araki, blood lactic acid (in hens)
by Saito and Katsuyama. Heffter found the acidity of the muscles of
carbon monoxid-poisoned cats decreased. That the lactic acid appearance
is due in part at least to reduced combustion accords with Araki's finding
that subcutaneously injected lactic acid passes unchanged into the urine.
If overproduction of lactic acid occurs in conditions of oxygen-lack, the
experiments of Lusk and Mandel and others make it appear that this ia
derived from glucose, the glycogen of the liver being especially drawn
upon.
Carbohydrate Metabolism. — Claude Bernard and Richardson gave the
earliest accounts of carbon monoxid glycosuria. Araki showed that it is
asphyxial. Straub(a) made the surprising observation that it is best ob-
tained with meat feeding ; after pure carbohydrate feeding carbon monoxid
produces no glycosuria. The sugar is derived as in other asphyxial
744
HENKY G. BAEBOIIR
glycosurias from the liver, and in the absence of liver glycogen none is
excreted. Starkenstein has demonstrated the central mechanism of car-
bon monoxid glycosuria and claims by histological and chemical tests to
have found the adrenal glands exhausted after carbon monoxid poisoning.
In view of the work of Kellaway on asphyxial glycosuria, it seems prob-
able that the central action is exerted through the nerves of the liver
as well as of the adrenals.
Other Blood Poisons. — Methemoglobinemia. — A number of poisons
besides carbon monoxid reduce the oxygen-transporting capacity of the
blood. Among the poisons which do this by causing methemoglobinemia
are the nitrates, chlorids, bile acids, pyrogallic acid, arsin, piperidin,
toluylenediamin, hydroxylamin and others. Antipyretics, phosphorus and
some heavy metals produce similar effects, but these constitute a minor
part of the.ir action.
When in its alkaline form, methemoglobin is much more readily con-
verted back into oxygen. In accord with this, herbivorous animals appear
less susceptible to its formation than the carnivorous. Alkali injec-
tions have therefore been suggested in the treatment of methemoglobi-
nemia.
Acid-Base Equilibrium. — Diminished alkalinity of the blood was
shown by Hans Meyer, Kraus, Kose and others to be commonly asso-
ciated with the blood poisons.
Protein Metabolism. — Nitrogen excretion is increased by relatively
small doses of chlorates (Mering(a)). Pyrogallol increases the excretion
of nitrogen (Noel Paton), of uric acid (Kiinau) and of neutral sulphur
(Bonanni(a)). Pyrodin (Frankel(&)), toluylenediamin, and bile acids
(Noel Paton), and large quantities of anilin, quinolin, salicylic acid, etc.,
also stimulate protein catabolism. Lawrence has shown that nitrites may
increase the nitrogen and solids of the urine in man.
Benzol is a blood poison causing especially destructive changes in the
hematopoietic organs, and diminution of the leukocytes and blood plate-
lets. Increased excretion of neutral sulphur and of ammonia (Sohn) and
a rise in body temperature also occur.
Carbohydrate Metabolism. — Hoffman observed glycosuria from amyl
nitrite inhalation. This was associated by Konikoff with the disappear-
ance of glycogen from the liver. Araki found the phenomenon associated
with lactic acid secretion in both fed and fasted animals.
Hydrogen sulphid is one of the. blood poisons that cause glycosuria
(Cahn), but since sulphhemoglobin is found only in traces during life,
E. Meyer believes the sulphid is directly toxic to the central nervous sys-
tem. Other blood poisons causing glycosuria are the chlorates (Stokvis(a)
ajid others) anilin (Brat), nitrobenzol (Magnus-Levy) and orthoni-
trophenol-propionic acid (Hoppe-Seyler).
Bukowski noted in phenol poisoning a rapid disappearance of liver
EFFECTS OF CEKTAIN DKUGS AND POISONS 745
glycogen and Borchardt (cited by Allen) found glycosuria in rabbits after
0.5 c.c. subcutaneous injections.
Piperidin glycosuria was shown by Underbill to be accompanied by
hyperglycemia and asphyxial in origin, disappearing under oxygen ad-
ministration. Biihl and others produced glycosuria by inhalation of
acetone, also an asphyxial poison.
Chlorid Excretion. — Kast found, as in carbon monoxid poisoning, an
increased chlorid excretion after pyrogallol and toluylenediamin in
chlorid-poor animals.
Syntheses. — Amyl nitrite inhibits ethereal sulphate synthesis (Katsu-
yama) and certain aromatic diamins which are also blood poisons were
found by Pohl(o.) 4o inhibit the synthesis of hippuric acid, but not of
glycuronic or of ethyl-sulphuric acid.
Cyanids. — A type of asphyxial poisoning occurs in which neither
the external respiratory mechanism nor the oxygen-transporting capacity
of the blood is disturbed.
Claude Bernard pointed out that the venous blood in cyanid poison-
ing is red, although the other changes are those of asphyxia. He deter-
mined that the action of cyanid upon the blood is not the same as that of
carbon monoxid since blood when mixed with cyanid will not turn red
in the absence of air. In other words, the red color of the venous blood
was ascribed simply to oxyhemoglobin. This was conclusively proven
when Zeynek showed that at body temperature hemoglobin will not unite
with cyanid, and oxyhemoglobin unites with it only after heating for
several hours.
That the blood returns from the tissues still laden with oxygen was
shown by Geppert(&), who obtained the following oxygen determinations
in cyanid-poisoned rabbits :
VOLUMES PER CENT OXYGEN
Arterial blood Venous blood Difference
12.2 10.9 1.3
13.0 12.4 0.6
In various ways this investigator showed that the power of the blood
to attach or to release oxygen is in no wise interfered with during cyanid
poisoning.
Geppert showed further that the first effect of moderate doses of prus-
sic acid upon the oxygen consumption of rabbits, cats, and dogs is one of
augmentation, which is soon followed by a marked diminution. The
return to normal in non-lethal poisoning is preceded by another wave of
somewhat high oxygen intake. These stages are illustrated in the follow-
ing table :
746
HENRY G. BARBOUR
C.C. OXYGEN CONSUMPTION PER MINUTE
Animal
rabbit
rabbit
cat
cat
cat
dog
dog
Normal
22.7
20.7
35.4
30.9
28.8
39.7
35.7
Poisoned
1st period
2d period
....
15.8-17.4
....
5.0-9.4
40.2
21.2-19.8-24.8
60.4
24.0-28.9
46.4
16.6-20.0
80-52
26.1
65-46
21.7
Return
to normal Normal
23.8
30.9
44.8
30.5-30.8
60.6-53.2
36.6-52.0
33.7
39.3
42.1
The "second period" presents the picture which is so characteristic
of the toxic action of the cyanids. Now Geppert showed that this marked
fall in the oxygen intake took place at a period when the ventilation was
not reduced, but was enormously increased, i. e., the asphyxial demand
for oxygen was present. Furthermore, the oxygen consumption was low
not only during rest but during all stages of muscular restlessness up to
actual spasms. During the convulsions, which often occurred, dogs occa-
sionally (not always) exhibited an abnormally high oxygen consumption.
In other species the oxygen intake was always subnormal even during the
spasms. Similarly during the tetanizing respectively of normal and of
poisoned animals Geppert found the oxygen consumption lower by two-
thirds to four-fifths in the cyanid animals than in the controls.
The oxygen consumption was thus found reduced under circumstances
in which an opposite effect would logically be expected.
The following are Geppert's figures for the carbon dioxid content of
arterial and of venous blood :
C.C.OOo IX 100 C.C. BLOOD
No.
34
35
36
33
37
Normal Poisoned
Arterial Venous Arterial Venous
41.1
43.7
40.3
41.4
50.3
22.0
18.0
23.6
17.7
23.9
48.2
30.2
Dog, art. at 1st spasm,
venous during paraly-
sis
Dog, moderate spasm
Rabbit, 6 min. after in-
jection
Rabbit, after spasm
Rabbit, ven. at end of
spasm, arterial during
paralysis
EFFECTS OF CERTAIN DRUGS AND POISONS 747
Normal Poisoned
No. Arterial Venous Arterial Venous
{Rabbit, ven. at begin-
ning of poisoning, art. 4
minutes after spasm,
77 17 0 I ven' ^ 3° min' after
[ spasm
38 36.0 46.2 11.0 33.1 ' Dog, severe paralysis
39 44.8 27.6 I Rabbit, beginning of
1 spasms
It will be seen that the carbon dioxid in the arterial blood was very
low, often sinking rapidly (cf. No. 36) ; that of the poisoned venous blood
was usually lower even than the carbon dioxid of normal arterial blood.
A considerable degree of acidosis was therefore indicated.
This acidosis or acapnia, together with the increased ventilation (fre-
quently the minute volume was more than doubled), was taken to account
for the high respiratory quotients which occasionally exceeded 130, Gep-
pert concluding that the actual production of carbon dioxid ran essentially
parallel to the oxygen intake.
Since the return to the lungs of oxygen-laden blood was thus found
associated with a profound depression of the oxidations Geppert
depicted cyanid poisoning as "an internal asphyxia of the organs in the
presence of superabundant oxygen."
This interference by cyanids with oxidation has been demonstrated
under widely varying conditions throughout the realm of biology, e. g., in
"salted" frogs (Oertmann), in excised kidneys (Vernon), and in many
lower animals and plants. Hyman has shown a reversible decrease fol-
lowing a temporary increase (cf. Geppert's first period) of oxidations in
sponges and presents an able review of certain theoretical aspects of
cyanid poisoning. Child has shown that previous exposure to cyanids
renders sponges more susceptible to oxygen-lack.
In hyperthyroidism it does not appear feasible to reduce the high total
metabolism by cyanid treatment. (Snell, Ford and Rowntree.)
Ferments. — The (reversible) effects upon oxidative, hydrolytic (e. g.,
alcoholic fermentation of sugar) and other fermentative reactions are
inhibitory (barring certain interesting exceptions). In Burge's experi-
ments cyanid poisoning was found associated with a decreased blood
catalase, but according to Duncker and lodbauer the inhibitory concentra-
tion for catalase is not reached in acute cyanid poisoning.
Whatever may ultimately prove to be the exact nature of the cyanid-
enzyme reaction in the tissues, Geppert's theory of "internal asphyxia"
appears firmly established.
HENRY G. BARBOUR
Body Temperature. — Increased heat elimination by blood dilution
probably plays a role in the cyanid temperature fall of mammals (dis-
covered by Hoppe-Seyler).
Carbohydrate Metabolism. — Zillessen describes an increased lactic
acid excretion, but contrary to the results of some authors obtained no
glycosuria.
Protein Metabolism. — Loewy finds that the total nitrogen excretion
is notably increased (mainly as urea), and that amino-acid excretion
occurs.
V. Phosphorus, Arsenic, Heavy Metals, Etc.
Phosphorus. — The effects of phosphorus upon the metabolism are
associated with two distinct conditions, one largely of a catabolic nature,
the other anabolic. To the first, the toxic syndrome, much attention has
been devoted.
Phosphorus poisoning is characterized by profound liver injury, in-
cluding fatty changes, in which respect the heart also is involved. The
liver glycogen is soon exhausted. There are a wasteful excretion of nitro-
gen, a somewhat high total metabolism and an acidosis associated espe-
cially with a high blood and urine content in lactic acid.
While phosphorus was formerly assigned by many to the category
of asphyxia! poisons, Oswald and others have maintained that it acts
chiefly by impairing the anti-autolytic agents of the body. The present-
day theory of Lusk hinges largely upon the lactic acid accumulation.
Total Metabolism. — Phosphorus poisoning is not, as once believed, as-
sociated with a low level of bodily oxidations. Lusk has found that the
oxygen consumption in this condition is augmented, which observation
has been confirmed by Hirz. The former attributes the increase both to
fever and to augmented protein destruction.
Fat Metabolism. — In spite of the obvious shifting of the bodily fat,
its total combustion was found unaltered by Lusk. Loewi has com-
piled the figures of a number of observers with regard to fat and water
content of the liver. The normal ether extract varied from 2.8 to 3.6
per cent of moist liver. The ether extract in phosphorus poisoning varied
from 19.5 to 37.7 per cent of moist lirer. The water content of the liver
is slightly reduced when the fatty changes are marked.
With regard to the origin of the liver fat, Lebedeff showed that fat
from other species injected subcutaneously in phosphorus-poisoned animals
can later be identified in the liver. Furthermore, in such animals fat
does not appear in the liver unless there is an ample store elsewhere in
the^body. The older hypothesis of true fatty degeneration (the fat being
derived from the impaired cells of the affected organ) therefore became
displaced by the theory of fatty infiltration. In support of this Taylor(a)
EFFECTS OF CERTAIN DRUGS AND POISONS 749
has shown in frogs that there is an actual loss of total body fat, that of
the phosphorus-poisoned animals when killed being 22 per cent less than
that of the controls. There was some increase in the gross weight of the
poisoned frogs which Taylor ascribed to edema.
Shibata confirmed in mammals the diminution of total body fat after
phosphorus.
Rosenfeld(a) (&) confirmed Lebedeff s results and found the blood con-
tent in fat increased under phosphorus, thus detecting the material in the
stage of transportation to the liver. Leathes(fr) showed that the liver alters
the depot fats in certain respects, regarding this as a necessary preliminary
to the utilization of the fats in metabolism. Fatty infiltration of the liver
would represent an excessive attempt at such a conversion ; it is found in
all conditions in which there is a high need for fat (starvation, etc.). If
such animals are freely fed, the fatty infiltration of the liver may disap-
pear within a day (Mottram(fr)). Rettig has shown that a carbohydrate-
rich diet tends to prevent the fatty infiltration.
Carbohydrate Metabolism. — The finding by numerous of the earlier
observers that glycogen soon disappears from the liver in phosphorus in-
toxication was confirmed by Welsch, Notwithstanding this, glycosuria is
a comparatively rare feature; for example, Walko detected sugar in the
urine of only 6 out of 141 patients. In these cases it was not associated
with -any special degree of severity or other definite feature. The blood
sugar as Neubauer, as well as Frank and Isaak, found is, if anything,
somewhat decreased. Thus phosphorus poisoning is differentiated from
typical asphyxial conditions where glycogen disappearance is regularly
associated with hyperglycemia and glycosuria.
Frank and Isaak regarded interference with the synthesis of
glycogen as the primary action of phosphorus. They attributed the in-
creased protein destruction to the need of compensation for a low energy
production from carbohydrates.
The lactic acid which accumulates in phosphorus poisoning arises from
glucose, as shown by Lusk and Mandel. For lactic acid disappears from
the urine as soon as the phosphorus-poisoned dog is treated with phlor-
hizin; the glucose is hurried away before the lactic acid can be split off
from it. In accord with this Fuerth has shown that the quantity of lactic
acid elimination in phosphorus poisoning may be increased by feeding
an excess of sugar.
Increased autolysis, especially in the liver, is regarded as the funda-
mental disturbance in phosphorus poisoning by Jacoby, as well as Forges
and Pribram. The latter authors attribute this to oxygen deprivation.
In this connection, Duncker and lodbauer, as well as Burge, maintain
that catalytic activity is somewhat decreased.
Ishikawa produced alimentary glycosuria early in phosphorus-poisoned
rabbits but obtained no hyperglycemia, which fact he attributed to dam-
750 HENRY G. BAEBOUR
aged kidneys. He states that the glycolytic power of muscles and liver
was low, that of the serum high.
Marshall and Rowntree demonstrated a decreased tolerance for galac-
tose and levulose in phosphorus-poisoned dogs.
Protein Metabolism. — Storch first observed profoundly increased nitro-
gen excretion in phosphorus poisoning, finding a surplus of 200 per
cent at times. Badt and others substantiated the increased catabolism.
In fasting dogs poisoned by phosphorus, Lusk, Ray and MacDermott found
the protein metabolism increased by from 83 to 183 per cent. They con-
trasted this gain with that obtained under phlorhizin which varied from
240 to 440 per cent. In the latter case, if phosphorus was given subse-
quently there was no further essential increase in protein metabolism. This
was interpreted to mean that phlorhizin glycosuria is the predominating
factor in such an experiment and that the anti-autolytic enzymes are in-
hibited rather by lactic acid than by the direct influence of phosphorus.
Lusk believes that "phosphorus may affect the conditions which lead
to the oxidation of the lactic acid derived from glucose, and the accumu-
lation of this acid may prevent the action of some of the deaminating
enzymes; and further its non-combustion may necessitate an increase of
protein metabolism."
Rettig has shown that a diet rich in carbohydrates prevents the in-
creased protein catabolism. Simonds(&) advocates the use of a sugar diet
in the treatment of phosphorus poisoning, not only as a source of energy,
but also to inhibit abnormal enzyme action.
The anomalies of the protein metabolism in phosphorus poisoning in-
clude the appearance in the urine of amino-acids, especially leucin, tyrosin,
cystin, and sometimes peptone-like substances. Gottlieb and Bondzynski,
who first demonstrated that oxyproteic acid' is a normal urinary con-
stituent, found it increased in phosphorus poisoning. Mendel and Schnei-
der found cynurenic acid increased. Wakeman has noted changes in the
relative amounts in the liver of the basic amino-acids, histidin, arginin
and lysin.
Lusk found the uric acid and creatinin excretion unchanged.
In Marshall and Rowntree's studies of the blood of phosphorus-
poisoned dogs, non-protein nitrogen, urea, and amino-acids were all found
increased. They noted a terminal acidosis.
Hauser showed that phosphorus inhibits the synthesis of hippurates.
Acid-Base Metabolism. — Hans Meyer and others have found the car-
bon dioxid content of the blood and the titration alkalinity markedly
diminished. Besides the lactic acid, Meyer inculpates the sulphuric and
phosphoric acids derived from protein.
Mineral Metabolism. — Welsch found the excretion of phosphates and
sulphates increased, but that of chlorids diminished. Kast, however,
EFFECTS OF CERTAIN DRUGS AND POISONS 751
observed subsequent to the chlorid retention, an unusually high excre-
tion of this ion.
Schloss(&) obtained negative results with phosphorus upon the calcium
metabolism in rickets, but Brown, MacLachlan and Simpson find that
phosphorus, especially in conjunction with cod liver oil, produces an in-
crease in the blood-calcium in tetany.
Phosphorus Deficiency. — Phosphorus deficiency leads to disturbances
Fig. 2. Leg bones in osteogenesis imperfecta. Seven-year-old boy untreated. (D. B.
Phemister, J. Am. M. Assn., 1918, LXX.)
in growth and nutrition, the bones becoming soft and flexible when their
content in the element has fallen by about one-sixth (Heubner).
Effects upon the Skeleton. — Wegner in 1872 first demonstrated the
favorable effects of phosphorus upon the formation of bone, thus bringing
to light the anabolic aspect of phosphorus action. Small doses given to
growing animals were found to result in a production of compact instead
of spongy bone from the epiphyses. In adults the canals became filled
with dense bone, having a normal structure and chemical constitution.
Kassowitz found that larger doses increased the vascularization of the
bone. He described favorable results from phosphorus in rickets, osteo-
752
HENRY G. BARBOUR
malacia and delayed healing of fractures, establishing the therapeutic dose
at 1 milligram daily with meals. Cod liver oil (10 milligrams phos-
phorus in 100 c.c.) is often used as a vehicle.
Jaw necrosis has been noted even with therapeutic doses. By laying
bare the periosteum of the jaw and other bones in rabbits which were then
exposed to phosphorus vapor Wegner showed that the necrosis is due to
the direct action of the poison.
Fig. 3. Same case as Fig. 2 after two years of treatment with 1/150 grain phos-
phorus twice daily. (D. B. Phemister, J. Am. M. Assn., 1918, LXX.)
Definite effects of phosphorus upon the growth of normal and dis-
eased bones in children have been shown by Phemister, employing the
X-rays. Figures 2 and 3 illustrate the effects in the leg bones of a seven-
year-old boy with osteogenesis imperfecta. Phemister administers 1/200
grain pills on an average of three times a day; the deposit of compact
bone continues after the cessation of treatment.
Organic Phosphorus. — The alleged superiority of organic phosphorus
compounds has not been substantiated; for example, Plimmer has shown
not only that the body can synthesize its organic phosphorus from the
EFFECTS OF CERTAIN DEUGS AND POISONS Y53
inorganic forms, but that the organic preparations themselves must under-
go hydrolysis in the intestine whence they are assimilated as inorganic
phosphates. On this subject reference should be made to the review by
E. K. Marshall.
Lecithin was shown by Danilewski to hasten the growth of frogs' eggs
and to augment assimilative processes in mammals. Cronheim and Miiller
produced with this phosphorus-containing lipoid a stimulating effect upon
the protein anabolism.
Cod Liver Oil. — Cod liver oil was selected as a vehicle for phosphorus
because for many years some unknown specific property as a nutritional
stimulant had been ascribed to it, but more critical authors were inclined
to regard it merely as a well assimilated food. Osborne and Mendel (/),
however, have demonstrated a specific influence of cod liver oil upon the
growth of white rats. Fats like lard, almond oil etc., do not possess this
property which appears to be due to the fat-soluble vitamin. Schloss has
apparently demonstrated for it a calcium-retaining power in rickets (see
Calcium), in which disease Mellanby(c) finds it superior to all other fats.
Howland and Park recently have demonstrated the deposition of cal-
cium in bone as a result of cod liver oil administration ; in human beings
this is demonstrable after three weeks. Marked increase in the blood
phosphorus was also observed.
It seems probable, therefore, that cod liver oil promotes in some way
the mobilization of phosphorus in the blood which in turn stimulates the
calcium metabolism, perhaps through its peculiar tendency to augment the
lactic acid content of the blood.
Hess(c) finds cod liver oil inferior to orange juice in the scurvy of
guinea pigs.
Arsenic and Antimony. — With respect to its effect upon the metabol-
ism, arsenic appears to occupy a position midway between phosphorus
and the heavy metals. The stimulating effect upon bone formation, the
fatty infiltration, the lactic acid excess, the loss of the capacity to store
or to retain glycogen although glycosuria is rare, all bring it into close
relationship with phosphorus. The fatty degenerative changes after arsenic
are, however, less marked and the fat balance is positive. On the other
hand, it appears to be a capillary poison, which fact is held to account for
those profound intestinal disturbances which suggest the behavior of
heavy metals.
The metabolic effects of antimony resemble those of arsenic.
T. Gies and others observed that repeated administration of small
doses of arsenic to animals resulted in the production of a positive fat
balance and new bone formation in which the long bones became thickened
and the Haversion canals filled. That the therapeutic administration of
arsenic improves the nutrition in a more subtle fashion than by merely
stimulating the appetite or improving digestion is shown by the investiga-
754
HENRY G. BAEBOUR
tions, among others, of Henius (a). This author fed arsenic to dogs on a
constant diet, observing increase in weight, a positive fat balance and
stimulation of bone growth. The red blood cells and hemoglobin were also
found increased under these conditions.
Total Metabolism. — The contribution of Henius includes perhaps the
only investigation relating to the effects of therapeutic doses of arsenic
upon the gaseous exchange in man. A chlorosis patient who was gaining
weight under atoxyl was found to exhibit no difference in the basal metab-
olism as a result of the drug administration, but the experiments were
not long extended.
Chittenden and Cummins gave rabbits 35 milligrams of arsenic daily
and observed with these toxic doses some apparent diminution in the
oxidations. Large doses of antimony gave similar results.
Nitrogen Metabolism. — When affected at all, the nitrogen excretion
has usually been found increased by either arsenic or antimony.
After arsenic Boeck found no effect upon the nitrogen excretion in
man, while Chittenden, Henius and others found an increase. With anti-
mony Gaethgens(a) (6) found a 30 per cent increase in a fasted dog's ni-
trogen excretion. Chittenden and Blake, however, found the protein bal-
ance unaltered when 1-1.5 grams antimony oxid were given to a well-fed
dog.
Arsphenamin induces metabolic effects similar to those produced by
the inorganic arsenicals, according to Postojeff. Capelli found in syphi-
litic patients a high nitrogen loss on the first day after arsphenamin treat-
ment, the only effect noted upon the metabolism. Sodium arsenate pro-
duced a nitrogen retention in two patients studied by Boyd. This may
have been due to renal injury.
Uric Acid Excretion. — Abl found that arsenic and antimony in com-
mon with other intestinal irritants increase uric acid excretion.
Carbohydrate Metabolism.. — Rosenbaum and others are agreed that
arsenic induces a prompt disappearance of glycogen from the liver. The
blood sugar content was not found increased, but work with newer methods
appears called for. As with phosphorus, glycosuria at all events is rare.
Saikowsky noticed that the arsenic or antimony liver becomes free of
glycogen before the beginning of fatty infiltration can be detected. He
was unable to produce glycosuria either by piqure or by curare injections
in arsenic-treated animals.
Konikoff showed that excess feeding of sugar did not restore the
glycogen in arsenic poisoned animals. Luchsinger found that arsenic
favors the production of alimentary glycosuria. Araki(a) found lactic
acid, but rarely sugar in the urine in arsenic as well as in phosphorus poi-
soning.
Acid-Base Equilibrium.. — Hans Meyer correspondingly observed a re-
duction in the alkalinity of the blood after toxic doses of arsenic. Mori-
shima, investigating the source of the lactic acid, noted that in autolysis
of fresh livers the disappearance of glycogen is closely paralleled by the
gains in lactic acid content.
Water Metabolism. — Arsenic, according to Magnus, exerts a specific
toxic effect upon the endothelial cells of the capillaries throughout the
body. To this the cholera-like diarrhea of arsenic has been ascribed. The
dehydration is sufficient to cause marked thirst and to account for
much of the hemoglobin increase. To this capillary effect Magnus also
attributes the edema which sodium chlorid injections are capable of pro-
ducing in arsenic-poisoned animals.
Karsner and Denis described in the glomeruli of the kidneys certain
effects of arsenic which they associated with anuria. In their experiments
nitrogen retention was rather slight, but caffein diuresis was frequent.
Body Temperature. — The well-known febrile reaction frequently fol-
lowing arsphenamin administration has been variously explained. It is
not necessarily attributable to stale distilled water or to salt diuresis.
Luithlen and Mucha have explained it as due to a destructive action of
the drug upon the pathological tissues of syphilis. A new cause for some
cases has been found in an alkaline-soluble substance extractable from new
samples of so-called "pure gum" rubber tubing. (Stokes and Busman.)
Ferments. — Duncker and lodbauer found an increased catalase action
after small doses of arsenic, larger amounts giving negative results. This
does not accord with the decrease after phosphorus. It must be borne in
mind that catalytic activity of the blood has never been clearly shown
to influence directly any vital process. Lacquer and Ettinger maintain
that small doses of arsenic increase liver autolysis, which is retarded by
large amounts.
Iron. — Stockman and Grieg have shown that five to ten milligrams
of iron ingested per day suffice to maintain an equilibrium. The effects
of iron deficiency are described by H6sslin(o.). Organic iron compounds,
whether or not the metal is readily ionizable, offer no real therapeutic
advantage over the inorganic forms.
Like arsenic large doses of iron may cause renal and intestinal irrita-
tion with anuria and diarrhea. The carbon dioxid content of the blood
is reduced with toxic doses (Hans Meyer).
Munk observed no changed in the nitrogen metabolism of dogs fed
0.3-0.5 gram daily.
Mercury. — The regular occurrence of nephritis and of glycosuria
sharply differentiates the effects of mercury (as well as of uranium, etc.)
from those of arsenic and phosphorus.
Certain effects common to the last two mentioned poisons are seen
also after small doses of mercury, especially fat deposition and red blood
cell increase. Schlesinger demonstrated these results in cats, dogs, and
756 HENRY G. BARBOUR
hens fed for months on small quantities of corrosive sublimate. Among
others Bieganski demonstrated similar effects in man.
Total Metabolism. — The total metabolism is not affected in fasting
rabbits (Schroeder).
Protein Metabolism. — Bock and others found the nitrogen metabolism
unaltered in syphilitics treated with mercury. Noel Paton observed a
slightly increased nitrogen excretion in a dog. Urea and uric acid may
also be increased after small doses. Schroeder and others have observed
some nitrogen retention, presumably of nephritic origin, for the blood
urea content is increased under such conditions.
Carbohydrate Metabolism. — Glycosuria was found by Schroeder and
almost constantly by many others. Hyperglycemia was not found by
Graf or Kissel in spite of the rapid disappearance of liver glycogen.
Franck finally showed the glycosuria to be of renal origin. Lactic acid
has not been demonstrated in the urine.
Fat Metabolism. — Fatty infiltration of various organs is frequently
seen.
Mineral Metabolism. — Decalcification, of bones with cachexia and
anemia are typical of chronic poisoning.
Prevost, like others, found that mercury may produce calcium de-
posits in the kidneys, and associated them with a diminution in bone
calcium.
Acid-Alkali Metabolism. — Hans Meyer first showed that the blood
alkalinity may be diminished, and MacNider(fc) found an acid intoxica-
tion in cases of delayed kidney injury.
Water Metabolism. — Jendrassik, the modern discoverer of calomel
diuresis, recommended 0.2 gram doses four times a day. In cardiac
dropsies seven to eight liters of urine were thus obtained daily with a con-
siderable washing out of urea and chlorids.
Fleckseder(fr) found that all mercury compounds by all methods of ad-
ministration produce a diuretic effect in rabbits. He believes that mercury
lessens the absorption of water from the small intestines ; correspondingly
larger amounts of water being absorbed from the colon, diuresis is more
readily brought about. This does not explain calomel action in cardiac
dropsies. The blood of rabbits becomes hydremic, but in man the hydremia
seems to occur only with the dropsies. Healthy individuals under mercury
may exhibit a concentrated blood associated with diarrhea.
Pleuritic exudates are not influenced by calomel.
Body Temperature. — Poisoning from inhalation of mercury vapor is
accompanied by a febrile reaction (Carpenter and Benedict). Further-
more fever generally accompanies the stomatitis or skin eruptions of mer-
cury poisoning, while in collapse there is of course a profound temperature
fall.
EFFECTS OF CERTAIN DRUGS AND POISONS 757
Uranium. — In uranium intoxication while renal and capillary per-
meability appear to occupy the center of the picture, a kinship to phos-
phorus poisoning is still discernible. Edema, due to capillary poisoning,
is often a feature.
Water Metabolism. — Leconte in 1854 described general anasarca and
ascites as a result of the hypodermic administration of uranium acetate.
Altered permeability of the capillaries was suggested by Richter as re-
sponsible for these changes. He found the edema not connected causally
with salt retention. Fleckseder(a) excluded the renal factor, for he was
able to produce the condition by giving uranium to nephrectomized ani-
mals, which do not develop hydrops without the poison. Further evidence
of altered capillary permeability was furnished by Bogert, Mendel and
Underbill, who showed that uranium interferes with the restoration of
blood volume after large saline infusions.
Uranium poisoning is associated with various degrees of nephritis,
and suppression of urine flow. In the earlier stages the oliguria may be
partially overcome by caffein and the saline diuretics (Mosenthal and
Schlayer). Diuretics do not, however, relieve complete uranium anuria,
according to MacNider(a) who found the nephritis associated with an acid
intoxication as evidenced by ketosis and a lowered alkali reserve. Inhibi-
tion of the nephritis with bicarbonate was found possible under some
conditions.
MacNider found polyuria (accompanied by glycosuria) in the milder
types of uranium poisoning.
Mineral Metabolism.- — Pearce, Hill and Eisenbrey found a decreased
chlorid excretion in uranium nephritis. Austin and Eisenbrey were
later able to show that the smallest nephritic doses cause, along with
the polyuria, some increase in the chlorids. Uranium (as well as
chromates) may diminish chlorid excretion by 4-0 per cent for twenty-four
hours.
Protein Metabolism. — The nitrogen excretion also ran parallel to
diuresis or anuria in the experiments of Pearce and others, who con-
firmed the findings of Chittenden and Lambert that uranium increases
protein catabolism, as shown by augmented nitrogen, sulphate and phos-
phate excretion. Mosenthal (c) found the non-protein blood nitrogen in-
creased and pointed out that aside from renal retention this might be
due to increase in the catabolism or to blood concentration. Karsner and
Denis found the increase in non-protein nitrogen of the blood parallel to
retention of phthalein.
Watanabe(a) finds in mild uranium nephritis that creatinin is less
readily eliminated than urea ; the opposite relation obtains in severe types.
Carbohydrate Metabolism. — Uranium glycosuria was discovered by
Leconte and has been sometimes but not regularly found associated with
hyperglycemia. Chittenden and Lambert found it dependent upon a sup-
Y58 HENRY G. BARBOUR
ply of liver glycogen. Cartier associated it with intense degenerative
changes in the liver. He failed to find lactic acid in the urine.
Fat Metabolism. — The degenerative changes in the liver in nraninm
intoxication have been associated by MacNider with acid poisoning. Fatty
infiltration of various organs is common.
Total Metabolism and Temperature. — Chittecden and Lambert founc
the carbon dioxid output increased in uranium-poisoned dogs. This ws
associated with some increase in body temperature.
Chromates and Cantharidin. — The toxic effects of chromates as well
as of cantharidin are said to resemble those of uranium. (Austin and
Eisenbrey.)
Lead, Platinum, Copper, Zinc. — These metals are poorly absorbed and
their effects upon the metabolism have received but little attention.
(Loewi(&)).
Radium. — Gudzent maintains that the inhalation of radioactive
emanations leads to an increased elimination of uric acid in the gouty, due
to the conversion of the lactim form of uric acid into the lactam.
Contrary to these and other claims Fine and Chace(a) failed to pro-
duce any effect on the uric acid of the blood by radium given either intra-
venously or by inhalation. Berg and Welker state that radium salts given,
per os increase both nitrogen excretion and urine volume.
In chronic arthritis McCrudden and Sargent (&) could find no effect of
radium water upon the excretion of uric acid, total nitrogen or water,
although they state that the creatinin excretion may be affected. Recently,
however, Theis and Bagg in the laboratory of S. R. Benedict have pro-
duced a marked increase in the uric acid excretion of Dalmatian hounds
by intravenous injection of active deposit of radium.
Theis and Bagg found further that the active deposit of radium in-
travenously injected also increased the total nitrogen output, the urea
curve running parallel ; ammonia excretion was relatively as well as abso-
lutely increased. Some increase in creatinin was noted after the in-
creased temperature had returned to normal.
\7ariable results have been observed upon the respiratory metabolism,
little effect having been demonstrated from the emanations. Benczur and
Fuchs(&) state that ingestion of 100 times the usual therapeutic dose of
radium has caused a 17 per cent increase in the total metabolism. Alkaline
radium water, on the other hand, is said to diminish the gas metabolism
in health but not in gout. (Staehelin and Maase.)
According to Darms inhalation of radium causes a rise in body tem-
perature followed by a fall, while a fall followed by a rise is seen aft
ingestion.
In the treatment of lymphatic leukemia Murphy, Means, and Aub
found that radium affected the basal metabolism but slightly during the
marked fall in the leukocyte count. In a similar case Knudson and Erdc
EFFECTS OF CERTAIN DRUGS AND POISONS 759
found under radium therapy very large increases in the excretion of total
urea, ammonia, and phosphate, the latter sometimes attaining 400 per
cent of the normal figure. The slight increase in uric acid excretion was
attributed to the disintegration of nuclein tissue in the spleen.
Phlorhizin. — Although not used in therapeutics this poison is of great
interest on account of the type of glycosuria it produces. Its effects upon
the metabolism resemble .somewhat those of the heavy metals.
Carbohydrate Metabolism. — Mering, the discoverer of phlorhizin
glycosuria, found dextrose values in the urine as high as eighteen per cent ;
the absolute amount may be very large. The condition is characterized
by absence of hyperglycemia, showing that it is essentially of renal origin.
Zuntz showed that the effect upon the kidney was peripheral rather than
central by injecting the poison into a single renal artery which gave rise
to glycosuria at first on that side alone.
Although the important factor of increased glomerular permeability
has recently been well demonstrated by Brinkmann(a) in Hamburger's
laboratory some have deemed it necessary to seek further for the origin
of such large amounts of sugar. Pavy, Brodie and Siau, for example,
maintained that the kidneys form sugar from the proteins of the blood.
Underbill, however, produced hyperglycemia by phlorhizin in animals in
which the renal arteries were ligated, thus excluding the kidneys. Le-
pine(&) has long championed the "virtual sugar" theory in which much
sugar is supposed to exist normally in combination with blood colloids,
being demonstrable only on hydrolysis. From this source he believes sugar
is derived in phlorhizin poisoning.
At all events the glycogen stores are never entirely exhausted by
phlorhizin, even during fasting (Sansum and Woodyatt(a) ). Epstein and
Baer even maintain that phlorhizin stimulates glycogenesis, as hepatic
glycogen seems to accumulate when the kidneys are excluded.
The sugar percentage in Brinkmann's perfusate being sometimes
higher than in the perfusion fluid and no opportunity existing for re-
absorption of water the renal secretory theory must still be given some
consideration.
In complete phlorhizin poisoning Stiles and Lusk found that dextrose
given subcutaneously fails to increase the respiratory quotient ; thus the
power to oxidise sugar becomes lost.
Protein Metabolism. — The body being deprived of the sparing influ-
ence of sugar there is often a very marked rise in the protein metabolism.
Reilly, Nolan and Lusk have found this as high as 450 per cent of normal
in dogs. After the extra sugar was flushed out the D:N ratio in this
species was found to be 3.65 as against 2.8 in rabbits, cats, and goats.
58.7 per cent of the protein is therefore excreted as dextrose.
Fat Metabolism. — Mering in his experiment3 noted fatty infiltration
of the liver when starving animals were phlorhizinized. This was asso-
760 HENRY G. BARBOUR
ciated with increased ammonia excretion and ketosis. Moritz and Praus-
nitz found that it could be prevented by carbohydrate feeding. Feeding
butter fat or butyric acid will increase it. Bang(t') finds that, although
the fat of the liver is increased, the blood fat remains unaltered.
Total Metabolism. — The heat production was found increased by Lusk,
who attributes the change to the specific dynamic action of the increased
protein metabolism. Recently Hari and Aszodi have observed a marked
increase in the energy exchange and body temperature of starving dogs
after subcutaneous injection of 0.05 gram per kilo of phlorhizin. Op-
posite effects were noted, with relatively larger doses, in rats. These
authors believe that since the increases protein catabolism occurs in both
cases it cannot be held to account for the increased heat production in
dogs. They therefore postulate for phlorhizin a specific action upon the
heat regulating centers.
VI. Narcotics
The total metabolism is reduced by all .narcotic agents, whether classed
as anesthetics or hypnotics, during the stages in which sleep is present.
(For details see Jaquet.) This is the natural result of diminished muscu-
lar activity. The reverse may easily be demonstrated in the stage of
excitement produced by some narcotic drugs.
The body temperature also has a tendency to fall during drug narcosis ;
as is well known this effect may result seriously if precautions to conserve
bodily heat are not observed. Since anesthetized mammals also become
more easily overheated than normal animals they may be described as
poikilothermic. This has been attributed to inhibition of the regulatory
influence of the "heat centers." (See Gottlieb, in Meyer and Gottlieb.)
Whether hydremia regularly results from the hyperglycemia and
anuria which commonly accompany the action of all narcotic drugs is not
known, but seems indicated from the reduction in hemoglobin described
by DaCosta and Kalteyer. Hydremia would contribute toward a poikilo-
thermic condition.
The narcotics will be further discussed under the following heads:
General anesthetics, hypnotics, alcohol, opiates.
General Anesthetics. Chloroform and Ether. — Protein Metabolism.
-The total nitrogen excretion is considerably increased both by ether
and chloroform, as was first noted by Strassmann. Taniguti and others
have found an increase in the chlorids and phosphates as well. Hawk
and Kleine found an increase in neutral sulphur. Pringle found the nitro-
gen excretion diminished (renal effect ?) during the anesthesia, but de-
cidedly increased during the following twenty-four to forty-eight hours.
Hawk(&) found that the total nitrogen increase may amount to forty-
five per cent. It is usually considerably smaller. Chloroform was espe-
EFFECTS OF CERTAIN DRUGS AND POISONS 761
cially studied by Howland and Richards and by Lindsay (a). The excre-
tion of ammonia, allantoin, diamino-acids, polypeptids, creatinin and or-
ganic sulphur was found augmented ; the urea and monamino-acids were
decreased. Increased urea as well as total nitrogen and ammonia has been
found by Aloi, however.
Rouzaud has recently reported interesting blood studies in surgical
cases before and after chloroform. The average urea content of the blood
was found increased from 0.048 per cent to 0.075 per cent. Under ether
the blood urea was still higher. This investigator also noted an increased
urea concentration in the urine.
Davis and Whipple have accomplished rapid reconstruction of liver
cells in chloroform poisoning by feeding either carbohydrate or fat. In
both cases the beneficial results were attributed to a sparing effect upon
the protein metabolism.
Carbohydrate Metabolism. — Rosenbaum observed the rapid disappear-
ance of glycogen from the liver under the influence of chloroform. Heins-
berg found this effect associated with hyperglycemia,
Pfmger(c) states that glycosuria is comparatively rare after surgical
anesthesia ; Pavy and Godden prevented chloroform glycosuria by sodium
carbonate. Hawk(c) described ether and chloroform glycosuria in dogs
and found it more intense when the animals were well fed.
King and his pupils found that ether glycosuria is independent of the
splanchnic nerves, but does not occur if the liver be excluded from the
circulation. King, Moyle and Haupt proved that both hyperglycemia and
glycosuria could be produced by intravenous injections of ether without
causing 'asphyxia which was thus excluded from a primary causal relation.
Ross and Hawk showed that ether glycosuria is not due to lowering of'
the body temperature.
Sansum and Woodyatt(a) made the interesting observation that both
ether and nitrous oxid increase the glycosuria and D :N ratio in phlorhizin
diabetes; the "extra sugar" is ascribed to glycogenolysis through tissue
asphyxia. Ross and McGuigan observed a greater ether hyperglycemia in
dogs on a pure meat diet than when carbohydrate was added. They ob-
tained the phenomenon in the absence of asphyxia or excitement. The
diastatic power of the serum was found unaltered. Watanabe(fr) believes,
however, that the blood diastases increase slightly just after the anesthesia.
Chloroform hyperglycemia was clearly shown by Scott to accompany
the glycosuria. Marshall and Rowntree(fr) have found that chloroform
diminishes the tolerance to levulose and galactose as well as to dextrose.
Killian has found that patients under ether or chloroform exhibit an
increase in both the sugar and diastase content of the blood, together
with a decrease in the alkali reserve. All three of these tendencies can
be reversed by the administration of 20-30 grams sodium bicarbonate.
According to recent work of Keeton and Ross ether hyperglycemia is
762 HENRY G. BARBOUR
not prevented either by Eck fistula or the reversed operation; unilateral
splanchnicotomy exercises some inhibiting influence, bilateral more. This
appears largely due to an influence upon the adrenals which become im-
plicated as iu asphyxial glycosuria. Rouzaud found an average blood
sugar content of 0.12 per cent in surgical chloroform anesthesia, ether
giving a similar result.
Fat Metabolism. — Rosenfeld(a) (6) and others described fatty infil-
tration of liver, heart and kidneys after chloroform. The fatty and other
changes of the liver have been extensively studied by Whipple and his
pupils. This investigator ascribes to the hepatic lesions: icterus, disap-
pearance of fibrinogen from the blood, diminution of liver lipase (with in-
crease of plasma, kidney and muscle lipase) and the occasional excretion of
leucin and tyrosin, as well as the other metabolic changes of chloroform
poisoning. . These claims appear well supported by the analogy to phos-
phorus poisoning.
That the blood fat is increased under ether more than any other anes-
thetic was maintained by Bloor(c), who found a rise of 40 to 100 per cent.
Its water-solubility was considered the factor which favors ether in this
regard. Berczeller gives 30 per cent as the maximum increase. Unless
animals had been stuffed previously with fat food, chloroform was found
ineffective until the second or third day when an "after rise" in blood
fat occurred, which Bloor ascribed to the liver necrosis.
On the other hand, a lowering of the percentage of blood fat is de-
scribed by Murlin and Riche ; the intensity of this effect was found pro-
portional to the degree of narcosis. Mann has found the cholesterol con-
tent of the blood unchanged under surgical ether.
Etherizatio/i of dogs for from one to one and a half hours on succes-
sive days has been found by Ducceschi(a) (&) to produce a marked in-
crease in the cholesterol of the serum. This may persist for several days
after the treatment. No untoward effects were noted in a twenty-five day
experiment. Chloroform under similar conditions caused death within
eleven days; the cholesterol remained high two or three days only, assum-
ing a subnormal level thereafter.
Acid-Alkali Metabolism. — Marked increase in the titration acidity of
the urine after long chloroform narcosis was described by Kast and Mester
and others. Becker described acetonuria and pointed out the inadvis-
ability of administering chloroform to diabetics. Thomas maintained that
while the titration alkalinity of the blood was diminished the carbon
dioxid content remained unaltered. This was ascribed to "carbon dioxid
congestion," or insufficient ventilation. Abram described acetonuria after
both choloroform and ether. Aloi recently found beta-oxybutyric acid in
nine out of eleven cases of chloroform anesthesia.
Ether, chloroform, or nitrous oxide may reduce the Ph of the blood
to 7.0 (neutrality), according to Meriten and Crile.
EFFECTS OF CERTAIN DRUGS AND POISONS 763
Graham has made interesting studies of chloroform acidosis illustrat-
ing the protective effects of alkali. The diminished alkali reserve of the
blood has been discussed in the section on alkalies.
Buckmaster has found the total gas content of the blood increased by
10.2 per cent under slight chloroform anesthesia. When the anesthesia
was complete this was increased to 26.2 per cent. The extra gas is nearly
all carbon dioxid, but there is also a low oxyhemoglobin content (40 per
cent reduction).
Henderson and Haggard have made the important observation that
the effects of ether upon the alkali reserve (as indicated by the carbon
dioxid capacity) of the blood are dependent largely upon how the anes-
thetic affects the respiration. Ether in lower concentration, so adminis-
tered as to cause hyperpnea, produces, acapnia, lowering the alkali reserve.
On the other hand, concentrations of ether high enough to depress the
respiration result in increasing the alkalinity of the blood. (Compare
morphin. )
Water Metabolism. — Oliguria or anuria have long been recognized
accompaniments of surgical anesthesia.
Rouzaud finds oliguria more pronounced with chloroform than with
ether in man, in connection with his studies on hyperglycemia and
azotemia. He recommends after-treatment with diuretics.
MacNider(c), however, has just reported some facts relating to anuria
under anesthetics which would tend to discourage the use of diuretics and
point rather to preventive measures. Dogs were anesthetized with ether,
chloroform, or chloroform and alcohol (Grehant's anesthetic). Ether
anuria was found attributable to low blood pressure and rarely associated
with depletion of the alkali reserve. Only in the latter case are diuretics
ineffective. On the other hand, chloroform anuria (with or without
alcohol) is invariably associated with loss of alkali, the kidney becoming
quite impervious to diuretics.
Alkali preliminary to operative anesthesia is therefore recommended
by MacNider from a new viewpoint — to protect the kidney.
Mineral Metabolism. — Kast found that chloroform, like some other
poisons, increased the chlorid excretion more in chlorid-poor animals
than in others.
Ferments. — Burge maintains that anesthetics lower the blood catalase
content. Reimann and Becker found it increased in 35 per cent and de-
creased only in 65 per cent of their cases.
Hypnotics. — Chloral. — Mild chloroform action is suggested by many
of the effects of chloral, although the former is not derived from the latter
in vivo as Liebreich supposed. Chloral glycosuria was described by Eck-
hardt. Harnack and Remertz found that chloral increases both nitrogen
and sulphur excretion, but later and to a lesser degree than does chloro-
form. Abl found an increased uric acid excretion.
764 HENEY G. BARBOUE
Sollmann and Hatcher pointed out that severe chloral coma in ani-
mals is followed by anorexia, marasmus and loss of weight. They de-
scribed the loss of heat-regulating power, Ginsberg the anuria and Winter-
stem (&) the decreased oxygen consumption. Cushny(a) describes a low-
ering of the carbon dioxid threshold for respiration after chloral and other
hypnotics.
Amylene Hydrate diminishes the excretion of nitrogen, according to
Peiser.
Sulphonal. — Stokvis identified the discoloration of the urine after
sulphonal as due to hematoporphyrin.
Paraldehyd. — Powell states that "hypnotic" doses of paraldehyd
lower the blood sugar in dogs without affecting the nitrogen excretion,
while "anesthetic" doses increase the former and decrease the latter.
Urethan. — Chittenden observed that small doses of urethan decrease
the nitrogen excretion, larger amounts having the opposite effect. Under-
bill^) found that this hypnotic sensitizes rabbits to epinephrin glycosuria,
while Bang(e) succeeded in producing hyperglycemia with large doses of
urethan itself. This is stated to have -.been independent of the liver
glycogen as well as of the adrenal secretion.
Alcohol. — As Atwater and Benedict (a) have shown, over 98 per cent
of ingested alcohol is completely oxidized to carbon dioxid and water in
the body. Its effects upon the metabolism are not extensive. The litera-
ture up to 1903 will be found reviewed in the report of Abel, Atwater,
Billings, Bowditch, Chittenden and Welch.
Total Metabolism. — Reichert found the total metabolism in dogs un-
changed by moderate doses of alcohol. In Higgins'(&) experiments on
man the oxygen consumption was shown to remain unaltered after doses of
30-45 c.c. except in one-fifth of the cases; in these a slight increase was
observed. Twenty to forty per cent of the total metabolism was due to
combustion of alcohol. Large doses act like other narcotics in diminish-
ing oxidations and paralyzing heat regulation.
Protein Metabolism. — Mendel and Hilditch in dogs and man found
that, while moderate doses spare protein, loss of nitrogen occurs when
large quantities of alcohol are administered. The partition of urinary
nitrogen remains constant except that "toxic" doses result in an increased
elimination of purins and of ammonia, accompanying other evidence of
perverted metabolism, as indicated by the appearance of levorotatory com-
pounds in the urine.
Salant and Hinkel observed in "subacute intoxication" in well-fed
dogs a diminished excretion of total nitrogen and sulphur, a much greater
decrease of inorganic sulphates and phosphates, and a tendency to chlorid
retention. Neutral and ethereal sulphur were increased.
Carbohydrate Metabolism. — Allen has been unable to verify the claims
of some authors that alcohol creates a diabetic tendency. Such was not
EFFECTS OF CERTAIN DRUGS AND POISONS T65
observed in cats and guinea pigs given either small or large quantities of
alcohol for periods up to one week in duration.
In diabetics Benedict and Forok observed that replacement of fifty
to eighty grams of food fat by isodynamic quantities of alcohol lessened
the excretion of sugar, acetone and nitrogen. Higgins, Peabody and Fitz,
however, could not prevent the appearance of acidosis in normal persons
on a carbohydrate-free diet by giving alcohol. Mosenthal and Harrop
found that the addition of alcohol to a carbohydrate-free diet does not
alter the nitrogen balance in diabetes. No positive value in this condition
has been demonstrated.
Fat Metabolism. — The fatty degeneration resulting from alcohol was
described by Rosenfeld. Ducceschi found that repeated doses of alcohol
sometimes tripled the total fat of the liver in association with an increase
in its cholesterol and total solid content. The adrenals, on the other hand,
lost forty per cent of their cholesterol, but gained slightly in total solids
and fat.
Reproduction and Growth. — No effects of chronic alcoholism upon the
offspring in man have been demonstrated as due to the poison itself.
Stockard has observed the production of defective offspring in guinea
pigs and other species, but Nice, on the other hand, finds in white mice
that the offspring are normal and the growth of the alcoholic lines exceeds
that of non-alcoholic descendants.
Opiates. — The opiates differ particularly from other narcotics in their
tendency to increase rather than to reduce the alkali reserve and in the
absence, in general, of changes in the fat metabolism.
Total Metabolism. — Various investigators have found the respiratory
exchange reduced under morphin, but to this no unusual significance at-
taches since the reduction is essentially parallel to the narcotic effect.
Higgins and Means, as well as Barbour, Maurer and von Glahn, have
observed that sixteen milligrams of morphin sulphate will usually cause
a definite depression of oxidations even when given after a fasting indi-
vidual has been lying practically motionless for from one and a half to
two hours. The latter group of investigators were able to diminish or
prevent this effect by simultaneous administration of forty-milligram
doses of tyramin hydrochlorid. Heroin (diacetyl morphin) in five-
milligram doses does not appear to affect the metabolism (Higgins and
Means), and the results of earlier observers with heroin and codein
(Dreser) and other morphin derivatives appear to lack much positive
significance.
Body Temperature. — The effects of morphin upon the heat-regulating
mechanism were extensively studied by Reichert, who demonstrated
that neither the depression nor the antagonistic pyretic effect of cocain
could be produced after an operation interfering with the caudate nucleus
of the corpus striatum. (For the effects upon total metabolism and body
766 HENRY G. BARBOUR
temperature which are common to narcotics see the introduction to this
chapter.)
Protein Metabolism-. — Boeck found a six per cent diminution ii
urinary nitrogen in dogs, but Luzzato maintains that it is augmented
by morphin in both fed and fasted animals, especially the latter.
Carbohydrate Metabolism. — Rapid disappearance of glycogen from
the liver was noted by Rosenbaum and morphin glycosuria has been fre-
quently described. Hyperglycemia and glycosuria were both found with
large doses by Luzzato. The effects were not obtained in animals accus-
tomed to morphin. Higgins and Means with therapeutic doses observed a
very slight hyperglycemia and some decrease in the respiratory quotient.
The latter seems attributable to the lowered ventilation.
Glycosuria may be simulated by the appearance of other reducing
substances in the urine after morphin. (Spitta.)
Diabetes. — Good clinical observers claim that the glycosuria, together
with thirst and polyuria, can be markedly diminished by the use of
morphin. In this connection Klercker(<i) has shown that, while opiates
have no effect on hyperglycemia of hepatogenous origin, they may inhibit
alimentary hyperglycemia. MacLeod suggests that this is due to retarded
absorption induced by the depressant effect of morphin upon the alimen-
tary canal.
Morphin, according to Kleiner and Meltzer(a), increases the renal
elimination of intravenously injected dextrose, but retards the return of
the blood sugar to its previous level, whence these investigators concluded
that morphin increases the permeability of the kidney cells while decreas- •
ing the same kind of permeability of the capillary endothelia elsewhere in
the body.
Ross (a) recently obtained marked hyperglycemia by the injection into
dogs of 10 milligrams (per kilo) of morphin. In thirty minutes the blood
sugar was increased by 59 per cent, in 45 minutes by 66 per cent, in
one and one-half hours by 77 per cent. Ether administration begun one-
half hour after morphin did not cause as much increase in the blood
sugar as if morphin had not been used, but the final degree of ether hyper-
glycemia was the same with or without morphin.
Fat Metabolism. — Murlin and Riche found the blood fat decreasec
under morphin.
Acid-Alkali Metabolism. — Filehne and Kionka observed a diminution
in blood oxygen but increased carbon dioxid after morphin. The latter
is indicative of depression of the respiratory center which was first shown
by Loewy to be less sensitive to carbon dioxid after morphin. The high
carbon dioxid content of the blood is indicative of the presence of a greater
alkali reserve.
The alkali reserve increase is proven by the increased alveolar carbon
dioxid (shown by Higgins and Means, who observed the same under
EFFECTS OF CERTAIN DKUGS AND POISONS 767
heroin, and by Barbour, Maurer and von Glahn), the alkaline urine of
dogs after morphin (Underbill, Blatherwick and Goldschmidt), and the
increased carbon dioxid capacity of the blood after morphin (Henderson
and Haggard, Hjort and Taylor). Henderson and Haggard interpret the
phenomenon as illustrative of the power of the respiratory mechanism to
exert an influence upon the alkali reserve of the blood. The extra alkali
must be obtained, of course, at the expense of the tissues.
This effect of morphin is probably of value in the prophylaxis of
operative acidosis (preventing acapnia with its consequent loss of blood
alkali), but the bicarbonate prophylaxis possesses the advantage of fur-
nishing new alkali to combat the acid production from various sources.
The superiority of opiates over other narcotics may be related to their
protecting effect upon the alkali of the blood.
Water Metabolism. — Ginsberg found that morphin decreases the
urine flow in dogs, a property commonly exhibited by anesthetics. Opiates
seem to promote the retention of water in the body by their action upon
most of the secretions. The prevention of the exudation associated with
colocynth diarrhea (Padtberg(&)) is pertinent in this connection. Fur-
thermore, Bogert, Mendel and Underbill found the drug very potent in
prolonging the retention of injected saline in the circulation. This hy-
dremic tendency accords with its temperature-depressing capacity.
VII. Antipyretics
Antipyrin, Acetanilid, Phenacetin, the Salicylates, Quinin, Cinchophen
(Atophan), and Related Substances.
In general the antipyretics resemble the narcotics in producing
analgesia, anuria, hyperglycemia and increased protein metabolism. They
differ from the last in failing to induce narcosis, glycosuria or fatty
changes. Furthermore, given in therapeutic doses, they exhibit their
hydremic, antipyretic and oxidation-depressing effects only in patho-
logical conditions associated with fever. Significant changes in the acid-
base metabolism have not been demonstrated in connection with their
action.
Total Metabolism. — A large number of researches, involving the
methods both of direct and indirect calorimetry, have been made upon
the total metabolism and heat balance under antipyretic drugs. It may
safely be regarded as established that antipyretic drugs, in man at least,
do not act primarily by diminishing the total oxidations. Furthermore,
marked increases in the heat elimination can be demonstrated.
In normal individuals so far as is known, therapeutic doses of none
of the enumerated substances reduce the respiratory exchange at all. The
quinin group, however, has occasionally been held to do this. In hitherto
768 HENRY G. BARBOUK
unpublished work Barbour, Harris, and Plant have in normal fasting
persons found the heat production increased in two experiments in which
one-half gram was taken and practically unchanged in two others. These
experiments accord with those of Zvintz as well as of Liepelt, who with
large doses raised the total metabolism. Means and Aub found quinin
of no value in reducing the basal metabolism in exophthalmic goiter.
/ With acetyl-salicylic acid in one gram doses there is produced in
normal individuals approximately a six per cent increase (Barbour and
Devenis). Wood and Reichert found the metabolism increased in dogs
after large doses of sodium salicylate, which, according to Stiihlinger,
also increases it in guinea pigs.
Denis and Means found after repeated doses of sodium salicylate a
fifteen per cent increase in the metabolism in one out of three surgical
convalescents ; the others exhibited no change.
With very large doses (two to three grams) of antipyrin Liepelt suc-
ceeded in producing a reduction in the oxygen intake varying from three
to seven per cent. In the carbon dioxid output was found a greater
diminution, probably attributable partly to retention. There was with
these doses no significant temperature change. Even with antipyrin,
however, there must often be an increase in the heat production. It
usually raises the temperature, for example, in normal dogs and rabbits
in doses which in fever are antipyretic ; furthermore, it has a similar
and more decided effect in decerebrate rabbits. This latter finding of
Barbour and Deming was confirmed by Isenschmid, who also imitated
it with sodium salicylate.
In fever the total metabolism is definitely depressed by therapeutic
doses of the antipyretics, the natural result of cooling the body. With
antipyrin Riethus observed reductions in the oxygen intake varying
from two to thirty per cent.
After one gram closes of acetyl-salicylic acid Barbour observed an
average diminution of 3.5 per cent in the heat production in associa-
tion with a drop of nearly 1° C. in the temperature; heat elimination is
greatly increased (see Fig. 4). Similar changes occur under phenacetin
and antipyrin.
Quinin in fever has usually reduced the total oxidations in man and
animals when the temperature was affected, for example, in a case of
erysipelas studied by Riethus. Tuberculosis and many other febrile con-
ditions respond to quinin by a rise in temperature and oxidations rather
than by a fall. The contention that quinin, which is far from being a
universal antipyretic, reduces temperature primarily by diminishing the
heat production, certainly does not hold for human beings.
Senta found that various antipyretics reduce the oxidations in isolated
muscles of mammals and birds, quinin and salicylic acid being the most
efficient in this respect.
EFFECTS OF CERTAIN DRUGS AND POISONS 769
Protein Metabolism. — After antipyrin the nitrogen excretion is not
much changed in man or in dogs. In fever it is often found reduced
(Miillcr). This effect may, however, be simulated by renal retention.
Salicylates increase the elimination of nitrogen, as has been repeatedly
demonstrated. Goodbody, for example, found urea and ammonia both
increased. According to Wiley repeated ingestion of salicylate results
in some loss of weight and of nitrogen.
Singer found both nitrogen and uric acid excretion increased after
acetyl-salicylic acid in rabbits. Denis (c) and many others have found
the uric acid excretion increased under salicylates. According to Fine
<T.C.
CM.
rrn
200
CO
37
100
T*
A.
*•*•
12.
j«r-
Fig. 4. Effects of acetyl salicylic acid on patient with tuberculous abscess;
broken line, oxygen c.c. per minute; lighter horizontal line, carbon dioxid c.c. per
minute; heavier horizontal line, calories produced per minute; dotted line, calories
eliminated per minute; continuous curve, body temperature. Drug administered at
arrow. (H. G. Barbour, Arch. Int. Med., 1919, XXIV.)
and Chace(&) this is due to increased permeability of the kidneys, for the
blood uric acid is lowered.
Hanzlik has thoroughly reviewed the literature on salicylates. With
Scott and Reycraft he demonstrated an accumulation of urea in the blood
(associated with renal impairment and edema) after administration of
full therapeutic doses of sodium salicylate.
Acetanilid in four to five gram doses increased the nitrogen metab-
olism of Kumagawa's dogs by over 30 per cent. Chittenden in normal
men found the nitrogen excretion unaltered, but the urea was diminished
by 10 to 20 per cent. Sulphates, phosphates, and chlorids were not
significantly altered.
Quinin reduces the nitrogen metabolism definitely, as shown by Noor-
den and Zuntz and many others. Loewi found the percentage of urea
nitrogen slightly decreased.
Reproduction and Growth. — Riddle and Anderson have shown that
quinin fed to laying ring doves reduces the size of the eggs, the yolks
770 HENRY G. BARBOUK
particularly being affected. They believe that the size attained is gov-
erned by restrictions placed upon the protein metabolism.
Carbohydrate Metabolism. — According to Lepine and Porteret and to
Nebelthau antipyretics (antipyrin and acetanilid) are capable of pro-
moting the storage of glycogen in both liver and muscles. Starkenstein's
claim that antipyretics prevent the mobilization of liver glycogen by
epinephrin has been disproved by Mansfield and Purjesz who found that
antipyretics exert no demonstrable effect upon the somewhat variable curve
of epinephrin hyperglycemia. Noorden examined the claim that salicy-
lates decrease the sugar output in diabetes and failed to establish it.
Herter (cited by Underbill) observed the production of glycosuria
after painting salicylate upon the pancreas of a dog. No other case of
glycosuria due to any of this group of drugs appears to have been re-
ported. Wacker and Poly have, however, described a rise in the blood
sugar content in rabbits and tuberculosis patients after phenacetin and
Silberstein found hyperglycemia after giving quinin to dogs.
Barbour and Herrmann demonstrated that hyperglycemia (without
glycosuria) occurs in both normal and'"coli fever" dogs after acetyl-
salicylic acid, sodium salicylate, antipyrin and quinin. The following
averages were obtained:
DEXTROSE CONCENTRATION IN BLOOD
Before Maximum
Antipyretics After Antipyretics
% %
0.137 0.186
0.139 0.218
Since the blood of the normal dogs became slightly concentrated and
that of the fever dogs diluted by the various drugs the absolute increase
in the blood sugar content of the latter was somewhat larger than would
appear from the concentration.
Antipyretic drugs cause no significant changes in the respiratory
quotient.
Water Metabolism. — Barbour and Herrmann found after antipyretics
a hydremia, as indicated by the hemoglobin content, in "coli fever" but
not in normal dogs, as has just been stated. This is induced, at least in
part, by the osmotic action of the extra blood sugar. The reason that
the hydremia is not seen in the normal dogs appears to be that fever
dogs are possessed of a store of available water in the tissues which is
not normally present. This contention is supported by Barbour and
Howard's demonstration of an increase in the percentage of blood solids
during the initial rise of "coli fever," without diuresis. Furthermore,
water would be liberated with the increased protein catabolism of fever.
EFFECTS OF CERTAIN DRUGS AND POISONS 771
In Hanzlik's demonstration of salicyl anuria one sees a further reason
why the hyperglycemia tends to keep the volume of the blood high.
Hirschfeld maintains that antipyretics relieve diabetes insipidus and
Gaulier finds that salicylates diminish the excretion of chlorids. These
and various other observations tend to support the belief that salicylates
induce oliguria.
In Hanzlik's non-febrile cases the hemoglobin remained constant.
Barbour has found the hemoglobin percentage diminished in fever patients
during the antipyretic action of both acetyl-salicylic acid and antipyrin.
The role of the excess sugar in producing hydremia is illustrated in
Barbour and Howard's results with dextrose in normal and fever dogs.
Intravenous dextrose injections, which in normal animals produce a slight
blood dilution with 110 temperature change, will dilute the blood two or
three times more extensively in fever animals coincidently with a marked
antipyretic action. These effects are short-lived when much sugar is used.
The sugar runs off in the urine presently and may leave the blood more
concentrated and the temperature higher than ever.
Theory of the Mechanism of Fever Reduction by Drugs. — All antipy-
retics act by increasing the heat elimination ; reduction in heat production
is incidental. Antipyretics increase the blood sugar concentration. In
fever extra water being available in the tissues, these drugs produce
plethora ; factors other than hyperglycemia may contribute to this result.
Plethora promotes the dissipation of heat by radiation and surface
evaporation. (Sweating is not essential to antipyretic action which pro-
ceeds unabated in the presence of atropin antidiaphoresis.) In health
no plethora occurs, — consequently there is no antipyretic effect.
The earlier work on the relation of "heat centers" to antipyretic action
is well presented by Gottlieb in Meyer and Gottlieb's pharmacological
treatise.
Barbour and Wing have showed that local applications of antipyrin,
chloral or quinin to the heat centers in rabbits all gave better antipyretic
effects than the same doses by the intravenous or subcutaneous routes.
Hashimoto later found that the antipyretic action of both antipyrin
and salicylate is enhanced by heating the centers but annulled by cooling.
After quinin only heat was found effective, cold having no effect. The
effects of heat and cold were prevented by morphin, as indeed the present
author has often noticed to be true of ether.
Vasomotor effects figure largely in these "heat center" reactions which
it is expected can be correlated ultimately with the blood dilution theory.
Acid-Alkali Metabolism. — Meyer found no change in the alkalinity
of the blood with salicylates. In fatal poisoning, however, Walter found
a low carbon dioxid content. Acetonuria is reported by Langmead and
by Lees from large doses of salicylates, and in children. Piccini found
that phenacetin and acetanilid, and, to a lesser extent, antipyrin, reduced
772 HENRY G. BARBOUR
the arterial oxygen in dogs, the carbon dioxid being reduced to a slight
extent. In general then the tendency is toward the side of acidosis.
Quinin and its congeners. — Although it is not a dependable anti-
pyretic in many instances, Solis Cohen has recommended the use of quinin
in pneumonia; the initial dose is 1-1.6 grams of the quinin-urea hydro-
chlorid, to be followed by 1 gram doses every* three hours until the tem-
perature is reduced to 102° F., which may require a day or two. Cahn-
Bronner maintains that in certain lung inflammations treated with 0.5
gram doses of quinin subcutaneously an early antipyretic effect was seen
and the mortality reduced to one-fourth. It may be of some real etiotropic
value in this condition.
In malaria the drug only prevents "chills" and further symptoms
rather than modifying the temperature curve after.it has begun to rise.
Certainly it does not compare favorably with other antipyretics in mild
fever. Quinin is probably only antipyretic in nearly or quite toxic doses,
when it acts very similarly to other types of antipyretic drugs.
Ethylhydrocuprein has a lesser antipyretic effect than quinin, as shown
by Smith and Fantus.
Cinchophea (Atophan). — Cinchophen, according to Starkenstein and
Wiechowski, reduces the temperature of normal rabbits by several degrees.
Its real therapeutic value perhaps lies more in its analgesic properties
(which it shares with other antipyretics) than in its influence upon the
purin metabolism. For example, a number of compounds chemically
related to cinchophen, but possessing no influence upon uric acid excretion
were found by Klemperer to diminish in time and intensity the inflam-
matory phenomena of acute gout attacks. Boeck as well as Rotter has
described the action of a number of other derivatives.
Purin Metabolism. — Nicolaier and Dohrn introduced cinchophen for
the treatment of gout, having noted that three grams given daily to
normal individuals increased the uric acid excretion sometimes up to 200
per cent of the normal. (6-gram doses tripled the output.) The in-
creased excretion begins within an hour, the maximum being reached
within two hours (Griesbach and Samson). The uric acid concentration
shows, according to Haskins(&) (c), a compensatory decrease, sometimes
during administration.
The increase of uric acid is often so great that it precipitates in the
urine before it is passed. Haskins has in fact shown that cinchophen in-
terferes with the urate-solvent action of the urine.
Zuelzer(&) maintains that the urate excretion is more prolonged in
gout than in health.
Among the theories advanced to account for the action of cinchophen
are increased destruction of nucleo-protein ( Schittenhelm and Ullman)
and conversion of absorbed uric acid into a filterable form (Frank and
Pietrulla). Since, however, Folin and Lyman(6) were able to show a
EFFECTS OF CERTAIN DRUGS AND POISONS 773
decrease of blood uric acid parallel to the urinary uric acid increase, little
need is found for an explanation beyond that of increased permeability of
the kidney for this metabolite. According to McLester the blood uric acid
eventually attains an irreducible minimum.
Fine and Chace have shown that when the administration of the drug
is stopped the initial blood concentration is restored in from two to
four days.
According to Starkenstein and Wiechowski the allantoin excretion is
reduced and the total formation of purin bodies is inhibited. The same
authors maintain that piqure and asphyxial glycosurias are inhibited as
by calcium, and that the drug besides an antipyretic possesses an anti-
phlogistic action, entirely inhibiting mustard oil chemosis.
VIII. Ammonia, Aniins, Alkaloids, Purins, Etc.
Ammonia. — Underbill and Goldschmidt showed that organic ammon-
ium salts are quickly and completely transformed into urea. The fate
of the inorganic salts is more complicated. While a part are converted
into urea another portion is excreted unchanged. Still a third part of
the inorganic salts are temporarily retained, following which an augmented
nitrogen excretion is noted.
Grafe found that ammonium salts increase oxidations in rabbits.
Hydrazin. — Underbill and Kleiner (a) showed that this poison pro-
duces fatty degeneration of the liver. Underbill and Murlin showed that
it increases the respiratory quotient of fasting dogs, the increased combus-
tion of sugar accounting for the hypoglycemia which occurs. It does
not specifically affect the heat production.
Ethylenediamin. — This proteinogenous amin lowers the body tempera-
ture of rabbits: a tolerance to this effect is acquired within a few days.
(Barbour and Hjort.)
Iso-amylamin, Phenylethylamin, and Tyramin. — All of these increase
the nitrogen metabolism, especially in thyroidectomized animals (Abelin).
Tyramin increases the total metabolism in man, lowering the alveolar car-
bon dioxid, as shown by Barbour, Maiirer and von Glalm. These effects
are antagonistic to morphin action. Phenylethylamin and tyramin raise
the body temperature of dogs. Morita found that tyramin and similar
drugs cause glycosuria, and Iwao that tryamin produces hemosiderosis
in rabbits.
Beta-tetrahydronaphthylamin. — This is the most powerful pyretic
poison known. Mutsch and Pembrey have shown that it increases the
carbon dioxid excretion but not that of nitrogen. DeCorral maintains
that it causes hyperglycemia and increases the hyperglycemia caused
by narcotics.
HENRY G. BAEBOUR
The Amino Acids. — Increase of the total metabolism and body tem-
perature (Lusk(e) ), also the uric acid metabolism, by the amino acids has
been well established (Lewis and Doisy).
Atropin, Pilocarpin, etc. — Total Metabolism. — Edsall and Means as
well as Higgins and Means found the respiratory exchange increased
after milligram doses of atropin in human subjects. On the other hand,
Keleman, employing large doses in dogs, finds a decrease in the carbon
dioxid output. This antagonizes the ten per cent increase in the
metabolism which he has found after pilocarpin, confirming the ob-
servations of Frank and Voit(fr). The relative role of secretory and
smooth muscle activity has been discussed by Loewi. An energetic pilo-
carpin sialorrhea may deplete the blood fluid sufficiently to cause a rise of
temperature with consequent increase in the total metabolism.
Protein Metabolism. — Either fifteen milligrams of pilocarpin or ten
milligrams of atropin increased the nitrogen excretion in Eichelberg's
experiments. There was a slight phosphate increase as well. With
scopolamin de Stella observed in two rabbits and two dogs a consistent fall
in nitrogen, chlorids, phosphates, and water in the urine. Uremia has
been described in muscarin poisoning by Clark, Marshall and Rowntree,
who found it due to renal impairment.
Purin Metabolism. — Abl found that atropin prevents the uric acid in-
crease after cinchophen ; Mendel and Stehle found the postprandial uric
acid increase inhibited by the same drug.
Carbohydrate Metabolism. — Raphael and others have described
glycosuria in atropin poisoning. Pitini, as well as MacGuigan(a), has ob-
served that large doses increase the blood sugar. The conception was
at one time prevalent that atropin was of value in the treatment of diabetes
and in fact that it inhibited glycogenolysis. Mosenthal(fe) has shown that
the view that atropin increases the tolerance for sugar is unsupported by
valid evidence.
Ross(6) finds that atropin reduces markedly the ether hyperglycemi*
for example, from a forty-one per cent increase to a nine per cent increas
in the first fifteen minutes, and from a fifty-seven per cent increase to a
twenty-one per cent increase in the first hour. Atropin alone did not
affect the blood sugar content.
According to MacGuigan pilocarpin may cause a delayed reductioi
in the blood sugar content. In massive doses atropin fails to lessen the
hyperglycemia due to stimulation of the celiac plexus.
Mushroom (muscarin) poisoning may provoke renal glycosuria, a(
cording to Alexander.
Water Metabolism. — Pilocarpin has no direct action upon the urine
(J. B. MacCallum), but owing to the great loss of fluid by other channel
Asher and Bruck state that it usually diminishes the water and chlorids
EFFECTS OF CERTAIN DRUGS AND POISONS 775
Cow has shown that a number of supposed effects of these drugs upon
the renal function simply arise from actions upon the ureteral muscula-
ture.
After repeated injections of large doses of pilocarpin Waterman ob-
served both diuresis and glycosuria, attributing these to increased renal
permeability.
It is not unusual for three liters of sweat to be removed by pilocarpin
diaphoresis, thus eliminating 2.5 grams of nitrogen. In nephritis this
could amount to eight grams, thus affording notable relief for the kidney.
' (Sollmann.)
Body Temperature. — Both pilocarpin and atropin may cause hyper-
thermia, the former by secretory (especially salivary) dehydration and
smooth muscle and gland stimulation (Reichert), the latter by central
stimulation, perhaps associated with depression of i\is sweat. Atropin
does not, however, hinder the action of antipyretic drugs.
Strychnin. — This alkaloid may be classed as an asphyxial poison for
the reason that such effects as it exerts upon the metabolism are, in part
at least, due to oxygen-lack. In view, however, of its most characteristic
action being a direct stimulation of the central nervous system it is natural
to invoke this stimulation in explanation of the glycogen discharge which
strychnin produces.
Carbohydrate Metabolism. — The knowledge of hepatic glycogenolysis
and glycosuria as a result of strychnin poisoning dates back to the work
of Schiff (1859). Zuntz made use of the drug to demonstrate the forma-
tion of glucose from the protein metabolism. After ridding a rabbit of
glycogen by strychnin convulsions he kept the animal fasting and
chloralized for one hundred and nineteen hours. During this time 5.25
grams of sugar were excreted in the urine, and yet 1.286 grams of
glycogen were still found in the liver and muscles. This must have arisen
from protein.
Araki observed that strychnin causes lactic acid as well as glucose to
appear in the urine, and classified it as an asphyxial poison, as did
Stark enstein.
Lepine(a) states that strychnin glycosuria. is unknown in man.
According to Blum strychnin is able to free the liver of glycogen if
either both vagi or both splanchnic nerves are cut. He concludes, there-
fore, that glycogenolysis resulting from excessive muscular work is brought
about through the blood.
Lusk has shown that strychnin and other convulsions cause the appear-
ance of lactic acid in the blood, to which phenomenon, however, an adequate
glycogen store is essential.
The alveolar carbon dioxid tension is unaltered by strychnin in thera-
peutic doses (up to 4.5 milligram's) in man, according to the results of
Iliggins and Means. These investigators, as well as Edsall and Means,
776 HENRY G. BARBOUR
were also unable to produce any change in the total metabolism by such
doses.
Some Other Convulsants — Camphor. — Edsall and Means, also Hig-
gins and Means, have observed a slight increase in the total metabolis
in man after 0.4-0.5 gram subcutaneous injections of camphor. The only
change observed by these investigators in the alveolar carbon dioxid tensio:
was a slight diminution in one case. This accords with Wieland's fin
ing that camphor lowers the respiratory threshold for carbon dioxid in
rabbits. The latter observed a similar result from coriamyrtin (a picro-
toxin-like convulsant).
Since camphor is excreted in the urine in combination with glycuronic
acid ( Schmiedeberg and Hans Meyer) it is of some importance that this
defensive mechanism should be intact when the drug is administered in
large amounts; its toxicity is said to be higher when glycuronic acid
formation is disturbed through starvation or deprivation of oxygen. In
Chiray's experiments glycuronic acid was produced by administering
camphor by mouth or the injection of camphorated oil in dogs, rabbits,
guinea pigs and man. The reaction re'ached a maximum at about the
third hour. With marked insufficiency of the liver there was no response
to the ingestion of 0.5-1.0 gram of camphor.
Camphor administration to dogs by Mandel and Jackson resulted in
decreased glycuronic acid production after glucose feeding, meat caus-
ing an increase. A proteinogenous origin of glycuronic acid was thus
indicated.
Santonin. — The increase in uric acid excretion after santonin is
attributed by Abl to intestinal irritation.
Body Temperature. — Many so-called "convulsant poisons," including
.strychnin, santonin, picrotoxin, camphor, phenol, etc., have been shown
by Harnack to produce characteristic changes in the heat regulation. The
salient result is a fall in body temperature. Small doses cause in-
creased heat loss and a slightly smaller heat production.
Larger doses cause increased metabolism, through muscular action,
(both heat production and loss being thus increased). Paralytic doses
diminish the heat production very greatly.
The temperature accordingly varies, but the smallest and the largest
doses lower it decidedly. The heat loss is seen especially in small and
young animals, larger animals showing some temperature rise with the
medium doses.
Curare. — This poison as is well known paralyzes all voluntary motor
nerve endings. Asphyxia therefore results by the interference thus pro-
duced with the external respiratory mechanism. The salient feature of
its action upon the metabolism is the glycosuria, discovered by Claude
Bernard. Penzoldt and Fleischer first called attention to the importance
of asphyxia as a causative factor. Araki pointed out its relation to the
1
EFFECTS OF CERTAIN DRUGS AND POISONS Y77
liver glycogen. MacLeod failed to produce glycosuria either by asphyxia
or by curare in Eck-nstula dogs after ligation of the hepatic artery.
Since, however, he was unable to prevent curare glycosuria entirely by
employing adequate artificial respiration, some other factor besides
asphyxia must be involved.
Diminution in the total metabolism was claimed by Rohrig and N.
Zuntz and others, who found a decrease of fifty per cent in the respiratory
exchange of rabbits. But O. Frank, Voit and Gebhard found no essential
difference between normal and curarized dogs when precautions were
taken to keep the body temperature from falling. Tangl has recently
confirmed this observation.
The nitrogen metabolism has been stated to be reduced by curare,
but this effect appears to have been simulated by a simple delay in excre-
tion (Voit).
Body Temperature. — The experiments of Rohrig and Zuntz were the
first in which it became clear that curarized mammals become poikilo-
thermic at ordinary room temperatures.
Krogh states that the curve of oxygen absorption as influenced by
body temperature is the same in anesthetized cold-blooded animals as
in the curarized dog.
Cocain. — Body Temperature and Heat Production. — The hyper-
thermia which cocain induces, while accompanied by greatly increased
muscular movements, can best be accounted for by the loss of much fluid
from the blood. (Unpublished work of the author.) The temperature
rise, according to Mosso, can be prevented by curare or chloral but not by
the antipyretics. In dogs Reichert found that ten milligrams of cocain per
kilo given subcutaneously caused in one hour a mean maximum increase
of 146.9 per cent in heat produced and a mean maximum rise of 1.81° in
temperature. He observed that cocain is sufficiently powerful to counter-
act the profound depressant actions of morphin upon heat production and
body temperature. The action is a central one, not occurring in the absence
of the cerebral hemispheres and basal ganglia.
In one experiment by Kopciowski in a fasting human subject a small
dose of cocain diminished the carbon dioxid output by thirteen per
cent.
Nitrogen and Fat Metabolism. — Maestro described a nitrogen reten-
tion in rabbits associated with oliguria. Large doses (20 milligrams per
kilo), as shown by Underbill and Black, lower both nitrogen and fat
utilization in dogs.
Carbohydrate Metabolism. — Cocain glycosuria occurs infrequently.
Schaer states that the hyperglycemia, in cats at least, when present is
due to excitement. In well-fed dogs and rabbits, but not in the starving
condition, Underbill and Black found a marked increase in the lactic
acid of the urine. They were inclined to associate this with muscular
778
HENRY G. BARBOUR
activity and to ascribe its origin to more than a single antecedent. The
ammonia output appeared to bear little relation to the lactic acid elimina-
tion.
Purins. — The chief therapeutic value of the purin bases lies in theii
diuretic property which quite possibly plays the chief role in all of theii
effects upon the metabolism.
Water Metabolism. — In purin diuresis the water of the urine is in-
creased proportionately more than the solids, which also show an absolute
increase. The extent of water excretion depends much upon the supply.
Widmer(a), for example, has shown that caffein diuresis is abundant ii
dropsical conditions, but fails altogether with dry feeding. On the other
hand, during the diuresis of diabetes mellitus E. Meyer has shown that
caffein produces no further effect. The reputed superiority of theobromii
and theocin as compared with caffein Sollmann ascribes to the fact that
the last mentioned is possessed of more toxic side actions which prohibit
its being administered in such large amounts.
Schroeder ( b ) observed that the water content of rabbit's blood is de-
creased by ten per cent after an effective caffein diuresis. Spiro states
that theocin also lessens the absolute amount of water in the blood besides
the percentage concentration of sodium chlorid.
The secretory theory of caffein diuresis was advanced by Schroeder.
It received strong support from the experiments of Eichards and Plant,
in which it was shown that when the in vitro perfusion flow is kept con-
stant caffein increases the artificial urine. On the other hand, there is
a mass of evidence which relates purin diuresis to an increased circula-
tion through the kidneys. For a full discussion of the mechanism the
reader is referred to Cushny's monograph.
Nephritic Conditions. — Pearce, Hill and Eisenbrey and others have
shown that the diuresis fails to occur in experimental glomerular nephritis.
Christian has found theocin of little diuretic value in nephritis except
in cardiorenal cases with edema. Here he finds that it increases the
sodium chlorid excretion and works best when given with digitalis or
intermittently.
MacNider finds purin and other diuretics ineffective in anurias pro-
duced by anesthetics except in those cases of ether anuria where the alkali
reserve has not been depleted.
Zondek has recently observed that in cases of high grade hydropic
nephritis many diuretics of the xanthin group cause a decreased flow
(with greater concentration) of the urine. This phenomenon, which as
yet lacks confirmation, is attributed to "fatigue" of the renal vessels.
To produce full caffein diuresis in man II. L. Taylor finds that at
least 0.5 gram four times a day is necessary. Theobrromin-sodium-
salicylate may safely be given in doses twice as large.
In the human experiments of Means, Aub and DuBois (see below)
EFFECTS OF CERTAIN DRUGS AND POISONS T79
the percentage of heat lost in the vaporization of water from the lungs
and skin was not significantly altered by caffein.
Body Temperature. — Binz appears to have discovered that caffein
hyperthermia, which is not usually intense, regularly results when con-
siderable doses are administered to animals and man. Pilcher found
that the lowered temperature of moderate, but not of deep narcosis, could
be successfully combated with caffein. Karclkiii states that the temper-
ature increase is much greater in thyroidectomized than in normal
dogs. The diuretic effect, which concentrates the blood, is probably re-
sponsible for the rise in temperature, but this should be determined by
experiment.
Mandel observed a correlation between purin excretion and tempera-
ture-fall in fevers. He produced fever in monkeys by xanthin injections ;
xanthin, if given with salicylate, failed to raise the temperature.
Total Metabolism.— Edward Smith in 1859 by a very large number
of carefully conducted experiments established the fact that caffein in-
creases the carbon dioxid output. The rise obtained was anywhere from
fifteen to thirty per cent, Reichert by direct calorimetry in dogs observed
greater increases in the heat production. Using more modern methods
Edsall and Means, and Higgins and Means found increases varying from
three to fourteen per cent.
Means, Aub and DuBois observed in four normal subjects receiving 8.6
milligrams per kilo of caffein alkaloid an increase of from seven to
twenty-three per cent in the basal metabolism. In these elaborate in-
vestigations the independent methods of direct and indirect calorimetry
gave results which agreed within one per cent.
F. G. Benedict and Carpenter (&) found that approximately three hun-
dred and twenty-five grams of hot coffee will increase the basal metabolism
eight to nine per cent.
Nitrogen Metabolism* — C. Voit, concluded from his experiments that
caffein did not alter the nitrogen balance, although there was possibly
some increase in the urea excretion. Ribaut found the nitrogen excre-
tion in man but little changed, while it was moderately increased in dogs.
In three of their subjects Means, Aub and DuBois found an increase in
nitrogen elimination varying from six to thirty-seven per cent. This was
attributed to the. diuresis.
Farr and Welker state that theocin decreases the nitrogen excretion
in both health and renal disease.
Creatin and creatinin elimination were found but slightly altered by
Salant and Rieger.
Purin Metabolism. — Mendel and Wardell have shown that the addi-
tion of strong coffee infusion to a purin-free diet causes a marked increase
in the excretion of uric acid. This increase was not obtained from de-
caffeinated coffee. The increase was found equal to the quantity of uric
780 HENRY G. BARBOUK
acid which would be obtained by the demethylation and subsequent oxida-
tion of from ten to fifteen per cent of the ingested caffein.
Astolfani maintains that caffein increases hippuric acid synthesis.
Carbohydrate Metabolism. — There is commonly a slight glycosuria
(discovered by Jacobj) during caffein and theobromin diuresis. It de-
pends on the presence of liver glycogen according to Richter(&), occurring
only when there is considerable hyperglycemia (Hirsch). It is usually
prevented by section of the splanchnic nerves, as shown by Pollak, am
by suprarenal excision (A. Mayer). Theobromin glycosuria is said bj
Miculicich to be inhibited by ergotoxin.
Mineral Metabolism. — The purins may increase the salt excretion
even when no diuresis is produced, e. g., in diabetes (E. Meyer). Ac-
cording to Saccone, on the other hand, theobromin and caffein may
diminish the chlorid excretion independently of the diuretic effect. In
rabbits Bock found that theocin increased both potassium and sodium
output, but not parallel with the diuresis. Sollmann found that the
chlorid-retaining mechanism which becomes broken down in rabbits re-
mains unimpaired in dogs and man.
Alkalinity. — Higgins and Means found that caffein diminishes the
alveolar carbon dioxid in man.
Growth. — Nice finds that caffein-fed mice exhibit subnormal activity.
Caffein increases their fecundity, but the viability of the young is re-
duced. The growth of the young is only inhibited if they themselves are
fed caffein.
Catalase. — Burge states that blood catalase is increased by caffein
and theobromin. Blood concentration was apparently not allowed for.
(Stehle(&)).
Guanidin Bases. — Watanabe(c) finds that the metabolic effects in-
duced by guanidin hydrochlorid resemble those of tetania parathyreopriva.
For example, besides the tetany there are an excess ammonia excretion, a
low content of calcium associated with high phosphates and a hypoglyce-
mia. Calcium lactate injection, however, fails either to restore the blood
sugar content or abolish the tetany.
IX. Endocrin Drugs
Epinephrin. — Total Metabolism. — Hari observed a diminution in the
total metabolism when epinephrin was injected into curarized dogs, either
intravenously or intraperitoneally.
Later investigators, however, find that the characteristic action is to
increase the total oxidations in the body ; for example, Tompkins, Stur"gis,
and Wearn have observed that the basal metabolism is increased after
epinephrin not only in normal individuals, but in hyperthyroidism and
EFFECTS OF CERTAIN DRUGS AND POISONS 781
in soldiers with "irritable heart." The metabolic increase runs parallel
to the circulatory changes. Sandiford finds in man that 0.5 c.c. per
kilo of 1-1000 epinephrin injected subcutaneously invariably causes an
increase in the metabolic rate. She attributes the increase in heat pro-
duction to an excess of carbohydrate in the circulation with possibly a
direct stimulation of the cells as well. (In addition acid metabolites from
circulatory stimulation are presumably involved, as is the case with the
increase in oxidations produced by tyramin.)
Evans and Ogawa found the total gas exchange of the heart notably
augmented.
Catalase. — Burge(6) states that the injection of epinephrin stimulates
the catalase output of the liver. Stehle believes that Burge's results here
and elsewhere are merely an expression of the red blood cell count ; "high
catalase" would then be equivalent as a rule to blood concentration, "low
catalase" to dilution.
Body Temperature. — It has long been known that large doses of
epinephrin cause collapse with a fall in body temperature. Freund ob-
served, however, an increased temperature in rabbits on a dry diet with
little change in temperature on a green diet. His correlation of epinephrin
fever to that produced by sugar or salt has been mentioned.
Hirsch found a decrease of temperature after epinephrin, ascribing
it to lowered heat production. Kondo in rabbits found no effect with
small doses, but depression of temperature when more epinephrin was
given; on the other hand, after thyroid preparations or peptone, and
sometimes after atropin, epinephrin raised the temperature.. Intracere-
bral injections in his hands gave a marked increase in temperature with
small or large doses. This effect was somewhat antagonized by antipryin
or by thyroidectomy. Barbour and Wing, however, reduced the tempera-
ture by intracerebral injections of epinephrin.
Hultgreen and Andersson first showed that adrenalectomy reduced the
temperature. Freund and Marchand found that removal of both adrenals
results in gradual diminution of body temperature and that the blood
sugar at the same time may fall as low as .01 per cent.
Water Metabolism. — While some of the earlier investigators main-
tained that epinephrin causes diuresis, it is now generally believed to
exert, temporarily at least, an opposite effect. Gunning, for instance, finds
that intravenously given in all effective doses epinephrin lowers the urine
flow both in anesthetized and unanesthetized dogs. The effect is probably
associated with renal vasoconstriction.
Lamson and Keith have shown that epinephrin increases the red blood
cell count, which phenomenon is associated, in part at least, with diminu-
tion of the blood volume. The water passes into the lymphatic system,
particularly of the liver. In some species these effects fail to appear.
Carbohydrate Metabolism. — Epinephrin glycosuria has received much
782 HENKY G. BAEBOTJR
attention since its discovery by Blum. Hyperglycemia was observed by
Zuelzer, Yosburgh and Richards and others. Doyon, Morel and Kareff
showed that glycogen is simultaneously lost from the liver. Iwanoff dem-
onstrated that epinephrin perfused through surviving livers stimulates
sugar formation, thus showing that the point of action is peripheral. The
glycosuria is not asphyxial, but nervouc stimulation of the adrenals may
contribute to asphyxial glycosuria. (MacLeod and Pearce.)
Pollak(a) finds that epinephrin glycosuria fails after repeated injec
tions, as the glycogen becomes exhausted. Kuriyama has shown that epi-
nephrin does not interfere with the storage of glycogen by the liver, earlier
investigators having neglected the factor of malnutrition in their animals.
Lusk demonstrated that epinephrin does not influence the oxidation of
injected glucose; in dogs the respiratory quotient rises to unity either
with or without the drug. Furthermore, Fuchs and Roth obtained the
following respiratory quotients in human beings with subcutaneous injec-
tions of epinephrin alone:
Before: 0.85-0.87; during effect, 0.91-0.96; after, 0.84-0.86.
Evans and Ogawa from experiments, upon isolated mammalian hearts
concluded that epinephrin does not alter the power of the tissues to use
carbohydrate.
Protein Metabolism. — Lusk has shown that there is no significant
change in the protein metabolism after epinephrin. The urea changes
noted are apparently due to renal effects. Addis, Barnett, and Shevky
observed increases in urea after subcutaneous injections of epinephrin ; but
large amounts of the drug decreased the urea excretion of dogs. Uric acid
and allantoin excretion are stimulated by large doses, according to Falta.
Mineral Metabolism. — Bulcke and Weiss described an inhibition of
sodium chlorid excretion under epinephrin. Schittenhelm and Schlecht
found that in "war edema" epinephrin (which apparently failed to raise
the blood pressure under the conditions) had a tendency to lower the
excretion of water and of chlorids.
Growth. — Chambers observed that suprarenal extract increases the
rate of division in paramecia.
E pinephrinemia from Drugs. — Stewart and Rogoff(a) have recently
described an increased output of epinephrin from the adrenal glands under
the influence of a variety of drugs. These results must often be taken
into account in the interpretation of the action of such substances.
Thyroid Gland Substance.— To combat the effects of thyroid defi-
ciency the administration of thyroid gland substance offers one of the
most striking achievements of modern therapeutics. The first patient
thus treated has just died at the age of seventy-one after enjoying twenty-
eight years under continuous treatment by Murray. The isolation of
thyroxin by Kendall has made available a crystalline substance the chemi-
cal structure of which is under investigation.
EFFECTS OF CERTAIN DRUGS AND POISONS 783
Total Metabolism. — Recent investigation by DuBois, by Means and
Aub and others have shown that the basal metabolism is a most im-
portant feature of Basedow's disease. It was first emphasized by Magnus-
Levy. DuBois showed that heat production is fifty per cent above the
normal in severe and seventy-five per cent in very severe cases. This test
is proving of value in indicating the proper treatment.
In eight cretins Snell, Ford and Rowntree have found that the basal
metabolism varied between — 7 and — 25. By administering four to five
Fig. 5. Effect of thyroxin in cretinism. (A. M. Snell, F. Ford, & L. G. Rowntree,
J. Am. M. Assn., 1920, LXXV.)
milligrams of thyroxin every few days these investigators have been able
to keep the metabolism close to the normal range. (See Fig. 5.)
Protein Metabolism. — Thyroid administration increases the excretion
of nitrogen as shown by Rohde, Stockholm and others. The appetite is
usually improved, but there is rapid loss of weight (Leichtenstern). The
first effect is on fat, the proteins being drawn upon when the fat is re-
duced to a certain minimum. On a meat-free diet, according to Krause
and Cramer, the nitrogen increase concerns especially the urea, ammonia
and creatin, the uric acid and creatinin being very little changed. Kojima
finds that thyroidectomized rats excrete less nitrogen and calcium than
normally. Curiously thyroid feeding in such animals appears to reduce
nitrogen and gaseous metabolism as well as body weight.
Studzinsky and Kaminsky found that thyroid increases the urate
excretion in hypothyroidism but not in normal subjects.
Carbohydrate Metabolism. — Thyroidectomized dogs do not utilize
sugar as well as normal animals, according to Underbill and Saiki. This
784 HENEY G. BAEBOTJE
was not found in rats by Cramer and McCall. Watanabe finds the blood
sugar and diastase unaltered.
Denis, Aub and Minot have shown that glucose tolerance may be used
as a diagnostic test in thyroid disease. The blood sugar is taken as the
criterion.
Fat Metabolism. — Thyroid substances must be employed only with
great caution if at all to reduce obese conditions not due to thyroid
deficiency.
Growth. — Gudernatsch discovered that thyroid feeding retards growt
but hastens development in frog larvae.
Pituitary Substance. — Total Metabolism. — No significant effect upon
the basal metabolism, according to Snell, Ford and Eowntree, is exerted
by the administration of pituitary substance.
Water. Metabolism. — While some observers have described fleeting
diuretic effects with pituitary extract its most striking influence is an-
tagonistic to the flow of urine. This is seen, for example, in rabbits,
which under the influence of the drug give no significant diuretic response
to administration of large amounts of 'water. (Motzfeldt.) Eees finds
no alteration of the daily urine output in cats under pituitary treatment.
The antidiuretic effect lasts but several hours. Diuresis due to continuous
intravenous injection of saline was not affected. Konschegg and Schuster
find that one to two c.c. given to normal individuals diminish both the
volume and the solids of the urine, the effect lasting sixteen hours.
In diabetes insipidus injections of pituitary reduce materially the
volume of urine and the thirst.
Barker and Mosenthal found that subcutaneous daily injections of at
least two one c.c. doses of pituitary extract (pars posterior and pars
intermedia) were effective in diabetes insipidus over a long period. The
urine was diminished in amount, its specific gravity raised; the per-
centages of sodium chlorid and of nitrogen became increased. Tethelin
treatment was not successful nor was the posterior lobe extract of any
value by mouth.
Kennaway and Mottram also found subcutaneous injections oi
pituitary extract effective in diabetes insipidus while orally it was value
less.
Clausen found in a boy of nine and one-half years the usual reduction
in fluid excretion by the kidney after pituitary treatment in diabetes
insipidus; the hourly chlorid excretion was much reduced. The hourly
excretion of urea, creatinin, uric acid and titratable acids was, on the
other hand, but slightly affected.
According to Leschke midbrain and not pituitary disturbances are
responsible for diabetes inspidus.
The galactagogic effect of pituitary is probably not secretory but due
merely to contraction of the smooth muscle of the glands. (Gaines.)
EFFECTS OF CERTAIN DKUGS AND POISONS 785
Carbohydrate Metabolism. — Pituitary substance does not alter the
blood content in diastase or sugar. (Watanabe.)
Anterior Pituitary Lobe. — Robertson found that feeding the anterior
lobe before adolescence retards growth. In adult animals growth how-
ever may be renewed. In mice growth retardation is followed by accelera-
tion, especially when tethelin is used.
Partial removal of the anterior lobe of the pituitary leads to obesity
and other nutritional derangements. Total metabolism, body temperature
and growth become subnormal, as shown by Crowe, Gushing and Homans,
and F. G. Benedict and Homans.
In acromegaly, which is associated with hyperactivity of the anterior
lobe, Bergeim, Stewart and Hawk found no change in the nitrogen or
sulphur metabolism, but have described a retention of calcium, magnesium
and phosphorus.
Labbe and Langlois abolished glycosuria in a diabetic acromegalic by
a four months' course of hypophyseal therapy. The polyuria was not
affected.
Other Gland Products — Thymus Gland. — Feeding thymus to am-
phibian larvae retards development while hastening growth. (Guder-
natsch.) According to Uhlenhuth(a) this gland secretes the substance
which induces the low calcium metabolism of parathyroid tetany. Thymus
injections produce emaciation and malnutrition in guinea-pigs, according
to Olkon.
Parathyroid Gland. — The relation to tetany has been referred to in
connection with calcium salts. Excision of the gland lowers carbohydrate
tolerance, as shown by Underbill and Hilditch. Koch (6) found that
removal of the parathyroid leads to the appearance of toxic bases (guani-
din, histamin, etc.) in the urine.
In parathyreoprival tetany injections of horse parathyroids reduced
the creatinin excretion from 1342 to 612 milligrams per day. In rats
Kojima found the calcium excretion increased after parathyroidectomy.
Spleen. — Asher and his pupils have recently observed that removal of
the spleen augments the respiratory exchange in rats. He regards this
organ as antagonistic to the thyroid. While thyroidless rats appear to
tolerate low pressure (oxygen-lack) better than normal, the tolerance of
spleenless animals is weakened.
Prostate Gland. — Macht showed recently that prostate feeding stimu-
lates both growth and development in amphibian larvae.
Testis. — Castration of male rats results in diminished oxidations.
(Agnoletti, Kojima.) Jean found an increased phosphate excretion.
Pineal Gland. — In animals administration of pineal extracts is said
to hasten growth and development. (McCord.)
The Intravenous Injection of Fluids Artie v. Bock
Introduction — The Fluids of the Body — The Uses of Intravenous Infusions —
Intravenous Infusions to Increase the Volume of Blood and Tissue Fluid
—Intravenous Infusions to Increase the Buffer Action of the Blood in
Acidosis — Intravenous Infusions to Combat Toxemia— Intravenous In-
fusions to Assist in Providing for the Calorific Requirements of the Body
— Solutions Used for Intravenous Infusions — "Saline" Solutions — Gum
Acacia or Gum-saline Solutions — Gelatin Solutions — Sodium Bicar-
bonate Solutions — Glucose Solutions: — Other Solutions — Reactions Due
to Infusions — Preparation of Infusion Solutions and Technic of Adminis-
tration.
The Intravenous Injection of Fluids
AELIE V. BOCK
BOSTON
Introduction
The rapid adoption of intravenous therapy has resulted from the devel-
opment of the technic of venous puncture. The simplicity of intravenous
injection for the administration of drugs and fluids has secured for this
method a wide field of usefulness. In the following pages the use of
immune sera and of drugs will not be considered, hut attention will be
paid rather to the use of injections or infusions of various solutions into
the blood stream for the treatment of certain clinical conditions.
The Fluids of the Body
Before entering in detail upon the subject of infusions, the role
of fluids in the organism will be briefly discussed. It is estimated
that the fluid content of the body is equal to from 60 per cent to TO
per cent of the body weight. This fluid consists of the blood, the
lymph, and the tissue fluid, all of which may be regarded as mobile fluids,
and the fluid within the cells which, in contrast to the rest, is com-
paratively fixed. The importance of water in the maintenance of life
has been emphasized by Starling(a), who points out that all of the
energies manifested by living cells are derived from substances in solu-
tion, and that all metabolic changes in the body relate to changes in and
between substances in solution. The organism as a whole strives to main-
tain a fairly constant quantity of total fluid, as well as to guard carefully
the chemical constitution of the fluid in the various systems. This control,
although exceedingly complex, since it involves physical and chemical
phenomena of an infinite order, and the cooperation of highly organized
absorbing and excreting organs, is nevertheless remarkably efficient.
Starling has also discussed the importance of the body fluids in
general, from the point of view of the variety of their adjustments to
local conditions, by which the cells of the body are enabled to carry
out the functions for which they have been differentiated. He has
787
788 AKLIE V. BOCK
suggested that the ability of man to withstand changes in his environ-
ment, such as extremes of heat and cold, is due to adjustments made by
the body fluid to meet the altered conditions. It is this facility to main-
tain optimum conditions for cellular activity, together with the regulation
of the total volume of body fluids that enables all higher forms of life to
exist in comfort within the environment.
The cellular fluid has been spoken of as fixed, in comparison with the
blood, for example. There is, however, a constant interchange between
the cells and the tissue fluid which is of necessity a local interchange.
With the details of cellular activity the present discussion is not
concerned.
With regard to lymphatic fluid, it need only be said that it repre-
sents tissue fluid collected into organized channels, to be returned to the
cardiovascular system in order to complete the major part of the cir-
culatory exchange of fluid in the tissues which began with the passage of
nutrient fluid from the capillary walls.
The tissues everywhere throughout the body are bathed in fluid that
fills the tissue spaces. Since the metabolism of tissue cells is carried on
through the activity of 'this medium the tissue fluid, in a sense, becomes
the most important of the body fluids, as Starling suggests. This fluid
traverses the system of tissue spaces that form a rather complete circula-
tory system which, as Meltzer(fr) has shown, may be in part independent of
the cardiovascular system. When the normal quantity of tissue fluid is
greatly altered through defect in absorption, or in elimination of fluid, or
by direct loss of fluid, there are definite symptoms traceable to such a
disturbance. The importance of the tissue fluid which is the last vehicle
for the transport of nutrient material to the cell, and the first to receive "
the waste products of metabolism, cannot be too much emphasized.
Of all the body fluids, the blood occupies the first place in the minds
of clinicians, and yet it is only one unit of the various fluid phases within
the body. It exerts, however, the controlling influence in the maintenance
of function in the normal organism. It is the main highway in the body
for distribution and elimination. Of its many characteristics we are
here concerned mainly with the question of the volume of the blood. This
is roughly one-eighth of the total fluid in the body, and has been found in
the normal individual to be a surprisingly constant quantity, subject
only to minor variations. Even in disease the variation from the normal
quantity is not often great. When the body is confronted with a loss of
fluid, such as may occur in severe diarrhea, fluid is withdrawn from the
tissue fluid to the blood. This is done in an effort to maintain nutrition
of the higher centers at the expense of the tissues in general. Thus,
individual cells may begin to suffer from failure of nutrition long before
the blood itself shows much evidence of depletion of fluid. This mech-
anism needs to be appreciated, since conditions in which actual concen-
THE INTRAVENOUS INJECTION OF FLUIDS 780
tration of blood occurs are usually extreme clinical states which may have
been avoided by the administration of sufficient fluid.
The intake of fluids is achieved normally by absorption from the
intestinal tract. This absorption occurs independent of the body needs,
and any excess fluid is readily eliminated by the kidneys. If the rate of
fluid intake exceeds the rate of elimination through the kidneys, the
tissues become a reservoir temporarily for such excess fluid which is later
reabsorbed from the tissue spaces into the blood and passed out through
the kidneys. The ingestion of large quantities of water, therefore, has
almost no effect in altering the quantity of circulating blood in the normal
individual, as shown by Haldane and Priestley. In pathological con-
ditions the same regulation of blood volume tends to occur.
Fluid loss from the body occurs to a certain extent through the lungs
and skin. The bulk of fluid, however, is eliminated by the kidneys. The
kidneys are responsive to changes in the blood, and their activity in the
secretion of urine is the best index as to the state of water balance in the
body. Experience has shown that if the intake of food and fluids is
sufficient to produce a daily urine output of at least 1,500 c.c. (for an
adult), the total volume of body fluids is approximately normal. When
the daily urine output falls below 1,500 c.c. it usually does so because
the intake of fluids as such, together with the water contained in the
food ingested, is not great enough for the needs of the body. Cases of
anuria due to nephritis, and cases of cardiac failure of the congestion type,
for example, are exceptions to this rule for obvious reasons. The prac-
tical importance, therefore, of measuring the amount of urine voided in
twenty-four hours in almost all cases of acute illness is that it provides
direct evidence as to whether or not the body is being furnished with an
adequate supply of fluid.
The Uses of Intravenous Infusions
Intravenous injections are employed usually for four main purposes:
(1) to increase the volume of the blood and tissue fluids of the body; (2)
to increase the buffer action of the blood in acidosis; (3) to combat
toxemia by what is generally regarded as a washing out process; (4) to
assist in providing for the calorific requirements of the body.
1. Intravenous Infusions to Increase the Volume of Blood and Tissue
Fluid. — The following conditions may deplete the store of fluids in the
body: (A) fluid loss by (1) hemorrhage, (2) abnormal sweating, (3)
severe diarrhea, and (4) polyuria; (B) insufficient fluid intake by (1)
starvation, (2) inanition, (3) vomiting, (4) coma, and (5) delirium.
The chief symptom manifested as a result of dehydration of tissues in
these conditions is thirst, which constitutes nature's indication for treat-
790
AELIE V. BOCK
ment. An attempt to restore the fluid loss in all of these conditions
be made by giving fluid by one or another of the following methods: by
mouth or rectum, permitting absorption from the alimentary tract; by
subcutaneous injections, intraperitoneal injections, or intravenous in-
fusions. The method adopted will depend upon individual indications.
In the case of acute hemorrhage, dilution of the blood rapidly occurs
by transfer of tissue fluid to the vascular system, and the original volume
of the blood plasma is promptly restored, if the hemorrhage is not too
great, and if the supply of tissue fluids is normal. The chief danger in
acute hemorrhage is due to the rapidity with which blood is lost, rather
than the amount of blood released from the circulation. If hemorrhage
occurs so suddenly that compensatory mechanisms such as vasoconstriction
and tissue fluid dilution cannot maintain the blood pressure at a safe level,
transfusion of blood, or intravenous infusion, may be immediately urgent.
Complete collapse of patients after hemorrhage is often the result of the
concurrent factor of shock, by which the volume of blood tends to be still
further diminished. When shock is present the transfusion of blood, or
the infusion of a fluid substitute for Wood, may be obligatory. A falling
blood pressure is a positive indication for such treatment in order to
relieve the anoxemia,1 particularly of the vital centers. A transfusion
of blood, or an infusion under such circumstances, by increasing the
volume of fluid in the vascular bed, increases the volume output of the
heart per systole, and thus tends to restore the arterial pressure to a
normal figure. If a state of shock has existed for several hours the
transfusion of blood should always be carried out in preference to other
intravenous therapy. In cases of hemorrhage, in addition *to transfusion
or infusion, an abundant fluid intake by the alimentary tract should be
maintained in order to satisfy completely, not only the blood plasma
volume, but. the supply of tissue fluid as well. The increased efficiency
of the circulation, and the good effect upon the rate of blood regenera-
tion as a result of a forced fluid intake in cases of hemorrhage has been
recently discussed by Bock and Robertson.
The question of the use of infusion for the treatment of acute hemor-
rhage and shock presents a problem not common to other conditions for
which infusions may be indicated, namely, the necessity for an immediate
increase in the total mass of circulating blood. Reduction in blood volume
below a certain level results in a fall of blood pressure, accompanied
the attendant difficulties which this failure of the circulation imposes upon
the organism. In order to restore the efficiency of the circulation, the
volume of the blood must be largely restored as rapidly as possible either
by transfusion of blood or by the intravenous infusion of a fluid sub-
stitute. In addition to the transfusion of blood, which is the most
'A comprehensive discussion by J. S. Haldane of the cause and effect of anoxemia
or oxygen want may be found in the British Med. Jour., 1919, 2, pp. 65-71.
THE INTRAVENOUS INJECTION OF FLUIDS 791
effective measure, many solutions have been used to accomplish this end.
In the case of a fluid substitute for blood, the solution, according to Bay-
liss(c), should possess the same viscosity as blood, in order to raise the
blood pressure to a -normal level, and to .exert the same osmotic pressure
is the colloids of the blood plasma, which will prevent the loss of fluid
from the circulation. If a solution possesses these properties it will tend
maintain the blood pressure at a normal level for many hours, because
e volume of fluid injected remains in the blood vessels for an indefinite
time. In order to insure this result, the solution, furthermore, must be
colloidal in nature, since the capillary walls are relatively impervious to
colloids. The best solution of this nature yet proposed is one containing
gum acacia, to the strength of 6 per cent to 7 per cent in 0.9 per cent saline
(gum-saline), as described by Bayliss(c). Rons and Wilson, on the other
hand, state that a fluid substitute for blood need not haA^e the same viscosity
as whole blood. They removed as much as 75 per cent of 'the hemoglobin of
rabbits by bleeding and replaced the volume by rabbit's plasma. No great
change was observed in the behavior of these animals. However, the fact
remains that no artificial solution of low viscosity used up to the present
time has proved to be so'useful for the treatment of hemorrhage and shock
as the solution recommended by Bayliss.
Of other colloidal solutions, gelatin in 2.5 per cent solution as recom-
mended by Hogan in 1915 has been found useful. More recently, Erlanger
and Gasser have proposed the simultaneous use of hypertonic gum-salt
solution and hypertonic glucose solution. They have used an 18 per cent
solution of glucose and a 25 per cent solution of gum-saline with good
results for the treatment of hemorrhage and shock in dogs, and also in a
small series of human beings. The beneficial effects thus obtained are
explained in part by these authors as due to the internal transfusion
effected by the hypertonic solution of glucose, resulting in a still further
expansion of the blood volume. This secondary increase of volume is
maintained by the hydration-of the excessive amount of gum acacia present
in the circulation.
The failure of isotonic salt solution to maintain blood pressure after
hemorrhage is well known. Physiologists have long ago shown that the
introduction of normal saline into the blood stream has only a fleeting effect
upon the blood pressure, because this fluid leaves the blood stream for the
tissues and urine within a few minutes after it is injected. The reason
for this is the low viscosity of the solutipn as compared with blood,
together with the fact that the walls of the capillaries are especially
permeable to all crystalloids. Modifications of normal saline, such as
Ringer's solution, hypertonic. and hvpotonic salt solutions, share the same
fate as normal saline.
It is to be remembered that all artificial fluids are substitutes for
Mood, and that in the treatment of hemorrhage, transfusion of blood is
792 AKLIE V. BOCK
the most efficient therapy in all severe cases. In shock without hemor-
rhage intravenous injection of a fluid substitute for blood is indicated.
In conditions other than hemorrhage and shock, in which fluid de-
pletion occurs, there is not usually the urgent necessity for an immediate
increase of the volume of the blood. Dehydration of the tissues in gen-
eral, however, is always a serious matter and demands energetic measures
to combat the deficit of fluid. Such fluid loss is met with in conditions
mentioned on page 789. To increase the store of body fluids in such
states it may be necessary to use one or more of the following absorption
routes: from the gastro-intestinal tract, which is the one of choice; by
subcutaneous injection, or intravenous infusion. If the treatment is
necessary because of vomiting, for example, large amounts of normal
saline may be absorbed from the subpectoral areas. Injections of this
type may be repeated as frequently as absorption occurs. If conditions
prevent the use of the alimentary tract, the same object can be achieved
with more comfort to the patient by the intravenous injection of fluids
such as normal saline or glucose solutions. Intravenous injection of
suitable amounts of fluid may be repeated every four hours.
2. Intravenous Infusions to Increase the Buffer Action of the Blood
in Acidosis. — It is not intended here to discuss the question of acid
intoxication in the body. However, the intravenous use of solutions of
sodium bicarbonate in combating acidosis requires a brief discussion of the
basis for the use of alkali in this condition. Henderson (&) has shown the
importance of the phosphates and carbonates in maintaining a constant
reaction of the blood. These bases exist in balanced solution in the
blood, and are able to take up relatively large quantities of acid or alkali
without greatly altering its normal alkalinity. This mechanism, together
with a similar action of the proteins of the blood, constitutes the buffer
action of the blood. For practical purposes the buffer salts may be
regarded as bicarbonates. They may be measured in terms of carbon
dioxid, with which they combine, by the method of ^^an Slyke(&) or Y.
Henderson and Morris. The constancy of the reaction of the blood is
maintained chiefly by the elimination of carbon dioxid in the lungs,
and of acid radicals by the kidneys. In each cycle of blood the bases thus
tend to be conserved in the body. In pathological conditions extreme de-
pletion of the bases may occur in an attempt to maintain the normal
reaction of the blood. In these conditions the administration of alkali
is advocated in order to renew the lost bases from the blood and tissues,
as well as to neutralize non-volatile acids being formed in the body.
Theoretically, the administration of an alkali such as sodium bicar-
bonate, first suggested by Stadlemann(a) in 1883, should be an efficient
means of restoring the alkali reserve of the body, and thus become an aid
in the treatment of the acidosis associated with diabetes. The earlier, a
most universal, use of bicarbonate for the treatment of this condition, how
THE INTRAVENOUS INJECTION OF FLUIDS 793
ever, has been given up, not only because it does not control the acidosis but
also because it produces deleterious effects. Allen, Stillman and Fitz
found that high dosage of bicarbonate by mouth seemed necessary in cer-
tain cases, but that its intravenous use failed to save any patients in their
series of cases. They emphasize the danger of the abuse of sodium bicar-
bonate in the treatment of diabetes, and in general deprecate its use at
all. Joslin has also discussed the harmfulness of sodium bicarbonate and
does not use it in the treatment of diabetes.
Beneficial results from infusion of solutions of sodium bicarbonate in
cases of acute nephritis complicating cholera, as well as in certain types
of nephritis from other causes have been reported by Sellards. The
cases of chronic nephritis which he treated required the intravenous injec-
tion of as much as 150 grams of bicarbonate to produce an alkaline reac-
tion of the urine, in contrast to a normal tolerance of 5-10 grams by
mouth. Howland and Marriott (c) also have found sodium bicarbonate in-
fusions useful in the treatment of acidosis incident to diarrheas of infancy
and childhood. Its use is advocated by Wright and Fleming for the
treatment of gas gangrene in which, in severe cases, there is a great re-
duction of the alkali reserve. Cannon, Fraser and Hooper used bicar-
bonate in the treatment of the acidosis accompanying shock, but a later
paper by the British Medical Research Committee asserts that the restora-
tion of the circulation by means of transfusion, etc., renders the use of
alkali unnecessary in this condition.
Good results from alkali therapy may be expected usually only in the
treatment of cases of acute acidosis, the development of which has been so
rapid that the chemistry of the body has not had time to compensate for
the changed conditions. Examples of this type are seen in methyl alcohol
poisoning and acute uremia. In such conditions, in addition to alkali
therapy, forced elimination is also essential.
The practice of administering bicarbonate as routine before and after
surgical procedures has no justification except in the case of a considerable
deficit of alkali. Caldwell and Cleveland determined the change in the
plasma carbon dioxid before, during and after surgical operations, and
concluded that the diminution in the alkaline reserve below the average
normal does not reach the point at which the earliest clinical symptoms
are observed to occur, namely, about 35 volumes per cent of carbon dioxid.
There is at present no indication for the use of bicarbonate by mouth,
or intravenously, unless an alkaline deficit is present sufficiently great to
produce symptoms. Solutions of bicarbonate have no more effect in main-
taining blood pressure than normal saline, according to Bayliss.
If treatment with sodium bicarbonate is instituted, attention should be
paid to the reaction of the urine. When this reaction becomes alkaline,
the administration of the alkali should be stopped. While the observ-
ance of this rule is a safe one for the majority of cases, Palmer and Van
794 ARLIE V. BOCK
Slyke have shown that in pathological conditions there is danger of giving
too much bicarbonate if the administration is continued until the urine
becomes alkaline in reaction. An alkalosis may result in such cases, a
condition probably not more desirable than the previously existing state
of acidcsis. For example, Wilson, Stearns and Thnrlow have shown
the existence of alkalosis in cases of tetany following parathyroidectomy.
Tileston has produced tetany in a case of Weil's disease by the overad-
ministration intravenously of sodium bicarbonate, having established
thereby an alkalosis of moderate degree. The onset of tetany in a case
of bichlorid poisoning after the administration intravenously of 60 grams
of bicarbonate has been reported by Harrop(a), and Marriott and Howland
(see Howland and Marriott (&)) have frequently observed the development
of symptoms of tetany in infants during the course of bicarbonate treat-
ment. Palmer and Van Slyke suggest that the administration of sodium
bicarbonate should be controlled by determinations of the plasma carbon
dioxid. The alkali should not be pushed beyond a level of about 70 vol-
umes per cent, which represents the level of plasma carbon dioxid at which
normal urine becomes alkaline following the ingestion of bicarbonate.
3. Intravenous Infusions to Combat Toxemia. — The importance of
an abundant intake of fluids in the treatment of acute toxemia is beyond
question. The fact, however, that the gastro-intestinal tract is the natural
route for the absorption of fluid is too often overlooked by the advocates
of intravenous therapy. Many intravenous infusions could be dispensed
with if a sufficient supply of fluid by mouth and by rectum was available.
In other words, the failure to recognize the insufficiency of the fluid
supply, as well as the excessive loss of fluid that may occur as a result of
sweating in a given case, often results in the clinical state for which intra-
venous infusions become necessary. It is surprising how rapidly and
how much fluid may be absorbed from the alimentary tract. When fluid
depletion prevails, normal saline, isotonic glucose solution, or tap water,
in amounts of 300 to 400 c.c. may be given by rectum every hour for four
or five doses, and may be repeated every three hours thereafter if neces-
sary. It should be recognized that many of the conditions requiring
increased fluids are ably met by means of absorption from the alimentary
canal, and that in many cases in which intravenous infusions are given,
the absorption of fluid from the intestine is a valuable adjunct in
treatment.
In the event of failure to maintain a sufficient fluid intake by other
routes, intravenous infusions in toxemic states should be frequently given.
There is a popular belief that intravenous injections of various solutions
are capable of washing out toxins from the blood stream and indirectly
from the tissues as well. The procedure has been used to diminish the
toxemia of pneumonia, typhoid fever, etc. Enriquez has reported good
results from the intravenous use of hypertonic glucose solution in the
THE INTRAVENOUS INJECTION OF FLUIDS 795
treatment of a great variety of such conditions. There is, however, no
analytical evidence to show that such therapy succeeds in removing from
the body substances responsible for the symptoms. Even if dilution of
the toxic substances does occur, which is doubtful, it does not follow that
their removal from the body is a necessary sequel. All of the symptoms
of toxemia are subject to spontaneous changes which make difficult an
attempt to judge the value of any single therapeutic measure. There is
no reason to believe that intravenous infusions in toxemic conditions have
greater value than an abundance of fluid absorbed from the gastro-
intestinal tract. The results obtained in the past by intravenous therapy
are probably due to the greater facility with which the functions of the
body are carried on in the presence of an adequate supply of body fluid.
4. Intravenous Infusions to assist in providing for the Calorific Re-
quirements of the Body. — The use of glucose solutions for intravenous
therapy has been fostered because of the availability of glucose in processes
of metabolism. Unlike sodium chlorid, glucose when introduced into the
tissues may be completely burned, and has, therefore, none of the toxic ef-
fects associated with sodium chlorid which cannot be destroyed in the
tissues. The fuel value of glucose makes its use for purposes of infusion
desirable, particularly in conditions in which nutrition for various reasons
is not being maintained. Enriquez, by the use of a 30 per cent solution,
has introduced intravenously an amount of glucose equivalent to 3,200
calories within twenty-four hours. Glucose requires simple dehydration
to transform it to glycogen, and it is a physiologically efficient food sub-
stance.
When an isotonic solution of glucose, 5.52 per cent, is injected intra-
venously, the sugar leaves the blood stream within a very brief period.
If a hypertonic solution is injected there is a temporary increase in the
blood volume caused by the withdrawal of fluid from the tissues that
persists until balanced osmotic relations are again established between
the blood and tissues. Usually this adjustment happens within thirty
minutes after the injection, but it may require as long as two hours, as
shown by von Brasol, Biedl and Kraus, Starling(a) and others.
The excess sugar is usually readily stored in the tissues as Kleiner found.
The amount of sugar excreted by the kidneys is variable. Kleiner
found in dogs that 60 per cent of the injected sugar was excreted in the
urine, but the degree of glycosuria and its duration depend not only upon
the state of the kidneys and the rate of blood flow, but upon the amount
of sugar and the rate at which it is injected as well. ' After intravenous
injection in man, at a tolerant rate of 300 c.c. of a 30 per cent solution,
Enriquez found at most 4-5 grams of glucose in the urine during the first
two hours after the injection and none thereafter. Woodyatt, Sansum
and Wilder, by means of timed injections, have determined the tol-
erance in man for sugar as 0.85 gram per kilogram per hour. For a
796 AELIE V. BOCK
man of 75 kilograms this corresponds to 63 grams of glucose per hour.
No sugar appears in the urine and no diuresis occurs at this, or subtolerant
rates, since glucose utilization presumably keeps pace with such rates
of injection. However, if the rate of administration is increased as high
as 5.4 grams per kilogram per hour, glycosuria with an active diuresis
occurs, which soon leads to excessive dehydration of the body unless a
large amount of water is supplied.
Essentially the "same phenomena were observed in dogs by Fisher and
Wishart after the ingestion of glucose, but the time relations necessarily
extend over longer periods owing to the longer absorption time. Hiller
and Mosenthal, however, found in man that ingestion of 100 grams of
glucose did not produce hydremia.
The routine use of glucose solutions, instead of normal saline, is now
the custom in certain clinics. There is much to be said in favor of this
change. Yet too much emphasis has been placed upon the food value of
glucose infusions. An intravenous infusion of 500 c.c. of a 10 per cent
solution of glucose has a fuel value of only about 200 calories. If such an
infusion is repeated every two hours in twenty-four the total calories
amount to 2,400. If solutions of greater concentration of glucose are
used, correspondingly more time for each infusion must be consumed in
injecting the fluid if diuresis and glycosuria are to be avoided. As
practical measure, therefore, the supply of the total calorific needs of the
body by means of intravenous injections of glucose is limited to circum-
stances of an exceptional nature.
Solutions Used for Intravenous Infusions
The use of normal saline for intravenous infusion has formed the basis
for the development of other solutions for purposes not served by saline.
The following list comprises those solutions that have been found to have
the greatest range of usefulness for intravenous injection: (1) "saline"
solutions; (2) gum acacia or gum-saline solutions; (3) gelatin solutions;
(4) sodium bicarbonate solutions; and (5) glucose solutions.
1. "Saline" Solutions. — A solution of normal saline (0.85 per cent
sodium chlorid) was first used for intravenous injection. It was found
by Sherrington and Copeman and many others, to leave the circula-
tion within a few minutes after injection. This is due to the rapid diffu-
sion of both, water and salt until the differences in potential between blood
and tissues are again adjusted. When used intravenously for cases of low
blood pressure, sodium chlorid has, therefore, only a transitory effect upon
the blood pressure. Fraser and Cowell found that such a solution
was of little use in the treatment of hemorrhage and shock for this reason,
and their experience led them to conclude that the blood soon becomes
THE INTRAVENOUS INJECTION OF FLUIDS 797
more concentrated than it was before the injection. Nevertheless, normal
saline may often be used to tide a patient over a critical emergency period,
and its usefulness in building up a tissue fluid reserve is established. The
work of Bogert, Underbill 'and Mendel may be referred to in this
connection.
Hypertonic solutions of saline tend to produce hydremia, but diffusion
processes quickly reduce the level of salt in the blood to the normal, and
the excess of water is likewise returned to the tissues, a small amount
being eliminated by the kidneys. There is no indication for the intra-
venous use of hypotonic salt solution.
Sodium chlorid has been shown by Loeb(a), Joseph and Meltzer, and
others, to possess toxic properties, and clinical experience has also demon-
strated this fact. According to Hort and Penfold, undesirable symptoms
include fever, rigors, subnormal temperature, diarrhea, intestinal hemor-
rhages and Cheyne-Stokes respiration. A. S. and H. G. Griinbaum
have reported several deaths due to edema of the lungs following the
injection of saline solutions in postoperative cases, in which ether was
used as the anesthetic, and in which nephritis was also present. On the
other hand, Joseph and Meltzer, in experimental work on dogs, rarely
encountered edema of the lungs which could be attributed to sodium
chlorid. The relation of salt to the edema associated with nephritis, as
suggested by Widal and Javal and others, also indicates that an excess of
salt may be a source of injury to the patient. Certain histological changes
such as vacuolation of liver cells, alteration of red corpuscles, and degen-
erative changes in heart muscle and capillary walls have been described
as due to salt. To the former idea that salt possesses only osmotic prop-
erties must therefore be added that of its chemical activity.
When normal saline is injected attention should be given to the
amount of fluid used. This, should be approximately 1 per cent of the
body weight, if rapidly injected into the circulation, but of course may
far exceed this amount if sufficient time is allowed for the infusion period.
There is almost no danger from embarrassment of the circulation unless
very large amounts of fluid are injected rapidly, or unless an injection
is undertaken when a patient is suffering from edema of the lungs. It
is to be remembered that the capacity of the vascular system is normally
much greater than the volume of the blood. The ability of the vascular
bed to contract and expand constitutes a valuable compensatory feature
of the circulation, as Meltzer has suggested, and it is usually adequate to
prevent embarrassment to heart action from intravenous injection of fluid.
However, as noted above, salt infusions immediately after anesthesia, in
cases having damaged kidneys, should be avoided, as well as giving ex-
cessive amounts of sodium chlorid as shown by a fatal case reported by
Brooks.
798 ABLIE V. BOCK
2. Gum Acacia or Gum-Saline Solutions. — The use of gum acacia for
infusion purposes is a development of the demand during the war for a
fluid substitute for blood in the treatment of hemorrhage and shock. Ac-
cording to Bayliss (c), gum acacia is a polymerized anhydrid of arabinose.
Erlanger and Gasser state that substances similar to gum acacia are widely
distributed in the plant kingdom, and are important factors in the nutri-
tion of herbivorous animals. When ingested by man these substances are
readily utilized in processes of metabolism. Erlanger and Gasser
state that about one-half of the amount of gum acacia injected intra-
venously is utilized by the organism in the course of twelve hours, but that
some of it remains in the body for over forty-eight. Bayliss obtained the
pentose test in the blood twenty-four hours after injection of gum-saline.
Gum acacia may be obtained either in the powder form or in lumps
(tears). The lump form is usually purer than the powder. For the
purpose of infusion, Bayliss found that a solution of gum between 6 per
cent and 7 per cent in strength, in a 0.9 per cent solution of sodium
chlorid, has the same viscosity as whole blood, and the same osmotic
pressure as the colloids of the plasma. ' Such a solution therefore possesses
properties requisite for use in conditions in which an increase in blood
volume and sustained elevation of blood pressure are desirable, because
it remains in the circulation long enough for the circulatory mechanism
to readjust itself. The results obtained by the extensive Use of gum-saline
by Drummond and Taylor(d), and others, justify the theoretical and ex-
perimental considerations put forward by Bayliss (c). Certain dangers in
connection with the use of this solution will be referred to under the sub-
ject of reactions.
The quantity of gum-saline which Bayliss recommended for injection
is 750 c.c. A safe rule to follow for this solution, as with others for
intravenous use, is to govern the amount given in relation to the body
weight. A dose equal to 1 per cent of the body weight, to be repeated,*' if
necessary, will usually meet requirements. If a greater addition to the
blood volume is desirable, more than this may be given with safety. Gum-
saline may be given to cases in shock without overburdening the heart.
Its use should be limited to conditions of low blood pressure as a result
of hemorrhage and shock. It is not a substitute for red corpuscles and,
therefore, can be of no use in treatment for an exsanguinating hemorrhage,
for which transfusion of blood alone is indicated.
The use of the combination of hypertonic solutions of gum acacia and
glucose, as recommended by Erlanger and Gasser, has not yet been ex-
tensively used clinically. When slowly injected, the great viscosity of 25
per cent gum-saline which they used, apparently does not contra-indicate
its use.
3. Gelatin Solutions. — A solution of gelatin, 2.5 per cent, in normal
saline, as recommended by Hogan on account of its colloidal properties,
THE INTRAVENOUS INJECTION OF FLUIDS 709
may be used for the same indications as grim acacia. Hogan demon-
strated by blood pressure readings and rate of urinary secretion that this
solution remained in the circulation for a considerable period of time.
It does not, however, possess the same viscosity as blood. Furthermore,
unless special care is taken, heat destroys the colloidal properties of
gelatin, upon which its usefulness in this connection depends. Steriliza-
tion of the solution also is difficult, owing to the frequent presence of
spores of tetanus bacilli. In spite of these disadvantages, gelatin solutions
may be of great use if they are made with the precautions suggested
by Hogan.
4. Sodium Bicarbonate Solutions. — Sodium bicarbonate solutions in
strengths varying from 2 per cent to 6 per cent are customarily made up
in normal saline. When such a solution is boiled in the process of steril-
ization, much of the bicarbonate is converted into carbonate. The car-
bonate is caustic, and is capable of producing extensive sloughing of sub-
cutaneous tissues. It may, however, be injected safely into the blood
stream. Carbonates, as such, should not be used as a. rule, even for in-
travenous injection, because of the possibility of infiltration about the
vein with consequent tissue destruction. After boiling a solution of
sodium bicarbonate, carbon dioxid should be bubbled through the solution
to reconvert the carbonate to bicarbonate. Contrary to statements in
the literature (Stadlemann(a)), not only is the alkalinity of a bicarbonate
solution altered by boiling, but also the caustic properties of carbonate in
such solutions cannot be neglected. Joslin is authority for the statement
that sterilization of bicarbonate is probably not necessary. If not ster-
ilized, it should be handled with sterile utensils and dissolved in sterile
normal saline. Solutions of bicarbonate or carbonate should not be in-
jected subcutaneously.
f Some of the effects following the injection of sodium bicarbonate are
easily measured. The carbon dioxid tension of the alveolar air is in-
creased, the carbon dioxid content of the blood rises, and urine becomes
alkaline usually when the tolerance is reached, and in some cases of
nephritis, as Sellards has shown, diuresis may be pronounced. Allen,
Stillman and Fitz suggest that great care is necessary when sodium
bicarbonate is given intravenously, not to force a blood having low alka-
linity suddenly to one having a normal or above normal alkalinity. A
favorable progress is indicated if the level of bicarbonate tends gradually
•upward.
5. Glucose Solutions. — Glucose is a monosaccharid which shares with
fructose the characteristic of being more readily assimilated than any
other sugar. It is highly soluble in water, is non-toxic, and may safely
be given in concentrations up to 30 per cent to 35 per cent. The isotonic
solution is one of 5.52 per cent . When injected into the circulation in
isotonic or hypertonic solutions, the excess of sugar is rapidly eliminated
800
AELIE V. BOCK
from the blood, a process shown by many observers to be independent of
the kidneys and other abdominal organs, and Kleiner has shown
that it may to a certain extent be independent of vital function. How-
ever, Bogert, Mendel and Underbill, and Boycott and Douglas have
found that in animals suffering from acute experimental nephritis,
the injected sugar remains for a longer time in the blood, than when the
kidneys are normal. This point may be of great clinical importance when
such infusions are contemplated for cases of nephritis in man, since it may
be associated with the onset of diuresis reported by several observers in
cases of anuria.
6. Other Solutions. — Certain other substances less widely used for
infusion purposes may be mentioned. Intravenous infusions containing
calcium and barium have been used for the alleged constricting action of
these substances upon arterioles. Bayliss(c) has shown that this action
lasts but a few minutes and is, therefore, of no great importance. The
use of calcium for the treatment of tetany has been suggested by McCal-
lum and Voegtlin, Wilson, Stearns and Thurlow, and others. It is
also useful to restore to normal the delayed coagulation time of the
blood in cases of obstructive jaundice, as shown by Lee and Vincent.
Likewise, the intravenous use of magnesium sulphate for the treatment of
tetanus, and for purposes of anesthesia, has been described by Meltzer(c)
and Auer and Meltzer.
Reactions Due to Infusions
As in the case of blood transfusion, the intravenous injection of
solutions is attended with a certain incidence of reactions. In the pre-
ceding discussion many of these have already been mentioned. The more
common reactions are characterized by symptoms similar to those associ-
ated with protein intoxication. The most important cause of these reac-
tions seems related to the water, used for the solutions. Chills and fever,
resulting from intravenous injections, are for the most part theoretically
due to reaction to foreign protein contained in the water. In certain
instances, reactions after infusion may be accounted for by the fact that
the solution injected was in effect a vaccine and the resulting chill and
fever a manifestation of a non-specific immune reaction. In the routine
use of infusions experience has shown that chills and fever result in a
small percentage of all cases regardless of the type of solutions used. It
is well known, however, that in man the rapid ingestion of very large
amounts of water may produce the same type of reaction, from which the
disturbance may be seen to be a very fundamental one involving the
water balance of the body. Hort and Penfold, after carefully in-
vestigating the matter, found that water distilled in a glass retort and at
THE INTRAVENOUS INJECTION OF FLUIDS 801
once injected did not produce fever, but tended to cause a fall in tempera-
ture. Samples of the same water, collected and sterilized with all the
usual precautions and allowed to stand, produced fever upon injection.
The cause of such a reaction is unexplained. These authors recommend
that water for intravenous use should be recently distilled and sterilized
before injection, as the only reliable method of avoiding fever. All water
used for infusion purposes should be distilled from water containing as
little organic material as possible, and sterilized at once after distillation.
It should then be preferably stored on ice if not immediately used.
The bad results that have been reported following the use of gum-
saline can generally be explained by investigation of the individual cases.
They have been found to be due to the use of impvire gum acacia, to im-
proper storage of gum-saline after it has been made up for use, and, as
DeKruif showed, to gross infection of the solution. Gum acacia is
protein-free and has been demonstrated by Bayliss and DeKruif to be
free from anaphylactic phenomena. Before use in man, the toxicity of
the stock gum acacia should be tested in cats or guinea pigs. When all
precautions have been observed in the preparation of gum-saline, chills
have occurred in 5 per cent to 10 per cent of cases after its injection into
the circulation. The failure to test the toxicity of the stock supply of
gum, and to observe the other usual precautions, has led to some fatalities
from its use.
In the case of sodium bicarbonate injections, reactions may consist of
convulsions or complete collapse, according to Joslin. The production
of tetany after bicarbonate injections has already been discussed.
Harrop(a) has called attention to the danger of the intravenous use of
bicarbonate when the excretory function of the kidneys is impaired, and
especially when oliguria or anuria is present.
Chills and fever occurring after intravenous injection of normal saline
are usually the result of carelessness in preparation of the solution. The
practice of employing as "normal saline" a solution of boiled water plus
an indefinite quantity of salt is not to be advised.
Preparation of Infusion Solutions and Technic of
Administration
If the general principles concerning the character of water, purity of
substances employed, etc., already discussed are followed, no special points
remain to be mentioned in the preparation of solutions for intravenous use.
The exception to the general rule concerns the preparation of gum-saline,
which, owing to difficulties of filtration of the gum, requires special technic.
A full description of the method of preparation of gum-saline is given by
Telfer.
802
AELIE V. BOCK
Solutions for intravenous use should always be made, not only with
care as to the character of water used, but also as to the nature and con-
centration of substances in the solutions. Also, great care must be taken
in filtration to remove extraneous or undissolved particles, and in steriliza-
tion. The storage of all solutions on ice in the interim before using them
is important. Before injection any solution should be warmed to body
temperature. In the case of fluids having no greater viscosity than blood,
the rate of injection is not significant unless excessive amounts of fluid are
given. When amounts of fluid exceeding 1 per cent of body weight, or
when solutions of high viscosity are injected, caution as to the rate of
injection is necessary. Special care is always advisable when intravenous
infusions are given to cases of nephritis.
The methods for administration of intravenous fluid are numerous.
The simplest of these depends upon gravity to force fluid into the vein.
The syringe method, with a three-way stopcock, so widely used for the
administration of salvarsan, is one of the most satisfactory and efficient
methods. The apparatus designed by Robertson for the transfusion of
citrated blood is also adapted for use 'with other solutions than blood. In
order to introduce known amounts of sugar at a tolerant rate, the method
of timed intravenous injections by means of a pump, as devised by
Woodyatt, Sansum and Wilder, and later improved by Woodyatt(&) is to
be recommended.
Artificial Methods of Feeding Herbert s. Carter
Gavage — Duodenal Feeding — Rectal Feeding — Formulae for Rectal Feeding —
Precautions and Technic in Rectal Feeding — Summary of Results for
Rectal Feeding — Subcutaneous Feeding — Intravenous Feeding.
Artificial Methods of Feeding
HERBERT S. CARTER
NEW YORK
There are times when the need for some method of nourishing the
body by other than the normal route is imperative, and has led investi-
gators to determine, if possible, some way that shall be reliable, easy,
and capable of supplying at least approximately the needs of the living
organism. That it is not reasonable to expect that an individual could be
permanently nourished in any artificial way (with the exception of gavage
and direct feeding in gastrostomy) goes without saying, but there are some
occasions in which an adequate method is indicated — as every clinician
can testify. So far, the results of experimentation have been only par-
tially successful, and while it has been found possible to supply prac-
tically about one-third the caloric needs of the body, principally in the
form of carbohydrate, the problem of furnishing the necessary protein
seems still far off.
It has long been known that a man can live many days on his own
protein and fat, provided he is given water, and there are numerous in-
stances of professional starvers who have gone forty to fifty days without
food, and have come back promptly to normal when they were again fed.
In this way we have gained considerable knowledge of the metabolism of
starvation over extended periods, a subject which forms an interesting
chapter in biological chemistry. The results of fasting experiments in
man and animals, Sherman (a) says, "show that in fasting the total metab-
olism continues at a fairly constant rate in spite of the fact that the
energy is obtained entirely at the expense of the body material." In long
fasts there has been found a somewhat greater decrease in heat production,
and Sherman says other factors than the simple sparing of the direct
effect of food come into play. Then, too, each type of food exerts a more
or less specific influence on energy metabolism, less sugar being required
to prevent loss of body substance than fat or protein — an observation of
practical importance in devising artificial methods of feeding.
In many of the artificial feeding procedures the metabolism of the
body, as shown by the nitrogen balance, body weight and findings of the
respiratory chamber, differ little from that found in actual starvation;
and although the patients seem to be deriving constructive benefit from
805
806 HERBERT S. CARTER
one or another method, accurate data of scientific investigation shows the
bettered condition is for the most part only apparent.
The forms of artificial feeding to be discussed are:
1. Gavage.
2. Duodenal feeding.
3. Rectal feeding.
4. Subcutaneous feeding.
5. Intravenous feeding.
Gavage. — By gavage is meant the introduction of food either through
the nose or mouth by means of a flexible rubber tube. This is an exceed-
ingly valuable procedure under certain conditions and gives most satis-
factory results because the food reaches the gastrointestinal canal through,
the normal route.
Indications. — The chief indications for the use of this method of
feeding are: First, in unconscious patients, particularly in those who
have lost the swallowing reflex ; second, in the insane who refuse nourish-
ment ; third, in conditions of ulcerat'ion of mouth or pharynx with painful
deglutition ; fourth, in 'babies, at times, who have had cleft palate opera-
tions ; fifth, in anorexia nervosa where it is necessary to feed in spite of
absolute anorexia ; sixth, in "hunger strikes," in prisons ; seventh, in
paralysis of deglutition.
Metabolism, — The metabolism in gavage is precisely that of normal
feeding, except that the preliminary mouth digestion is lacking. On
this account, foods used in gavage should be either in a liquid form
or so finely communicated that they will run through the tube in a
liquid medium. The food requirements should be calculated for each
patient.
As the psychic stimulus to digestion, so far as taste goes, is not a
factor in gavage, it is only necessary to combine the food elements in
sufficient amounts and proper proportions to satisfy the nutritional re-
quirements cf each case, calculating the caloric value of the foods used
on the basis of the patient's activities, according to the well known rules.
Thus an insane, hyperactive patient will take many more calories per kg.
than one lying unconscious in bed, therefore it is unreasonable to try to
supply food formulae ready made.
Foods Used in Gavage. — The most convenient foods used in gavage are
milk, cream, sugars, butter, oils, meat powders, eggs, cereals, cooked
starch, etc.
Method of Performing Gavage. — The patient should be placed in as
comfortable a position as possible. If in bed, with the head slightly
raised ; if out of bed best in the upright position ; if insane or resisting,
tied in bed or to a ehair. The tube should be lubricated best with some
non-greasy emollient and slipped down the throat at least well bevond
AETIFICIAL METHODS OF FEEDING 807
the epiglottis — although not necessarily into the stomach. An ordinary
stomach tube may be used or any convenient sized catheter to which is
attached a glass funnel. If the tube is passed through the nose, a small
sized catheter must be used and the end passed to a point well beyond the
epiglottis. Before pouring food into the funnel, one should listen to be
sure that the patient is not breathing through the tube, showing it to be
in the trachea — a not unusual occurrence, particularly in unconscious
patients.
The number of feedings given during the day will depend on circum-
stances; but three or four feedings in the twenty-four hours should be
enough, too frequent passage of the tube being irritating to the mucous
membrane. At times it is necessary to insert a mouth gag before passing
the tube, and in restless patients who bite the tube it is well to use a spool
gag with a good flange, passing the tube through the hole.
Duodenal Feeding. — This method of feeding was devised by Einhorn
some years ago, and has found a field of usefulness in certain cases.
It has been recommended especially for use in peptic ulcer, chronic gastric
dilatation to prevent weight on the gastric walls, allowing them gradually
to recover their tonus and contract, provided, of course, the dilatation is
not secondary to pyloric obstruction; in cases of difficult nutrition on
account of absolute anorexia, nervous vomiting, or asthenia — also in severe
hepatic disease when it is supposed to reduce the congestion of that
organ — although this is a questionable result; in carcinoma of the stomach
where the ingestion of food is painful; in some forms of chronic
indigestion.
The metabolism of duodenal feeding is, of course, essentially normal,
and follows the same lines as in gavage.
Method of Introducing the Duodenal Tube. — The bulb of the tube is
placed in the patient's mouth and a swallow or two of water is given to
help in its deglutition — care being taken not to have it swallowed too
rapidly as it might curl up in the pharynx. When the tube is in the
stomach the patient is placed on the right side, and the tube fed in its
entire length, gradually working its way into the duodenum by gravity.
The length of time necessary for it to reach the duodenum depends on
several factors, on the degree of gastric acidity, the motor power of the
stomach muscle and pylorospasm ; entering the duodenum most rapidly in
hypoacidity when this is associated with good muscle tone and no pyloric
contraction either functional or organic. In favorable circumstances, it
may enter the duodenum in ten to twenty minutes — possibly two or three
hours for, normal persons — up to twelve or thirty-six hours in less favor-
able cases.. When -the end of the tube has passed the pylorus it is diffi-
cult to obtain any fluid and what few drops can be aspirated with a syringe
are alkaline and usually contain bile. If the tube is still in the stomach
the fluid will probably be acid. If there is an achylia present (and this
808 HEEBEKT S. CARTER
acid test of no use) a little milk can be given by mouth or some colored
fluid and aspirating at once; if the tube has gone beyond the pylorus no
colored fluid or milk will be obtained. The tube's location can also be
determined, if necessary, by fluoroscopy after filling it with a solution of
barium. The length of time that the tube is left in situ depends on the
condition for which it is used, but it can remain for from twelve to fif-
teen days without detriment, keeping the mouth clean by washes and
brush.
Duodenal Feedings. — The feedings recommended by Einhorn consist
of milk 210-240 c.c. (1 to 8 ounces), one egg, a tablespoonful of lactose
•(15 gm. 1/2 ounce). If the bowels are made too loose, reduce the lactose,
and when it is necessary to increase weight, 4 to 8 gm. (1 to 2 drams) of
butter may be added to each of the eight feedings given at two-hour inter-
vals. For those patients who cannot take milk, cereal gruels may be sub-
stituted, made thin and smooth enough to pass through the tube readily.
It will then be necessary to give the protein of the diet in the form of
meat powders — egg albumin — or some one of the artificially prepared
protein foods, e. g., plasmon, 70 per cent protein; nutrose, 90 per cent
protein; beef meal, 77 per cent protein; peptones, e. g., panopeptones,
Witte's peptones, Armour's or Cranick's, all of which vary from 1.5 to 10
per cent nitrogen. These latter peptones may easily upset the digestion,
causing diarrhea, and are therefore suitable only for short periods. Aleu-
ronat, a vegetable protein, contains 80 to 90 per cent protein, 7 per cent
carbohydrate. All these preparations are good as well for reenforcing
the milk formulae.
The food should be given at about 100° F., slowly either by the
drop method or by a syringe directly into the tube, or by using a three-
way stopcock drawing the food up from a glass. If the food is given
rapidly, it distends the duodenum and causes pain. After each feeding
saline is run through the tube to cleanse it, followed by air. This is very
essential or the tube shortly becomes blocked and has to be removed for
further cleaning. Einhorn (&) reports 95 per cent of ulcer cases healed
at once, and 90 per cent after two years in 132 cases, and other favorable
results.
Buckstein(c) reports experiences with this method of feeding, using an
average mixture of peptonized milk 150 c.c. (5 oz.), glucose 70 gm. (21/}
oz.), 2 eggs, butter 40 gm. (li/^ oz.).
DUODENAL FEEDING — ROUTINE EINHORN FEEDING
7:30 a. m. Oatmeal gruel ................... 180 c.c. (6 oz.)
One egg
Butter .......................... 15 gm. (l/2 oz/
Lactose ......................... 15 gm. (l/2 oz.
ARTIFICIAL METHODS OF FEEDING 809
9 :30 a. m. Pea soup 180 c.c. (6 oz.)
One egg
Butter 15 gm. (l/2 oz.)
Lactose 15 gm. (^ oz.)
11:30 a. m. Same as at 9:30 a. m.
1 :30 p. m. Bouillon 180 c.c. (6 oz.)
One egg
3 :30 p. m. Oatmeal gruel 180 c.c. (6 oz.)
Butter 15 gm. (l/2 oz )
One egg
Lactose 15 gm. (^ oz.)
5:30 p. m. Same as at 9:30 a. m.
9 :30 p. m. Bouillon 180 c.c. (6 oz.)
One egg
Total amount: Calories.
Oatmeal gruel 360 c.c. (12 oz.) 1,476
Eggs 8 800
Pea soup 720 c.c. (24 oz.) 384
Lactose 90 gm. ( 3 oz.) 369
Bouillon 360 c.c. (12 oz.) 39
Butter 90 gm. ( 3 oz.) 715
3,483
This diet list may, of course, be modified downward where fewer
calories are needed.
Rectal Feeding. — Rectal feeding has been employed since earliest
times in one form or another, and, later, von Leube and Riegel kept
patients alive for considerable periods by this method, in one case almost
a year, and it was thought it was possible to do this regularly when indi-
cated. Modern scientific experimentation, however, has shown that at
best it is a form of partial feeding only, and results in subnutrition. This
form of artificial feeding is, nevertheless, the most efficient that we pos-
sess so far, and has a field of usefulness in tiding patients over periods
when mouth feeding is impossible or inadvisable. The length of time
it should be employed and is of practical use is from one to eight weeks,
or less; the success of the longer periods is probably due to causes to be
dealt with later.
Indications. — The indications for rectal feeding may be summed up
as follows: 1. In temporary obstruction from any cause. 2. Inability
to swallow,, as in stricture of the esophagus. 3. Gastric diseases, e. g..
810 HERBERT S. CARTER
ulcer, cancer, pyloric stenosis, protracted vomiting, etc. 4. Increasing
emaciation.
Physiology of Rectal Feeding. — The large bowel is ordinarily thought
of as a reservoir where the liquid of the chyle, including the salts, is ab-
sorbed, where the bacteria continue to break down cellulose, and the feces
are compacted. Little if any enzyme action on the foods is carried out
except, in the ascending colon, where the small intestine digestion is
continued for a short time, the large bowel secreting no digestive juices.
The substances absorbed are those which travel easiest by osmosis and in
the case of rectal enemata reverse peristalsis carries any food solution the
whole length of the bowel and into the small intestine if the ileocecal
valve is incompetent. It is more than probable in the cases of rectal
feeding that have been kept alive for months the success of the procedure
has depended on this factor to a large extent, the small intestine being
responsible for the greater part of the absorption.
In 1902 Cannon showed by bismuth enemata with food that if small
in amount they were carried only^ to the cecum, but if large and thick,
were carried into the small intestine, segmentation taking place following
antiperistalsis, particularly if considerable pressure was used in their
introduction.
Metabolism of Rectal Alimentation. — As rectal feeding has been sub-
jected to more accurate laboratory methods, the clinical observations indi-
cating almost complete nutrition by this method, have of necessity been
modified, and at best it has been found that only about 30 per cent of the
total caloric needs of the body can be supplied, save in exceptional cases.
Of the different food elements introduced by enema it is necessary
to speak more in detail concerning the fate of protein, carbohydrate, fat,
alcohol, salts and water.
Protein. — Almost every conceivable form of protein has been used at
one time or another in rectal feeding, and Bauer and Voit(d) in 1869
proved by the increase in urinary nitrogen that protein, when properly
prepared, was absorbed to some extent.
Edsall and Miller (e) found in two patients 3.04 gm. N (19 gm. P) and
3.8 gm. N" (23.8 P) absorbed; Boyd in six patients receiving an average
of 44.6 gm. protein (7.16 X) there was absorbed 8.87 gm. protein (1.42
N) i. e., 20 per cent of the intake, and the nitrogen balance was in every
instance a negative one. Adler, using peptonized milk per rectum, gave
3.9 gm. N, 2 gm. being found in the feces, proving that approximately
one-third of the protein was absorbed.
Short, and By waters (/) analyzed reports of cases fed by rectal enema
together with weight charts and urinary findings and concluded that : 1.
The daily output of urinary nitrogen from patients given enemata of
peptonized milk and eggs (peptonized twenty to thirty minutes) showed
that almost no nitrogen was absorbed, and the total nitrogen in the urine
AKTIFICIAL METHODS OF FEEDING 811
was little, if any, higher than that seen in the urine of fasting men or of
patients who received only saline by rectum. 2. Modern physiological
opinion holds that proteins are absorbed principally as amino-acids, and
the failure of the rectum to absorb ordinary nutrient enemata is largely
due to the fact that peptones are usually given instead of amino-acids. 3.
Chemically prepared amino-acids or milk pancreatized for twenty-four
hours, so that the amino-acids are separated, allows a much better absorp-
tion of nitrogen as shown by the high nitrogen output in the urine. 4. The
low output of ammonia nitrogen shows that the high total nitrogen was
not due to the absorption of putrefactive bodies when the amino-acids
were used.
Bauer showed that peptones, meat juices and alkali albuminates were
absorbed by rectum but only when salt was added, also that propeptones,
milk, casein, globulins and egg albumin salted or mixed with pepsin were
absorbed.
From the foregoing, it is seen that some confusion still exists as to
just how well the various forms of protein are absorbed, but in general it
may be said that "the nearer the protein molecule approaches its ultimate
fate in normal digestion, i. e., as amino-acids, the better is its absorption."
So we find peptone better absorbed than albumin, amino-acids than pep-
tone, the best rate of absorption being seen when salt is added to the enema.
Amino-acids may be most conveniently produced by the pancreatization
of milk for 24 hours, in which condition a fair amount is absorbed but not
enough to prevent a constant negative nitrogen balance. There are also
amino-acids produced chemically from beef, but they are not so well borne,
causing rectal irritation.
Fats. — The role of fats in rectal feeding is a very minor one, and
authorities differ again as to this. Friedenwald and Riirah believe that
fat in fine emulsion, as in egg yoke, is fairly well absorbed. Short and
Bywaters conclude that very little, if any, fat is absorbed, which agrees
with Brown's (g) observation that fats given by mouth increase fats in the
urine, while if given by rectum they do not. There is no objection to
using a finely emulsified fat in the nutrient enema, but there is little
object in doing so, as dextrose is well absorbed and takes the place of
fats in sparing protein.
Carbohydrates. — These, so to speak, form the sheet anchor in rectal
feeding and experimental evidence is definite that they are absorbed fairly
readily when offered in proper form and concentration. This has been
proven, as in giving dextrose the respiratory quotient was raised and
acidosis diminished. Even raw starch has been used and not found in the
feces, but dextrinized or malted starch is less irritating than the sugars,
according to some authorities, and may be used in their stead. Lactose
is poorly absorbed, as shown by the rapid rise of ammonia nitrogen in
the urine when this was substituted for dextrose, although it is of some
812 HEKBEKT S. CARTER
use in milk enemata by its action in reducing fermentation. The mono-
saccharids are all well absorbed by the colon in considerable quantities,
and of them dextrose is the best for general use. Boyd and Robertson
found that 9/10 of a 10 to 20 per cent solution of dextrose was absorbed
up to 40-50 gm., but decided that a total of 30 gm. was less apt to irri-
tate the colon. Goodall found with a 10 per cent solution 157 to 163 gm.
was absorbed and with a 15 per cent solution a total of 144 to 193 gm.,
not more than 0.5 to 1 per cent being lost by bacterial action. Boyd gave
patients an average of 55 gm. dextrose with an average absorption of 53
gm. Gompertz, using a 3 per cent solution gave 60 gm. dextrose and
found 52 gm. absorbed in 24 hours, 8 gm. being recovered from the stools;
using a 10 per cent solution 200 gm. were given, 163 gm. absorbed; of a
15 per cent solution, 300 gm. were given, 144 gm. absorbed; and ali-
mentary glycosuria did not occur.
For the most part, therefore, it has been found* that solutions of
dextrose up to 5 per cent were best tolerated and can be used over con-
siderable periods without irritation. If fermentation is a factor it can
be controlled by adding 1 part of thymol in 4,000 parts of the solution.
Salts and Water. — -It has been abundantly proven that these substances
are rapidly absorbed by the rectum and really largely account for the
success of rectal feeding. Gompertz (h) did experiments with both potas-
sium iodid and sodium chlorid and found both well absorbed. Apparent
gains in weight are no doubt due in some instances, as Coleman points out,
to water retention.
Formulae for Rectal Feeding
Among the most easily prepared and satisfactory foods for rectal feed-
ing is milk, preferably skimmed, and pancreatized from 8 to 24 hours,
after which enough dextrose is added to make a 5 to 10 per cent solution
and salt 5 gm. to the liter. The milk should be scalded after peptoniza-
tion to sterilize it, and then kept on ice. Of this solution, 6-8 ounces (180-
240 c.c.) may be given by rectum every four to six or eight hours, de-
pending on the ability of the patient to take it. This may also be given
advantageously by the Murphy drip, thirty-five drops to the minute, three
pints or more being given this way in twenty-four hours.
The following combination of dextrose, alcohol and pancreatized
milk represents a fair sample formula, although in some patients the
alcohol has to be omitted and the lower percentage of dextrose used.
Dextrose 20 to 50 gm. — 80 to 205 calories
Alcohol 20 to 50 gm. — 140 to 350 "
Pancreatized milk 1,000 c.c. — 650 — 650 "
Salt 5 to 9 gm.
870 to 1,205 "
AETIFICIAL METHODS OF FEEDING 813
This may be given in a 250 c.c. dose every four to six hours, and if well
tolerated aids materially in helping the patient to tide over an emergency.
By omitting the milk, the solution is useful in : 1. Simple exhaustion.
•2. In septic conditions. 3. As an antidote to chloroform; in phosphorus
poisoning ; or anything that causes fatty degeneration of the liver, e. g.,
toxemia of pregnancy. 4. In diabetic acidosis and acetonemia. 5. After
abdominal operations, especially in undernourished or desiccated' in-
dividuals.
Instead of the pancreatized milk, one may use white of egg, plasmon,
casein, somatose or aminoids, etc., but they offer no particular advantage
over milk and are sometimes irritating to the rectum.
Fitch (i) recommends:
Eggs, two whole 100 gm. 160 calories
Dextrose, l^ teaspoons .... 6 gm. 30 "
Pancreatized milk, 10 oz 300 c.c. 210 "
Salt, 1/2 teaspoon 2 gm. 0 "
400 calories
Cornwall (;') uses two formula?: No. 1 contains protein 20 gm. in
arnino acids, glucose 90 gm., vitamins, salt and water 1,500 c.c., and 700
calories, given as follows : 6 a. m., glucose 30 gm., strained juice of half an
orange, soda bicarbonate 2 gm., salt 2 gm., water q. s. ad 300 c.c. ; 8 a. m.,
150 c.c. skimmed milk thoroughly pancreatized; 12, same as at 8 a. m. ;
4 p. m., same as at 6 a. m. ; 6 p. m., same as at 8 a. m. ; 10 p. m., same as
at 6 a. m. ; midnight, same as at 8 a. m.
Every second day, at 4 a. m., a colon irrigation .is given with saline
0.9 per cent solution, and the glucose enema at 6 a. m. omitted. The per-
centage of glucose may be reduced or increased according to reaction. A
culture of acidophilic bacteria may be added.
Formula No. 2 supplies 700 calories, salts, vitamins and water 1,800
c.c., but no protein, as follows: 6 a. m., glucose 30 gm., strained juice of
half an orange, soda bicarbonate and salt of each 2 gm., water *300 c.e.
Repeat this at 10 a. m., 2, 6 and 10 p. m., and 2 a. m.
Precautions and Technic in Rectal Feeding
1. The rectum must be kept clean by a saline irrigation or
enema, once a day.
2. All food should be sterilized before injecting.
3. // the rectum becomes irritated, give a. rest of 6 to 8 hours,
or use only saline solution for a time.
814
HERBERT S. CARTER
4. Enemata should be given with the patient on the left side, or
with the foot of the bed raised on shockblocks, which are left in place
for an hour after the injection.
5. In certain cases of excessive peristalsis, it is necessary to use
o to 10 drops of deodorized tincture of opium in the enemata.
6. Injections should be given slowly, -the rectal tube lubricated
and passed not more than 6 to 8 inches, and the reservoir containing
the solution should not be more than 18 inches or two feet above the
level of the patient's back.
7. All fluids should be as nearly blood temperature as possible
on entering the rectum. This can be facilitated by placing an electric
light bulb in the reservoir and placing a hot water bag over the feed
tube just before it enters the rectum.
If the Murphy drip method is used, Kemp has devised a special heat
retaining bottle to use and has worked out the following table for deter-
mining the temperature:
Table of Temperature of
Fluid in Bottle
Length of Tube
Number of Drops
per Minute
Temp, in Rectum
190° F.
160° F.
150° F.
140° F.
30 inches
tl K
tl (I
« «
60
20 or less
40-50
150-200
115° F.
100° F.
100° F.
105°-110° F.
Summary of Results of Rectal Feeding. — 1. Only about 25 to 35
per cent of nourishment required to maintain nitrogenous equilibrium
and weight is absorbed per rectum.
2. Metabolism experiments show that even under the best of con-
ditions this method, although the best we have, results in subnutrition,
and is really semi-starvation.
3. As a practical method, it should not be relied upon to bring up a
patient's condition as, e. g., for an operation except where there has been
actual starvation as in a marked esophageal or' pyloric stenosis. It is a
false prop.
4. It is useful in tiding over short periods when from one reason o:
another it is necessary to give the patient water, salts, and some nouri
ment in the form of protein and carbohydrates.
5. Its usefulness is, therefore, limited, more so than many people
suppose.
Subcutaneous Feeding. — There are occasions when this form of feed-
ing would be of great value even for a few days if 'it could be done com-
fortably and efficiently, .but as yet it has not been possible to accomplish
this with any degree of satisfaction. Although considerable experimenta
tion has been done towards this end, at present the rectal method is mu<
815
more satisfactory and useful and the future will have to determine the
possibilities of subcutaneous feeding, although a, certain amount can be
clone in this way now. Any substance used must be capable of direct
assimilation, non-irritating and easy of sterilization.
Protein. — Protein has been used in many different forms, as egg
albumin, peptone, alkali albuminate and propeptones, but it was found that
all these forms of protein lead to severe local reactions — abscess formation
and breaking down of the tissues. Experimentally (&), it was found pos-
sible in dogs by small and repeated injections of skimmed milk peptonized
one and a half hours, to supply a certain amount of protein, the nitrogen-
ous balance showing a loss of only 0.3 to 0.5 gm. per day. These injections
were toxic and particularly so unless the dose was begun low and very
gradually increased, so that this form of protein is not practical and
should not be used. Ascitic fluid and blood serum have also been used
with better result and a certain amount of protein can be supplied and
made use of without toxic symptoms, although large doses were found .to
cause renal irritation. Blood serum contains practically 1 per cent
protein, and ascitic fluid 0.17 to 1 per cent, hence in order to supply
sufficient protein it would be necessary to give even on the basis of
Chittenden's low estimate of 0.12 gm. nitrogen per kilo daily, 840 to
4,200 c.c. of fluid for a man weighing 70 kg., depending on whether blood
serum or ascitic fluid was used, certainly too large an amount to be readily
obtained or used on account of mechanical objections. At the same time,
it is possible to use from 300 to 400 c.c. daily probably without detriment
to the organism, although the urine should be watched for signs of renal
irritation. In dogs, even large amounts were used and apparently utilized,
although there was always a negative nitrogen balance in two- or three-day
periods of from 0.04 to 4.35 gm. nitrogen; in starvation the balance being
for two days, 3.83 gm. nitrogen daily (Z).
When serum or ascitic fluid is aseptically drawn, it can be used safely ;
if there is any question it should be heated to 55° C., which makes it
opalescent, but does not coagulate it.
Horse serum heated to 65° C. in amounts of 100 to 120 c.c. was used
by Salter(w), who noted that the urinary nitrogen was increased. This,
however, is not an homologous serum and could not be used for nutritional
purposes without first testing the patient for serum reaction, and is not
suitable for hypodermic feeding.
Fats. — Fat injections have been tried in various forms but too few
accurate metabolic estimations have been carried out to place the matter
on a firm footing. Von Leube used subcutaneous oil injections 20 to 30
gm. at a time two or three times daily, and concluded that the oil was
absorbed and metabolized as evidenced by lowered excretion of nitrogen
in the urine. Absorption is very slow, and care must be taken not to
inject the oil into a vein which of course would result in fat embolism.
816 HERBERT S. CARTER
Mills(n), who has done much work on this, and presents the best historic;)]
resume of the subject, finds that -fats similar in composition to fats of
the body are best absorbed, emulsions better than plain oils, the best
being a 3' to 5 per cent emulsion o^f egg lecithin in sterile water. Sixty
grams of oil may thus be given slowly. He also used oils of lard, cocoanut
and peanut oil emulsified with egg lecithin, and proved that fats introduced
subcutaneously may be burned directly, sparing body fat, and may be
either retained in the body in their own form or may be reconstructed
into body fat.
Lard, according to Winternitz, can be given by subcutaneous injection,
but is of slight usefulness except in an emergency.
Carbohydrates. — The only form of carbohydrate which has been suc-
cessfully used has been dextrose. Voit(o) in 1896 found he could inject a
10 per cent solution without producing glycosuria, although it was too
painful a process, caused too much tissue infiltration and was not prac-
tical. Kausch used a 2 per cent solution, injecting as much as 1,000 c.c.
In an 8 to 10 per cent solution i^ was promptly excreted in the urine,
although it produced no renal irritation. It was also observed by him
that the poorer the patient's nutrition, the better was the sugar borne.
Gautier found he could use 60 to 80 gm. in 1,000 c.c. of sterile normal
saline solution, and that it was well absorbed; but this furnishes only
about 240 to 320 calories, which is not more than a fraction of the neces-
sary amount. A four and one-half per cent solution of dextrose is isotonic
with the blood, and would seem the best strength to use.
Salts and Water. — The hypodermic method of getting water* and salts
into the system has long been used with complete success and has formed
one of the easiest and safest ways of supplying these necessary elements
when the normal route is closed. This can be given as sterile normal saline
solution (0.6 to 0,9 per cent) or in the following solution, which forms
a more complete reproduction of the saline elements in normal serum:
Sodium Chlorid 0.9 gm.
Calcium Chlorid 0.026 "
Potassium Chlorid 0.01 "
Aq. destil 99.064 "
Taken then altogether, it can easily be seen that as yet the subcutaneous
method of maintaining nutrition is of minor importance and practically
about all that can be done is to supply a small amount of protein in the
form of blood serum or ascitic fluid (with a little emulsified fat given
separately?) and dextrose in a 4.5 per cent solution in normal saline.
The serum or ascitic fluid may prove of benefit eventually in treating
certain diseases, e. g., cholera where the loss of fluids and nitrogen is
excessive, care being taken to rule out the presence of syphilis or tubercu-
losis in the donor before using either ; but even here the" intravenous route
AETIFICIAL METHODS OF FEEDING 817
is better and more satisfactory. It must also be said that for short periods
the intravenous route is better for giving glucose solutions also.
Intravenous Feeding. — The intravenous method of giving medication
for varying conditions has come into vogue more and more, and is now an
established method of practice. The application of this principle to
supplying nourishment to the body is of very recent date, and a field of
usefulness has been opened that may be fruitful of very definite results.
There are certain dangers connected with this method that do not
obtain in other forms of artificial feeding and must be taken into account.
Embolism is a possibility, but is probably of slight moment with anything
like surgical cleanliness and is certainly a rare occurrence in giving medica-
tion. Overfilling of the blood vessels is another potential danger, and
with a weakened heart muscle must be kept in mind, and the amount in-
jected into the vein carefully regulated as to speed of introduction and
total quantity used.
INDICATIONS. — The chief indications for this form of feeding may be
summoned up as follows: 1. When all other routes are closed. 2. In
conditions of severe acidosis. 3. In severe acute infections. 4. To pro-
duce massive diuresis. The last three indications are to meet medical
rather than nutritional demands.
Protein. — The use of protein by the intravenous route, except in the
form of serum, is still in the experimental stage and no reference can be
found in recent literature bearing on the subject, Woodyat reports that
he and his collaborators have been doing experimental work with proteins
but is not yet ready to publish it. It would seem a simple matter to supply
protein in a limited way intravenously by using human serum, but the
difficulty would naturally arise in securing a supply to carry on the food
requirements. Horse serum could be used for a short time, provided the
individual was not sensitive to it. The process is still in a speculative and
experimental stage with as yet no definite solution of the problem of
supplying easily the protein requirements of the body by this method.
Fat. — From what is known of fat embolism it would seem that the
giving of fat by the intravenous route was pretty definitely precluded, and
although a 3 per cent lard emulsion has been used experimentally in ani-
mals, it is not without danger and should not be used in man.
Carbohydrates. — Again, as in the rectal and subcutaneous methods of
feeding, carbohydrate in the form of dextrose is the most easily used and
readily absorbed and forms, so far, the only important constituent of this
method of artificial nutrition.
Woodyat, Sansum and Wilder, by means of a special apparatus, de-
scribed in the Journal of Biological Chemistry, tested glucose tolerance by
intravenous injection, and showed that by delivering it at a uniform rate
of speed in 10 to 50 per cent solutions, a rate closely corresponding to 0.85
gm. of glucose per kilo of body weight and hour of time, for from six to
818 HERBERT S. CARTER
twelve hours, it was possible to give such solutions without producing
glycosuria or diuresis. The following conclusions were drawn from these
experiments :
1. A man weighing 70 kg. may receive and utilize 63 gm. of glucose
by vein per hour without glycosuria, which equals 252 calories per hour
or 6,048 calories per day, which is about twice his resting requirements.
2. This is in accordance with Blumenthal's conclusions in animal
experiment by repeated small doses.
3. These experiments discredit the idea that the 'glycogcnic function
of the liver is indispensable for the utilization of sugar.
4. The theory that any large amount of glucose given by vein always
causes glycosuria and diuresis must be given up.
5. The tolerance limit of levulose was 0.15 gm. per kilo the hour;
galactose about 0.1 gm. ; lactose practically zero.
6. When glucose is given intravenously faster than 0.9 gm. per kg.
the hour, glycosuria appears, then later, diuresis, these are all of practical
importance.
7. If given faster than 0.85 gm. per kg. the hour, "the unburned
glucose begins to accumulate in the tissues and pass out chiefly in the
urine and carries water with it," extensive diuresis resulting.
To make 12.5 gm. glucose pass out of the body via the kidney at
least 100 c.c. of water is necessary ; if too much water is given, there is
danger of mechanically stopping the heart.
In the practical application of these conclusions to intravenous feed-
ing, it would seem unwise and unnecessary to try to supply the limit of
the body tolerance 0.85 gm. per kg. the hour, and that the most that can
be done is to furnish a fraction of this limit, enough to partially spare
the protein destruction, and prevent marked acidosis. To furnish not
over one-half the caloric needs of the body at rest, e. g., for a man of
70 kg., using an isotonic glucose solution (4.5 per cent), it would be
necessary to give 305 gm. glucose in 24 hours, using 6,800 c.c. of the
solution, altogether too large an amount even if divided up into two or three
injections. If a 10 per cent solution were used, it would require 3,050 c.c.,
and if given at the rate of 63 gm. per hour, it would require 4.8 hours to
give. This, of course, could be done, but could not be kept up for more
than a few days (even dividing the dose into three of 1.6 hours for
each dose) on account of the inability to use the veins over and over
again. So far as using the special pump described by Woodyat goes,
this would hardly be practical in humans, but the solution could
be given from an irrigator kept warm by a jacket, and warming
the solution just before it enters the vein by passing the tube under a
hot water bottle, using about 180 drops per minute. The same rate of
How and temperature curve could be used as recommended in Kemp's
table (see rectal feeding, p. 814). The solution in which the glucose ia
ARTIFICIAL METHODS OF FEEDING
819
dissolved should be a normal 0.9 per cent saline, freshly distilled and ster-
ilized. This, of course, furnishes 110 protein and the patient would have
to burn his own protein, although a certain amount would be spared on
account of the glucose. Whether later it will be found possible to incorpo-
rate blood serum or some form of amino-acid compound to supply the
protein of the diet must remain for future investigation. Intravenous
feeding must at best be only for very temporary use in exceptional cases.
The use of glucose solutions for the other demands mentioned will be
found under their appropriate heading in Diabetes Mellitus, Acute Infec-
tions, and Renal Disease, q. v.
Transfusion of Blood . . George R. Minot and Arlie V. Bock
Introductions—General Effects of Anemia on the Body — Beneficial Effects of
Transfusion — The Effect upon the Oxygen Capacity of the Blood — The
Effect upon the Blood Volume — The Effect upon the Factors of Coagu-
lation— The Effect upon Blood Regeneration — The Effect upon Immune
Bodies — The Effect upon the Basal and Nitrogen Metabolism — The
Effect upon the More Immediate Symptomatology — Indications for
Transfusion — Conditions in Which Transfusion is a Necessity — Con-
ditions in Which Transfusion is Of ten 'Desirable — The Amount of Blood
to be Transfused — The Choice of a Donor — Reactions from Transfusion
— Reactions Due to Recognized Incompatibility — Reactions Not Due to
Recognized Incompatibility — Methods of Transfusion.
Transfusion of Blood
GEORGE R. MINOT
AND
ARLIE V. BOCK
BOSTON
I. Introduction
Transfusion of blood is a standard therapeutic measure. Its useful-
ness has outgrown the older conception that it is only an emergency opera-
tion. Holtz has traced the history of transfusion back to Cardanus' work
in 1556. The simplification of transfusion methods has made it possible
for those not particularly trained in surgical technic to transfer blood
from one individual to another, while the possibility of avoiding hemolysis
by preliminary tests has eliminated the chief risk. In spite of these facts,
the majority of physicians still regard transfusion as a formidable opera-
tion. It is our purpose here to discuss the transfusion of blood from
different aspects, especial emphasis being placed upon the physiological
principles that form the basis for its use in therapeutics.
II. General Effects of Anemia on the Body
In order to appreciate some of the effects of transfusion in cases of
anemia it is desirable to consider briefly certain disturbances which occur
when there is a diminished amount of circulating hemoglobin in the body.
In general, it may be said that anemia impoverishes the functions of all
the organs of the body and produces certain deleterious changes. Well
known clinical manifestations indicate the existence of the condition.
These vary according to the degree of the anemia, but they may include
dyspnea, palpitation, gastro-intestinal disorders, disturbance of kidney
function, symptoms referable to the central nervous system, and, in
extreme cases, complete prostration may result. The latter condition is
often regarded as cardiac failure, the underlying anemia having been
overlooked.
Very little definite knowledge is at hand to show the relation of such
clinical manifestations to altered function of the body. Strauss (6), quot-
821
822 GEOKGE K. MINOT AND ARLIE V. BOCK
ino- the work of Von Noorden, Krause, Ribbert, an$ others, states that the
fatty infiltration and degeneration of tissues occurring in chronic anemia
is an indirect result of the low hemoglobin content of the blood. He
assumes that the excessive effort of the tissue cells to procure oxygen
from the anemic blood produces such an alteration in the cells as to
predispose them to fatty infiltration. Until recently the only available
metabolic observations in anemia were those made upon scattered cases by
various observers, and those which concern the effect of acute hemorrhage
in animals. Xo precise agreement in either series of observations is
apparent. There often has been found in anemia of all types a negative
nitrogen balance, usually not great. The notable exceptions to this finding
occur in the work of Von Xoorden, Goldschmidt, and his associates, Mosen-
thal(d) and Minot(a). The problem of nitrogen excretion after hemor-
rhage in normal animals is somewhat different, but Haskins and others
have found an increase in protein metabolism which is only temporary.
Studies of basal metabolism in anemia have also shown great varia-
tions. Anemia does not necessarily result in a sluggish metabolism, since
the demand for oxygen may be somewhat greater than in health. Meyer
and DuBois determined, the metabolism in five cases of pernicious anemia
and found an increase of from 2 per cent to 33 per cent. Tompkins,
Brittingham and Drinker have shown that the basal metabolism in anemia
may vary within normal limits, or be above or below normal. Although
they found no close parallelism between the degree of anemia and the basal
metabolism, they concluded that the cases of anemia with acute symptoms
have a high metabolism while the chronic cases have a diminished oxygen
consumption. Zuntz(.fr) and his associates showed that muscles poorly sup-
plied with oxygen are functionally less efficient. Accessory muscles are
therefore called upon for the accomplishment of any task, as in respira-
tion, thus increasing the demand for additional oxygen, a factor which
may account for part of the increased metabolism in some cases, according
to Meyer and DuBois. Lusk(/i) expresses the view that the general oxida-
tion of the body is normally maintained in anemia provided the anemia
is not of extreme severity, and that lack of oxygen renders the anemic
individual incapable of great muscular work without quick exhaustion.
In view of the fact that in anemia the body suffers from decreased
function of many organs, and in view of the possibility of a normal or
augmented metabolism in the presence of anemia, the question arises as
to how the oxygen requirements of the body may be met. Certain phe-
nomena may be mentioned which may for long periods of time partially
compensate for the oxygen deficit. These are increased rate of blood flow,
increased ventilation by the lungs, and increased utilization of oxygen
in the blood. Often the immediate purpose of transfusion is to relieve
the body of these excessive compensatory efforts and thus to restore normal
function.
TRANSFUSION" OF BLOOD 823
III. Beneficial Effects of Transfusion
Whatever the purpose for which transfusion may be done, there are
various beneficial results to be obtained by the procedure which may be
enumerated before a discussion of them is undertaken. They are as
follows: 1. The effect upon the oxygen capacity of the blood. 2. The
effect upon the blood volume. 3. The effect upon the factors of coagula-
tion. 4. The effect upon blood regeneration. 5. The effect upon immune
bodies. 6. The effect upon the basal and nitrogen metabolism. 7. The
effect upon the more immediate symptomatology.
1. The Effect upon the Oxygen Capacity of the Blood. — One of the
chief objects of transfusion is to increase the power of the recipient's blood
to carry oxygen. In normal blood the total oxygen capacity which depends
upon the hemoglobin content of the corpuscles is about 18.5 volumes per
cent. After acute hemorrhage or in severe anemia this figure may be
reduced to one-fourth or one-fifth of the normal, and in such conditions
it is obvious that more hemoglobin must be introduced into the circulation
in order to avoid oxygen starvation of the tissues. This can be done only
by giving red corpuscles for which there is no known substitute.
In the resting normal individual the venous blood returns to the heart
with a reserve oxygen supply of 12 to 14 volumes per cent. In a state of
grave anemia, however, as Lundsgaard(e) has pointed out, the tissues may
demand the last residuum of available oxygen from the blood, just as
readily as the first part, and the blood may return to the heart in a
nearly completely asphyxiated state. At the present time there are no
%-ures showing complete asphyxiation of venous blood in man, but the
blood of many cases of severe anemia closely approximates this condition.
Pfliiger and Voit also showed that the demand of the tissues for oxygen
was independent of the supply. The reduction of the oxygen combining
power of the blood may be so great in extent that the ordinary compensa-
tory factors may not be sufficient to maintain the internal respiration
of the body even in a completely resting individual. A condition of this
nature is perhaps most often seen in pernicious anemia in which the
occurrence of great prostration and tissue changes of serious extent form a
familiar clinical picture. What may be immediately accomplished in
such a patient is illustrated in Table I, in which is presented the data
of a case before and after transfusion of 600 c.c. of blood, together with
the oxygen figures for the blood of a normal individual for compari-
son.
In contrast to a normal oxygen reserve of 12 to 14 volumes per cent,
this patient had less than two volumes per cent which accounts for his
complete physical disability. The longer an individual remains in such a
condition the greater the irreparable damage to body structure. Thus if
824
GEOEGE R. MINOT AND AKLIE V. BOCK
TABLE I
Diagnosis
Red
Count
in
Mil-
lions
Pulse
Rate
per
Min-
ute
Blood
Press,
in mm.
Hg
Arterial Blood
Venous Blood
Hemo-
globin
Oxygen
Cap. in
Vol. %
Oxy-
gen
Cont. in
Vol. %
Oxy-
gen
Cap.
in
Vol.
Oxy-
gen
Cont. in
Vol. %
Pernicious Anemia
After Transfusion
0.82
1.5
4.5
112
100
72
100/50
110/50
128/80
4.42
19.6
4.20
18.5
4.42
6.67
19.6
1.95
2.45
11.96
23.8
36.
106.
A normal man
transfusion is decided upon in cases of chronic anemia the procedure
should not be postponed for weeks to see first if the patient will not regen-
erate some of his own blood. After this case had received 600 c.c. of blood
the increase in hemoglobin was equal to 50 per cent of the amount in the
circulation before transfusion. Even so, the total hemoglobin remains
only one-third of the normal. Though this amount of hemoglobin is in-
sufficient to enable the organs of the Body to function well, it permits them
to act distinctly better than with the amount of hemoglobin present before
transfusion. In fact, it is rather striking that a slight elevation of the
hemoglobin level will often largely remove the symptoms of anemia.
The actual increase per c.c. of blood in the number of red corpuscles
after transfusion depends upon such factors as the amount of blood trans-
fused, the amount of plasma in the recipient's circulation, the degree of
anemia present and certain unknown factors among which may be a
possible redistribution of blood, as Huck has suggested. When about
600 c.c. of blood is given, the usual increase in the number of corpuscles
is from 200,000 to 700,000 per c.mm., and the hemoglobin is increased
within a range of 5 to 20 per cent. There may not be a very close rela-
tionship between the increase in the number of corpuscles and the per-
centage increase in hemoglobin. Rarely, after transfusion, no increase in
red corpuscles can be demonstrated by counts.
The beneficial effect of the transfused red cells in increasing the oxygen
carrying capacity of the blood must be regarded as only temporary. This
is because they do not remain indefinitely in the circulation of the re-
cipient. According to the work of Ashby the life of transfused corpuscles
may be as long as thirty days and under certain conditions even much
longer. Previous work has suggested that 10 per cent of the red
corpuscles are destroyed daily. Though the transfused red cells them-
selves increase temporarily the oxygen carrying capacity, transfusion will
often tide the patient over a period of time until he can furnish enough
cells to serve satisfactorily the functions of the body.
In considering the necessity for transfusion, emphasis usually is to be
placed upon the hemoglobin content of the blood. Fluid substitutes for
TKA^SFUSION OF BLOOD 825
blood have their uses but they cannot take the place of blood if increased
oxygen carrying power is needed.
2. The Effect upon the Blood Volume.— In most conditions for
which transfusion is indicated, a diminished volume of circulating blood
usually exists, either by reason of a mechanical reduction in the whole
blood, as after acute hemorrhage, or on account of a diminished content
of red corpuscles which is associated with most types of anemia, Keduc-
tion of the plasma volume, may occur following blood loss, and in other
anemias when the hemoglobin is below 30 per cent. Transfusion of blood
after a severe hemorrhage may help to restore the plasma volume to about
its normal figure but the total blood volume may not be regained except
through regeneration of corpuscles unless it is made up by repeated trans-
fusions. Hypertransfusion should be avoided because of the possibility of
bone marrow depression, as demonstrated experimentally by Kobertson(c).
In chronic anemia, in contrast to acute anemia due to blood loss the
volume of the plasma is usually not abnormal if the patient has a normal
fluid intake. When transfusion is undertaken for such a condition, the
only gain in total blood volume is due to the addition of corpuscles.
Under such a circumstance the plasma of the transfused blood rapidly
leaves the circulation for the tissues. This consideration is an important
one, since it shows that alterations in the blood volume in anemia are
almost wholly dependent upon variations in the total mass of corpuscles,
as discussed by Bock. There is no method of increasing the total blood
volume in chronic anemia except by the addition of corpuscles.
3. The Effect upon the Factors of Coagulation. — In the various
forms of purpura hemorrhagica there occurs a deficiency in the number
of blood platelets which is associated with the pathologic hemorrhage
frequently encountered in these cases. In hemophilia, as Minot and
Lee (a) have shown, there occurs a qualitative deficiency of the blood plate-
lets. In other conditions in which pathologic hemorrhage occurs, there are
often unknown alterations in the physical chemistry of the blood which in-
terfere with normal clot formation. This may be due to an upsetting of the
balance of prothrombin and antithrombin as, for example, by a decrease
of the former or increase of the latter substance, or there may be a de-
ficiency of fibrinogen or some other not well recognized alteration. The
only truly efficient way of remedying a defect in one or more of the
factors that promote clotting, is by transfusion of normal blood which
contains all of the factors. It is to be recognized that serious bleeding
associated with a deficiency in the numbers of platelets, does not occur
until these elements have been reduced from their normal number of about
300,000 to 60,000 per c.mm. or below. If a liter of normal blood is trans-
fused the platelets will be increased in the recipient's blood by about
70,000 per c.mm. Thus, when transfusion is necessary to stop bleeding
due to a deficiency of platelets, a large amount of blood should be given
826 GEOKGE K. MINOT AND ARLIE V. BOCK
iri order to restore a sufficient number of platelets to prevent spontaneous
bleeding. It is, however, probable that other elements in the blood assist
to check a hemorrhage particularly associated with a deficiency or a defect
in the platelets.
The duration of the life of the platelets is but a few days in contrast
to the longer life of the red corpuscles. Thus if a patient does not make
up some of his platelet deficiency within 3 to 5 days following a trans-
fusion for such a defect, one must anticipate, a recurrence of the spon-
taneous hemorrhage. Hence further transfusion will be necessary if it is
desired to continue to check the bleeding. In hemophilia, in contrast to
the various forms of purpura hemorrhagica, hemorrhage is not spontaneous
but follows as a result of trauma, though this may be exceedingly slight.
In order to check a severe hemorrhage in hemophilia, enough blood should
be given to reduce the clotting time of the patient's blood to approximately
normal. By means of such a procedure, hemorrhage is checked and thus
the bleeding point allowed to close. Later, as the transfused platelets
disappear from the circulation, the clotting time of the hemophiliac's blood
again becomes abnormally prolonged. Hemorrhage does not recur unless
the external or internal' wound has not healed sufficiently. Hemorrhage
will of course recur when there is sufficient further trauma. Transfusion
may also be undertaken in hemophilia to prevent bleeding when operation
has to be performed. Under such conditions it may be desirable to remove
some blood before the normal blood is injected.
In Table II is shown the effect of transfusion on the blood of a hemo-
philiac in whom rather severe bleeding was to be anticipated from the
extraction of teeth, if no normal blood had been given.
The foreign blood, with its normal platelets, held the clotting time of
the patient's blood, with its qualitatively defective platelets, close to
normal for enough time to permit primary healing of the wound.
In hemorrhagic disease of the newborn, the effect of transfusion is,
in a very high percentage of the cases, very striking, for here it seems
that normal blood is capable of doing more than tiding a patient over a
critical period. Following adequate transfusion in such cases there nearly
always occurs a permanent correction of the blood defect which is associ-
ated with a prolonged coagulation time and prothrombin time. To ac-
complish this result it may be necessary to give several doses of blood,
but frequently 40 c.c. suffices.
In other conditions in which pathologic hemorrhage occurs due to
recognized or unrecognized blood defect, the principle outlined above
applies, namely, that if transfusion is to be used, enough blood, which will
furnish all the factors for coagulation, must be given to accomplish the
desired result,
4. The Effect upon Blood Regeneration. — When the bone marrow
is functioning deficiently, an increase in its regenerative activity often
TRANSFUSION OF BLOOD
827
TABLE II
Date
Coagulation
Time in
Minutes *
Transfusion
Remarks
May 1
10 A M
60
Slight bleeding from about carious teeth
10.30 A.M.
1000 c.c.
11 30 A M
10
Teeth reipoved — no abnormal bleeding
May 2
15
No bleeding
May 3
10 A.M.
20
Slight bleeding
11A.M.
500 c.c.
11.30A.M.
8
No bleeding
May 4
15
No bleeding
May 5
20
No bleeding
May 6
30
No bleeding
May 7
50
No bleeding
May 8
65
No bleeding
1Time required for 1.5 c.c. of venous blood to clot in a test tube 8 mm. in diameter.
Upper limits of normal 15 min.
occurs following transfusion. This may be due to a direct or indirect
effect of the transfused blood. Increased bone marrow activity may be
manifested not only by increases of young red cells but increases also of
platelets and marrow white cells above a level due to the transfused blood.
In other instances, when the regeneration is not so rapid, significant in-
creases of young red cells do not occur, but the platelets and marrow white
cells remain at a higher level than before transfusion. If a suitable for-
mation occurs the count of the red cells remains elevated and increases
while the transfused cells gradually cease to exist in the circulation. Such
a picture indicates that the bone marrow elements are being delivered into
the circulation at a desirable rate.
Alteration in the white count following transfusion may be associated
with a mechanical redistribution of the blood in the same manner as the
red cells. Thus, elevation of the white count does not necessarily indi-
cate a general increase of bone marrow activity. A sharp leukocytosis
following transfusion may be only a further manifestation of a reaction
due to the foreign blood, as described on page 840, rather than a sign
of general marrow activity. Still the degree of leukocytosis indicates
roughly the ability of the marrow to produce blood even though the
transfusion may not be followed by an increase of blood production. Al-
terations in the platelets may occur after transfusion in a similar manner.
828 GEOKGE K. MINOT AND ARLIE V. BOCK
However, if both the platelets and marrow white cells increase in number
and remain elevated after transfusion, these rises should be interpreted
as evidence of increased marrow activity. With increased regeneration
the platelets usually begin to increase in number slightly later than the
white cells. With an orderly increased activity of the marrow such as
may occur in pernicious anemia, the reticulated red cells (young cells)
begin to increase still later — that is, in about three to five days.
The response of normal bone marrow to the stimulus of hemorrhage
is more rapid and proceeds more uniformly with respect to all of the blood
elements than may be seen after transfusion in cases having pathological
bone marrow. There may occur with regeneration of blood, with or with-
out transfusion, a distinct qualitative change in the process of regeneration
such as a disproportionate output of platelets, or of young red corpuscles,
in relation to the other elements produced by the bone marrow. If the
marrow is aplastic the response to transfusion may be very feeble or more
often does not occur. Distinct inactivity or depression of the bone marrow
following transfusion is a bad prognostic sign. Likewise the presence
in the peripheral blood of very large numbers of immature marrow cells
of the red and white series is unfavorable and indicates what may be
termed a dissolution of the marrow. For a further discussion of the
question of bone marrow activity, reference may be made to the work of
Drinker, Vogel and McCurdy, and Minot and Lee.
5. The Effect upon Immune Bodies. — Theoretical considerations
have led to the use of transfusion for the transfer from one individual
to another of immune bodies, particularly for the treatment of disease.
Experience up to the present is variable in character and, for the most
part, disappointing.
In sepsis the supportive effect of fresh blood has long been thought to
be beneficial, but in practice little good has been accomplished by such
therapy, probably because normal blood has less bactericidal power than
the blood of the patient. Wright and Colebrook have recently sug-
gested a method of "immuno-transfusion" for cases of sepsis, in which the
blood to be transfused may be rendered bactericidal in vitro, and then
injected into the circulation of the patient. The vaccine used for this
purpose need not be specific. The blood transfused in a case reported
by Wright and Colebrook was thus immunized against the patient's strep-
tococcus ; the protective action of the serum against the patient's organism
was previously demonstrated by a simple laboratory study. A cure re-
sulted in this case in which operative and other therapeutic measures
had failed.
6. The Effect upon the Basal and Nitrogen Metabolism. — Trans-
fusion of blood in cases of anemia, according to Tompkins, Brittingham
and Drinker reduces the basal metabolism to a normal or diminished level.
They suggest that the basal metabolism may serve as a guide in knowing
TRANSFUSION OF BLOOD 829
when to push transfusion in the treatment of anemia, and when little may
be expected from the procedure. For example, if the metabolism is
minus 10, only temporary comfort to the patient is to be expected. If
the result is plus 10 more will be accomplished by transfusion. Trans-
fusion provides relief for certain compensatory phenomena such as in-
creased pulse rate and increased ventilation of the lungs, but the demand
of the tissues for increased oxygen may continue for days after the trans-
fusion. Transfusion is regarded by these authors as a measure by which
early cases of pernicious anemia may be assisted toward a remission.
Studies at the Massachusetts General Hospital, yet incomplete, tend to
show that the basal metabolism is not always indicative of what trans-
fusion will accomplish in anemia.
Little is known as to the effect of transfusion upon nitrogen metab-
olism. Mosenthal(c?) found a lowered nitrogen balance after transfusion,
owing to the output in the urine of the nitrogen contained in the trans-
fused blood. In dogs, Haskins(a) found that transfusion after hem-
orrhage does not prevent the destruction of protein which occurs as a result
of hemorrhage.
7. The Effect upon the More Immediate Symptomatology. — Symp-
tomatic improvement following transfusion depends not only upon the
cause of the anemia but also upon the state of the patient The greatest
clinical change is seen in patients transfused after sudden loss of much
blood. The usual signs of restlessness, rapid pulse, increased respiration
and sweating, are improved at once or entirely relieved. A general sense
of well being is substituted for a state of anxiety, and a condition of
doubtful outcome may be changed at once to one having a favorable prog-
nosis. The improvement is due to a number of complex factors, chief
among which is the increased efficiency of the circulation as manifested
by higher blood pressure in certain cases, slower pulse rate, and increased
oxygen carrying power of the blood.
The more immediate symptomatic improvement in chronic anemia is
not so pronounced, owing to structural changes in the body and to the
probable persistence of the cause of the anemia, toxic or otherwise.
Weakness, palpitation, dyspnea, and visual and auditory disturbances
are often relieved. If fever is present due to the blood condition, the
temperature may subside after transfusion. Improvement of appetite and
diminution of gastrointestinal symptoms frequently occur shortly after
transfusion, especially in states of chronic anemia. Although achylia
may persist in pernicious anemia the stomach distress present before
transfusion may entirely disappear afterward. Troublesome diarrhea
occasionally met with in pernicious anemia may also be controlled. It has
been shown that the kidney function is deficient in chronic anemia, and,
among other benefits that result from transfusion is improvement in the
functional state of the kidneys.
830 GEOKGE E. MINOT AND ARLIE V. BOCK
IV. Indications for Transfusion
No detailed account of all of the conditions for which transfusion is
indicated will be undertaken here. In a general way they belong to two
groups, namely, conditions in which transfusion is an absolute necessity
in order to save life and conditions in which the procedure may be desii
able either for the comfort of the patient or to shorten convalescence.
1. Conditions in Which Transfusion is a Necessity. — The usus
conditions in which transfusion may be obligatory in order to save life
are hemorrhage and shock. Since moderate or severe hemorrhage is always
accompanied by a state of shock, these two conditions may present the
same indications for treatment. They have in common diminished blood
volume and low blood pressure, both of which may be corrected, at least in
part, by transfusion. In the case of hemorrhage, danger to life lies not so
much in the extent of hemorrhage as in sudden loss of blood. The latter
may result in a rapid fall of blood pressure to a dangerous level, a state in
which the tissues of the body are deprived of oxygen owing to the failure
of the circulation. Keith has shown that the blood volume in shock, not
complicated by hemorrhage, may be diminished to the same extent as in
hemorrhage. In such a. condition the body may not survive for more
than a brief period unless energetic measures are taken to increase the
volume of the circulating blood, which in turn reacts favorably upon the
blood pressure. Fluid substitutes for blood, such as gum-saline, may
serve to restore the circulation and may be used instead of blood when
the blood loss has not been too great. In shock gum-saline is highly useful
if it is used soon after the advent of the condition. However, if such a
fluid is not available, normal salt solution may temporarily tide a patient
over a brief period of time until transfusion can be carried out.
The criteria upon which to judge the condition of the patient are blood
pressure readings, hemoglobin determinations and pulse rate, as has
been discussed by Robertson and Bock. A very low systolic blood pressure,
TO mm. of mercury for example, after acute hemorrhage, or in shock,
usually means a great diminution in blood volume. Subsequent blood
pressure determinations are important to note whether the reaction of
the patient is favorable or not. For example, a rising blood pressure is a
good prognostic sign. A single hemoglobin estimation, especially if made
soon after hemorrhage has occurred, is of little significance. It is im-
portant to know whether subsequent hemoglobin readings at hour inter-
vals are the same or steadily becoming lower. A flow of fluids from the
tissues to the circulation, or internal transfusion, as Gesell has called it,
will dilute the hemoglobin, and if this does not fall below 30 per cent,
transfusion is not urgent though it may be advised. Cases of hemorrhage
and shock in which the hemoglobin remains at a stationary figure for sev-
TKANSFUSION" OF BLOOD 831
eral hours are almost always fatal, even with repeated transfusions.
Large amounts of fluids administered by the alimentary tract may often
accomplish the purpose for which transfusion or infusion seems indicated.
Xo absolute indication for transfusion exists so far as oxygen need is
concerned, as long as the hemoglobin remains above 30 per cent. There is
abundant evidence to show that animals, after bleeding to as low as 25
per cent of hemoglobin, will survive providing the fluid volume of the
blood is maintained by intravenous injection of fluid substitutes for
blood. In case the hemoglobin is below 30 per cent transfusion should
be looked upon as a necessity and not as a matter of choice. Life itself
may be immediately endangered, other things being equal, only when the
blood contains less than about 30 per cent of hemoglobin.
As has been mentioned, transfusion may be necessary to control hemor-
rhage due to pathological blood defects such as occur in hemophilia, hem-
orrhagic disease of the new born, and other hemorrhagic conditions. It is
reiterated here that it may be necessary to transfuse more than once to
control hemorrhage of this type. Often in hemorrhagic conditions, trans-
fusions also must be used in a preventive manner when operation becomes
necessary.
2. Conditions in Which Transfusion is Often Desirable. — In the
group of conditions now to be discussed transfusion of blood may be done
to improve the general state of the patient though the procedure may not
be a life-saving one. The articles by Pemberton, Garbat, McClure and
Dunn, Lewisohn, Lindeman, Ottenberg and Libman, Bernheim, and
Minot, among many others, consider this aspect of transfusion.
Transfusion in pernicious anemia has been discussed by Anders,
and Lee (6), and many others. It is generally agreed that trans-
fusion in this disease helps to bring about remissions which probably would
not otherwise occur. It appears to make remissions about 10 per cent and
perhaps 20 per cent more frequent. It undoubtedly often adds greatly to
the comfort of the patient. While remissions may be favored by trans-
fusion, the natural course of the disease is not altered by such treatment.
Transfusion probably should be employed before the stage of great
anemia and prostration has developed. The gradual failure of an adequate
oxygen supply to the tissues is always critical because of the transforma-
tion of normal tissue to fat and water. Good results cannot be expected
from any measure of therapy after such changes have occurred in the
body. The value of transfusion in pernicious anemia at present is based
for the most part upon its use in the treatment of cases in the stage of
prostration due to such tissue changes. It is important that the diagnosis
of pernicious anemia should be made early, and the cases transfused
while the hemoglobin is still at a relatively high level in order to attempt
to forestall the inevitable results of anemia. A detailed discussion of
transfusion in this disease cannot be entered into here, as it is not our
832 GEOKGE K. MINOT AND AKLIE V. BOCK
purpose to discuss the treatment of pernicious anemia. One must consider
the probability of remission as told by the history of the case, the character
of the blood, etc., as well as the desires of the patient and his family when
considering transfusion in this disease.
In other, forms of chronic hemolytic anemia transfusion may be used
similarly as in pernicious anemia. However, it is possible that in a case
with increased blood destruction transfused corpuscles may perhaps re-
main in the circulation a shorter time than when a normal amount of
hemolysis is occurring. For this reason, among others, in some forms
of hemolytic anemia, such as chronic hemolytic jaundice, splenectomy is
the best treatment and transfusion then may be used to improve the con-
dition of the patient for operation.
In anemia from blood, loss both acute and, particularly from chronic
types, in which no emergency exists for transfusion, remarkable results
may follow the use of this therapy. In addition to an increased output
of corpuscles from the marrow, a definite permanent alteration of the color
index of the corpuscles has been noted, in that the hemoglobin content per
corpuscle seems definitely increased. '' In such cases transfusion restores the
patient to health considerably sooner than with any other method of ther-
apy. In cases of chronic anemia due to blood loss, when the bleeding has
been stopped, the marrow may regenerate very sluggishly. Transfusion
enables such patients, who may be chronic invalids, to regenerate blood
and regain health often months earlier than without such treatment.
Single and often repeated transfusion is also of value in aiding a
return to normal in other forms of chronic anemia, particularly if the
cause has been removed, or if it is anticipated that transfusion will
diminish the activity of the cause. A striking example of the effect of
many transfusions, when the cause of anemia has been removed, is seen
in severe benzol poisoning. This poison tends to produce aplasia of the
marrow and the resulting clinical and blood picture is that of aplastic
anemia with secondary purpura hemorrhagica. When the influence of the
poison is removed the blood may return to normal. However, in the severe
cases the trap seems to be sprung so far that the marrow is unable to re-
generate at the moment enough blood to maintain life. In some such
cases repeated transfusion performed about as often as bleeding recurs,
permits the patient to live during the time the marrow regenerates to a
point at which it can supply sufficient blood elements to maintain satis-
factorily the needs of the body.
In idiopathic aplastic anemia transfusion appears to result in only
temporary benefit, for, unlike the cases of benzol poisoning, the unknown
cause is not removed.
Besides the use of transfusion to stop hemorrhage and to prevent its
occurrence at operation in a patient having a hemorrhagic disease, repeated
transfusions may be used in certain conditions to accomplish the same
TRANSFUSION OF BLOOD 833
results as in benzol poisoning. Cases of acute idiopatkic purpura nemor-
rhagica best illustrate this. Here repeated transfusion checks hemorrhages
and supplies red corpuscles, and in so doing the transfused corpuscles may
keep the individual alive until the unknown cause diminishes so that the
platelets can return to normal as sometimes occurs. In cases of secondary
purpura hemorrhagica, and other hemorrhagic states, where the cause can-
not be removed, no real benefit can be anticipated from repeated
transfusion.
Transfusion also finds valuable use in improving the condition of the
patient with anemia before operation is undertaken, even though the
anemia is not great. Ottenberg and Libman, among others, have com-
mented on the value of transfusion preparatory to operative procedures.
Transfusion has been .used to combat sepsis and toxemias such as
eclampsia, but no definite beneficial results have been obtained.
From time to time transfusions have been reported for the cure of
carbon monoxid poisoning, but there is almost no evidence forthcoming
to show that transfusion is beneficial in this condition. Crile and Lenhart
found that transfusion was the most efficient therapy in the restoration
of dogs overcome by carbon monoxid gas, but clinical results have not met
with the same success. Henderson has summarized our present knowledge
concerning the effects of carbon monoxid as follows: It is a physio-
logically harmless gas except in its affinity for hemoglobin, and its toxic
effects are entirely due to the inability of the blood combined with carbon
monoxid to transport oxygen. Hemoglobin has a very great affinity for
carbon monoxid, but the combination is not a permanent one and is rapidly
broken up in the presence of oxygen or pure air. Injury resulting from
this gas occurs during the time in which the patient breathed carbon
monoxid. When placed in an atmosphere of pure air almost all of the
carbon monoxid is eliminated from the body within a period of one to
three hours, if recovery is to occur. Transfusion cannot repair the injury
caused by this gas. The treatment consists mainly in fresh air and symp-
tomatic measures. However, in some instances transfusion may be very
beneficial, as suggested by Lindeman's case.
In other conditions, such as nitrobenzene poisoning, there occur other
forms of altered hemoglobin than CO-hemoglobin, namely, methemoglobin
and NO-hemoglobin, which prevent oxygen from being transported. The
amount of these abnormal forms of hemoglobin may be so great that ex-
treme cyanosis is present and less than 30 per cent of oxyhemoglobin re-
mains. Under such conditions transfusion may be required. Usually
with the formation of altered hemoglobin the patient's condition is not
severe enough to require transfusion. Cases of nitrobenzene poisoning
show a surprising tendency toward spontaneous recovery when the source
of the poisoning is removed, as is the case in CO poisoning. However,
we have seen death occur from the effects of this substance and others,
834 GEOKGE K. MINOT AND AELIE V. BOCK
as Dona'von, have reported the same result. Two cases of nitrobenzene
poisoning that we have personally observed had their oxyhemoglobin re-
duced to 30 per cent and 35 per cent, respectively. Both recovered with
transfusion.
V. The Amount of Blood to be Transfused
It is generally agreed that a donor may give blood up to one quarter
of his blood volume without serious discomfort. A man weighing TO
kilograms has a blood volume of about 5,500 c.c., hence blood may be taken
from him for purposes of transfusion up to about 1,300 c.c. It is seldom
necessary to use such a mass of blood for transfusion, but it may be helpful
to have in mind the limit of safety for the donor. This limit varies
directly with the body weight.
What constitutes a proper amount of blood to be given for the different
conditions in which transfusion is indicated has been suggested by various
authors as a result of clinical experience. It has not been possible to
make definite quantitative measurements of the various factors involved,
and therefore only a general statement can be made with reference to this
important subject. In every instance the weight of the patient to be
transfused should be considered in order to avoid hypertransfusion. A
normal individual has a volume of blood equal to 80 to 85 c.c. per kilo-
gram of weight. A patient weighing TO kilograms, with severe anemia,
may have his blood volume reduced to 50 c.c. per kilogram, representing a
reduction in blood volume of approximately 40 per cent. It would be
futile to attempt to restore the normal blood volume by means of trans-
fusion in such a case and fortunately this is never necessary. On the
other hand, if repeated transfusions are done at intervals of a few days tc
control hemorrhage, as in hemophilia, hypertransfusion causing polycy-
themia should be avoided.
In the routine use of transfusion, owing to the great elasticity of
the vascular bed, hypertransfusion seldom occurs. It is manifested chiefly
by cough, by pain in the back, and, in rare instances, pulmonary edema
may develop, as linger has recently described. These symptoms may
occur regardless of the rate at which blood is transfused. It is probable
that the same symptoms might be produced by a relative hypertransfusioi
that is, by the introduction of a large amount of blood into the circulation
of a patient having a greatly reduced blood volume, such symptoms being
due to temporary embarrassment of the circulation.
When transfusion is indicated for loss of hemoglobin after hemorrhage,
a large transfusion, 1,000 c.c., may be necessary. In chronic anemic con-
ditions smaller amounts of blood, 300 to T50 c.c., may serve as well as
larger amounts. In chronic anemia there is some evidence to show that a
small quantity of blood, repeated within a few days, may be more bene-
TKA^SFUSION OF BLOOD 835
ficial than a single transfusion of a large amount. As an explanation for
the fact, it has been suggested that the bone marrow reacts better follow-
ing a small than a large transfusion. When transfusion is indicated in
hemorrhagic conditions enough blood should be given to stop the hemor-
rhage. This is usually a large amount rather than a small one.
VI. The Choice of a Donor
The donor must be in good health. He should have a negative Wasser-
mann reaction, and should be able to provide the requisite amount of
blood desired for the particular case. It must be realized that the amount
the donor can spare and the amount the patient may receive should be
considered in relation to the body weight of each. A donation of 500 c.c.
of blood from a donor weighing 50 kilograms is equivalent to a donation
of 800 c.c. from a man weighing 80 kilograms.
The blood of the donor should be compatible with the blood of the
patient, that is, the red corpuscles of the donor's blood should not be
agglutinated by the serum of the patient. It is also desirable, but not as
important, as explained below, that the serum of the donor should not
agglutinate the patient's red cells. The test for compatibility is a simple
one and no transfusion should be done, except in an emergency of an
extreme nature, unless the donor's blood is shown to be suitable for the
patient. It is important not only to avoid iso-agglutination, but also iso-
hemolysis, which is a greater danger than iso-agglutination. Iso-hemo-
lysins are found in many but not all adults in whom iso-agglutinins are
present, but they are not present if iso-agglutinins are absent. This is
convenient, because by tests for agglutination, one may rule out the possi-
bility of iso-hemolysis occurring as well as iso-agglutination. The results
of iso-agglutination tests obtained in vitro, if carefully performed, are a
reliable index as to what will occur in vivo, so far as iso-agglutination and
iso-hemolysis are concerned.
Through the work of Moss and Jansky, it is now known that the blood
of each adult falls into one of four definite groups, as shown by the
agglutination reactions of the red corpuscles and serum.
These groups are shown in Table III.
The blood of each group is absolutely compatible within the group;
that is, no iso-agglutination or iso-hemolysis will occur when two bloods
of the same group are mixed in vivo or vitro. The group characteristic
may not be fully established at birth. If it is not, in most cases it is
established during the first year of life. Once established, the group of
each human being appears never to alter in health or disease. Studies
on the iso-hemolysins and iso-agglutinins of infants are reported in the
recent papers of Happ and Basil B. Jones.
836 GEOKGE K. MINOT AND AKLIE V. BOCK
TABLE III
Red Corpuscles of Group *
1
2
3
4
Serum of •
"Group 1
0
0
0
0
" 2
+
0
+
0
" 3
+
+
0
0
« 4
+
+
+
0
Per cent of frequency
5
40
10
45
0 = no agglutination + = agglutination
1 The classification given here and referred to in the text is that given by Moss.
Since this paper was originally sent to the press, it has been officially recommended
(Jour. A. M. A., 1921, 76, 130.) that on the basib of priority the Jansky classifica-
tion be ad9pted, in spite of the fact that the Moss classification has been in wide
use in America and Europe. The Jansky classification is considered identical to
Moss' except that groups 1 and 4 are interchanged. However, it is not known that
Moss' groups 2 and 3 are actually identical to Jansky's. This is because there is
no evidence that anyone has compared the blood of an individual belonging to group
2 or 3 as determined by known sera of cells originating from Moss against the
blood of individuals classed by Jansky as group 2 or 3.
When a donor is to be tested for the compatibility of his blood with
that of a patient, it can be accomplished in two ways. The first one
involves testing directly the donor's cells and the patient's serum for
agglutination, and the patient's cells and the donor's serum. If no agglu-
tination occurs with both of these combinations of cells and serum, it
indicates that the two individuals belong to the same group, thus their
bloods are compatible. If either of the tests is positive it indicates
that the individuals belong to different groups. These tests do not tell
us to what group the individual belongs. This is of no real consequence,
for our object is only to transfer blood which is compatible. The second
way in which one may determine whether a donor's blood is compatible
with that of a patient is to determine the blood group of each. This may
be done by testing the blood of each (either cells or serum) against
bloods (either serum or cells) whose groups are known. If both belong
to the same group, their blood is compatible. The blood of individuals
of a certain group may be given to those of another group, as is referred
to later, even when the subjects belong to different groups and their
bloods are not strictly compatible.
The determination of the blood group of a patient and prospective
donor frequently simplifies the selection of a donor in that the blood tests
may be carried out at different times and in different places. Furthe
more, blood only need be taken once from the patient. However, in order
to control all possible errors, it is distinctly advisable just before each an
every transfusion to test the recipient's serum against the cells of tfo
selected donor.
837
The simplest way to determine to what group a given blood belongs
is to test its cells against the sera of groups 2 and 3. The reason why
one may determine the group by these two agglutination tests is because,
as will be seen by reference to Table III, there are but four possible com-
binations of positive and negative reactions of unknown cells with known
sera of groups 2 and 3. These four different combinations, one for each
of the four groups, allow identification of unknown cells by the presence
or absence of their agglutination by groups 2 and 3 sera. It serves as an
excellent control if when the group is determined a test is made between
the unknown cells and group 4 serum, in addition to groups 2 and 3 sera.
While it is always advisable to choose a donor who belongs to the
same blood group as that of the patient, this is by no means always neces-
sary. This is because, owing to certain protective mechanisms associated
with a preponderating blood whose cells can be agglutinated by other
sera, it is possible to give plasma which can in vitro agglutinate and
hemolyze the cells of such blood. However, in the body, the blood of
the recipient will prevent agglutination or hemolysis of its cells by the
donor's plasma if the transfusion is given under suitable conditions and in
at least the usual amounts. One can never give, without serious risks,
red cells that can be agglutinated by the patient's plasma, which is under
usual conditions the preponderating plasma following transfusion. Con-
sequently, a group 4 donor may be regarded as a universal donor, since
his cells cannot be agglutinated by any plasma, and a member of group 1
can be regarded as a universal recipient since his plasma can agglutinate
the cells of no other group. It is, as stated, desirable to transfuse blood
within the same group, yet as a practical measure it has been demonstrated
repeatedly that blood of group 4 can be utilized for transfusion in any
one of the four groups.
The practical advantage of regarding a member of group 4 as a uni-
versal donor is, of course, obvious. It merely requires the testing of a
donor and does not require the testing of a patient. This enables one to
have a supply of group 4 donors on hand for possible emergency trans-
fusions. With the presence of a combination of a great reduction of
blood volume, a marked reduction of red cells, an anticipated transfusion
of a large amount of blood, and a strong iso-hemolysin in the donor's
blood, it is unwise to transfuse from a group 4 donor into a recipient of
another group. Clinical experience justifies this exception to the rule of
the use of group 4 individuals as universal donors, when it is difficult to
obtain a donor of the same group as that of the patient. It is, however,
more desirable under any circumstances to use a group 4 donor for an
individual of another group than one thought to belong to the same
group as the patient, but whose group designation is not clear cut. This
is particularly true when dealing with groups 1 and 3 patients whose iso-
agglutinins and red cell receptors are apt to be of a weaker nature than
838 GEOKGE E. MISTOT AND AELIE V. BOCK
those of groups 2 and 4. For a more detailed discussion regarding the is
agglutinins, iso-hemolysins and the selection of donors, the reader is
f erred to the references cited above and to those by Brem, Minot(&), Goes
Vincent (&), Sanford, Rous and Turner, Karsner(fr), Karsner and Koecl
ert, Clough and Richter.
It is not the purpose of this article to disctiss technic, but it seems
desirable briefly to summarize a suitable method for performing these
agglutination tests. This summary is essentially the same as that previ-
ously given by Minot and Lee.
In order to make a test between serum (fresh or stock) and the red
cells, the following simple procedure with chemically clean glassware
will usually suffice. A suspension of cells (about 5 per cent) is obtaine
by the addition of 3 to 5 drops of blood to about 2 c.c. of 1 per cent solu-
tion of sodium citrate in 0.9 per cent sodium chlorid solution. These
cells need not be washed. A drop of the red cell suspension is mixed
with a drop of serum. It is important to make the mixture complete.
This may be done upon a glass slide with a cover glass put over the
mixture. The cover glass should always be raised and the cells and serum
remixed several times before a negative reading is made. A hanging drop
preparation permits neater technic and avoids drying. The test often
may be read macroscopically, but should always be read microscopically,
in order to avoid any possible errors except when it is rapidly and un-
doubtedly positive. In order to guard against possible errors, it is always
wise to allow the mixture of cells and serum to remain for at least 30
minutes, preferable in the incubator. While there are few opportunities
for confusion in this simple test, nevertheless the penalty of transfusion
of incompatible blood may be so great that every reasonable care should
be given to the performance of the test. Confusion may be caused by
weak agglutination. It is always possible by employing different amounts
of cells and serum, by incubating the mixture for some hours and by
thoroughly washing the red cells, to decide the problem of doubtful reac-
tions. However, if by the method described the reaction is not cleai
and perfectly definite, the test must be repeated and perhaps amplified.
A safe rule is never to regard a reaction in which there is any doubt as
negative. Rouleaux formation may be easily demonstrated as quit
different from agglutination. Confusion may be caused by atypical agglu-
tinations, that are very rarely intense, due to auto-agglutination and allit
phenomena which are little understood. Stock sera for determining tc
what group a human being belongs will keep many months and even yt
if sterile, carefully sealed and in the ice-box. Stock sera have an ad-
vantage over fresh sera in that they are less liable than fresh sera tc
produce reactions with red cells, which may be confused with iso-agglu-
tination. It may be again emphasized that when carefully done the re
action of agglutination is in a very large proportion of cases clear anc
TEANSFUSION OF BLOOD 839
definite. In practice it is always expedient to discard as a donor one
whose blood causes any doubt about his group or about the reaction of his
cells with the patient's serum.
VII. Reactions from Transfusion
Previously, the beneficial effects of transfusion have been discussed.
It is now necessary to point out the harmful effects which may result from
this procedure. If a donor is used who is not healthy, syphilis, malaria
and other diseases may be transferred to the patient. Hypertransfusion
has been previously referred to and can always be avoided. Keactions
due to incompatibility of blood, as shown in vitro, may occur if improper
tests are made. The deleterious effects of transfusions done with com-
pletely proper technic are those in the nature of a reaction from some un-
known alteration in the transfused blood, and, in some instances, depen-
dent upon the state of the patient. Such reactions are very rarely serious.
1. Reactions Due to Recognized Incompatibility. — Keactions re-
sulting from the transfer of blood incompatible with that of the patient's,
in that iso-agglutination or iso-hemolysis occurs, may vary from a state of
temporary discomfort to a grave disturbance which may be fatal. The
reasons for variations in the degree is due, at least in part, to quantitative
variations in the amounts of the factors involved in iso-agglutination and
iso-hemolysis. The selection of donors by means of proper agglutination
tests eliminates reactions of this type. Very rarely, as is referred to below,
similar hemolytic reactions may occur when bloods apparently have been
properly tested.
When blood is given to an individual whose serum can agglutinate
the donor's red cells, the symptoms due to this incompatibility may develop
after a very small amount of blood has been injected. Typically this
reaction may be described as follows: The patient becomes restless, com-
plains of pain in the back, develops an increased respiratory and pulse
rate and may soon vomit and have a chill followed by a sharp rise of
temperature. With hemolysis, jaundice may develop rapidly and become
severe, and the urine may be scanty and filled with hemoglobin. The
patient may become unconscious and appear as in shock. Death may
follow rapidly or within a few days, though the severity of the reaction is
usually over within twenty-four hours and the patient much more usually
recovers than dies. The temperature often remains elevated for several
days and the jaundice may persist for a similar length of time. The
degree of anemia following severe reactions is usually more pronounced
than before transfusion. Occasionally, such a reaction is followed by in-
tense activity of the bone marrow and a surprisingly rapid improvement
in the anemia occurs.
840 GEOEGE K. MINOT AND ARLIE V. BOCK
The severity of the reaction may vary greatly not only in different
patients, hut also in the same patient, even when the same donor is used
for a subsequent transfusion. A mild reaction following a first trans-
fusion may consist of but a very temporary rise of temperature and a
chill. On the contrary, a second transfusion from the same donor may
induce a severe hemolytic reaction. A presumptive explanation for this
change in reaction is the development in the interim between the trans-
fusions of an increase in strength of the agglutinins and the development
of hemolysins in the patient's blood.
2. Reactions Not Due to Recognized Incompatibility. — These are
of two types. First, those that are distinctly rare and that resemble an iso-
hemolytic reaction. Second, those that are the commonest and mildest re-
actions that follow transfusion, and that are associated with the instability
of blood when removed from the body.
(a) Reactions That Resemble Those Due to Recognized Iso-hemr
olysis. — In some diseased conditions, particularly sepsis and blood dis-
eases, the blood sometimes seems to be altered with a production of
hemolysins and agglutinins not normally present. To these abnormal
hemolysins and agglutinins are attributed some of the rare reactions of a
hemolytic nature which may be fatal following transfusion performed
with donors selected by the usual tests. Such reactions appear to be
delayed usually some hours in their onset in contrast to the classical iso-
hemolytic reactions that develop at least shortly after transfusion. (See
Bowcock, and Robertson and Rons.)
Sydenstricker, Mason and Rivers have observed serious hemolytic re-
actions following repeated transfusion in pernicious anemia, when the
donors were properly chosen. The cause of these reactions is unknown.
These hemolytic reactions associated with properly tested donors are not
to be confused with true iso-hemolytic reactions dependent upon improper
agglutination tests. Some hemolytic reactions that have been reported
when the donor's and patient's blood was tested, undoubtedly have been
due to improper laboratory tests. The tests were probably incorrectly
read owing to the presence of weak agglutination reactions in vitro.
(b) Reactions Associated with Instability of Blood When Removed
from the Body. — The commonest reactions seen after transfusion cannot
be foretold and they are not definitely associated with agglutination or
hemolysis. These reactions are of a milder nature than those previously
described though they rarely may be distinctly severe. The onset of
symptoms is usually about an hour after transfusion. In the majority of
cases they subside within twenty-four hours. The symptoms usually begin
with a sharp rise of temperature of a degree to four or five degrees, and
even more. With the symptoms of fever, nausea, vomiting and diarrhea
may occur. Chills may be associated with temperature rise. Urticaria,
and other lesions of the erythema group, and rarely edema and purpura,
TRANSFUSION OF BLOOD 841
may occur. Herpetiform vesicles may develop about the mouth. The
symptoms are rarely alarming and usually the reaction consists of only a
simple rise in temperature. '
These reactions follow the giving of hlood by any method. They are
apparently much more common when blood is altered by an anticoagulant
than when blood is given without addition of such a substance. The fre-
quency of such reactions varies greatly according to different observers.
It seems that in round numbers outspoken definite reactions occur fol-
lowing transfusion of blood, as such, in about 15 per cent of the instances
and with citrated blood in about 35 per cent of the instances.
Reactions of this type are generally considered as dependent upon some
not clearly demonstrated alterations of blood, associated with its removal
from the body. In some cases, alteration of the patient's blood seems to
play a part. This is thought to be the case because these reactions appear
to be commoner in patients with extensive pathology of their hematopoietic
organs, such as occurs in pernicious anemia, than in those whose hemato-
poietic system is of a normal type, such as is found in cases with anemia
due to acute blood loss.
Satterlee and Hooker, in a review of the known facts concerning such
reactions, suggest three possible mechanisms by which they may be pro-
duced. One is that the trypsin-antitrypsin balance in the circulating
blood of the recipient is so disturbed as to result in the immediate forma-
tion of serotoxin from cleavage products. A second theory is that the
action of the protective colloids in the body cells of the recipient may be
upset so that these cells are exposed to a reaction of the antigen and
antibody present in the circulation of the recipient, but harmless to the
protected cells. The third theory, one which is substantiated by many
facts, concerns the possibility of a toxic disturbance in the circulation of
the recipient by the introduction of blood which, though perfectly fluid,
may be undergoing incipient coagulation changes due to the physical
influences to which it is subjected in the process of transfer. The experi-
mental work of Drinker and Brittingham and Wright and Minot, as well
as the clinical results of workers experienced in the technic of trans-
fusion, suggests that the coagulation changes may account for most of
these reactions.
Novy and DeKruif attribute the toxicity of blood in the precoagula-
tion stage to the presence of poison, anaphylatoxin, which is also present
in greater or less concentration in normal serum. The mechanism of the
production of this substance is the subject of an interesting theory pro-
posed by these authors, and it may explain certain post-transfusion reac-
tions. Novy and DeKruif believe that the matrix of the poison is always
prc.-cnt in the circulating blood and is a substance as labile as fibrinogen,
and that just as fibrinogen is changed by thrombin to fibrin, so the matrix
is converted through the action of a great variety of substances into
842 GEORGE E. MINOT AND ARLIE V. BOCK
anaphylatoxin. A foreign blood plasma could thus easily act as an accel-
erator of this action and suddenly convert the circulating blood into a
toxic substance.
Another factor to be considered is the influence of an anticoagulant
such as sodium citrate. Experience with citrated blood, as stated before,
has resulted in a much larger percentage of reactions of mild type than
when blood is used to which no substance has been added. Drinker and
Brittingham have suggested that this may in part be due to the action
on the red cells of sodium citrate which promotes hemolysis.
It is certainly true that the less blood is altered the less chance there
is that these reactions will occur. Such alterations are often beyond con-
trol, for at least a small number of these reactions will develop despite
scrupulous technic in transfusion. Even so, neat technic with rapid
transfer -of blood will permit the fewest possible reactions.
By no manner of means is it to be thought that transfusions with
citrated blood should not be done, because these reactions are usually
slight and rarely alarming, and fatality, if it occurs, must be very rare.
However, reactions appear to be less frequent when blood without an anti-
coagulant is used, so that in certain instances it may be preferable not
to give citrated blood.
VIII. Methods of Transfusion
Indirect methods of transfusion have entirely replaced the original
direct methods. The simplicity of the indirect methods, together with the
ease with which hemolysis may be avoided, has led to the general use of
blood transfusion. Such methods are designed to transfer blood either
as unaltered whole blood or blood mixed with an anti-coagulant, especially
sodium citrate.
The chief advantage of transfusion of blood to which no substance has
been added is that it produces fewer reactions, not due to recognized
incompatibility, than citrated blood. In view of the reactions associated
with transfusion, it is theoretically desirable to transfuse blood in its
natural state as far as it lies within technical means to do so. The dis-
advantages encountered in the transfer of blood to which no substance has
been added consist in difficulties with a more cumbersome technic for
transfusion, usually requiring two or more persons, and more experience
than is necessary with the citrate method. There is also a more frequent
necessity for cutting down on veins when certain methods for transfusing
blood without anticoagulant are employed. In the hands of experts, these
difficulties are not troublesome, and in such cases transfusion of unaltered
whole blood is the method of choice.
Descriptions of methods for the transfusion of blood to which no
TRANSFUSION OF BLOOD 843
substance has been added may be found in the papers of Kimpton and
Brown, Vincent (a), Lindeman, and linger (a) (&).
The reasons for the use of an anticoagulant for transfusions are sim-
plication of technic ; the necessity for haste becomes a secondary considera-
tion and it is often more convenient since the donor and recipient need
not be in the same room. One person can perform a transfusion with the
citrate method, and it is usually possible to avoid exposure of veins by
skin incision.
There is theoretical ground for objection to the use of sodium citrate
on the grounds of toxicity, but the experience of Weil, Lewisolm(a) (&),
and many others, shows that in doses up to 5 grams the drug has 110 dem-
onstrable ill effects. Investigation of the effect of citrate upon the coagula-
tion time of the blood in vivo has demonstrated that in animals the
coagulation time is greatly shortened. In man, there has been observed
no important change in the coagulation time after the injection of citrated
blood, when the coagulation time was not abnormal. However, transfusion
of citrated blood appears to be able to shorten a patient's abnormally long
coagulation time in the same manner as blood to which no substance
has been added. The effect of citrate upon hemolysis of red cells has
been referred to.
For details of the methods for the use of citrated blood, the reader
may consult articles by Robertson, Drinker and Brittingham, and
Lewisohn.
Mineral Waters Henry A. Mattttl
Saline Waters — Alkaline Waters, Including Carbonated — Bitter Waters — Sul-
phur Waters — Iron Waters — Arsenic Waters — Radioactive Waters.
Mineral Waters
HENRY A. MATTILL
ROCHESTEK, N. Y.
On no subject in medical literature probably has there appeared so
much worthless writing as on that of mineral waters. Our own country
is not guiltless but by far the largest mass of advertising under the guise
of science has appeared in Europe particularly in Germany, France and
Austria. While there may be virtue in many of the "drinking cures"
the careful dieting and well ordered living which are a part of the
"cure" are in themselves of great therapeutic value, and the ingestion
of water without any mineral has very definite effects on metabolism,
effects which indeed may outweigh any others attendant upon the pres-
ence of a small amount of mineral salts. While the combined action of
mineral substances as they are found in natural mineral waters is un-
doubtedly different from that of the individual substances, it is not, to be
supposed that the action would be different if the natural mineral water
were exactly reproduced. In considering the relation of mineral water
to metabolism only such investigations as have been made with natural
mineral waters themselves will in general be reviewed, since the metab-
olism of mineral matter is considered elsewhere. Until the laws govern-
ing mineral metabolism are more clearly understood than they are to-day
the therapeutic value of mineral water administration must remain in the
realm of the empirical.
A clear cut classification of mineral waters is not easily made since
a water may contain several ingredients ; according to their predominating
characteristics, they may be divided into the following classes : saline, alka-
line (including carbonated), sulphate or bitter water, sulphur, iron or
chalybeate, arsenic and radioactive waters.1
1 From a geochemical standpoint the fundamental character of a mineral water is
best expressed in terms of the "properties of reaction" as suggested by Palmer. Pri-
mary salinity is caused by strong acid salts of the alkalies (as NaCl, K2SO4, etc.);
secondary salinity by strong acid salts of the alkaline earths (as CaS04, MgCl2, etc.) ;
primary alkalinity is caused by weak acid salts of the alkalies (as NaHCO3KHS, etc.) ;
secondary alkalinity by weak acid salts of the alkaline earths (aa CaHCO3)2, etc.) and
tertiary alkalinity *by colloidal oxids of iron and aluminum and free weak acids, as
Si02 and C02. These "properties of reaction" can easily be calculated from a water
analysis in which the values are given in terms of the ionic substance and the quality
or character of the water though not its actual content of minerals, is then expressed.
845
846 HENRY A. MATTILL
Saline Waters. — The first important work on the effects of saline
waters on gastric secretion was done by Dapper(&) on persons suffering
from gastric disorders ; when the usual amount of saline water was given
before breakfast he was able to note normal amounts of hydrochloric acid
in cases of hypoacidity due to catarrh. Hypoacidity of nervous origin
was not affected, while in a number of patients hyperacidity of nervous
origin was considerably reduced by the same treatment, thus indicating that
the result was not merely a stimulation or inhibition of acid secretion,
but a modification of the processes in the epithelium. Later work on
patients (Meinel) and experiments on a dog with accessory stomach re-
ported by Bickel(a), also showed that saline water given before a test meal
caused a slight increase in acidity, a slightly more rapid appearance of
the hydrochloric acid and emptying of the stomach.
Similar experiments on the Homburg Springs (Baumstark) (saline,
CO2) showed that these waters brought about a very noticeable increase
in the amount of gastric secretion (av. 74 per cent) as compared with ordi-
nary water, and also an increase ip. acid content. The opposite result ap-
peared when milk was given with the water, from which it was concluded
that the digestion period must not be identical with that in which mineral
waters are ingested. The presence of CO2 may explain the greater stim
lating effect of the water alone (see below).
Sasaki, who obtained like results, claimed that the per cent of hydro-
chloric acid in gastric juice was not changed but that the larger amount of
secretion was the fundamental thing. Casciani(a) and Coleschi(a) em-
phasized the fact that the hypotonic hydrochloric acid waters especially
have a stimulating effect, while hypertonic waters act as depressants,
isotonic having no effect. Whether the tonicity of the gastric contents as
svich is an important factor has been the subject of considerable experiment
and discussion. The existence of a "diluting secretion" was affirmed by
Strauss and Roth such that the higher the molecular concentration of a
water, the longer it remains in the stomach and the greater the retardation
in the appearance of hydrochloric acid (Strauss, b). Other investigators
(Bonniger; Sommerfeld and Roeder; Otto) have not confirmed the ex-
istence of a diluting secretion and the behavior of mineral water in the
stomach bears no simple relation to its molecular concentration (Tauss).
However, the delay of gastric function by concentrated waters is, accord-
ing to v. Noorden, a matter of therapeutic importance. Hypotonic solu-
tions (Wiesbaden Kochbrunnen) rapidly become less so in the stomach
Since these chemical qualities are not likewise "physiological" qualities, it seemed
best to retain the older and more familiar classification. As Albu and Neuberg suggest,
balneotherapy may become more useful when the ionic composition of a mineral water
is properly considered. While they express great hope for the future of mineral
water therapy along the lines of Koeppe's investigation on the osmotic pressure and
dissociation constants of mineral waters, no such development seems as yet to have
taken place.
MINERAL WATERS 847
(Bickel(a) ) and the stimulating effect of water alone (King and Hanford;
Sutherland; Hawk(e)) first shown by Pawlow probably plays an impor-
tant role. In this connection may also be mentioned v. Noorden's opinion
that experimental results of value in therapeutics cannot be obtained in the
normal organism but must be secured in one that is deranged by disease.
On pancreatic secretion saline waters have a stimulating effect
(Bickel(c) ) as shown in experiment on dogs with pancreatic fistula. The
question as to the influence of these waters on the utilization of food has
long been of interest and the monograph of v. Noorden summarizes his
own results and those of others on persons in health and in disease. Fats
especially had customarily been contra-indicated during the cures because
of their supposedly defective absorption and this idea is completely refuted,
for the changes in fat excretion were within normal limits, during the
mineral water periods sometifnes above and sometimes below the original
values. This was found true even when unusual amounts of fat were in-
gested ; no marked decrease in its assimilation occurred despite the simul-
taneous administration of maximum quantities of fat and mineral water
together. Even small supplements of (Kissingen) bitter waters (SO4)
did not always increase the fecal content of fat and of nitrogen though
their laxative action was noted.
In their long series of cases the stimulation of protein metabolism, a
phrase which appears ad nauseam, in so much of the balneological litera-
ture, was not observed. The excretion of uric acid was generally increased
by drinking weak saline waters, especially in gouty patients (v. Noorden
and Dapper(a) ; Leber) a statement for which v. Noorden has no explana-
tion, but which must be accepted on the basis of the figures given ; opposite
findings on well persons are reported by Bain and Edgecombe and v.
Noorden also observed the opposite in nephrolithiasis.
A diuretic property has also been the marvelous possession of all min-
eral waters. Water is the best diuretic, said Osier, and mineral waters are
seldom properly compared with ordinary water nor are the relations of
diet, muscular activity and external temperature and humidity ever con-
sidered. A transient diuresis (15-30 min.) is indeed often observed after
drinking mineral water and the increased rapidity with which some min-
eral waters leave the stomach as compared with ordinary water may in
part account for this ; some of the salts they contain do also act as stimu-
lants to the renal epithelium but no one has addressed himself properly to
the task of determining the behavior of the kidney under the prolonged and
immediate influence of mineral waters, and to the temporary and perma-
nent effects on the body of such behavior. The ingestion of larger amounts
of water (1200 c.c. in 1 hr.) with consequent enormous diuresis has very
little effect on the blood according to Haldane and Priestley. Its conduc-
tance is slightly diminished whereas when salt solution is ingested its,
conductance is increased but hemoglobin percentage is lowered. It has
848 HENRY A. MATTILL
been stated that the mineral content of the blood usually increases, always
within physiological limits after drinking various mineral waters, with
proportionate changes in A (v. Szabohy ; Grube), but most observations
are to the effect that the molecular concentration of the blood is maintained
with great tenacity (Grossmann; Strauss(c)) though here again the be-
havior of normal cases may not properly indicate that of pathological ones.
The tissues rather than the blood are the regulating factors in this con-
nection (Bogert, Underhill and Mendel).
Alkaline Waters, Including Carbonated. — Earlier work on the im-
mediate effect of alkaline waters taken with a meal on gastric secretion was
inconclusive because the variations found were within normal limits.
Later work indicates that such waters taken with food have very little in-
fluence (v. Noordeii and Dapper (a) ; King and Hanford). When given
before meals in the usual spa fashion sodium carbonate according to some
earlier investigations has very little if any effect on the secretion of
hydrochloric acid (Reichmann), according to others a stimulation up to
the point of neutralization and perhaps beyond (Linossier and Lemoine) to
an abnormally high amount. The earlier work on Carlsbad water (alka-
line-saline, containing also small amounts of Glauber's salts) which pointed
to a slightly stimulating effect on hydrochloric acid secretion for the gen-
eral digestion period has been supplanted by results secured on dogs with
accessory stomach or human cases with esophageal fistula. According to
Bickel(6) such water has no influence on gastric secretion, although clin-
ically favorable results are reported both in hyperacidity and hypoacidity.
However, it cannot be claimed that these effects are other than temporary
and transient. Dieting, according to v. Noorden, is a much more satis-
factory and efficient remedy. According to Sasaki these waters are
generally slightly inhibitory, a statement with which most later investi-
gators are in agreement (Bickel(d) ; Casciani(fr) ; Heinsheimer; Pime-
now; Rozenblatt).
The results obtained with alkaline-saline waters from certain Rou-
manian springs suggest that chlorid and bicarbonate are to an extent an-
tagonistic in their influence on gastric secretion and that the resultant
effect is dependent on the proportions present (Teohari and Babes).
Carbonated waters are generally found to be stimulating in their ef-
fect on the gastric mucosa (Penzoldt(6) ; Casciani(a)(&) ; Coleschi(a.))
and also on pancreatic secretion (Becker) (perhaps as a result). The
stimulating action of alkaline waters containing CO2 is therefore to be
credited to the influence of CO2 as neutralizing the inhibitory tendency of
the alkali. Gaseous CO2 in the stomach stimulates secretion and acidity
in the accessory stomach (Pincussohn) and such stimulation of alkali as
has been observed is credited to CO2 formation (Pimenow) since about the
same results are obtained when using water saturated with CO2. The ef-
fect of calcium carbonate in producing a "stormy" (Heinsheimer) increase
MINERAL WATERS 849
in secretion is likewise probably to be credited to the carbon dioxid evolved,
pei haps also to calcium (Polimanti). The effect of lithium salts and
water is to be explained in the same way (Mayeda).
Purely alkaline waters also depress pancreatic secretion, while car-
bonated waters, like the saline waters stimulate it; these also increase
biliary secretion (Jappelli), all of which effects can probably be traced
back to a gastric origin.
Information as to their influence on the utilization of food is scanty.
Early experiments indicate little if any change in the utilization of pro-
tein and fat as a result of drinking 1 liter of alkaline water, and ethereal
sulphates were also unchanged. The influence of alkalies themselves on
ethereal sulphates is variable and there is need of data on the effect of
mineral waters in cases of high ethereal sulphates and indican. By the
ingestion of alkaline water the ammonia content of the urine is decreased,
and the normally acid reaction of the urine may be changed to an alkaline
reaction with sufficient alkaline water, but with wide variations in indi-
vidual cases. Such results are also reported in the case of infants (Ylppo).
More recently in an experiment on four men lasting 18 days the effect of
an alkaline mineral water (Manitou) on digestion and utilization was de-
termined (Mattill). This water contains a large amount of lime (secon-
dary alkalinity), some chlorids and sulphates and a considerable amount of
free carbon dioxid. During the mineral water ingestion a true alkalinity
of the urine was observed together with marked reduction in urinary am-
monia. There was a slight retention of nitrogen in all four subjects.
Uric acid and indican excretion were very slightly reduced, the latter,
however, not because of a better utilization of the food. Fecal moisture
and fat in particular were somewhat increased, nitrogen only very slightly.
The larger proportion of the added lime was excreted by the intestine;
during the mineral water periods all subjects showed a marked retention
of lime and the positive balance continued with a gradual decrease in
the post-water control period. Earthy phosphates in the urine were
slightly increased but total urinary phosphate was reduced, presumably
through a deviation into the intestine by lime.
Alkalinization of the urine has been of interest because of the greater
solvent power of such urine for uric acid. For such alkalinization the
carbonates and citrates of the alkaline earths (especially calcium) offer
some advantage over those of the alkalies because Ca is excreted for the
most part by way of the large intestine and because, since it tends to
divert phosphate from the urine to the feces (Rose) a relative as well as an
absolute decrease in primary phosphates occurs (Strauss(a)). In his
short experiment on alkaline earth waters Heim found no decrease in
monosodium phosphate but the diet was not kept constant. But although
alkalinized urines possess greater solubility for uric acid, the ingestion of
alkaline mineral waters to provide such a condition has little or no effect
850 HENRY A. MATTILL
on the excretion of uric acid (Ludwig; Laqueur(a) ; Klemperer; Gilar-
doni; Bradenburg; Leva (a) ; Croce (&)); if the amount excreted is
changed at all it is just as apt to be increased as decreased by alkaline
waters. The same may be said of various alkalines administered as such
(Herrmann; Strauss (a) ; Salkowski(fc) ; Gorsky). v. Xoorden remarks
upon the two centuries of treatment of gout with alkalies in the absence of
any findings even upon gouty patients, to justify the supposed ability of
alkalies and alkaline mineral waters to remove uric acid. In nephrolithia-
sis on the other hand alkalies often seem to increase the uric acid output
considerably.
A decreased urinary acidity is also often desirable in glycosuria and
can be secured by the ingestion of large amounts of alkali (10-40 gr.
NaHCO.,, even 100 gr. daily) amounts which are not supplied by the drink-
ing of 1-arge amounts of mineral waters. In milder forms of such acidosis
the amount of alkali in some mineral waters may be adequate to render
the urine alkaline. The transitory nature of this reduction in acid is ob-
vious as is also the fact that the reduction in acid excretion is not the real
object. Any reported improvement in diabetic conditions resulting from
mineral water cure can not be credited to the water but must be explained
by the many other contributing factors.
The acidosis of nephritis particularly as it is related to retention of
phosphates in the blood (Marriott and Howland(a)) requires further
investigation as to the therapeutic value particularly of calcium and of
the alkaline mineral waters containing it.
The fate of alkalies and their influence on the blood and tissues are
questions that have not been answered for the isolated elements and their
salts, much less for their wide variety of combination as they occur in
mineral waters. Too little is known of the role of mineral substances in
the processes of metabolism profitably to employ the information in a ,
consideration of mineral waters.
Bitter Waters. — Bitter waters depress the secretion of gastric juice
and may cause a secretion of water into the stomach, similar to their be-
havior in the intestine. In experiments on Pawlow dogs the inhibitory
effect was not observed if saline and carbonated waters were added
(Odaira). Acidity is said not to be markedly changed by the administra-
tion of 30 per cent sodium or magnesium sulphate solutions though pepsin
is decreased (Heinsheimer). Pancreatic secretion is also interfered with
(Pewsner), even by relatively small doses when food is given an hour
afterward (Bickel(c)). These waters are laxative in their action and
a less complete utilization of all the food constituents is to be expected as
a result of their use. Such findings have been reported for nitrogen and
fat utilization by many investigators (Leva (a) ; Vahlen ; Katz(a) ; Dapper
(a) ; Jacoby). In a metabolism experiment on eight persons Kolb found
fecal carbohydrate also increased as well as ash. Such waters have been
MINERAL WATERS 851
found to increase urinary ethereal sulphates (Rosin) though not in-
variably (Forges). On the basis of urea determinations in a dog in
nitrogen balance, and in patients, it was concluded that absorption of
nitrogenous substances during a drinking cure was not interfered with
since the urea values were not changed (Zorkendorfer). This type of
water has usually been employed in obesity cures.
Sulphur Waters. — A diminished gastric acidity as the result of drink-
ing sulphur waters has been reported from observations on a few hyper-
acidity cases and is recommended by Heubner(fr) for the treatment of
chronic alimentary catarrh in children. It is probable that the alkalinity
of the water is the determining factor and such waters if they contain
carbon dioxid may have the contrary effect (Coleschi(6)).
Several metabolism experiments with sulphur water are reported by
Brown in which during the sulphur water periods the amount of urinary
nitrogen was increased, as well as the excretion of creatinin and endog-
enous uric acid. The laxative action of the water caused a considerable
increase in the amount of feces of which no account is taken in the nitro-
gen calculations. Indican was almost doubled during sulphur water Di-
gestion. The value of sulphur water as a therapeutic agent is doubtful.
Iron Waters. — Iron waters have long been used with some success in
anemia but only one investigation deals with their actual influence on
metabolism. From this investigation by Vandeweyer and Wybauw on
two normal persons it appears that protein and carbohydrate in the feces
decreased during the iron water periods, fat on the other hand was in-
creased. Since the nitrogen intake was not entirely uniform in all the
periods, conclusions as to the effect on nitrogen metabolism are not easily
drawn. In one case there was a considerable minus balance during the
iron water periods as compared with the final ordinary water period;
in the other case there was a plus balance, but nevertheless they conclude
that during the iron water periods nitrogen catabolism is stimulated. Uric
acid was relatively decreased.
The therapeutic value of iron in chlorosis is discussed elsewhere and
while improvement in hyperacidity and increased hemoglobin and erythro-
cytes are shown to follow upon several weeks of iron water cure other
factors such as rest, out of door life and proper food must be considered.
The amount of iron ingested through drinking iron waters is less than
is usually administered in medicinal preparations but the former are often
more effective, perhaps for the reason just given, perhaps because of the
manner of administration. Iron carbonate waters deteriorate when bot-
tled and on standing due to precipitation of iron oxid.
Arsenic Waters. — Arsenic waters usually also contain iron, and for
certain types of anemia it would seem that administration of iron alone
is useless but that with arsenic good results are sometimes obtained. Aside
from such information (Henius(6) ; Brenner) no reliable metabolism data
852 HENRY A. MATTILL
on arsenic waters are at hand. Uric acid elimination during the arsenic
water period is said to be decreased with an increase in the after period
(Croce(fr) ), but the presence of other salts is probably responsible for such
results as have been noted. The excretion of arsenic in the arsenic water
cures is subject to considerable individual variation (Nishi). A more
rapid increase in weight in animals receiving arsenic water as compared
with those receiving ordinary water has been reported for rabbits (Lar-
delli; Bachem) and for rats (Croce(a)) which is only partially explained
by an effect on the appetite.
Radioactive Waters. — The literature on radioactive waters is exten-
sive and much of its content is entirely characteristic of the bulk of min-
eral water literature. Radium is undoubtedly not without influence oil
metabolism but a great many statements about it are quite without experi-
mental foundation. As ordinarily used in "cures" radium emanation is
taken into the body by drinking radioactive water. When so taken it has
no influence on gastric secretion (Olszewski). In a bath in radioactive
water radium emanation enters not by the skin but through respiration
(Loewenthal), but that any considerable amount gets into the blood by this
means is improbable '(Gudzent(/)) since the amount in the blood was
found always to be about one-fifth of that in the expired air (Kemen).
After injection into the duodenum of animals (rabbits) Strasburger(&)
found it in three-fourth hours in the blood; after two hours only
a trace was left, and the time curve of emanation content of the blood
and of the expired air were the same ; by divided doses the content could
be maintained, but only about a third of the ingested radium emanation
gets into the systemic circulation at all, and only a very small fraction
is found there at any one time. Similar results were found after drink-
ing radium emanation water. In seemingly careful experiments by Pieper
the results of Strasburger were verified and it was estimated that two-
thirds of the ingested radium emanation was lost by way of the lungs.
A small fraction (1/4000) of the ingested radium emanation was also
demonstrated in the urine from which it had disappeared after three
hours (Laqueur(6)). In longer periods of radium emanation ingestion
the amount found in the urine gradually fell (Kalmann). Radium is
also excreted by the feces and in greater amounts than in the urine, and
in whatever manner given it may be found in the tissues (Meyer).
Thorium X seems to behave similarly and the bone marrow is said to be
most rich in it after administration (Brill). Measurements of radium
emanation in expired air are a good measure of the blood content (Spartz).
Radium emanation is reported as having been used successfully for
the reduction of blood pressure, in the relief of anemia (Th. X), and for
the cure of gout ! and the literature on the latter is particularly extensive
and vacuous. The supposed transformation, solution and destruction
of uric acid by radium emanation (Gudzent(a) (c) (d) \ Engehnami;
MINERAL WATERS 853
Mesernitzky(a)(c)(rf) ; Sarvonat) either could not be verified (Knaffl-
Lenz and Wiechowski) or was found (in vitro) to be the result of bacteria
and molds '(Kerb and Lazarus) or took place just as rapidly in the body
without radium emanation as with it (Hockendorff), and the cases of
true gout which improved under the influence of radium emanation did
not show any change in the uric acid curve (Mandel). Radium-contain-
ing waters may not even owe their value to their content of radium emana-
tion (Lazarus(a)). Trustworthy information on the effect of radium or
radium emanation on metabolism is meager. When given with meals
certain radioactive saline waters were found to have an inhibitory effect
on the action of pepsin, but only after the water had lost its radioactivity
through storage (Bergell and Bickel) which the authors consider an evi-
dence of activation of pepsin by radium emanation and a removal of the
inhibitory effect of the water on gastric activity. After feeding radium
bromide to dogs Berg and Welker were unable to show any change in
protein metabolism ; the total sulphur of the urine was increased. Accord-
ing to Skorczewski radium therapy causes an increased output of nitrogen
and uric acid, as well as of neutral and oxidized sulphur. Using the
respiration chamber Kikkoji demonstrated increased gaseous exchange and
increased nitrogen and uric acid elimination which was not invariable.
After intravenous injection of radium Rosenbloom found increased nitro-
gen elimination, but nitrogen partition showed no constant behavior. He
verified the previous findings on sulphur excretion and found that the
effects lasted about three days after the injection. Intravenous doses of
an active deposit of radium emanation produced a decided increase in
urinary nitrogen excreted by dogs (Bagg(6)). The destruction of cellu-
lar material as indicated by the fall in number of blood cells probably
accounts for this as well as for the rise in body temperature. In a five
and one-half weeks' continuous metabolism experiment on a gouty subject
(Kaplan) the ingestion of radium emanation and alkaline mineral water
decreased the excretion of uric acid as compared with the alkaline water
alone, purin bases showed a slight absolute but a high relative increase.
On the other hand, Chace and Fine found it impossible to change the uric
acid concentration of the blood in gout and arthritis by emanatorium,
drinking water or injections, a conclusion confirmed by others (McCrudden
and Sargent (6)). An increased elimination of uric acid in arthritis
after treating with large doses of radium emanation is considered by v.
Noorden and Falta as definitely shown. This is possibly connected with
cell destruction. An influence on respiratory metabolism has not been
established except that after large doses a slight increase was observed
(Benczur and Fuchs). A transient decrease in blood pressure has been
noted (Loewy and Plesch). Despite the claims which are made for
radium and radium emanation therapy in metabolic disorders (v. Noorden
(e)) it can hardly be considered well established on an experimental basis.
Hydrotherapy Henry A. Mattill
Cold Baths — Hot Baths — The Influence of Mechanical and Chemical Stimu-
lation Accompanying Baths — Effervescent Baths — Baths and Sweat Se-
cretion.
Hydrotherapy
HENRY A. MATTILL
ROCHESTER, N. Y.
The external use of water as a therapeutic measure was first advocated
in England by Sir John Floyer in 1697. A hundred years later Dr.
James Currie of Liverpool, inspired by Dr. William Wright, published
his reports on the effect of cold and warm water as a remedy in fever and
other diseases. The works of these men bore their first fruit in Germany
and Austria, where some of the claims put forth by the advocates of hydro-
therapy were put to experimental test. Among the investigators Winter-
nitz occupies the foremost place as his many monographs and his larger
works testify. . His efforts and those of similarly minded men that followed
him have done much to illuminate the really valuable contributions of
hydrotherapy shrouded as they often are under a cloud of pseudo-scientific
effusions. Recent books in this country are by Baruch, Hinsdale and
Kellogg. Among the recent English authors may be mentioned Fox and
among the German, Matthes whose valuable chapters on baths and bathing
in v. Noorden's Metabolism and Practical Medicine cites the older litera-
ture, and Schutz.
The skin is the organ through which baths produce their effects on the
body. The foundation of hydrotherapy must therefore rest on the func-
tions and activity of the skin as they may be modified by external treat-
ment, and may in turn thereby modify the functions of the internal organs.
Probably the most important function of the skin is that of regulating
the body temperature, the mechanism of which is described elsewhere.
By virtue of its activity in temperature regulation the skin is both a
vascular organ and an organ of excretion. To the cutaneous sensations
of heat and cold involved in temperature regulation must be added those
of touch, pressure and pain, and the skin is thus a sense organ of first
importance. The influences of hydrotherapeutic measures may therefore
be sought in the effect of temperature changes and other cutaneous sensa-
tions on the processes of metabolism, including the activity of organs
'other than those of digestion and absorption merely, and in the effect of
these stimuli on the excretory functions of the skin.
It may be recalled that the temperature of the warm-blooded animals is
regulated by physical and chemical means, both mechanisms being under
855
856
HENKY A. MATTILL
the control of the autonomic nervous system. The physical regulation
governs heat losses by a variable cutaneous circulation and the activity
of the sweat glands. The chemical regulation controls heat production
through increased muscular activity. By means of the protection of
clothing, man aids these methods of regulation through surrounding him-
self with an atmosphere but little cooler than the body. While the internal
temperature of the body is about 3T.5°C. the temperature of the skin is
usually only a few degrees below this, such that a bath at about 34° C.
neither adds to nor subtracts from the body supply of heat. Such a bath
is called an indifferent bath. This indifferent point may vary with differ-
ent individuals and in different conditions and has been given variously
from 34.2° to 37°.
There is fairly general agreement that exactly indifferent baths have no
demonstrable influence on metabolism, whatever their duration, but while
the effect of such baths or of those slightly above or below can not be meas-
ured in terms of metabolism, their importance in the treatment of many
forms of insanity and in psychoses mjust be mentioned (Beyer). The con-
tinuous flow bath at indifferent temperature produces relief from nervous
symptoms and frequently exercises a more powerful and effective sedative
action than any drug. Such effects are secondary to those produced on
metabolism itself but they far outweigh the latter in importance.
Cold Baths
The immediate effect of a cool or cold bath is a contraction of the
cutaneous blood vessels, more or less proportional to the degree of cold,
whereby loss of heat by radiation, conduction and evaporation is dimin-
ished. Depending on the extent of the cold, respiration also becomes more
deep and rapid and muscular activity is excited reflexly. These responses,
especially the muscular contractions known as shivering, are an attempt
to produce more heat, loss of which from the body has been compensated
to a slight degree only by physical regulation (Loewy). If cold application
is prolonged, heat production fails to keep pace with loss, anemia gives
place to hyperemia which unless it is only local (as from an ice bag)
produces a rapid fall in body temperature and the circulation begins to
fail. If, however, the cold is withdrawn before this time a ^secondary
hyperemia, the "reaction" in hydrotherapy, is secured and by thus prem-
aturely breaking off the physical regulation, the stimulus due to the tem-
perature change is artificially enhanced. In the opinion of Matthes the
stimulus due to a short exposure to cold is probably of small importance
compared with the effect of the "reaction." According to Fox the whole
effect of baths of .every description is founded on the power of reaction
possessed by the organism. The extent of the reaction is diminished
HYDROTHERAPY
857
when the abstraction of heat is gradual or prolonged or when the individual
is already cool or remains quiescent during and after the bath; it is in-
creased when the application of cold is rapid and when a mechanical stimu-
lus is added.
A transient fall in body temperature, even several degrees, may follow
a cold bath and the effectiveness of a bath only slightly below body tem-
perature in reducing fever temperature has long been known (Palmer).
The contrary findings of different investigators (Liebermeister(&) ; Le
Fevre(c) ; Durig and Lode) often of a single investigator on the same
subject, are evidence that body temperature is not a simple resultant or
that physical regulation does not behave uniformly, a possibility suggested
by the ability of adaptation to repeated cold. Jiirgenson found the great-
est lowering of temperature by a cold bath not during but after the bath,
a "primary after effect" that has been found by others (Mattill(o.))
and may be due in part to evaporation of water retained on ,and in the
epidermis, in part to the failure of physical regulation during the active
hyperemia and its increase of heat loss. After the cooling period (5-8
hrs.) the temperature may rise higher than the corresponding daily tem-
perature and remain there some hours as a result of the "after-effect."
The duration ,and extent of these variations in body temperature are ex-
tremely variable (Loewy, Miiller, et al. ; Hoffman). Local applications
of cold may markedly lower the temperature of the part treated as well as
of the underlying tissues and organs (Riehl).
The effect of cold baths on heat production is marked and the small
magnitude of body temperature changes is in fact very good evidence of
the efficiency of the thermoregulating mechanism. Widely quoted figures
(Matthes(&)) for the effect of bathing on heat production appear in
Table I.
TABLE I
EFFECT OF BATHING ON HEAT PRODUCTION
Te
mp. of Ba
th
15° C.
20° C.
25° C.
30° C.
35° C.
Heat production in calories
480
370
240
150
80
Heat — 18 calories for heat loss in
resp
498
388
258
168
98
Heat — 91 calories which a man of
CO kg. normally produces
407
297
167
77
7
Metabolism reduced to grains of fat.
After-effect of bath reduced to grams
of fat
43
9
31
6
18
4
8
1
0.7
0.0
Total effect and after-effect reduced
to grams of fat
52
37
22
9
0.7
Similar results were obtained by Ignatowski who, in a bath at 17° C.
lasting 2.5 minutes found heat production 14 times normal. Of the 65
858
HENRY A. MATTILL
Cal. thus expended, 44 were given out during the first minute, 21 in the
subsequent one and one-half minutes, and the subject was 0.3° warmer at
the end. In a bath at 26.75° C.'for fifteen minutes the heat loss in the
three successive five-minute periods was 43, 17, and 17 calories. An ab-
normal loss of heat therefore takes place before physical regulation be-
comes entirely efficient and the cooling of the skin itself tends to reduce
heat loss. This investigator also found that when his patients were real
cooled down, if no "reaction" occurred heat loss after the bath continuec
to decrease and heat production also. With a prompt "reaction" a diminu-
tion in heat loss could not be observed.
TABLE II
Form of Bath
Duration
Temp.
Increase in
Respired
Air %
Increased
C02 Output
Increased
Os Intake
Resp.
Quotient
Douch
3-5 min.
16°
54.5
149.4
110.1
0.87-1.02
Tub bath
3-5 min.
16°
22.9
64.8
46.8
0.88-1.0
Rubner's(fc) experiments on the effects of baths and douches given in
Table II show the marked effect of douches as compared with baths
at the same temperature (compare mechanical stimulation below) and the
respiratory quotient indicates that carbohydrates were the source of the
extra energy expended. The experiments of Lusk in which men in a post-
absorptive condition bathed in water at 10-16° C. are summarized in
Table III. The shivering induced caused a fall in the respiratory quo-
tient to the fasting level indicating complete exhaustion of the stores of
glycogen ; in one muscular individual this did not obtain. Severe shiver-
ing in one case produced a respiratory quotient of 0.67, indicating the
formation of glycogen from protein, but there are no data on nitrogen
elimination.
TABLE III
Form of Bath
Duration
Temp.
Increased
Cal. per Kg.
per Hr. %
Increased
C02 Output
%
Increased
02 Intake
%
Resp.
Quotient
Subject I, Tub
bath
6 min
10°
29
OJ.
99- 82
Subject I, Tub
bath
12°
33
99
4ft
QQ. 7K
Subject II, Tub
bath
9 min
10°
181
160
188
95- 85
Subject II, Tub
bath
10 min
10°
116
158
TOfi
fi7- 84
Observers agree that the extra energy called out by ordinary cold baths
comes from non-nitrogenous material only. When body temperature falls
and warm-blooded animals, obeying the laws to which cold-blooded ani-
HYDROTHERAPY 859
mals are always subject, decrease their metabolism, protein disintegration
rises above normal, as shown on dogs (Lepine and Flavard; Dommer)
and also on men whose temperatures were reduced to 32° (Formanek(6)).
On nitrogen distribution following cold fresh-water baths, the data of
Schilling are considered reliable ; he found a marked increase in ammonia
excretion not associated with a simultaneous increase in nitrogen elimina-
tion. The findings of Krauss showed an increased acidity after cold baths
and temporary albuminuria may often appear after prolonged cold baths
(Araki(fr) ; Rem-Picci). Under normal bathing conditions as employed
in hydrotherapy, short cold baths cause an increase in metabolism of non-
nitrogenous materials only, the energy derived therefrom being used
for heat production and for the increased muscular work which this neces-
sitates. Any energy changes due to the cooling itself are obscured by the
energy expended in muscular activity and it is probable that both of these
are influenced somewhat by the adaptive power of individuals to repeated
heat deprivation, as well as by their physical characteristics and state
of nutrition. Whether the additional heat production necessitated by cold
baths takes place in the absence of muscular activity need not be discussed
at this time since under ordinary conditions there is no restraint upon
movement. In experiments on men it was shown that the cooling of the
body in cold baths was accompanied by a rise in respiratory metabolism
only where involuntary shivering occurred (Silber). It must be expected
that even in the absence of such movement the additional work performed
by the respiratory muscles, the heart and the vasomotor system provides
some heat as a by-product.
The redistribution of blood under local or general application of cold
is considerable (Hewlett, van Z. and M.) and organ activity and local
metabolism are thereby modified in so far as they are dependent on blood
supply. Also, since cold can penetrate more deeply than heat, it is possi-
ble to limit its eifect on individual organs more accurately than is the
case with heat. The general effects of cold baths on the circulatory
system involve the many hydrostatic as well as reflex vascular factors
affecting the bulk and the flow of the blood, and are therefore very com-
plex. After a cold bath the pulse is slowed (Beck and Dohan), the volume
pulse and minute volume are increased (Schapals), arterial blood pressure
is often increased and venous pressure decreased (Winternitz(e) ; Edge-
combe and Bain), the extent probably depending in part on internal com-
pensations and antagonisms (Muller(a)). According to Strassburger
systolic blood pressure during a cold bath may show two or three phases, a
rapid rise, the more rapid as the bath is colder, a decrease (corresponding
to the ''reaction") and a final increase, depending on the balance between
the heart action and the condition of the capillaries. After the bath there
is a fall in blood pressure, usually under the original level. The transient
increase in blood pressure has been given as the cause of the diuresis tern-
860 HEKRY A. MATTILL
porarily occasioned by cold baths (Lambert), but the vasomotor changes in
the skin, perhaps also in the kidney (Delezenne; Werthheimer), probably
influence urine secretion somewhat. An increase in the number oi
erythrocytes takes place during a cold bath and is maintained for as long
as two hours according to Winternitz but this is not confirmed by Tuttle.
An increased elimination of urobilin after cold baths has been reported
(Siccardi) and leucocytosis has also been observed (Rovighi; Thayer).
The occurrence of paroxysmal hemoglobinuria after cold baths
common ; a fairly complete review of this condition is given by Donath who
concludes that a hemolytic property is imparted to the plasma by cold.
Cold baths usually have a refreshing effect; whether this comes as
a result of modifications in the cutaneous sensations (Santlus) or in muscle
sense (Vinaj) or as the result of changes in muscular efficiency (Uhlich) i«
uncertain.. That baths produce these changes is also questioned ( Tuttle j.
Hot Baths
The body possesses no chemical regulation for lessened heat production
and when, in surroundings warmer than the body, the utmost heat loss by
radiation and evaporation has been secured, the body temperature must
rise. Rise of temperature means increased metabolism, as was first shown
by Pfliiger on animals and later by Winternitz and others (Ignatowski;
Linser and Schmid) on man. Even moderate heating without any change
in respiration causes an increase in oxygen consumption in excess of that
due to fever ( Winternitz (&)). Some of this increased heat production
can be accounted for by increased work of the heart, of the muscles of
respiration and of the sweat glands, but Winternitz's calculation still
leaves 30-75 per cent unaccounted for, and it is probable that under these
conditions warm-blooded animals, having overstepped the limits set by
the heat-regulating mechanism, are subject to the effects of the general
law applying to all chemical reactions.
The after-effects of a hot bath are less uniform than those of a cold
bath. A continuation in the rise of body temperature after a hot or vapor
bath is explained (Speck) as a natural result of the higher temperature oi
the skin and subcutaneous tissues as compared with that of the muscles and
internal organs (Hirsch and Miiller), a reversal of the ordinary condition.
A compensating abnormal fall in temperature is seldom observed but in
the two hours after a hot bath during which normal temperature is re-
gained (Wick) there is a continued loss of heat in the various ways at
double or three times the normal rate (Ignatowski). Winternitz (&)
found oxygen consumption still 29 per cent above normal, 75 minutes
after a hot bath. Even in hot baths of short duration without appre-
ciable heat disturbance the volume of inspired air, the oxygen in-
take and the CO2 output are increased but to a much smaller extent
HYDROTHERAPY 861
than in cold baths. In both cases Rubner found the respiratory quotient
rising from 0.86 to 1, as if the organism were called upon to do increased
work alike by cold and hot baths. Rubner also found that an hour after
a short hot bath or douche the volume of respired air and the metabolism
decreased considerably, and there is thus a considerable difference in the
after-effects of hot baths according to their duration. The absolute rela-
tion between the amount of heat applied and the increased heat production
varies according to different investigators (Linser and Schmid; Salomon),
and the differing activity of the sweat glands in physical regulation may
be an adequate explanation. Marked increases in oxygen consump-
tion, 40-111 per cent, are usually not accompanied by a proportional
increase in CO2 output, with the result that the respiratory quotient
assumes low values. Similar low values are common in fever and
after violent exercise, suggesting, as in Lusk's ice bath experiment, the
complete exhaustion of glycogen and the breakdown of protein for its
formation. An increase in protein metabolism after hot baths was long
ago found in animals (Richter, Koch) and later in men (Formanek(a) ;
Topp). However, Tuttle (with Folin) in careful experiments was unable
to show any changes in metabolism as a result of hot baths. Since these
were usually hot air baths at 190° F. or below for 5 minutes followed by
indifferent and cold douches lasting one minute, or indifferent douches
followed by cold douches lasting between one and two minutes, it is possible
that the total heat effect was inadequate to produce changes in nitrogen
metabolism. They made no determination of gaseous metabolism. An
increase in protein metabolism according to Voit is not a primary result
of increased body temperature but follows upon the exhaustion of readily
available non-nitrogenous material since he found only a very small amount
of glycogen in the liver after artificial overheating and since the admin-
istration of 30-40 gm. of sugar prevented an increased nitrogen excre-
tion. This relation of rise in temperature to glycogen stores was not-
confirmed (Senator and Richter). It is probable that hyperthermia
does not always cause increased nitrogen metabolism, according to
Winternitz in only about one-third of the cases, and Linser and Schmid
found that in fever, carbohydrate administration limited nitrogen
elimination to a less extent than when the temperature was normal. Ac-
cording to these investigators the application of external heat even for
many days does not increase nitrogen output if the body temperature
remains at 39° C. or below, though when 40° C. is reached it usually
does, particularly if the heating process is abrupt. They do not agree with
Voit that it is a question merely of inadequate oxidizable material of a
non-nitrogenous nature, and consider that in fevers the toxemia plays a
part. The nitrogen loss as a result of hot baths is, according to Reilingh
de Vries, only momentary since he finds that during a considerable period
in which not excessively hot air baths were taken a compensatory nitrogen
862 HENRY A. MATTILL
retention took place, but with great individual variation, depending also
on the bathing procedure and on the amount of liquid ingested. As to
the nitrogen distribution in the urine, ammonia runs parallel with total
nitrogen though slightly below proportionate amounts (Linser and
Schmid; Schilling; Formanek(a)). Phosphoric acid also parallels
nitrogen. There may be a very slight though not marked increase in
purin bodies. The hydrogen ion concentration of the urine is increased by
15-20 minutes of heating in a sweat cabinet (Talbert(&)). Urinary de-
terminations alone are not sufficient since in conditions of overheating the
amount of sweat and its solid content are greatly increased.
The effects of very hot baths (105-110° F.) on pulse and blood pres-
sure were investigated by Hill and Flack. After 15-20 minutes in such a
bath body temperature rose 4-6° F., pulse increased to 160 and blood
pressure fell 60, thus confirming earlier observations (Bain, Edgecombe
and Frankling). They also verify previous findings as to increased
respiratory frequency and volume (Edgecombe and Bain) accompanied
by a notable fall in carbon dioxi,d tension with corresponding rise in
oxygen tension. An increased systolic pressure during a hot bath was
obtained by Strassburger(a), the hotter the bath the greater the final rise,
which he considered due to increased work of the heart. The pulse vol-
ume (Schapals) and the heart volume (Beck and Dohan) are decreased.
The viscosity of the blood is said to be decreased (Hess, W.) and certain
of the antibodies have showed slight increase after various forms of heat
treatment (Laqueur), but these changes are probably as transient as are
the more readily determined variations. The non-protein nitrogen content
of the blood in nephritis is not reduced by sweat baths (Austin
and Miller). The oxidation of benzol to phenol in the organism is, ac-
cording to Siegel, greatly accelerated by sweating processes, also by cold
baths and by salt water baths more than by ordinary baths at the same
temperature. The effect extended beyond the period of treatment, but
there was great individual variation. It is stated that hot baths increase
the secretion of bile (Kowalski) and that hot poultices or packs induce a
secretion of gastric hydrochloric acid (Penzoldt(a)). It has long been
known that the hyperemia produced by local application of heat accelerates
absorption (Sassezky).
The Influence of Mechanical and Chemical Stimulation
Accompanying Baths
Under this heading will be considered the effect of mechanical
factors in the application of baths in ordinary water, and the mechanical
and chemical stimuli arising from the presence of gases, salts and other
substances in the bathing water.
HYDROTHERAPY 863
The markedly increased stimulation to heat production (more than
double ) from a cold douche as compared with a cold tub bath at the same
temperature is evident from the table given above. Winternitz(a) showed
that the application of friction in a cold bath caused an earlier fall in
temperature and a greater increase in oxygen intake and CO2 production
than a similar bath without friction. He also observed a very marked
increase in heat production in a hot sand bath as compared with the re-
sults of hot air baths. Two factors, a premature breakdown of physical
regulation and a direct stimulation probably come into play. Brush-
ing the skin causes rise in temperature in man (Paalzow) ; so also the
application of mustard paste. Mustard added to a bath at indifferent tem-
perature increased O2 consumption and CO2 output by 25 per cent though
without affecting the respiratory quotient. By far the greatest interest
naturally attaches to sea baths and to the various other natural and artifi-
cial baths containing salts. That it is not a question of absorption through
the skin is pretty well agreed upon, since the sebaceous secretions forms a
barrier to water and all water soluble substances unless they act chemically
on the skin. Fats and their solvents on the other hand may be imbibed
by the cells or make their way through the capillary spaces and it has been
reported l that water soluble substances may be taken up by ether-cleansed
skin. Most of the investigations on sea and brine baths seem to show that
their effect on energy metabolism is no different from that of baths in ordi-
nary water at the same temperature (Jacob(a)(&) ; Leichtenstern) al-
though as early as 1871 Rohrig and Zunz showed a greater gaseous exchange
in rabbits in a sea salt bath than in a fresh water bath. Winternitz(e)
concluded that such baths produce very little change in the metabolism of
healthy adults, not more than 15 per cent after baths lasting one hour. The
careful work of Loewy and Miiller on sea air and sea baths showed an in-
creased metabolism as evidenced by greater oxygen consumption and a
decreased respiratory quotient extending beyond the duration of the bath,
but there are no comparative data for fresh water bathing with similar
climatic influence. The influence of salt water baths on nitrogen and in-
organic especially salt metabolism has been the subject of more extended
work and discussion. Some early results (l)ommer) tending to show that
4 per cent Nad baths caused a marked increase in nitrogen output (in a
dog) have generally not been corroborated. The one investigator who does
uphold this idea (Robin) probably had too short a preliminary period to
observe nitrogen metabolism properly. Koestlin found a decrease in
nitrogen excretion after warm sool baths (Stassfurt salt) while fresh water
baths had no influence nor did sodium chlorid or magnesium chlorid baths,
hut potassium chlorid baths gave the same results as Stassfurt salts from
which he concluded that potassium chlorid was the active factor. How-
ever, he did not account for fecal nitrogen or for the nitrogen given out in
'Kahlenberg, private communication to the author.
864: HENKY A. MATTILL
the sweat and his results are questioned by Bahrmann and Kochmann who
conclude that even sool baths have effects no different from those of baths
in ordinary water at the same temperature, nor do they trust the various
reports on the usually increased chlorid excretion as a result of bathing
(Keller; Eobin) because of too brief preliminary periods and because the
laws of sodium chlorid metabolism are not yet well enough understood.
In the careful work on sea bathing above referred to an increased excre-
tion of sodium chlorid was recorded during the bathing periods, an amount
that would have required an intake of 100 c.c. of sea water, and the
accidental gulping of water was avoided.
In experiments on the metabolic effects of bathing in the Great Salt
Lake (20 per cent solids, mostly sodium chlorid) it appeared (Mattill(a)
(&) ) that the excretion of urinary nitrogen and salt increased progressively
during the progress of the bathing periods. Most of the extra elimination
appeared during the three hours following the bath and in amounts of from
15 to 50 per cent above the excretion during the same period on non-bathing
days (Fig. 1). There was no evident compensatory decrease during the
other periods of the day and the accidental swallowing of salt water was
studiously avoided. The fairly uniform parallelism between nitrogen and
chlorid excretion has no obvious explanation; it is similar to the find-
ings obtained by various investigators in experiments on the influence of
water ingestion. Other urinary constituents, ammonia, uric acid and crea-
tinin were uninfluenced by the bathing. The mechanical effect of the
pressure of water was much greater in this case because of the high concen-
tration of solids, and the residual effect of the salts on the skin was cor-
respondingly higher. This, according to Hiller may be as great as that
of the bath itself. Such salts may be demonstrated spectroscopically on
the skin as long as a week after a bath and various physical as well as
chemical effects have been ascribed to them (Lehmann; Frankenhauser ;
Schwenkenbecher). The amounts remaining after a salt bath vary with
different individuals perhaps as a result of varying amount of body hair
(Loewy and Muller).
The clinical investigations as to the influence of salt baths on metabo-
lism seem to show more significant results than the purely experimental.
The experiments of Heubner on two strumous children and those of
Schkarin and Kufajeff on rachitic infants show that these baths have a
very definite influence on the child's organism, perhaps because of the
relatively greater surface area. The former investigator used gradually
increasing salt concentrations and found no increase in body weight in
spite of liberal feeding. Nitrogen elimination increased as the bathing
period progressed with highest values in the final period leading to a nega-
tive balance in one case in which there was poorer utilization of food.
In this case there was chlorid retention, in the former sodium chlorid
excretion remained practically uniform. Heubner considered that metab-
HYDROTHERAPY
865
olism was affected (1) by the tide of the blood between the surface and the
interior of the body, and (2) by the stimulation of the peripheral vaso-
motor and sensory nerves. The Russian investigators in their five cases
observed a considerable decrease in nitrogen retention during the bathing
periods, which was not a result of poorer utilization of the food. In three
cases in which a final period was also possible nitrogen retention was seen
:b*'~ -, r L.^l0!"1)!!!6.
r— i TotolN
Wfl 12 i 4 6 8 /o « x? 4
Subject I.
6 a
&Vttl \l i 4 6 8 /O « ^ >» 6 f
Subject 2.
Fig. 1. Total nitrogen and sodium chlorid in tenths of grama, creatinin in
hundredths of grams. B = Bath. (Reproduced by permission of the American Jour-
nal of Physiology.)
to increase toward the values found in the preliminary periods and the
possibility that all children may not react to the "cure" in this way indi-
cates that the use of sool baths in pediatrics must rest on a scientific founda-
tion.
Blood pressure measurements made by Loewy and others in the sea-
bathing experiments mentioned above showed a pronounced rise in systolic
pressure, scarcely any change in the diastolic, with the result that pulse
pressure reached high levels. There was usually also an increase in pulse
late. Within five minutes after the bath these phenomena had practically
8G6 HENRY A. MATTILL
disappeared. The comparative findings in a cold tub bath during which
both svstolic and diastolic pressures are raised and pulse is slowed show
the great difference in the effects of the two kinds of baths on the circula-
tion, and they consider that a sea bath involves, in addition to the effect of
a cold bath, three factors, the salt content of the water, the mechanical
effect of the waves on the skin and the muscular work involved in buffeting
the waves. Similar data from fresh water seem not to be at hand. Blood
pressure values following bathing in Great Salt Lake, although obtained
during the bath, were normal perhaps because the factor of exercise in
resistance to waves was absent.
It is a common experience that the skin feels "smoother" after a salt
water bath than after a fresh water bath. This may be associated with
modifications in skin sensitivity (Santlus).
Effervescent Baths
The presence of a dissolved gas in water lowers the indifferent tem-
perature of the water; that is, the temperature at which heat is neither
added to nor taken from the body. Water at 25° C. feels cool ; CO2 or O2
at that temperature feels warmer (Senator and Frankenhauser) . In a
cold effervescent bath when the body becomes covered with bubbles the
points of the skin in contact with gas feel warmer than those in contact
with water and the former 'also give off heat less rapidly since gas is a
poorer conductor than water, CO2 only one-half that of air. However,
the tactile end-organs of the skin as well as the warm and cold spots are
stimulated (Goldscheider) and the tendency to heat loss and to secondary
heat production is greater in an effervescent bath because physical regula-
tion is prematurely broken down by the mechanical stimulus. Hyper-
emia of the skin, the "reaction" appears more quickly and with
less feeling of cold than in an ordinary bath at the same temperature.
After due allowance has been made for these different and variable factors,
it may be questioned whether an effervescent bath introduces into hydro-
therapy any new features beyond the possibility of further combinations
of the effects secured by ordinary procedures. The resultant temperature
effect is the determining factor.
The original experiments of Winternitz showed that CO2 baths caused
an increase in the total volume of respired air and a remarkable rise in
CO2 output without corresponding increase in oxygen intake ; he explained
the increased CO2 output by assuming an absorption of CO2 by the skin.
During the last two decades a very considerable body of literature has
appeared on the effects of CO2 and O2 containing baths particularly on
blood pressure (Groedel), much of it contradictory and propagandist in
nature. According to Swan the influence of carbonated baths on blood
"
pressure is variable and any favorable results secured in cardiac cases are
independent of the effect on blood pressure.
Peat and mud baths have a point of thermal indifference considerably
above that of water, as high as 39° C. ; in the absence of convection cur-
rents and because of the non-conducting layer next the skin the effects of
heat are equalized and the skin temperature remains more constant. Pos-
sibly the chemical action of the acids and salts found in peat and mud
and the physical effects of friction and pressure may affect metabolism ;
but there are no entirely trustworthy data as to the effects of such baths
and such as are at hand (Tuszkai; Silber) do not show results that are
not attributable to temperature effects on metabolism. Sulphur baths
seem to have no specific influence on metabolism (Bain, Edgecombe and
Frankling; Winternitz and Popischil).
Radioactive baths and springs have given the opportunity for the
publication of a number of papers dealing with the supposed benefits at-
tending their extensive use. Radium emanation does not enter the body
by the skin (Nagelschmidt and Kohlrausch) and when it was added to a
fresh water bath no influence on gaseous metabolism was observed (Silber-
gleit(aO).
Baths and Sweat Secretion
The influence of baths on the rate of secretion and on the composi-
tion of the sweat is of special interest because of a possible vicarious skin
excretion under the influence of heat treatment, especially in diseases of
the kidney. The data on the composition of human sweat are fragmentary
and conflicting partly because of the wide variety of conditions under
which sweat has been collected, because the composition changes with
changing rate of secretion (Kittsteiner(a) (&)), varies with the different
parts of the body from which it comes, and may vary with the diet (Kitt-
steiner(c) ; Berry). It is thus not possible to tabulate the results that
have been obtained ( Argutinsky ; Benedict (a) ; Schwenkenbecher and
Spitta ; Taylor(d), Talbert(a)). The values for nitrogen elimination
under different conditions vary from 0.07 to 0.75 gr. per day (or part
of a day), half of which is in the form of urea (Plaggemeyer and Mar-
shall). Salt excretion is said to vary from 0.33 gr. to 1 gram in profuse
perspiration. Whether nephritics eliminate more solids in the sweat than
normal persons seems undecided (Kohler; Tachau ; Riggs; Loofs; Strauss
(a) ) and figures on the A of the blood in nephritis as influenced by sweat-
ing procedures (Bendix; Georgopulos) are not extensive enough 1o be
convincing. Even if perspiration leads to a decrease in the urea of the
urine, which it does not, always (Leube; Dapper (a ); v. Noorden(c))
the amounts of nitrogenous material and salts which can be eliminated
by the skin are a very small fraction of those eliminated by the kidney,
868
HE^RY A. MATTILL
or of those present in the blood and tissues in renal disease, and in
v. Noorden's opinion there is no evidence of a 'Vicarious" excretion on the
part of the sweat glands. A reported suppression of alimentary glyco-
suria by rapid perspiration and appearance of sugar in the sweat (Bendix)
requires confirmation. While hot baths may be of value in nephritis
(Strasser and Blumenkranz) the excessive water lost in perspiration must
be restored and in the light of the information on the influence of hot baths
on nitrogen metabolism, the heat application should not be so powerful or
rapid as to cause a rise in body temperature.
The Influence of Roentgen Rays, Radioactive Substances,
Light and Electricity upon Metabolism
Thomas Ordway, Arthur Knudson
Roentgen Rays and Radioactive Substances — Introduction — Measurement
(Standardization) of Radioactive Substances and of Roentgen Rays —
Distribution and Elimination — Effect on the Blood and Blood Forming
Organs — Effect on Immunity — Effect on Normal Metabolism — Effect on
Metabolism in Disease — Constitutional Effects — Theories of Action —
Light — Electricity.
The Influence of Roentgen Rays,
Radioactive Substances, Light
and Electricity upon Metabolism
THOMAS OEDWAY
AXD
ARTHUR KNUDSON
ALBANY
I. Roentgen Rays and Radioactive Substances
Introduction. — This discussion of the effect of Roentgen rays and
radioactive substances upon metabolism will be limited almost exclusively
to the more recent investigations upon man and other mammals. Xo at-
tempt will be made to duplicate the comprehensive surveys of previous au-
thors, nor can any detailed description of the physical nature of these forms
of energy be considered here. In studying the effects of radiations both ra-
dium and x-rays have been used as a means of experiment and the litera-
ture of both may be considered together. As a working basis for experiment
the effects of both are comparable especially in the case of the gamma rays
of radium. The effect of the other rays is not however to be considered
negligible but seems to differ in degree rather than in the kind of their
action so that the results do not conflict with our working hypothesis.
In a survey of the subject of radiotherapy Ordway(a) (&) has briefly
described the methods of use of radioactive substances and Roentgen rays
for external or so-called surgical, and internal or medical conditions. He
has shown that our knowledge of the former is far greater than that of the
latter, which is to be advanced almost exclusively by a careful study of
the effect of these physical agents upon metabolism.
Much of the earlier work has been rendered very uncertain because
of the faulty physical or biological methods. It is also unfortunate that
the application of the results has been in certain instances prema-
turely made to clinical therapeutic work on the assumption that any
changes in the metabolism were necessarily beneficial.
Great caution should be used in estimating the therapeutic effect of
physical agents because of the marked fluctuations which occur in the
871
872
THOMAS ORDWAY AND ARTHUR KNUDSON"
course of chronic diseases, independent of treatment. The importance
of the psychical effect of any treatment must also be considered in thera-
peutic work. Encouragement from the fact that something- (frequently
the more unusual the greater the effect) is being done is often, at least
temporarily, very beneficial to patients suffering from a chronic disease.
It is important to establish definitely in an objective manner how metab-
olism is affected by these physical agents and then to proceed very cai
fully to their therapeutic application.
Measurement (Standardization) of Radioactive Substances and of
Roentgen Rays. — It is extremely important that detailed information of
the exact technique be included in reports, so that the work may be dupli-
cated by others. In the past the difficulty of standardizing the energy of
x-rays has led to varying results and the measurement of the activity of the
x-rays by their effect upon chemical pastilles or photographic films have not.
proven satisfactory. The development of the Coolidge tube has made it
possible to secure the desired milliamperage as distinct from the voltage
and the recently devised stabilizer prevents fluctuations in the current.
The relation of the methods of measurement of x-rays as expressed
in erythema dose is indicated in the following table :
TABLE I
TABLE OF COMPARATIVE X-RAY DOSAGE
Erythema Dose ..
Designation
Author
Position
Tint B
Sabouraud
% target skin dis-
tance
E 16
Kimura
*/6 target skin dis-
tance
5 H
Holzknecht
% target skin dis-
tance
1-% H
tt
Pastille on the
skin
10 X
Kienboeck
Strip on the skin
4 Ha
Hampson
Pastille on the
skin
16 Ha
«
Pastille at 1/2 dis-
tance
Coolidge tube — 40 milliampere minutes at a distance of
10 inches, 60 kilovolts and without any filtration; 60 mil-
liampere minutes with nitration of 1 mm. of aluminum.
Special ionization chambers have been devised to measure the n
tensity of Roentgen rays. A chamber termed the ionto quantimeter for the
clinical measurement of x-rays, suggested by Szillard of Paris, is de
scribed by Knox. Duane made a similar apparatus and placed it betweei
the source of the x-rays and the object to be rayed. Glockner and Reus
Amplified after U. S. A. X-ray Manual. New York: Paul B. Hoeber, 1919.
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 8Y3
have also described an ionization chamber for measurement of the dosage
of Roentgen rays. Kronig and Friederich have made ionization cham-
bers, the so-called ionto quantimeters, so small that they can be placed
within a cavity in close proximity to the part of the body to be rayed.
Such ionization chambers connected with an electroscope or an electro-
meter give an indication of the relative or absolute dosage of x-rays and
should therefore greatly facilitate a comparison of x-rays and radio-
active substances.
Estimation of the activity of radioactive substances when expressed in
milligrams may be misleading unless it is based upon the activity of the
gamma radiation of the radioactive element solely, as indicated by its
power of ionization. This is the method adopted by the United States
Bureau of Standards. Unless the standardization by weight conforms
to the above there may be great variation due to the type of salt used, to
the presence or absence of water of crystallization and particularly to
the variable amount of impurity such as barium. The unit activity of
radium salt should be expressed as above indicated in milligrams of
radium element. The emanation or radioactive gas in equilibrium with
one milligram of radium element has been designated one millicurie. For
measuring the radioactive strength of solutions for bathing and drink-
ing and of. air for inhalation the so-called "Mache" unit is commonly
used. One Mache unit is equivalent to one three-millionth part of a milli-
curie. Three thousand Mache units are equivalent to one-thousandth of
a milligram of radium element. One-thousandth of a milligram is equiva-
lent to one-millionth of a gram and is ^frequently designated as a micro-
gram. The French formerly took the radioactivity of uranium as their
standard. Uranium was considered as having a radioactivity of 1 and
pure radium 2,000,000 times as great. An activity of 500,000 frequently
reported in literature would represent one-fourth of pure radium and
three-fourths of impurity.
In a quantitative study of the effect of radium radiations on the fer-
tilization membranes of Nereis limbata Redfield and Bright obtained
a physiological reaction to these radiations which could be measured with
such precision that the thickening of the membrane served as a physio-
logical index of the intensity of the radiation. Wood and Prime suggest
for an intensity unit of radium the rays emitted by 1 milligram of radium
element (1 millicurie of radium emanation) located at a point 1 centimeter
distant and they designate this as 1 milligram or millicurie centimeter.
Mottram and Russ consider the biological x-ray unit, which they designate
by the name rad, as equal to the exposure to beta and gamma rays from
2.75 milligrams of RaBr2H2O per square centimeter for one hour. This
is just sufficient to prevent the growth of a rat sarcoma and to produce an ^
erythema when applied to human skin.
874 THOMAS ORDWAY AND ARTHUR KNUDSON
Distribution and Elimination. — Radioactive substances differ from
the x-rays from the fact that in solution in the form of a salt, or as active
deposit of radium emanation, or the emanation itself in solution, thej
may be ingested or injected into the animal body. The emanation, th(
radioactive gas evolved from a solution of radium, may also be taker
into the body by inhalation. A method of condensing the emanation anc
the deposition of the active deposit upon sodium chlorid which may be
dissolved in water to make an isotonic solution has been described bj
Duane.
Berg and Welker found that after subcutaneous injections the radium
(bromid) like barium and calcium is eliminated chiefly by the intestinal
tract. Meyer after intravenous injection of solutions of radium bromide
showed the presence of radium in the liver, lungs, and kidneys. The
ultimate fate was not materially different if the radium was injected in any
other manner, that is, subcutaneously or intraperitoneally or if a solu-
tion were taken by mouth.
Salant and Meyer conclude that the elimination of radium is chiefly
by way of the liver, kidneys, and the small intestine and to a less extent
through the large intestine in some herbivora. Brill and Zehner found
that radium chlorid injected into dogs and rabbits was eliminated almost
exclusively by the feces and there was very little in the urine. Bagg(a)
found that following the injections of active deposit from radium emana-
tion there is diffusion of radioactive substance throughout the animal
body, resulting in pathological changes in various organs, notably the
liver, lungs, kidneys, adrenals, spleen, bone marrow, brain and vascular
system.
Effect on Tissues. — It is well known that radiations of Roentgen rays
and radioactive substances affect different tissues to a varying degree
and that the lymphatic tissue, spleen, lymph glands, bone marrow and
sex glands are particularly susceptible (Heinecke and Warthin). Hauscht-
nig in describing the technique for radium treatment shows that the mucosa
of the intestines and bladder is sensitive to one erythema dose while
the muscles of the cervix uteri are resistant to forty, those of the corpus
uteri to thirty, and the vaginal mucosa to five or six erythema doses. The
dose which destroys carcinoma cells is practically the same as the erythema
dose of the skin. Nervous tissues are very resistant to radiations.
Nakahara, and Nakahara and Murphy believe that by a carefully
measured dose of x-rays (Coolidge tube, spark gap % inch, milliamperage
25, distance 8 inches, time 10 minutes) within four days there is an ab-
normally large number of mitotic figures found in the lymphoid tissue
of the spleen and lymph glands. They believe that this indicates accelera-
tion of the proliferative activity of this tissue by exposure to x-rays of
low voltage. The great variation in the activity of lymphoid tissue nat-
urally at different ages and also when due to Intel-current infections and
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 875
of the small number of animals in these experiments render the results
uncertain.
Kimura has studied the effects of x-rays on living carcinoma and sar-
coma cells in tissue cultures grown in guinea pig plasma to which was
added mouse serum diluted with Ringer's solution and found that the
outspreading growth was not stopped by the action of the x-rays with
a dosage of E 4 to E 12. The mitotic figures were limited to a minimum
after an exposure to a dosage of E 8 and after an exposure to E 12 the
mitoses disappeared entirely and the tissue so treated produced no tumors
when inoculated into mice. The growing power of the sarcoma after
exposure to a dose of E 4 was apparently somewhat stimulated and the
carcinoma was not appreciably influenced. The process of oxidation of
the tissues in both the sarcoma and carcinoma cultures was stimulated
by x-ray action of the dosage of E 4 and retarded by exposures to E 12.
The histological changes in tissue, induced by exposure to radiations
of x-rays and radium, have been described in detail by many investigators.
They consist of a necrobiosis of the cells, a chronic inflammatory reaction,
followed by fibrosis. The changes depend on the intensity of the radia-
tion and the type of tissue radiated.
Effect on the Blood and Blood Forming Organs. — The chemical ef-
fect of radiations of radium and x-ray upon the blood will be referred
to later. Gudzent(<;) has summarized the work prior to 1913. It may be
briefly stated that 'the lymphocytes are apparently stimulated to both
relative and absolute increase by small doses and reduced in number
by large doses of x-rays ; and that the spleen and lymph glands undergo
profound change by destruction of the cellular elements as the result of
exposure to x-rays and radium. Gudzent and Halberstaedter found
in the blood of radium workers striking relative increase in lymphocytes
(36 to 63 per cent), in an average of ten cases 40.4 per cent and a relative
and absolute decrease in neutrophils, the average number being 50.3 per
cent. There was little change in the red blood corpuscles, slight diminu-
tion in the white cells, the hemoglobin was lowered in only two cases, 70
and 71 per cent respectively. Ordway(c) found a similar though some-
what less marked change in a series of clinical workers who showed local
occupational injuries due to the handling of radium.
Millet and Mueller in a study of the blood of ten patients with squam-
ous cell carcinoma of the cervix uteri and the vagina, for the immediate and
remote effects of radium and x-rays, found an immediate drop in the total
white count reaching a maximum in one-half to six hours after applica-
tion, and a return to normal within twelve to twenty-four hours. Oc-
casionally there was a secondary rise in from 12 hours to 3 days. The
polymorphonuclear count followed the total white count. The total lym-
phocytes tended to follow the white count but were not constant. There
was a tendency for the relative lymphocyte count to drop and the poly-
876 THOMAS ORDWAY AND ARTHUR KNUDSON
morphomiclear to rise during treatment but this tendency was reversed
immediately following the removal of the radiations. The remote effects
consisted of a fall in the lymphocyte count for two to four weeks after
treatment, sometimes lasting until the end of the second month. The fall
in the polymorphonuclears was usually less than' the lymphocytes, the lat-
ter after from three to nineteen weeks rose to the normal level. When
the patient's resistance weakened they found an increase in the polymor-
phonuclear leucocytes and decrease in the lymphocytes but without leu-
cocytosis due chiefly to an absolute increase in the polymorphonuclear leu-
cocytes and usually a decrease in the lymphocytes. Such changes in the
blood, however, are subject to considerable fluctuations owing to secondary
infections. This is not only true in human beings but particularly ii
the experimental study of radiation effects in the blood of animals.
Woglam and Itami have shown that it is not easy to establish a normal
standard for certain laboratory animals, notably mice, that there is great
variation in the activity of the hematopoietic tissues in apparently healthy
individuals. The age as well as^ intercurrent infections are factors whicl
must be taken into consideration.
Aubertin and Beaujard studying the action of x-rays on the blood
and bone marrow show that the marrow is much less sensitive to raying
than the lymphoid tissue. They believe that leukopenia may be produced
by the x-ray, either by the direct action of the rays upon the leucocytes in
the circulation or by its action on hematopoietic tissue which prevents
normal regeneration of white blood cells. Brill and Zehner injected a
soluble salt of radium (RaCl2) subcutaneously into dogs and rabbits
in doses of 0.0025 and 0.093 mgm. and found that almost immediately the
number of red cells per cu. mm. was greatly increased. On the day fol-
lowing there was another marked increase. This polycythemia persisted
for a week and for several weeks the number of red blood cells was con-
siderably above normal; the hemoglobin did not rise so markedly. The
leucocytes increased rapidly after small injections and in certain instances
rose to 200 per cent above the normal. The larger injections on the other
hand inhibited leucocyte production.
Effect on Immunity. — X-rays and radioactive substances have such
a pronounced effect on the blood and blood forming organs, the bone
marrow, spleen, and lymphoid tissue generally that it is not surprising
that variations in immunity and susceptibility are produced by exposure to
radiations. Hektoen(a) (&) found that long exposure to x-ray at the time
the antigens were injected into white rats markedly reduced the production
of hemolytic antibodies. He assumed that this was due to the destructive
effect on the lymphatic tissues, spleen and bone marrow. In some further
experiments he exposed dogs to x-rays for ten minutes, followed the next
day by a two and a half minute exposure (approximately ST1/^ Kienboeck
units) ; they showed slight apparent disturbance of general health and no
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 877
great change in the leucocytes in the peripheral blood but there was a
marked reduction in the production of antibodies hemolytic for red blood
corpuscles of the rabbit.
Morton found .that exposure of guinea pigs to x-rays rendered these
animals more susceptible to experimental tuberculosis and suggested
such preliminary radiation for the routine diagnosis by the guinea pig
method. Kessel and Sittenfield, however, believe that after a certain stage
radiation tends to prolong the life of a tuberculous guinea pig and to
promote healing. Kellert finds that in routine work preliminary radiation
does not hasten the diagnosis by rendering guinea pigs more susceptible to
tuberculosis but that the increased susceptibility of such animals to sec-
ondary invaders and contaminating organisms interferes with the
routine work. Corper and Chovey, by subjecting mice to a single non-
lethal dose of x-rays or to a single non-fatal injection of thorium-x, sub-
sequently found that these animals showed an increased susceptibility when
inoculated with pneumococci (four types) and hemolytic streptococci (hu-
man and bovine).
Russ, Chambers, Scott and Mottram in experimental studies with
small doses of x-rays, following the work of Murphy and Morton (a), 011
the blood of rats in its relation to rat susceptibility in Jensen rat sar-
coma find that the natural immunity which these animals have towards
inoculation of spontaneous tumors can be broken down by an x-ray ex-
posure sufficient to cause the disappearance of the lymphocytes. Prime
on the other hand did not succeed in rendering rats naturally immune to
the Flexner-Joblmg rat carcinoma, more susceptible by reducing the lym-
phocytes as advocated by Murphy. Murphy and Taylor have shown that
the acquired immunity resulting from the inoculation of blood or other
cells into normal animals can be similarly destroyed. The acquired im-
munity found in animals in which tumors have disappeared, according
to Mottram and Russ, can be broken down only so long as lymphoid cells
are reduced in number. Tumor cells from a foreign species which on in-
oculation will grow only with great rarity multiply rapidly in an x-rayed
animal until such a time as the depleted lymphoid tissues are well
advanced in regeneration (Murphy).
On the other hand Russ, Chambers, Scott and Mottram, and Murphy
and Morton (a) have shown that an immune condition can be produced in-
stead of destroyed by suitable doses of x-ray. After the removal of tumors
from mice by operation Murphy and Morton (&) gave small dose of x-rays
and found that grafts of the same tumors when inoculated did not grow
in twenty-six out of fifty-two mice and that there' was no recurrence at
the site of operation in forty-one animals. In twenty-nine control mice
who were not given small doses of x-rays the grafts grew in twenty-eight
and there was local recurrence in fourteen.
878 THOMAS ORDWAY AND ARTHUR KNUDSON
From the above it appears that the x-rays have two actions aside from
the direct effect upon the tumor. First a large dose destroying the im-
mune condition will favor the growth of tumor, a small dose producing
the immune condition helps to inhibit the growth of tumor.
Such studies indicate that in treating growths by radium or x-ray a
treatment directed solely toward the primary growth may favor metastasis
by lowering the natural powers of resistance of the patient, especially if.
comparatively large doses are repeated at too frequent intervals. Murphy
believes that great caution should be used about destroying the lymphocytes
which seem to play the defensive role in malignant growths.
Up to the present time the x-ray has only increased the resistance to
inoculated cancer. Yet there is a distinct analogy between such and
metastatic deposits of a spontaneous growth. Hence it is suggested by
Murphy -that repeated small doses of x-rays at intervals might similarly
increase resistance against the development of secondary, metastatic
growths.
Rohdenburg and Bullock by «heat and exposure to radium have in-
creased the susceptibility in mice and rats to the immunizing action of
homologous living cells and the additional immunity thus obtained may
be one hundred per cent over the usual figure. The growth energy of
transplanted tumors also can be depressed by radium (Wedd and Russ).
This retardation of growth energy persists only a few generations of
transplants (Wood and Prime).
Believing that there might be a relation between the number of lym-
phocytes in the disease poliomyelitis and the susceptibility of monkeys to
experimental poliomyelitis Amoss, Taylor and Witherbee reduced the
circulating lymphocytes in such animals by properly controlled doses of
x-rays such as were used by Taylor, Witherbee and Murphy. Six Holz-
knecht units of unfiltered x-rays was given at each dose on the dorsal and
ventral surface of the animal. Spark gap was three inches, milliamperage
ten, distance twelve inches (Coolidge tube), time four minutes. The
animals were treated every day or every other day until the total lym-
phocytes per c.mm. were about 1000 to 2000. Animals thus exposed to
x-rays were susceptible to three-fourths of a dose which was not infective
for non-rayed controls. This suggests a relation between the lymphocytes
and one factor of resistance in poliomyelitis. They were not able to reduce
the immunity by exposure to x-rays in a monkey immune from a previous
attack of poliomyelitis.
Effect on Enzymes. — Richards (6) believes that the biological reactions
resulting from exposure to radiations are due in large part to the effect
upon the body ferments. Richter and Gerhartz in studying the action
of x-rays upon rennin, yeast, pepsin, pancreatin and papain concluded
there was no effect on these ferments. Richards (a), however, believes that
the experiments of these authors do show slight changes which may be at-
.
•
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 879
tributable to the effect of x-rays. He concludes from his experiments oil
flu digestion of egg albumin by pepsin and of starch by diastase that a
short radiation by x-rays has the effect of accelerating enzyme activity
while a longer radiation inhibits it, and that between these two intervals
then- is a non-effective point. The experiments of Richards show that the
effects are slight but definite.
Radium rays, which are in general comparable with x-rays in their
action, have been thought to be the cause of quite marked changes in the
course of enzymatic action. Neuberg(fr) found an acceleration of the auto-
lytic processes under the action of radium emanation. Packard considers
that radium radiations, by activating autolytic enzymes, act indirectly
upon the chromatin and protoplasm and thus bring about the degenera-
tion of the complex proteins and probably affect other protoplasmic sub-
stances in the same manner. Influence of radium emanation upon
autolysis of normal and pathological tissues has been studied by Lowen-
thal and Edelstein. They found that the rate of increase in autolysis
varied with the character of the material allowed to autolyze, but
the greatest accelerating influence was found in the case of human car-
cinoma.
Henri and Mayer in studying the action of radium on ferments found
that invertin, emulsin and trypsin exposed to radiations decreased and
finally lost their activity. Bergdell and Bichel observed that the activity
of pepsin is enhanced by the influence of radium rays. 'Schmidt-Nielson
showed that radium preparation of 1,800,000 activity has slight inhibiting
action upon rennin. Wilcock has reported that radium rays are in-
jurious to digestive ferments such as pepsin, trypsin, and ptyalin. Ac-
cording to Lowenthal and Wolgemuth radium emanation is capable of ac-
celerating the activity of the diastatic enzyme of the blood, liver, saliva, or
pancreas, that there may be a slight retardation which is replaced by
acceleration if the experiment is sufficiently prolonged. Brown found
that the very radioactive radium D, radium E, and radium F have a
marked inhibitory action upon pepsin and pancreatic diastase; but no
effect upon the autolytic enzyme of the dog's liver. Marshall and Rown-
tree's(a) investigation showed that the radium emanation has no accelerat-
ing influence upon the lipase of the pig's liver or castor oil bean, while in-
hibition of the enzymatic activity is suggested. Schulz(&) observed that
radium emanation has a certain amount of accelerating action upon the
uric-acid forming enzymes of the spleen.
From the fact that alterations in permeability may cause cell division
and such metabolic changes as increased elimination of carbon dioxid, of
catalase, and an increase of oxygen absorption and various other physio-
logical reactions in the cell Richards (c) performed experiments on x-radia-
tion as a cause of permeability changes but was unable to find any evidence
that alterations in cell metabolism are due to permeability changes. Min-
880 THOMAS ORDWAY AND ARTHUR KNUDSON
ami has shown that thorium-x emanation accelerates or retards peptic,
tryptic and diastatic digestion. The duration of such action depends in
part on the time the radiations act. He believes that possibly the autolytic
ferments are influenced by the alpha rays.
From the foregoing it will be seen that radiation affects enzymes defi-
nitely, but the effects are variable, probably depending upon the duration
or the amount of radiation.
Funk(e) investigated the influence of radium emanation on the yeast
vitamins and reported that radium emanation has no destructive action on
beri-beri vitamin or on the growth-promoting factors in yeast. Suguira
and Benedict, however, subjected portions of yeast to the rays of radium
and tested this for their growth-promoting powers upon young white rats
as compared with the same yeast not treated with radium. They ob-
served that the growth-promoting factors in yeast may be partially in-
activated by means of exposure and believe that this may account for
some of its effects on tumors.
Effect on Normal Metabolism. — Most of the contributions dealing
with metabolism studies under the influence of radioactive substances and
x-rays have been concerned with abnormal human beings, but some work
has been done upon normal animals and human beings. Quadrome studied
the influence of x-rays on one guinea pig and six rabbits and although his
results were not uniform he got in most cases a slight increase in the urine
of the total phosphates (P2O5). Baermann and Linser obtained an in-
creased nitrogen excretion immediately after raying their patients; this
increase lasted two or three days and on the third or fourth day the nitro-
gen excretion usually returned to normal. In a man, normal except for
chronic eczema, Bloch observed after repeated raying a small increase
of basic nitrogen output in urine also an increase of phosphates. The me-
tabolism of one dog rayed with large doses of roentgen rays was studied by
Benjamin and V. Reuss. An immediate increase in nitrogen elimina-
tion was observed after the first exposure and rapidly returned to normal.
In a second exposure to the rays the increased elimination lasted several
days. The basic nitrogen (product formed by precipitation with phos-
photungstic acid), non-basic nitrogen, ammonia and urea, which were
determined on the urine specimens along with the total nitrogen, all
showed an increase. The basic nitrogen increased proportionately more
than the others. The phosphate output of the urine also increased tran-
siently. In the first exposure it rose to 33 per cent above normal and the
second to over 100 per cent. During the high phosphate output in the
urine a transient appearance of cholin in the blood was demonstrated,
which the authors attributed to the breaking up of lecithin and substances
derived therefrom. Metabolism observations reported by Lommel on three
young dogs showed similar results; that is, increased nitrogen and phos-
phate elimination. Linser and Sick, in studying the effect- of x-rays on
IXFLUEXCE OF ROENTGEX RAYS UPON METABOLISM 881
several individuals with various skin diseases, noted in all an increase
in the urinary nitrogen. The uric acid output was tripled in some cases
and the purin bases also increased. Similar results were observed in one
experiment on a normal dog.
The effect of radium salts upon the metabolism of dogs has been studied
by Berg and Welker. The doses employed were very small and they
concluded that the ingestion of radium per os was without any special
influence on metabolism. In one experiment a stimulation of the cata-
bolic processes as indicated by slightly increased output of nitrogen in
the urine was noted, but in another experiment the catabolic processes were
inhibited to about the same degree. An increased volume of urine was also
noted. In order to determine the effect of the active rays upon the general
metabolism of the dog Theis and Bagg used a solution of sodium chlorid
which contained active deposit from radium emanation. The dogs were
given doses of two to six millicuries per kilogram. One dog was a Dal-
matian in which variety uric acid is excreted in the urine. The total nitro-
gen in the urine always increased reaching a maximum of ten to twenty-
five per cent on the second day after injection. Urea nitrogen paralleled
the total nitrogen, but the ammonia nitrogen increased in greater propor-
tion than the total nitrogen indicating a possibility of acidosis. Uric
acid in the Dalmatian dog increased both absolutely (15 to 50 per cent)
and relatively to the total nitrogen. This may have been due to the
destruction of the white cells for the phosphate excretion was also in-
creased. Creatinin in one experiment was increased but not proportion-
ately to the total nitrogen. Jastrowitz has recently reported that injection
of thorium into dogs has a tendency to increase excretion of uric acid
above normal.
After deep massive doses of hard Roentgen rays Hall and Whipple
noted marked metabolic changes in experiments on dogs. The nitrogen
excretion of the urine increased immediately following exposure to rays
and remained high until death. There was often an increase of fifty
to one hundred per cent above normal. A marked increase (twice normal)
of the non-protein nitrogen of the blood was commonly observed on the
day before death and often more than three times normal on the day of
death. The authors do not believe that the heaping up of nitrogenous
split products can be explained alone on an increased breakdown of body
protein but that there may be faulty elimination. They could observe,
however, no evidence of any nephritis from a study of the urine nor by
anatomical changes.
Denis and Martin in studying the relative toxic effects produced by
iviii.mal radiation found that exposure with massive doses of Roentgen
rays over the intestines of a rabbit gave evidence of the presence of an
acidosis. This was shown by a fall in the alkaline reserve and^a rise^in
fat and inorganic phosphates of the blood of most of the rabbits which
882 THOMAS ORDWAY AND ARTHUR KNUDSON
received the heavy exposure over the intestine. In some of the rabbits
a slight increase in non-protein nitrogen was also noted.
A number of investigations on the influence of radioactive substances
and x-rays on uric acid and purin base metabolism have led to the gen-
eral belief that these agents lead to an increased elimination of uric
acid and purin bases, endogenous as well as exogenous. Gudzent. and
Lowenthal believe that radium emanation has a very pronounced effect oil
purin metabolism and is due to the activation of those enzymes re-
sponsible for the building up or cleavage of uric acid. Purin metab-
olism is altered according to whether synthesizing or cleavage enzyme
action predominates. Wilke and Krieg report increases of uric acid excre-
tion with ingestion of radioactive water. Kikkoji obtained a similar result
with water impregnated with radium emanation and in one of his cases
observed- an increase of ninety-five per cent. Kaplan reports that ingestion
of alkaline radium water increases the excretion of uric acid and purin
bases. Abl also observed increased elimination of endogenous uric acid by
use of thorium-x.
The mechanism of these effects is not established. Gudzent (a) (d)
claims to have induced a complete and lasting disappearance of blood uric
acid by inhalation of air containing two or four Mache units of emanation
per liter. In apparent confirmation of this fact he noted in vitro experi-
ments an increase in the solubility and gradual decomposition of sodium
urate by radium D, which is relatively very inactive and is a further decom-
position product of radium emanation. Falta and Zehner claim that
thorium-x also increases the solubility of urates and destroys uric acid.
Mesernitzky(&)(e) reported that radium emanation can destroy trioxy-
purin (uric acid) very well but that it had slight effect on dioxypurin
(xanthin) and no effect on oxypurin (hypoxanthin). He also claims that
uric acid in the blood is decreased under the influence of radium emanation
and that there is an increased excretion of uric acid in the urine. Other
observers have been unable to confirm these results. Kerb and Lazarus were
unable to detect any influence of radium emanation upon sodium urate.
Using radiation from radium emanation in very large amounts Knaffl-Lenz
and Weichowski likewise failed to note any increase in the solubility or
decomposition of sodium urate. Kerb and Lazarus were of the opinion that
the increase in solubility and decomposition of sodium urate noted by
Gudzent is to be attributed to bacterial contamination or accidental intro-
duction of small amounts of alkali, either of which conditions could cause
decomposition of the urate.
Schultz could detect no change in the activity of the uricolytic enzyme
of the liver and kidney under the influence of radium emanation but did
observe a ten to twenty per cent increase in the formation of uric acid
in autolyzing spleen under these conditions. This latter observation
and that of Kehrer (which bespeaks a mobilization of uric acid in the
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 883
body attributable to emanation) would lead one to expect, if any change at
all, rather an increased concentration of uric acid in the blood than a de-
crease, much less complete disappearance as Gudzent would have us
believe.
Investigations by Fine and Chace with inhalation of radium emana-
tion (containing as high as one hundred Mache units per liter) over
long periods, radium emanation in drinking water, and injection of fifty
micrograms of soluble radium bromid in no case had any influence what-
ever upon the concentration of uric acid in the blood. Likewise they could
observe no increase in the excretion of uric acid in the urine.
Very few observations have been made on the effect of radiation on
the basal metabolism in normal animals and human beings. Silbergleit(&)
studied the influence of baths containing radium emanation on the gaseous
exchange of normal men, but his results were negative. Kikkoji found a
distinct increase in the basal metabolism of normal men who received
during the experimental period three doses of 330 Mache units per os.
The respiratory quotient was also sometimes increased. Bernstein de-
termined the basal metabolism of several persons before and after a two-
hour interval in an emanatorium containing from 220 to 440 Mache units
per liter of air. One of these was carried out on a normal individual
and showed an increase of about six per cent. A slight increase of the
respiratory quotient was likewise noted. The respiratory quotient re-
mained practically unaffected according to Benczur and Fuchs(a) with in-
gestion of radium emanation water containing 300,000 to 400,000 Mache
units. With radium alkaline waters Staehelin and Maase found the gas-
eous exchange considerably decreased. This decrease refers only to values
following the taking of food and not to fasting values.
The carbohydrate metabolism is apparently increased according to
the observations of Kikkoji and Bernstein who found in their basal metab-
olism studies an increase in the respiratory quotient in most cases.
Lipine(c) found that exposure of dogs to x-rays for one hour is followed
by an increased glucolysis which is more marked if impacted with eosin
before radiation.
That radioactive substances and x-rays have an effect upon normal
metabolism is well established by the results of investigations reported
above. According to Musser and Edsall the effect of x-rays upon metab-
olism is unqualled by any other therapeutic agent and we might apply
that statement equally to radium. The changes produced by these agents
is manifested by an excessive elimination of the products of protein de-
struction indicated by the increased elimination of total nitrogen, uric
acid, purin bases and phosphates, and the accumulation in some cases
of non-protein nitrogen in the blood. That these agents have an effect upon
carbohydrate metabolism and fat metabolism is not so well established
by the meager results so far reported.
884 THOMAS ORDWAY AXD ARTHUR KXUDSOX
The cause of these effects on metabolism is at present difficult of
explanation. One may ascribe the effects of x-rays either to a stimulating
effect upon autolytic enzymes or as Neuberg(a) does to an inhibitory action
of x-rays anil radium rays upon the other intracellular enzymes without
corresponding deleterious effect upon the autolytic enzymes present. This
hypothesis agrees with the facts at hand but. more details concerning the
effects of these rays upon various enzymes are needed.
3d
3(
!•
from the lymphatic structures has led to their study particularly ii
by x-rays and radioactive substances in various diseases have been studied
connection with the treatment of leukemia. Following the therapeutic use
of x-ray and radium in leukemia there has been observed a marked effe
on metabolism.
Lossen and Morawitz in a case of myeloid leukemia treated by x-i
found that the volume of urine was decreased, that total nitrogen, urk
acid and phosphorus excretion lowered. Heile found an increase in bot
uric acid and purin bases in three cases. Koniger in myeloid leukemii
found that under influence of Roentgen rays the uric-acid excretion
creases parallel with the diminution in size of the spleen and the break-
ing up of the leucocytes and that the uric-acid excretion is a positive
measure of cell breakage, but not an index to the extent of the cell destruc-
tion. Ammonia and phosphates were also increased at times, generally
parallel with the nitrogen increase and also with the betterment in the
leukemic symptoms. No increase in the total nitrogen or uric acid
could be found, however^ by Cavina in a case of lymphatic leukemia treated
with Roentgen rays.
In this connection the observations of Musser and Edsall are of interest.
In those cases in which the roentgen ray caused a reduction in number
of white cells and there was clinical improvement, there was a definite
increase in uric acid and purin base output, a marked loss of nitrogen
and an increased elimination of phosphates. In a case in which x-rays
had no beneficial effect clinically, there was likewise no effect or very
little on the nitrogenous metabolism.
Murphy, Means and Aub studied the basal metabolism of a man with
chronic lymphatic leukemia. Observations were made before and after
exposure to x-ray and also after exposure to radium. When first observed
the metabolism was 44 per cent above the average normal, falling a little
with rest in bed. Intensive treatment with x-rays caused a drop in the
leucocyte count but did not appreciably affect the level of the metabolism.
Water elimination through the skin and respiratory passages was unusually
high. Direct and indirect calorimetry gave total results which were al-
most identical and no abnormal respiratory quotients were found. After
treatment with radium a further very marked fall occurred in the leueo-
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 885
cytc count, at the same time there was a slight fall in the basal metab-
olism.
Radium has been found to have a similar effect upon the nitrogenous
metabolism in leukemia as do x-rays. Knudson and Erdos in a case of
myelogenous leukemia treated by surface application of radium observed
in each of the three series of treatments marked changes in metabolism.
The total nitrogen, urea, ammonia and phosphates are immediately in-
creased and reach a maximum in about seven days after each application.
The uric acid excretion also increased some the first seven days and then
remained at about the same level throughout the observations. An exam-
ination of the uric acid in the blood at relatively long intervals during the
treatment showed little change. In another case of myelogenous leukemia,
Ordway, Tait and Knudson obtained results in conformity with the case
described above. An examination of the blood for creatinin and non-
protein nitrogen before, during and immediately following radium treat-
ment shows that there is apparently no change during the radiation.
Martin, Denis and Aldrich have studied the chemical changes in the
blood following Roentgen ray treatment in leukemia. In the more severe
cases they found the non-protein nitrogen was high and after treatment
a gradual but steady fall was noted. The creatinin was not affected. The
uric acid content was much increased but a large diminution in the num-
ber of white cells which occurred as a result of treatment caused no ap-
preciable decrease in this constituent.
The iron metabolism in myelogenous leukemia before and after expos-
ure to x-rays has been studied by Bayer (6). He found that isolated ex-
posure of spleen to x-rays causes an absolute increase in iron excretion in
the feces greater than in the isolated exposure of the long bones. The iron
excretion in pathological conditions of the spleen is greater after exposure
to x-rays than in* the normal.
The chemical changes observed in the treatment of leukemia with x-rays
and radium apparently depend upon the excessive quantity of leucocytes
and lymphoid tissue, which undergo processes of disintegration during
treatment, with the result that products of nucleoprotein destruction (total
nitrogen, uric acid, purine bases, and phosphates) appear in the urine in
increased quantities.
The use of radium in the treatment of gout directed early the attention
of investigators to the influence of radium on uric-acid metabolism. As a
result of the investigations in His' clinic it was affirmed that uric acid
occurs in the blood in gout in a specially insoluble modification and that
under the influence of radium the insoluble pathological form of uric acid
becomes changed to a more soluble physiological form which is easily
destroyed and excreted ; the net result being a rapid solution of the gout
tophi, an increased elimination of uric acid in the urine and a disappear-
ance from the blood (Gudzent and Lowenthal, Gudzent(a)(6)(eZ)).
886 THOMAS ORUWAY AND ARTHUR KNUDSON
The experiments on which these investigators based their theory of
gout and action of radium were at first apparently confirmed. Mesernitsky
and Kemen, Kikkoji; Von Xoorden and Falta, and Skorczewski and Sohn
report increased excretion of uric acid in cases of gout under the influence
of radium emanation. Plesch and Karczag observed a similar effect with
thorium-x.
With reliable methods and carefully controlled observations Chace and
Fine could not confirm these observations. Inhalations of radium emana-
tion (containing as high as 100 Mache units per liter) and injection of
fifty micrograms of radium bromid in no case had any influence upon
uric acid concentration in the blood of patients with gout. McCrudden and
Sargent(fr) likewise could observe no effect on the concentration of uric
acid in the blood of a patient with gout receiving water impregnated with
radium emanation. The patient received daily 20,000 Mache units. No
effect could be found on the rate of uric acid and total nitrogen excretion
but they did observe a slight increase in the creatinin excretion which per-
sisted for a few days after discontinuing the radium treatment.
Chace and Fine and McCrudden and Sargent (6) have also studied the
effect of radium emanation on cases of chronic arthritis. They could ob-
serve no effect on the concentration of uric acid in the blood or the rate of
its excretion in the urine. McCrudden did observe, however, a slight
increase of creatinin excretion. In a case of rheumatoid arthritis treated
by intravenous injection of fifty micrograms of radium salts Rosen-
bloom (&) noted an increased nitrogen excretion and a marked increase in
the amount of total sulphur and neutral sulphur in the urine. The increase
of nitrogen and sulphur lasted for about three days following the injection.
The metabolism of cases of pernicious anemia, rheumatoid arthritis,
and unresolved pneumonia treated by x-ray have been reported by Edsall
and Pemberton. In the cases of pernicious anemia and rheumatoid ar-
thritis x-ray exposure produced a toxic reaction. The chief point of interest
in these two cases is the remarkable drop in excretion of nitrogen, phos-
phates and uric acid that followed the exposure. The drop was followed
subsequently by an equally striking rise in excretion to a point much be-
yond that at which it had previously been. In the first case the drop oc-
cuired directly after exposure and in the second it was postponed two days
but occurred as in the-first case when the man had become seriously ill. In
the cases of unresolved pneumonia the effects were striking. There was an
immediate marked increase in the nitrogen and chlorid excretion. The
phosphates were increased somewhat less and uric acid was little affected.
This effect upon- metabolism was coincident with a rapid improvement.
The only apparent explanation the authors give to these results is
that in those cases, such as unresolved pneumonia and leukemia, which
responded favorably to x-ray treatment an increased tissue destruction
occurs directly after exposure resulting in an increased excretion of
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 887
the products of metabolism. The cases without an immediate increase
in the nitrogen excretion were unfavorably influenced by x-ray applica-
tion. It seems to the authors that the organism in these two cases was
overwhelmed by the enormous amount of the products of tissue destruc-
tion, resulting in a retention of decomposed tissue products. After a time
the organism reacted somewhat and a complete disintegration couki
be accomplished and the products were excreted.
Ordway, Tait and Knudson have studied the influence upon metabolism
of surface application of radium emanation upon a case of sarcoma and of
carcinoma respectively. In the former they observed increases in the vol-
ume of urine, in total acidity, ammonia, total nitrogen, urea, and uric acid.
Great inin and phosphates were considerably increased. In the case with
carcinoma there was no increase of the nitrogenous fractions or phosphates
of the urine. The changes in the nitrogen metabolism depend apparently
upon the amount and nature of tissue autolysis. In the case of sarcoma
there was a definite softening and fluctuation of the growth while in the
case of carcinoma of the breast the lesion consisted of hard brawny
fibrous tissue in which one would expect little or no autolysis.
Ludin has observed that radium reduces the high cholesterol values
observed in the blood of carcinoma patients and emphasizes the fact that
this may play an important part in the beneficial effect of radium therapy.
De Niord, Schreiner, and De Niofd have studied the influence of Roent-
gen rays on the blood of cancer patients in order to note whether radia-
tion produces any appreciable change in their blood chemistry. Blood
specimens were taken before exposure to x-rays, one half hour and
twenty-four after exposure. Radiation had no effect upon the sodium
chiorid content nor upon the percentage of corpuscles and plasma. The
changes in the urea nitrogen, creatinin, uric acid, sugar and diastatic
activity are inconsistent, which makes it difficult to draw any conclusions.
In a number of the cases these constituents were found to be increased
and in an equal number they were found to be decreased or to have no
effect.- The cholesterol, fatty acids and total fats were found to be
generally increased in the cases of malignancy. After exposure to x-rays
the total fatty acids were found to be reduced in 72 per cent of the cases
and the total fat was reduced in 83 per cent. The cholesterol content
in 61 per cent of the cases was higher and in 31 per cent was lower after
exposure. The increase in cholesterol was not proportional to the time
of exposure or the type of tumor.
Rudinger studied the influence of Roentgen rays on protein metabolism
in Basedow's disease. He found exposure to the rays induced a retention
of nitrogen as indicated by a gradual fall of elimination. No relation
could be found between the phosphorus and nitrogen metabolism.
Constitutional Effects. — The local inflammatory reactions produced
by x-rays and radioactive substances in those engaged in such work are
888 THOMAS ORDWAY AND ARTHUR KNUDSON
now well known. The action of x-rays may also result in the develop-
ment of cancer, even with metastases (Tyzzer and Ordway). The more
acute constitutional effects of radiations have also been the subject of
research.
Edsall and Pemberton have described a toxic constitutional reaction
following exposure to x-ray and advanced a theory which they believe
to be the basis of this reaction, that is, that the tissue destruction accom-
plished by Roentgen rays involves chiefly tissues rich in nucleoproteiu.
The decomposition products of this form of protein are especially rich
in substances that are more or less toxic and difficult to metabolize and
excrete. The intoxication does not seem to be dependent directly upon
alterations of the excreting power of the kidneys because examinations
of the urine of two patients showed no evidence of retention. It is prob-
able, however, according to the view of Edsall and Pemberton that in many
cases after a time the kidneys do become overtaxed by the added labor
thrown upon them and their excreting power fails to a greater or lesser
degree and this may increase the toxic symptoms.
Hall and Whipple suggest that Roentgen ray intoxication is due to
a disturbance in protein ' metabolism. They have produced this in dogs
by deep massive doses of hard Roentgen rays. The dogs were given lethal
doses of x-rays and showed remarkably uniform and constant general
constitutional reaction. There was usually a latent period of twenty-four
hours or longer when the dogs appeared perfectly normal. After this
there were vomiting and diarrhea ; death usually occurred on the fourth
day. Upon post-mortem examination the spleen of these animals was small
and fibrous; the intestinal mucosa was congested and mottled and there
was evidence of epithelial injury. The crypts occasionally showed in-
vasion of polymorphonuclear leucocytes. The epithelium showed re-
markable speed of autolysis. The authors believe that this injury to
the small intestine explains the general intoxication. They find no
support for Roentgen ray anaphylaxis or hypersensitiveness to a second
properly timed exposure, but there was on the other hand some evidence
of a slightly increased tolerance to a second dose. There was no evidence
of a Roentgen ray nephritis. The severity of the constitutional reaction
was greatly increased by widening the spark gap. The long, latent period,
even three weeks, was not explained by these investigators.
Dennis and Martin in experiments on rabbits limited the exposure
to various areas of the body and found that toxic constitutional reactions
were produced only in animals exposed over areas in which some portion
the intestine was included. Even those rabbits exposed over areas
ntammg only a small portion of the intestinal tract developed toxic
symptoms after a rather long latent period, while a particularly severe
reaction followed radiation over an area which contained none of the
viscera other than portions of the intestinal tract. The animals radiated
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 889
over the thighs, the neck and chest continued in good condition and showed
absolutely no symptoms although kept under observation for a period of
several weeks. It seems to these authors, therefore, tending to confirm
the opinion of Hall and Whipple, that injury to the intestinal epithelium
plays no small part in the systemic reaction following exposure to
roentgen rays. Denis and Martin have suggested also that the reaction
after exposure of the abdomen may be due, in part at least, to acidosis
on the basis of a lowering of the alkaline reserve, since the administration
of sodium bicarbonate by mouth for twenty-four hours following ex-
posure serves to ameliorate or prevent the constitutional symptoms iu
many instances.
Strauss in a study of the local reaction due to x-rays concludes that
there is no real idiosyncrasy but a lessened local resistance in some cases.
Various general symptoms such as headache, malaise, weakness, undue
fatigue, unusual need of sleep, fretfulness, irritability, disorders of men-
struation, attacks of dizziness have been said by Gudzent and Halber-
staedter to be caused by repeated and long continued exposure to radio-
active substances. Ordway(c) in a study of the occupational injuries due
to radium points out that such symptoms are common in many people at
times and as they cannot be accurately and objectively recorded they
may have been due to close confinement, tiring routine, lack of outdoor
exercises and other causes. The exposures of some of the cases reported,
however, were doubtless large, some were engaged in the manufacture of
radium apparatus and others in the therapeutic application of radio-
active substances. It is therefore probable that certain general symptoms
did occur as a result of this exposure.
Mottram and Clark estimated by photographic method the daily
amount of radiation received by clinical workers making daily applica-
tions of radium. These workers received daily scattered over the entire
body about 1.4 per cent of the total radiation received by a patient during
a course of treatment for superficial carcinoma.
Because of these constitutional symptoms and the effects of radiation
upon the blood forming organs great caution and even frequent alternation
of service is necessary for those engaged in the use of radioactive sub-
stances.
We have personally seen a profound constitutional reaction in a
patient injected intravenously with active deposit. Because of this
and the widespread character of the lesions produced great care should
be exercised in the internal administration of radioactive substances.
Theories of Action. — Hertwig and his school believe that radiations
cause a specific destructive action upon the chromatin of the cells. Swartz
considers that the injury to the cells is due to the destruction of the
cell lecithin by the radiations. Packard suggested that radiations acted
indirectly on the chromatin and protoplasm by activating autolytic en-
890 THOMAS ORDWAY AND ARTHUR KNUDSON
zymes. !N"euberg(a) ascribes the effects of radiation to an inhibitory action
of x-rays and radium rays upon the other intracellular enzymes without
a corresponding deleterious effect upon the autolytic enzymes. Rich-
ards (&) maintains that the radiations affect the activity of the various
enzymes or ferments ; that a short radiation may accelerate the activity and
a longer be inhibitive so that life processes are subject to marked changes
under the influence of radiation.
Radium emanation according to Bovie (&) affects the nucleus in a man-
ner similar to the effect produced by quartz rays. Cell division is inhibited
as well as locomotion and ciliary action. He finds no reason to believe,
however, that rays are more strongly absorbed in the nucleus than in the
cytoplasm nor that the nucleus is more photo unstable than the cytoplasm.
The effect upon the nucleus may be due to the more intricate nature of its
mechanism' and to its inability to undergo rapid recovery from injury
caused by radiation. The radiations affect the protoplasm at the place
where they are absorbed and the observed physiological disturbances are
responses on the part of the organism to its injured protoplasm. Bovie
believes that it is the instability of the physiological mechanism rather
than the wave length of the radiation used which determines the nature
of the physiological effect produced. The effect of course is different
if one wave length penetrates deep and the other only affects the surface,
but the difference is apparently due to the penetrating power rather than
any specific effect of the wave length per se.
Kronig and Friedrich agree with Bovie that it is not the quality but
the quantity, that is, the total energy absorbed, which produces the bio-
logical effect.
II. Light
Light has been used as a therapeutic agent for a number of years
and its general action is based largely upon hypothesis. From the prin-
cipal action outside of the living organism and from the constitution of the
latter as well as from its known action upon plants and lower animals a
certain amount of speculative theory has been indulged in to explain
its action.
Light is composed of different kinds of rays. These rays are ex-
plained as transverse electromagnetic vibrations having their origin in
the rapidly oscillating electrons whose periods are the same as the
periods of the wave motion. These wave impulses travel with the same
velocity in free space (about 186,000 miles per second). The different
colors correspond to different wave lengths (or more properly, to differ
ent rates of vibration) and vary in length from approximately 3.9 to 7.6
ten-thousandths of a millimeter. Waves of a similar character whose
lengths fall above or below the limits mentioned are not perceptible to
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 891
the eye. Those between 3.9 to 1.0 ten-thousandths of a millimeter con-
stitute ultra-violet light. Those exceeding 7.6 ten-thousandths of a milli-
meter in length are the infra-red waves. The ordinarily used unit of wave
length is the Angstrom unit, equal to one ten-millionth of a millimeter.
Another unit frequently used is the micron, |x = 0.001 mm.
It is a general law of photochemical action that only those rays are
effective which are absorbed by the substance in which the reaction occurs.
Visible light rays are not as a general rule active but may be rendered
active by impregnating the tissue or other material with certain sub-
stances which in such cases act as the photochemical absorbent or senti-
tizer. Ultra-violet light rays are active as they are the easiest absorbed.
Experience has shown that light can bring about a variety of chemical
changes. Neuberg(c) (d) (e) (/) (g} observed that the general effect of
light acting on organic substances present in animal and plant cells is to
produce from carbonyl containing materials aldehyds or ketone compounds,
whose reactivity and availability for important synthetic changes are con-
spicuous. These changes, however, could only be produced by the addition
of certain salts such as uranium, mercury, arsenic and manganese which
acted as photocatalytic agents. Neuberg and Schwarz have shown that iron
salts can act as photocatalyzers. They believe that in the presence of light
these photocatalyzers take oxygen from the air and pass it on to the
organic light receptors. This photocatalytic light action consists in oxida-
tion and cleavage processes. From their investigation they conclude that
sensitiveness to light is increased by giving mineral waters containing
heavy metals. Pincussohn ( c) has reported that a solution of sodium urate,
containing eosin, exposed to light shows a diminution in the content of uric
acid. The proteins of egg white and of the crystalline lens exposed to ultra-
violet light were found by Chalupechy to be considerably altered. The
albumins were decreased, the globulins increased and some coagulated
protein was formed.
The action of light energy on tissues and skin has been studied quite
extensively. Bering sums up the work previous to 1914. He states that
the action of light manifests itself in cell destruction produced through
direct destruction or by edema and thrombosis as a result of a direct
action upon the endothelial membrane and musculature of the vessel wall.
There also results a hemorrhagic inflammation which terminates with a
productive connective tissue formation. The histological changes were
almost exclusively produced by ultra-violet light rays. The blue rays
possessed only a slight action and the green, yellow and red rays produced
no change. Sensitizing of tissues with substances such as eosin increased
the action of light but slightly.
Schanz(a) has observed that light may alter the cell proteins, especially
in the presence of organic and inorganic substances such a silicates, sugar,
lactic acid and urea which act as sensitizers. The pyknosis and hyaline de-
892 THOMAS ORDWAY AND ARTHUR KNUDSON
generation of cells resulting from influence of ultra-violet light rays are be-
lieved by Krebich to be caused by the proteins being rendered insoluble,
and as a consequence the catalase is more firmly bound and inhibited
in its action. Burge(rf) believes that ultra-violet radiation kills cells and
tissues by changing the protoplasm of the cells in such a way that certain
salts can combine with the protoplasm to form an insoluble compound or
coagulum. He found the effective region of spectrum to be from 0.254 H
to 0.330 [A. The action of the sun's rays on the non-pigmented skin of
animals is ascribed by Beijers to the action of the ultra-violet rays on sen-
sitizing substances which are present in the blood.
The action of light on the blood of animals has been studied quite
extensively by Oerum(6). He found that the blood volume and the hemo-
globin are decreased in the dark. Red light has a similar effect but in
blue light a plethora is produced and hemoglobin is increased. Light baths
increase the blood volume in the course of four hours about twenty-five
per cent. The photodynamic action of light on blood has been reviewed
by Bering. By photodynamic action is meant the ability of certain fluores-
cent substances to produce in light strong biological action. The red blood
corpuscles are dissolved, some substances attacking the corpuscles within
the cell membrane, in others the primary attack is intercellular. Immune
serum loses its specificity. Polynuclear leucocytes and lymphocytes are
destroyed. The proteins of serum form a substance having a hemolytic
action. Traugott could observe no effect on the number of red blood
corpuscles in man following exposure to ultra-violet rays for ten to fifteen
minutes. An increase of leucocytes, however, was noted. Another effect
observed was that blood coagulated sooner and the number of blood plate-
lets was increased. Schanz(&) extended the observation of Chalupechy and
studied the effect of ultra-violet light on proteins in the blood and found
that after exposure of blood for eight hours there was a decrease in the
albumin from 27.0 mg. to 3.9 mg. per 100 c.c. of diluted serum and an
increase of globulin from 2.1 to 24.2 mg. per 100 c.c. Hausmann and
Mayerhofer noted that salted plasma exposed to ultra-violet light did
not coagulate when diluted with water, while untreated salted plasma co-
agulated in a few minutes. Likewise he observed that oxalated plasma
coagulated much more slowly after addition of calcium chlorid when
subject to the action of light. From these observations the authors em-
phasize the necessity of carefully adjusting the action of ultra-violet
light upon patients.
The activity of most enzymes is found to be decreased after exposure
to light. Agulhon observed that ultra-violet rays may attack enzymes in
the absence of oxygen. Chauchard found that the activity of pancreatic
amylase is rapidly attacked by rays of wave lengths less than 2800 Ang-
strom units but not appreciably affected by rays of longer wave length.
Lipase was destroyed in part by rays equal to 3300 Angstrom units and
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 893
their destructive action increases with decreased wave length, although.
O O
more slowly than in the case of amylase. The actual percentage loss in
activity due to the action of rays less than 2800 Angstrom units is much
greater in the case of lipase than in the case of amylase. They could
observe no direct relationship between the absorption of ultra-violet rays
by pancreatic juice and their action on pancreatic enzymes. Pincussohn
noted that the protease activity of the blood of animals injected with a
fluorescent substance (eosin) was greater after exposure to light. The
rate of destruction of pepsin, trypsin, enterokinase, ptyalin, amylopsin,
and the pro-enzyme trypsinogen was reported by Burge, Fischer and Neill
to be proportional to the amount of energy applied. The active wave
length they used was between 0.302 M. and 0.297 \i.
Metabolism in general is believed to be stimulated by light energy. The
experiments of Pettenkofer and Voit(a), Johansson, and Lehman and
Zuntz show that metabolism with complete muscular rest is slightly greater
during the day than at night. Zuntz was first to call attention to the
significant fact that even when perfect muscular relaxation ensues there
may be still influences such as light on the retina or sounds which may
act reflexly on the organism and slightly increase the metabolism.
Cleaves who has reviewed the literature to 1.904 concludes that one
set of experiments apparently proves that light increases the oxygen
carrying capacity of the red blood cells and therefore influences oxidative
processes of the organism. Other experiments show increased output of
CO2 when animals experimented on were exposed to light and this in-
crease was supposed to be due td stimulation of the protoplasm, prob-
ably due to both stimulation and the increased supply of oxygen. Adult
animals therefore fattened more easily in the dark as there is less
combustion.
Rubner(a) remarks that while the radiant energy of the sun is large
in quantity, he has been unable to find any influence upon a man under
ordinary circumstances. Zuntz while living on the summit of a high
mountain of the Alps observed the basal metabolism increased as much
as 40 per cent and that exposure to sunlight was almost without effect
on the metabolism. Hasselbalch(&) found that if the naked body of a man
was strongly exposed to ultra-violet rays the rate of respiration was di-
minished while the depth was increased. The skin was red with dilated
capillaries and the blood pressure fell. Lindhard(a), in 1910, showed
there is a yearly periodicity of the respiratory rate in the Arctic region, it
being less in the spring and summer than in the winter. The enormous
variations in the chemical intensity of the sun's rays in the Arctic region
are undoubtedly the cause of this effect. The same phenomenon has
been observed by Lindhard(&) in Copenhagen. The volume of respiration
increases 25 per cent- in the summer but the intensity of metabolic proc-
esses are not affected. While these investigators noted that the ultra-
894 THOMAS ORDWAY AND ARTHUR KNUDSON
violet rays of the sun reduce the frequency and increase the depth of
respiration, Hasselbalch and Lindhard(a) found that exposure to the effect
of such rays in the high Alps has no effect upon metabolism.
Animals injected with fluorescent substances such as eosin showed,
according to Pincussohn(&) (c), greatly increased metabolism after ex-
posure to light. The purin bases, amino acids, ammonia and oxalic acid
of the urine were increased. Hoogenhuyze and Best have studied the influ-
ence of light 011 the endogenous metabolism of man as indicated by the
elimination of creatin and creatinin of the urine. The experimental sub-
jects were put on a creatin and creatinin free diet and normal excretion de-
termined. Following the normal period the subjects were put in a box lined
with incandescent lamps for a twenty-minute period and the temperature of
the box was 40°-45° C. when closed and 30°-35° C. when ventilated.
A series of four experiments showed that exposure to light and heat or to
light alone always produced a considerable increase in the creatinin.
Creatin was always absent. A negligible effect was produced by exposure
to heat alone. A similar increase in creatinin occurred in two patients
after a sun bath.
The entire subject of light energy in the physiological relation still
calls for careful scientific study and experiment. That light energy
influences metabolism is apparently evident by its action on various
organic substances of plant and animal origin ; by its well-known action on
skin and tissues; its action on the blood and enzymes; and by the in-
creased respiratory and endogenous metabolism.
III. Electricity
Various forms of electricity have been used for many years in treat-
ing a wide range of pathological conditions but in a very few instances
have carefully controlled metabolism studies been made. A literature
has grown up among those dealing in electrotherapeutics containing a
terminology which is peculiar to this form of medicine. It is for the
most part difficult for the scientifically trained physicist to interpret
and to estimate dosage accurately in units of electrical measurement. With
the active cooperation of competent physicists and clinicians it may be
possible to denote measurements, forms and conditions for use of elec-
tricity so accurately that the results of metabolic and therapeutic work
can be more carefully controlled.
Electricity in various forms is a powerful agent for stimulating nerves
and contracting muscles in experimental, diagnostic, and therapeutic
procedures. As is well known, death may be caused by electric currents.
When these are of low voltage, according to Tousey death is usually due
to the production of fibrillation of the ventricles and to interference with
INFLUENCE OF ROENTGEN RAYS UPON METABOLISM 895
the respiration from the muscular contraction produced. With currents
of high voltage there is impairment of the respiratory center. The path
of the electrical current through the body and the conditions under which
the exposure occurs are variable but very important factors in determin-
ing the effect produced.
Electrolysis is commonly used in various conditions for its local de-
structive effects, notably in the removal of superfluous hair and for the
treatment of certain skin diseases such as nevi. A method has been em-
ployed known as ionic medication by which certain substances are intro-
duced a varying distance through the skin by means of electrical current.
Hardy in a study of the coagulation of protein by electricity has shown
that under the influence of a constant current the particles of protein
in a diluted and boiled solution of egg white move with the negative
stream if the reaction of the fluid is alkaline and with the positive stream
if the reaction is acid. The particles under this directive action of the
current aggregate to form a coagulum.
Stewart (a) (&) has shown that the red blood corpuscles have a very low
electrical conductivity in comparison with that of the serum or the
plasma and that the conductivity of the blood serum in which the hemo-
globin of red blood cells has been dissolved by various methods of laking is
increased.
Burge(a) has found that in a solution containing both pepsin and ren-
nin the passage of a direct current of ten milliamperes for twenty-five hours
results in the complete disappearance of the peptic power, as tested on
milk and fibrin, while the action of the rennin is apparently unchanged.
In further experiments Burge(&) has demonstrated that ptyalin is de-
stroyed by the passage of the direct electric current. * This destruction is
not due to the electrolytic products ; the rate of destruction is uniform, that
is, 2.5 per cent per coulomb. The rate of destruction of pepsin by the
passage of the direct electric current has been estimated by Burge(c) by
the decreased amount of egg white digested in proportion to the number
of coulombes that were allowed to pass. His conclusion is that the di-
gestive activity of a solution of pepsin is decreased by the passage of the
direct electric current at a uniform rate per unit of current. The solu-
tions were kept from polarizing by rapid shaking.
Tousey in his extensive work has described the use of electricity in
many pathological conditions. Meyer and Gottlieb in their clinical and
experimental pharmacology state that nothing is known about the direct
action of electric energy on the metabolic processes of the cells. Steel has
reviewed the literature up to 1916 on the influence of electricity on metab-
olism and concludes that two or more totally different types of electrical
currents may have practically the same effect on metabolism. The high
frequency type whose action is largely thermic seems to cause an increase
in practically the same urinary constituents as the static type whose ac-
896 THOMAS ORDWAY AND ARTHUR KNUDSON
tion is largely mechanical, yet it is obvious that the data analyzed is ob-
tained by the work of various investigators under different conditions ;
particularly to be mentioned is the variation in the amount and form of
electrical energy and in the diet of the patients. Steel finds that no ex-
tensive metabolic study had been previously attempted and presents the
results of his own experiments, using various fqrms of electricity desig-
nated by him as faradic sinusoidal current, directional and autocondensa-
tion current with thick dielectric, autoconduction method, the direct
d'Arsonval current, combination of direct d'Arsonval current with the
autocondensation current with thin dielectric, the static wave current, the
galvanosinusoidal current. The special physiological properties of high
frequency currents were first published by d'Arsonval(&) in 1891.
Steel has shown that relatively strong electric currents of the various
types demonstrated caused a stimulation of metabolic processes. The
volume of urine is increased by those currents which do not have a pro-
nounced thermic effect and decreased by those currents which have a
strong thermic effect and the latter type causes perspiration. All cur-
rents increased the total solids, total nitrogen and sulphur of the urine;
the most striking and consistent effects were an increase in the urea and
creatinin. The greatest increase of urea was obtained with a static wave
current and the greatest increase of creatinin with the faradic sinusoidal.
Increased elimination of urea was attributed to quickened cellular metab-
olism and the increased elimination of creatinin to muscular contraction.
It is noteworthy that recovery was always prompt and complete in so far
as the data indicated. Usually after two days there was no effect. It
is important that further study be made of the effect upon metabolism
of electrical currents using standard units of physical measurement that
can be readily duplicated.
Many patients suffering from a wide variety of conditions undoubtedly
derive, at least temporarily, benefit from the various forms of electro thera-
peutic procedures yet there is no definite agreement as to the pharma-
cological action and much more carefully controlled experimental work
is necessary before such physical agents as light and electricity, x-rays
and radioactive substances can be said to be established in the rational
therapy of internal diseases.
Climate » Edward C. Schneider
Temperature and Humidity — Air Movement and Winds — Light — The Psycho-
logical Factor in Climatotherapy — The Variety of Climate — General Con-
siderations in the Choice of Climate — Altitude — Altitude Sickness —
Acclimatization — The Blood Adaptive Changes — Respiratory Adaption to
High Altitudes — Metabolism — The Circulatory Mechanism — General
Considerations.
Climate
EDWAED C. SCHNEIDER
MIDDLETOWN
The old view which placed the influence of climate upon health above
all other factors has very largely been replaced by the view that good
hygiene is the all-important health factor. Doubtless careful and intelli-
gent attention to hygiene is more important than climate, and every health
seeker should realize that "care without climate is better than climate
without care." However, the influence of climate is by no means to be
disregarded. The pendulum has swung too far to the side of hygienic
living. It must be admitted that even though the health seeker recognizes
that the results of following the simple rules of hygiene are restored health,
and possibly high efficiency ; yet the average individual finds these simple
things irksome, and that it requires strength of mind to follow them day
in and day out. Climate affects our bodily comforts and causes physio-
logical changes which may play an important part in the curative process.
Huntington has demonstrated that human efficiency, as tested by the
amount of daily work performed, is determined by physical atmospheric
conditions and that the development of the human race is controlled by
climate. "Man can apparently live in any region where he can obtain
food, but his physical and mental -energy and his moral character reach
their highest development only in a few restricted limited areas."
Climate, as ordinarily denned, is the resultant of the average atmos-
pheric conditions, considered daily, monthly and annually. It is made up
of temperature (including radiation) ; moisture (including humidity, pre-
cipitation and cloudiness) ; wind (including storms); pressure; evapora-
tion ; and also, but of less importance, the chemical, optical and electrical
properties of the atmosphere. It is only recently that definite progress
in our knowledge of the physiological action of atmospheric conditions has
been made. Even now this knowledge is fragmentary; so that medical
climatology, which deals with the hygienic effects of climate, is still far
from being anything like an exact science.
The physical influences that cause physiological changes are tem-
perature, humidity, air movement and pressure, as met at high altitudes.
Light has apparently been found to be a minor factor. The physiological
899
900 EDWAED C. SCHNEIDER
influence of each of these atmospheric factors will be briefly considered.
Pressure will be discussed under altitude.
Temperature and Humidity
Although man is a homothermal organism, there is a certain relation-
ship between his body temperature and the temperature of his environ-
ment. His internal temperature, in health, remains fairly constant wher-
ever he may be, varying not more than 1° or 2° F. Man readily adapts
himself to extremes of temperature through responses made by his vaso-
motor system and sweat glands. He is constantly and of necessity elimi-
nating heat. The loss of heat results from radiation, conduction and evapo-
ration. The amount of heat lost by radiation and conduction depends
largely upon the temperature of the surrounding air, while the amount
lost from evaporation depends upon the relative humidity of his immediate
environment. Some conditions permit loss of heat by radiation and con-
duction only. In a dry hot climate loss of heat by evaporation is at its
maximum. The New York State Commission on Ventilation found that
during the months of June and July the rectal temperature of man at 8
A. M. was conditioned by the average atmospheric temperature of the
preceding night ,and that a difference of about 1° F. resulted from a
difference of 36° F. in atmospheric temperature. The temperature of a
chamber influenced the body temperature of healthy human beings, con-
fined for periods ranging from 4 to 7 hours, the body temperature falling
in an atmosphere of 68° F. and fifty per cent relative humidity; rising
in one of 86° F. and 80 per cent relative humidity; and remaining
nearly stationary in air of 75° F. and 50 per cent relative humidity. A
stay of three and one quarter hours in an atmosphere of 104.7° F. and 95
per cent relative humidity caused the body temperature to rise 6° F. (25).
Shaklee, working with the native monkey in the Philippine Islands,
found that exposure to the sun by placing the animal on the ground or a
roof caused death within six hours from a rise in body temperature. It
was possible to gradually acclimatize the animals, this being accomplished
by an increased capacity for sweating, which kept the body heat well
within the killing temperature, although it rose several degrees.
In hot climates radiation and conduction become less important and
evaporation the most important factor in eliminating heat. Evaporation
in its turn depends upon the relative humidity of the air and, to some
extent, upon the presence of winds.
The circulatory system is also affected by the temperature and hu-
midity of the atmosphere, the rate of heart beat being increased con-
comitantly with the body temperature; it is increased in warm humid
air and decreased in cool, dry air. Eastman and Lee found that the pulse
CLIMATE 901
rate increased by 39 — from 67 to 106 — as the atmospheric temperature
rose from 74° to 110° F. and the relative humidity from 58 to 90 per
cent. The effect of humid heat upon the blood pressure does not appear
to be uniform. Young, Breinl, Harris and Osborne found the systolic
pressure rose at times and fell slightly at others. The New York State
Commission on Ventilation observed that excessively high temperatures
and high humidities were accompanied by an elevation of both systolic
and diastolic pressures. The reactions of the vasomotor mechanism, as
judged by Crampton's scale of vasotone, indicate that a distinct vascular
benefit follows the exposure of the body to a cool dry air.
The influences of atmospheric heat and humidity on the respiration are
varied in character. A moderate degree of both seems to be without effect
on the rate of respiration ; but more extreme rises cause a quickening of
the breathing, which is probably accompanied by more shallow respira-
tions. Young and collaborators found that the alveolar air in inhabitants
of tropical Queensland showed a lower carbon dioxid content than the
European average. A slight seasonal influence has been noticed by Boy-
cott and Haldane, in which a higher alveolar carbon dioxid partial pressure
was found in cold and a lower in warm months. These changes were not
attributed to variations in the body temperature but to the contact of the
body with cold or warm air. A marked increase in relative humidity also
lowers the alveolar carbon dioxid content.
The influence of high temperature and high humidity on the capacity
for physical work, the amount of blood per kilogram of body weight, and
the concentration of sugar in the blood is pronounced. Lee and Scott ex-
posed cats for periods of six hours to an abundance of moving air, varying
in respect to temperature and humidity, using a "low" condition in which
the average temperature was 69° F. and the humidity 52 per cent; an
"intermediate" condition in which the average temperature was 75° F.
and the humidity 70 per cent; and a "high" condition in which the
temperature was 91° F. and the humidity 90 per cent. Muscles taken
from these animals and stimulated to exhaustion showed that the average
duration of the working periods and average total amounts of work per-
formed decreased progressively from the low, through the intermediate,
to the high condition. The amount of blood taken from the cats was less
after exposures to the high than the low condition. The concentration of
sugar in the blood also decreased progressively in the three groups from
the low to the high condition. The evidence indicates that the distaste
for physical labor which is felt on a hot and humid day has a deeper basis
than mere inclination ; that it is founded upon physiological factors.
Atmospheric conditions likewise influence the nasal mucosa. Miller
and Cocks demonstrated that exposure of the body to heat increased the
swelling, redness and secretion of the nasal mucosa ; and that the effects
were more marked when the humidity of the air was high. High tern-
902 EDWARD C. SCHNEIDER
perature with draughts diminished the swelling, secretion and redness;
while cold draughts increased these conditions. The effects produced
upon the nasal mucosa are direct rather than reflex in nature.
Miller and Noble found that respiratory infection of rabbits was
favored by chilling after they had been accustomed to heat. They con-
clude that the weight of experimental evidence does not justify the
elimination of exposure to cold as a possible though secondary factor in
the incidence of acute respiratory disease. A change from low to high
temperature has even a more marked predisposing influence than that
from high to low.
Environmental temperatures likewise exert an influence upon the
metabolism of men. \roit(e) subjected fasting men to many different tem-
peratures, in the Pettenkofer-Voit respiration apparatus, while he de-
termined the carbon dioxid and nitrogen elimination. Changes in tem-
perature from 57° to 80.6° F. scarcely changed the carbon dioxid output;
a lowering of temperature to 50° and less stimulated the metabolism;
also above 80.6° it was markedly increased, as shown by the rise in carbon
dioxid elimination. These observations on man are similar to metabolic
changes recorded by Rubner(j) for the dog and other animals. Rubner has
shown that increased humidity at temperatures above 82° F. increases
the metabolism. For a given high temperature the rise in metabolism
will not be as great where the evaporation of perspiration occurs readily
as when there is difficulty in evaporation, due to increased humidity, that
prevents effective elimination of heat.
All studies on the influence of temperature and humidity indicate that
cool and comfortable atmospheres, with a temperature of about 68° F.
and 50 per cent relative humidity are beneficial ; while a temperature as
high as 86° F. and 80 per cent relative humidity are deleterious. The
bad effects are due primarily to the inability of the body to properly cool
itself because of the temperature and moisture conditions of the sur-
rounding air.
Air Movement and Winds
Here again the gain to the body is to be found chiefly in the influence
of moving air on heat loss. The air surrounding the body soon becomes
saturated with moisture and approaches the body heat in temperature.
Hence this thin envelope of air surrounding the body may establish
the degrees of temperature and humidity that are known to be delete-
rious.
The effect of wind of moderate humidity and different temperatures
on the metabolism of a man clad in summer clothes as compared with the
metabolism in calm air was shown by Wolfert(&) to be stimulating. A
breeze having a temperature of 59° to 68° F. and moving at the rate of
CLIMATE 903
about 15 miles per hour increased the metabolism approximately 19 per
cent.
A recent investigation by Aggazzotti and Galeotti on the influence of
wind on the respiration and the pulse has shown that if the wind is not
too strong the lung ventilation is favored. The alveolar carbon dioxid
tension is lowered. In strong wind the breathing shows irregularity in
rate and depth.
Light
The opinion has been held that the intense light of the tropical skies
causes the backwardness of mankind in these countries. Sun baths have
been employed in the treatment of tuberculosis with some degree of success.
However, the physiological effects of light have not been clearly demon-
strated. Wohlgemuth, in a study of desert climates at Assuan, found
the number of red corpuscles and the per cent of hemoglobin to be slightly
increased. That the increase was not the result of the loss of water from
the blood because of sweating was shown by the observations that neither
the sodium chlorid nor the sugar content of the blood was changed. He
attributes the increase in red corpuscles, which in one man rose from
4,900,000 to 5,680,000 in five months, to the action of light; and cites
that Bickel, on exposing rabbits to the light of the mercury arc, produced
an increase in the red corpuscles. Other possibilities were not eliminated.
Huntington, in his investigation on human efficiency, as measured by the
amount of daily work performed, found that the effect of light was at
best only slight.
Rubner, under ordinary conditions, and Durig and Zuntz, on Monte
Rosa, did not find that sunlight influenced metabolism. Hasselbalch and
Lindhard(a), studying the ultra-violet rays of the sun, obtained no effect
upon the metabolism. They did, however, find a reduction in the fre-
quency and an increase in the depth of respiration as the effect of the
exposure to such rays.
The importance of climatic conditions in the life and efficiency of
mankind has been well demonstrated by Ellsworth Huntington in his
book on "Civilization and Climate." He points out that for the pro-
duction of good fruit the three factors of good stock, proper cultivation,
and favorable climatic conditions are absolutely necessary. Recognizing
the importance of these three for man, he then proceeds to study con-
ditions of human progress and power of achievement He finds that
wherever civilization has risen to a high level, the climate appears to have
possessed those qualities which to-day are recognized as most stimulating.
He derives the important climatic factors by various statistical com-
parisons. Assuming that the best and fullest test of efficiency is a person's
daily work, the thing to which he devotes most of his time and energy, ho
904
EDWARD C. SCHNEIDER
studies the output of thousands of industrial workers in various parts of
the United States; mental activity of certain classes at West Point and
Annapolis ; and strength tests of school children in Denmark. The annual
work curves are quite similar. The lowest period of efficiency occurs in
December, January and February, reaching the minimum at about the
end of January. The efficiency curve then gradually rises to a first
maximum in May and June, falling moderately until the end of July,
rising again in September, with the greatest maximum in November. He
also presents a curve of gain in body weight based on a report of patients
suffering from tuberculosis in a sanatorium at Saranac Lake. This is
similar to the work output curve with the least gain or no gain in February
and March, and the maximum gain in October. A study of death rate
reveals another of the same type of curves, a marked reduction in May and
June, an increase in July and August; followed by another reduction in
which the low death rate occurs in October, November, and December,
with November showing the lowest rate for the year. All these data
combine to demonstrate that the period of greatest physical and mental
efficiency occurs in the late spring and late autumn.
An analysis has convinced Huntington that changes in the barometer,
in the localities studied, seem to have little effect. Humidity possesses a
considerable degree of importance, but the most important factor is clearly
temperature. He came to the conclusion that the optimum temperature
of outside air for physical well being is from 60° to 65° F., that is when
the noon temperature rises to 70° F. or even more ; and for mental work
the optimum is reached when the outside temperature averages 38° F.
Another highly important climatic condition is that of the temperature
change from day to day. "It seems to be a law of organic life that variable
temperature is better than uniformity." The ideal conditions are mod-
erate temperature changes, "especially a cooling of the air at frequent
intervals." Variations in temperature give one of the best tonics provided
by nature.
All experimentation and observation go to demonstrate that climate
exerts a noteworthy influence on the physical and mental life of mankind.
This effect is largely due to the movement, humidity and temperature of
the air. Another physical factor, altitude, is still to be discussed.
The Psychological Factor in Climatotherapy
The principles of climatic treatment are founded on psychology as well
as physiology. The external conditions which we see and feel make a
greater conscious impression than the physiologic effects which do not come
into the field of consciousness; unless, as is rarely the case, they are ex-
treme and unusual. A climate that is conducive to out-of-door living
CLIMATE 905
awakens an interest and zest and produces a cheerful serenity and happi-
ness that permit the physiological climatic effects to more completely re-
store health. Unquestionably both physiological and psychological con-
ditions influence physical well-being; a patient worried about financial
resources and family cares rarely secures the full advantage of the physio-
logical effects of climate, because of the absence of serenity and
cheerfulness.
The only way to use a climate is to give it every chance to help in the
cure. Careful and intelligent attention to personal hygiene and to the
psychical side of the environment are essential. Climate does not cure,
but it is an important help to the body in overcoming weakness and disease.
The Variety of Climate. — The physical factors have served as a basis
for classifications of climate. It has long been recognized that there are
four factors that enter into the production of the climate of any locality:
(1) Distance from the equator; (2) distance from the ocean; (3) height
above the sea-level; and (4) the prevailing winds.
The classic zones, tropical, temperate and polar, recognize the relation
to the sun and are based on sunshine distribution. Irregularities in the
distribution of land and water and the prevalence of particular winds
break the uniformity of these zones and lead to a more rational scheme
of classification. "The great differences in the climatic relations of land
and water, recognizes a first large subdivision of each zone into land
and water areas. Then as continental interiors differ from coasts, and as
windward coasts have climates unlike those of leeward coasts, a further
natural subdivision would separate these different areas. Finally, the
control of altitude over climate is so marked that plateaus and mountains
may well be set apart by themselves as separate climatic districts."
A maritime climate is equable, that is without extremes of tempera-
ture, with a prevailing high relative humidity, a large amount of cloudi-
ness and a comparatively heavy rainfall. The continental climate is more
severe; the annual temperature ranges increase, as a whole, with increasing
distance from the ocean ; the regular diurnal ranges are also large, reaching
35° or 40° F., and even more. The humidity is lower and cloudiness,
as a rule, decreases inland, reaching its minimum in the arid plains and
deserts. The evaporating power of a continental climate is much greater
than that of the more humid and cloudier coast climate. A climate with a
relative humidity up to 50 per cent is unusually dry, with 50 to 70 per cent
relative humidity is dry, with 70 to 85 per cent relative humidity is
moist, and with 85 to 100 per cent relative humidity is unusually moist.
General Considerations in the Choice of Climate. — While climatic
studies are difficult to evaluate certain things now stand out somewhat
clearly. The humid tropics are disagreeable and hard to bear. Energetic
physical and mental actions are difficult or even impossible. "The monot-
onously enervating beat of the humid tropics weakens, so that man becomes
906 EDWAED C. SCHNEIDER
sensitive to slight temperature changes." James is of the opinion that
an even temperature lowers the tone of the vasomotor system by lack
of proper exercise. In drier tropics, cooled by trade winds, as found in
the Hawaiian Islands, the white population lives and carries on business
in "American style" without signs of tropical enervation and deteriora-
tion. It appears that many elderly persons and others who are over-
worked may find rest from nervous tension in portions of the tropics.
Extraordinarily low temperatures are easily borne if the air is still
and dry, and large ranges in temperature are well tolerated when the air
is dry. On the other hand, cold air with a high moisture content has a
depressing effect. At the margins of the polar zones the change from
winter to summer is so sudden that the transitional season disappears.
Hence, in the seasonal changes the intermediate periods that add so much
to human efficiency are lacking.
It has been suggested that unless invalids are of very delicate constitu-
tion, or greatly run down in health, the bracing qualities of a northern
winter in a dry climate under proper safeguards will probably do them
more good, though at times they will be less comfortable, than a warm
southern atmosphere. Too large variations of daily temperature may be
overtrying, but as a rule a definite drop in the daily temperature is a
necessity for stimulation.
Altitude
The mountain and high plateau are characterized by a similar climate
in all the geographical zones. The characteristics are decrease in pressure,
temperature and absolute humidity; an increase in the intensity of sun-
light and radiation ; and larger ranges in soil temperature. . The climatic
action of the heat, humidity and light have been discussed, leaving only
the factor of pressure for consideration. Some maintain that the real
benefit of mountain climate to the health seeker is to be found in the
favorable heat and humidity and the mental reaction to the beauty of
the environment.
An early suggestion made by Jourdanet is still to be borne in mind
when mountain and high plateau climates are recommended. He divided
these climates into the mountain climate, below 6,500 feet, and altitude
climate above that height. The former was considered beneficial because
of the stimulating quality of clean, clear, cool air and the latter injurious
because of low pressure. Men live comfortably and work well in the
mines of the Andes at 15,400 to 16,200 feet. Such altitudes, however,
are for the robust and not the health seeker.
Residence at a high altitude brings about striking and definite physio-
logical changes in the body. There have been many opinions held as to
the essential cause. A common belief has been one that regarded the
CLIMATE 907
pressure, acting in a mechanical manner, as the responsible cause. It has
been natural to expect that a diminution of external pressure would have a
"cupping glass" effect that would lead to a congestion of the skin and
lungs and in some way cause a readjustment of internal parts of the body.
However, all recent investigators hold that the physiological effects noted
at high altitudes are due to the lack of oxygen, resulting from the lowered
partial pressure of oxygen that occurs proportionately with the decrease
in barometric pressure.
Altitude Sickness. — It is now clearly established that during the first
few days spent at a high altitude an attack of altitude sickness may occur.
Some persons are affected at a comparatively low and others at a higher
altitude. An elevation of 10,000 feet, or even less, provokes it in a few
individuals; but many go to 14,000 and more feet without distress.
There are two forms of altitude ("mountain") sickness; the acute, which
breaks out suddenly on entrance into the rarefied air ; and the slow, which
manifests itself much later.
The acute form is characterized by a rapid pulse, nausea, vomiting,
physical prostration which may even incapacitate for movement, livid
color of the skin, ringing sensation in the ears, dimmed sight and faint-
ing attacks.
In the slow form, which may be called the normal type, lasting from
one to three days, the newcomer at first complains of no symptoms. Some
hours later he begins to feel "good for nothing" and disinclined for
exertion. He goes to bed to spend a restless and troubled night. A frontal
headache and periodic or Cheyne-Stokes breathing interfere with sleep,
there may be nausea and vomiting. The next morning the patient may
feel slighly giddy on arising and any attempt at exertion increases the
headache. The face may be slightly cyanosed and the eyes dull and heavy,
with a tendency to water. The tongue is coated and appetite gone. There
may be diarrhea and abdominal pain. The pulse and arterial blood
pressure are usually high. The temperature is normal or slightly under.
There are wide divergencies from this slow type of which Ravenhill has
well described those in which cardiac and nervous symptoms predominate.
A weakened heart does not seem to predispose to the cardiac type of
altitude sickness.
Acclimatization. — The process of acclimatization is slow, while certain
of the changes may begin almost at once with entrance into rarefied air,
it ordinarily requires several days for these to wholly restore the patient
to normal well being. The complete process of acclimatization requires
six and more weeks.
Adaptation to altitude consists in physiological responses that increase
the supply of oxygen, which is at first decreased because of lowered
pressure, until it again reaches normal. These include, among others, the
following: (1) An increase in the percentage and the total amount of
908 EDWAED C. SCHNEIDER
hemoglobin in the blood of the body; (2) a fall in the lung alveolar carbon
dioxid partial pressure and a rise in the alveolar oxygen pressure, the
result of increased ventilation of the lungs due to deeper breathing ; and
(3) at some altitudes a temporary or permanent increase in the rate of
blood flow.
The Blood Adaptive Changes. — In spite of an occasional contrary
observation the prediction made by Paul Bert in 1878 that the blood at
high altitudes would be found to have a greater oxygen capacity than the
blood of similar individuals at lower levels, has been demonstrated to be
true. Investigators have found an increase in the number of red corpuscles
per cubic millimeter and in the percentage of hemoglobin. Miss Fitz-
gerald (a) (6), by a study of inhabitants of the Southern Appalachian and
the Rocky Mountains, found that as the altitude increases the percentage
of hemoglobin in the blood is augmented about 10 per cent of the normal
value, for men and women at sea level, for every 100 mm. fall of barometric
pressure. The physiological significance of this increase in hemoglobin
and red corpuscles is that a unit volume of blood can carry for a given
oxygen pressure more oxygen than normally.
When a rapid ascent -is made to a high altitude, as in an aeroplane,
the changes in the blood may be detected as early as in from 20 to 60
minutes. When the ascent is made more slowly, as by automobile or
railway, it may not be evident for 12 or more hours. The increase is
rapid for the first two to four days and is followed by a more gradual
increase extending over a period of six weeks. The increase occurs most
rapidly in subjects in excellent physical condition. Fatigue, as from
walking up a mountain, delays the increase in hemoglobin and red
corpuscles.
At the present time the evidence accounts for the increase in hemo-
globin and erythrocytes as follows: the initial rapid increase is due to a
concentration by a loss of fluid from the blood and possibly by throwing
into the general circulation a large mass of reserve corpuscles. The more
gradual increase, extending over several weeks, is brought about by the
increased activity of the bone marrow resulting in an increase in the total
number of corpuscles and amount of hemoglobin which may finally not
only restore, but sometimes actually increase, the low altitude blood
volume.
The number of leukocytes per cubic millimeter is not increased with
altitude, but the larger lymphocytes are increased and the polymorpho-
nuclear cells diminished. The blood platelets are also increased at high
altitudes.
Respiratory Adaptation to High Altitudes. — The first effects observed
on going to a high altitude are caused by an insufficient supply of oxygen
to the tissues. It is to be expected, therefore, that the amount of air
pumped in and out of the lungs will be increased almost immediately.
CLIMATE 909
The respiratory response to altitude is ordinarily the first of the several
compensatory changes to appear. Miss Fitzgerald found that the breath-
ing of persons living permanently at an altitude of 2,200 feet, as indicated
hy the alveolar carbon dioxid, snowed a larger lung ventilation than under
similar conditions at sea level; and further established the law that
approximately a 10 per cent increase in the ventilation occurred for each
100 m'm. of diminution of the barometric pressure. The full extent of
the change in breathing is reached in from 7 to 14: days.
The type of breathing that is best suited to the need of the body at
high altitudes is slow and deep rather than rapid and shallow. After
adaptation the depth rather than the rate of breathing will ordinarily have
increased. However, during vigorous physical exertion, where even at
sea level the depth of breathing is about maximal, at a high altitude
such as Pikes Peak the rate shows a marked increase. A subject, who
had breathed when in bed at sea level at the rate of 16.8 breaths per
minute, on Pikes Peak had a rate of -only 17.3; while walking, at the
rate of 5 miles per hour at sea level, the rate was- 20, and on Pikes Peak
36 breaths per minute.
The increased breathing augments the alveolar oxygen tension in the
lungs. If, for example, on Pikes Peak, with a barometric pressure of
457 mm., the respiration did not change, then the alveolar oxygen tension
in the dry alveolar air would fall proportionately with the barometer to
about 36 mm. The increase in breathing, however, raises this at that
altitude to about 52 mm. As a result the blood will be just that much
more saturated with oxygen, thus remedying to some extent the defective
saturation of the arterial blood with oxygen.
The explanation of the manner in which respiration is modified has
recently been more fully elucidated. The hormone of breathing is the
hydrogen ion concentration in the blood, and not the total carbon dioxid
in the blood, nor the concentration of HCO3 ions as has sometimes been
claimed. Haldane(^) has pointed out that the IT-ion concentration of the
blood is regulated with great delicacy by the respiration on the one hand
and the kidneys and liver on the other. The respiration doing the rough
and immediate work by increasing or decreasing the elimination of the
carbon dioxid, and the kidneys the finer and slower work. When a person
goes to a high altitude the want of oxygen acts as an additional stimulus
to the respiratory center with the result that an excess of carbon dioxid
is eliminated. This decreases the H-ions and causes a state of alkalosis
in the blood. To offset the excess of alkali the kidneys and liver attempt
to redress the balance. It has been shown by Haldane, Kallas, and Kenna-
way and by Hasselbalch and Lindharel(a) (6) that excretion of acid and of
ammonia diminish for a period of several days. During this time the
alkalosis will have been diminished and the normal H-ion concentration
of the blood almost restored to its previous level. This, as Haggard and
910 EDWARD C. SCHNEIDER
Henderson (a) have shown, results in a reduction of blood alkali. While
after acclimatization the H-ions are again probably nearly the same as at
sea level, the restoration is never complete and in the end the stimulating
action of diminished oxygen leads to a greater ventilation of the lungs
than on the first day, and a permanent level is then established for that
barometric pressure. Haldane makes clear that if the initial alkalosis
should be maintained the dissociation of oxyhemoglobin would be less
than normal, thus accentuating oxygen want in the body. By restoring,
or nearly restoring, the H-ion concentration of the blood the curve of
oxyhemoglobin dissociation is again shifted back to or toward the normal
for sea-level.
Metabolism. — Investigations, in spite of an occasional positive finding,
lead to the opinion that metabolism is independent of the variations in
atmospheric pressure. Sundstroem found that the assimilative power for
the energy in the food remains normal at all altitudes.
In 1883 Fraenkel and Geppert placed a fasting dog under the influ-
ence of diminished barometric pressure and found an increased protein
metabolism. Zuntz(a) and collaborators, on Monte Rosa at 2,900 m., failed
to show an increase in metabolism; but at 4,560 m., barometer 443 mm.,
obtained an increase of approximately 15 per cent. Later Durig and
Zuntz, in an expedition to Teneriffe, altitude of 3,160 m., failed to show
an essential difference in metabolism. The Anglo-American expedition
to Pikes Peak found no difference in metabolism either during rest or
when taking exercise. Hasselbalch and Lindhard observed a man for 14
days in a pneumatic cabinet, at 455 mm. barometric pressure, and found
that the consumption of oxygen and the urinary ammonia and amino-acids
were unaffected. Sundstroem showed that the iron balance did not alter
nor the retention of iron exceed that observed in low altitudes.
The diminished excretion of ammonia observed by Hasselbalch and
Lindhard and by Haldane and collaborators during the period when blood
alkalosis was being overcome has already been pointed out. Hasselbalch
and Lindhard found that an increased oxygen consumption might occur
during the process of acclimitization. Von Wendt(6) noticed a retention
of nitrogen, iron and potassium on Monte Rosa which he attributed to the
construction of new red corpuscles.
The Circulatory Mechanism. — Altitude, if great enough, increases the
heart rate; but it is generally recognized that at moderately high alti-
tudes, 6,000 to 8,000, or even 9,000 feet, there is no augmentation.
Shortly after ascending to such an altitude as 14,000 feet the heart rate
gradually increases during a period of several days. In persons who
develop "altitude sickness" and in those fatigued by climbing, the accelera-
tion begins sooner and is greater. With the development of acclimatiza-
tion the heart rate will return toward, and in some cases reach, the low
CLIMATE 911
altitude normal. The same amount of physical exertion increases the
pulse rate more at a high than at a low altitude. The difference becomes
greater as the amount of work done increases.
The arterial blood pressures are not altered by altitude in the majority
of men ; but in a considerable number of cases there occurs a slight lower-
ing of the systolic pressure; while occasionally, very likely in a poor
reactor, there is a rise in both the systolic and diastolic pressures. During
an attack of "altitude sickness" there is usually a marked increase in
both pressures.
The blood pressure in the capillaries is either unchanged or less than
at sea-level. In the veins, at altitudes of more than 6,000 feet, the pressure
is less than at sea-level. Contrary to common opinion bleeding from the
nose, lips, lungs, and stomach rarely occurs. The experience of aviators
has dispelled the belief that altitude causes hemorrhages.
Physical exertion makes greater demands on the heart and blood vessels
at high than at low altitudes. The rise in arterial pressure is greater
for a given exertion at a high than a low altitude, the difference being
less after acclimatization. It would be an easy matter to seriously injure
the heart during the early days of residence at high altitude. However,
in men who are physically strong because of athletic training the risk is
slight; and in all who become acclimated the ordinary forms of exercise
will be well tolerated.
General Considerations. — Anemia is regarded by Sewall as the domi-
nant disorder at high altitudes. Anemia reduces the working efficiency
and the reserve power of the tissues insofar as it permits deprivation of
oxygen. That the physiological response to the stimulation of lowered
barometric pressure may be slow or deficient is a common observation.
Hence it is to be expected that many functional disorders are originated
or accelerated at moderate altitudes owing to the existence of com-
paratively mild grades of anemia. Moleen has called attention to the
fact that individuals who exhibit nervous symptoms or complain of
"nervousness" while living at high elevations show a relative or abso-
lute anemia. It is significant that the plethoric type of person rarely
finds it necessary to leave high altitudes for "nervousness." It is main-
tained that if measures are taken to stimulate the blood forming centers
there is no more difficulty in living tranquil lives in the high altitudes
than at sea level.
The dangers to the heart in high altitudes are, according to Hall,
precisely the same as elsewhere, but very sharply exaggerated in certain
directions; particularly because the newcomer is likely to overdo in
physical exertion. Cardiac overstrain from exercise is often the real cause
of distress and not the altitude. Schrumpf found in Switzerland that up
to 7,000 feet pathological blood pressures are improved, that is, high
pressures are reduced and low ones increased, together with an improve-
912
EDWAED C. SCHNEIDER
ment in the general condition. Compensated valvular lesions and mild
cases of myocarditis were also favorably influenced.
Because the adaptive compensations to high altitudes are slow in their
development, the newcomer should remain quiet for a day or two. If
symptoms of "altitude sickness" occur rest in bed with windows open is
advisable and at least a day of quiet after all symptoms have disappeared.
During the first days it is best to make no exertion which causes any
considerable dyspnea.
The changes in the breathing and the blood are permanent in character,
and do not diminish during a protracted residence at the high altitude.
Changes in pulse rate and in the rate of blood flow are less permanent,
and tend to disappear with acclimatization. On returning from a high
to a low altitude the changes in the respiration and blood are maintained
for a time as an "after effect." The longer the residence at the high
altitude the more prolonged the period of "after effect." During this
period the individual may gain in weight and health.
INDEX
Abderhalden's experiments, on nitrog-
enous equilibrium and body weight,
123, 124, 125.
Absorption, of alcohol, 297.
distribution after, 299.
— of carbohydrates, 249.
— effect on, of alkalies, 318.
of calcium, 318.
of water, 291.
— of fat from the intestine, 194.
changes in fats during, 196.
emulsification, 200.
factors in, bile, 198.
pancreatic secretion, 197.
in fat metabolism, paths of, 196.
synthesis of fats during, 196.
— in fat metabolism of stomach, 190.
— of magnesium, 323.
— of vitamins, 347.
Acapnia, 741.
Acclimitization, 907.
Acetates, effect of, on metabolism, 726.
Acetone bodies in the blood, 449.
Acid-alkali metabolism, effect on, of
anesthetics, general, chloroform and
ether, 762.
of antipyretics, 771.
of mercury, 756.
of opiates, 766.
Acid-base equilibrium, and blood poi-
sons, 744.
— effect on, of arsenic, 754.
— of phosphorus, 750.
Acidosis, alkalies treatment of, 734.
— of anesthesia, 734.
— cause of, 458.
— definition of, 733.
— of diabetes, 734.
— in diarrheal attacks of infants, al-
kaline treatment for, 735.
— intravenous injection of sodium bi-
carbonate for, 792.
— of nephritis, 735.
— retention, 735.
Acids, effects of, on metabolism, 733.
Acids or acid-forming foods, prolonged
administration of, 334.
Aoromegaly, effect on, of pituitary
gland substances, 785.
Adamkiewiez-Hopkins-Cole reaction of
proteins, 98.
Adenase, distribution of, 156.
Adenine, 137, 138.
Adrenalin, influence of, on blood sugar,
258.
Adrenals, and sympathetic system, in-
fluence of on glycogenolysis, glyco-
genesis and glucolysis, 257.
Age, influence of, on basal metabolism,
612.
of infants from two weeks to
one year, 646.
- old, See Old Age.
Agglutination test for transfusion, 835.
— method of performing, 833.
Air, combustion and respiration of,
Boerhaave (1668-1738), 11.
-Kobert Boyle (1621-1679), 8.
-Hales, Stephen (1677-1761), 11.
John Mayow (1640-1679), 9.
-Stahl (1660-1734), 11.
-Willis (1621-1675), 11.
— dephlogisted, 16.
— "eminently respirable" of Lavoisier,
or oxygen, 22.
— fire, of Scheele, 17.
— fixed, 15.
— ' — Lavoisier, 22.
— in history of metabolism, Robert
Boyle, 8.
— inflammable, or hydrogen, 15, 23.
— outdoor, analysis of, 541.
— residual, or nitrogen gas, 16.
— spoiled, or nitrogen, of Scheele, 17.
Air analyzers, Haldane's method, 540.
Air currents, cooling power of, at dif-
ferent velocities, 604.
Air movements, effects of, 902.
Alanin, 84, 107.
Albumin, 428.
Albumins, 82.
Albuminoids, 83.
Alcohol, absorption of, 297.
— combustion of, 300.
— in diabetes, 301.
— distribution of, after absorption, 299,
— effect of, on metabolism, 764.
carbohydrate, 764.
913
914
INDEX
Alcohol, effect of, on metabolism, fat,
765
-protein, 300, 764.
purin, 300.
— reproduction and growth, 765.
total, 299, 764.
— excretion of, 298.
— metabolism of, von Liebig, 49.
— and muscular work, 301.
— nutritive value of, 297.
— in rectal feeding, 812.
Alcohol soluble proteins, 83.
Aldol condensation, 225.
Aldohexoses, dulcital series, 224.
— isomerism of, 222.
— maniiitol series of, 223.
Aldopentoses, table of, 241.
Alimentary catarrh in children, sul-
phur water as therapeutic agent in,
851.
Alimentary lipemia, 201.
Alkali therapy. See Alkaline Treat-
ment.
Alkalies, action of, 227.
— administration of, to man, effect of,
334.
— effect of, on absorption, 318.
— on metabolism, 732.
— in acidosis, 734.
of infants during diarrhea,
735.
— in anesthesia, 734.
in diabetes, 734.
— • -neutrality regulation, 732.
in retention acidosis, 735.
in uranium nephritis, 735.
— in human body, 315.
Alkaline treatment, of acidosis, 734,
792.
— of anesthesia, 734.
— of infants during diarrhea, 735.
— retention, 735.
— in diabetes, 316, 734.
— in gout, 739.
in nephritis, 793.
— reaction of urine in, attention to,
793.
— as routine before and after surg-
ical procedures, 793.
— of uranium nephritis, 735.
Alkaline-saline waters, effect of, on
gastric secretion, 848.
Alkaline waters, carbonated, effect of,
on gastric mucosa, 848.
— effect of, on gastric secretion, 848.
on metabolism, 849.
— on pancreatic secretion, 849.
— therapeutic value of, 850.
Alkalinity, effect on, of purin, 780.
Alkalinization of urine, 849.
Aloin, effect of, on metabolism, 719.
Altitude, blood adaptive change, 908.
— and circulatory mechanism, 910.
— high, effects of, 906.
— dangers of, 911.
Altitude, high, respiratory adaptation
to, 908.
— and metabolism, 910.
Altitude sickness, 907.
Aluminum, effect of, on mineral metab-
olism, 732.
Amidomyelin, of brain, 470.
Amino-acid content of different pro-
teins, 96.
— relative, table of, 97.
Amino acids, absorbed, fate of in the
blood, 104.
— aromatic amino acids, 89.
— phenyl-alanin, 89, 113.
tyrosin, 90, 113.
— of the blood, 442.
— of brain, 471.
— compounds of, 93, 94.
— possible, number of, 95.
— deaminization of, by bacteria, 675.
— diamino-acids, 88.
— arginin, 89, 112.
-lysin, 88, 112.
— ornithin, 89, 113.
— dibasic mono amiiio-acids, 86.
— aspartic acid, 86, 110.
— combinations, 87, 110.
— effect of, on metabolism, 774.
— fate of, in the body, table summariz-
ing, 115.
— in the tissues, 105.
— fate of non-nitrogenous fraction of,
107.
— heterocyclic amino acids, 90.
-histidin, 91, 114.
— oxyprolin, 90, 114.
prolin, 90, 114.
— tryptophan, 91, 115.
— hydroxy- and thio-a-amino acids, 87.
— ^-hydroxyglutamic acid, 88, 110.
- — cystein, 88, 111.
— cystin, 88, 111.
serin, 87, 111.
— monobasic mono amino acids, 84.
— alanin, 84, 107.
— a-amino butyric acid, 85, 108.
— combinations of,
carboxyl, 86.
— glycocoll hydrochlorid, 86.
— sodium glycocollate, 86.
glycocoll, 84, 107.
I^DEX
915
Amino-acids, monobasic mono amino
acids, iso-leucin, 85, 109.
-leucin, 85, 109.
— normal leucin, 86, 109.
-valin, 85, 109.
— number of, 95.
— physiological value of, experiments
illustrating, of Osborne and Mendel,
127, 128, 129.
— role of, in structure of protein mole-
cule, 91.
— of the urine, 490.
Amino-butyric acid, 85, 108.
Amino-purins, adenine, 137.
— chemical relation of, with oxy-
purins, 138.
— guanin, 137.
— formation of oxy-purins from, 151.
Amins, aromatic, formation of, 687.
— physiological action of, 687.
— formation of, 680.
— effects on, of utilizable carbohy-
drate, 685.
Ammonia, of the blood, 442.
— change of, into urea, 675.
— effect of, on metabolism, 773.
— endogenous, 676.
— of the urine, 489.
Amylen hydrate, effect of, on metabol-
ism, 764.
Anemia, arsenic waters in, 851.
— and blood lipoids, 446.
— from blood loss, blood transfusion in,
indications for, 832.
— blood transfusion in, beneficial ef-
fects of, 822.
— chronic forms of, blood transfusion
in, indications for, 832.
— chronic hemolytic, blood transfusion
in, indications for, 832.
— general effects of, on body, 821.
— idiopathic aplastic, blood transfu-
sion in, indications for, 832.
— iron waters in, 851.
— before operation, blood transfusion
in, 833.
— pernicious, blood transfusion in, in-
dications for, 831.
— treatment of, by x-rays, 886.
Anesthesia, acidosis of, alkaline treat-
ment of, 734.
Anesthetics, general, chloroform and
ether, effect of, on metabolism, 760.
— acid-alkali, 762.
carbohydrate, 761.
fat, 762.
— ferments, 763.
• mineral, 763.
Anesthetics, general, chloroform and
ether, protein, 760.
water, 763.
Animal calorimetry or heat. See Cal-
orimetry.
Animal nucleic acids, 145.
Antiketogenesis, 271.
Antimony, effect of, on metabolism,
753.
— nitrogen, 754.
on uric acid excretion, 754.
Antineuritic vitamin (water-soluble
B), 342.
— sources of, in food, 346.
Antipyretics, effect of, on metabolism,
767,770.
— acid-alkali, 771.
— carbohydrate, 770.
— ethylhydrocuprein, 772.
— in fever, 768.
— protein, 769.
— quinin and its congeners, 772.
of reproduction and growth,
769.
-total, 767.
— theory of reduction of fever by, 771.
Antiscorbutic vitamins, 345.
— sources of, 346.
1-Arabinose, 241.
Arginin, 89, 112.
— as source of creatin of urine, 494.
Aristotle, on food, 5.
Aromatic oxyacids and derivatives, 499.
Arsenic, distribution of, in body, 308.
— effect of, on acid-base equilibrium,
754.
on body temperature, 755.
— on ferments, 755.
— on metabolism, 753.
— carbohydrate, 754.
nitrogen, 754.
-total, 754.
v ater, 755.
— on uric acid excretion, 754.
Arsenic waters, effects of, 851.
Arthritis, chronic, treatment of, by
radium, 886.
— rheumatoid, treatment of, by x-rays,
886.
Artificial methods of feeding. See
Feeding, artificial methods of.
Ash, in the brain, 471.
— in diet, amount of, required, 394.
— in diets, ordinary constituents of,
396.
— in the feces, 510.
— in milk, 478, 479.
— minimum of constituents of, 411.
916
INDEX
Ash, relation of constituents of, to one
another, 413.
Aspartic acid, 86, 110.
Asphyxial glycosuria, 740.
Asphyxiants, effects of, on metabolism,
740.
— asphyxia! glycosuria, 740.
blood poisons, 744.
carbon dioxid, 741.
— carbon monoxid, 742.
— cyanids, 745.
Asymmetry, 218.
Atoms, relation of, to one another in
the molecule, Pasteur, 219.
Atophan, effect of, on metabolism, 772.
Atropin, effect of, on metabolism, 774.
Atwater and Benedict's apparatus for
measuring respiratory exchange,
524.
Atwater and Rosa's apparatus for
measuring respiratory exchange, 518.
Bacillary dysentery, treatment of>
buttermilk, 709.
lactose-protein, 709. •
Bacteria, analogy between metabolic
waste products of man and, 675.
- classification of, parasitic, 666.
— pathogenic, 667.
— — saprophytic, 666.
— cycles of, 667.
— decomposition of proteins by, of
tryptophan, 682.
— of tyrosin, 681.
— differentiation from majority of
plants and animals, 665.
— endotoxins of, 677.
— evolution of, from one type to an-
other, 668.
— in the feces, 504.
— intestinal, of normal nurslings, ef-
fects of sugar upon intestinal flora,
experimental evidence, 694.
— relation between diet and micro-
bic response, 691.
— living chemical reagents, 668.
— pathogenic, specificity of action of,
and its relation to proteins and car-
bohydrates, 673.
— phases in life history of, 665.
— rate of increase among, 665.
Bacterial action, specificity of, 668.
— ultimate chemistry of,- 668.
Bacterial cells, 665.
— cytoplasm of, 679.
— elementary composition of, 674.
— relations between surface and vol-
ume of, 666.
Bacterial metabolism, chemical require-
ments for bacterial development,
668.
— energy, 669.
— structural, 669.
— chemistry of, 678.
decomposition of tryptophan,
682.
decomposition of tyrosin, 681.
— phases of, 678.
anabolic or structural, 678.
-ketabolic, 678.
— reactions, effects of utilizable
carbohydrates on formation of phe-
nols, indol and amins, 685.
— formation of phenols, indol
and indican, amins, 680.
illustrative of decomposition
of proteins by bacteria, 681.
— physiological action of aro-
matic amins, 687.
— general nature of products of bac-
terial growth, arising from utiliza-
tion of proteins and of carbohy-
drates for energy, diphtheria toxin,
669.
— indol formation, 670.
— protein-liquefying enzymes, for-
mation of, 670.
— general relations between surface
and volume of bacteria and the gen-
eral energy requirements of bacteria,
665.
— influence on, of saprophytism, para-
sitism and pathogenism, 666.
— intestinal bacteriology, 690.
— adolescent and adult, 696.
— exogenous intestinal infections,
706.
— of normal nurslings, 691.
— sour milk therapy and, 700.
— nitrogenous, illustrative data, 676.
— quantitative measures of, 674.
— significance of, 663.
— sour milk therapy and, 700.
— specificity of action of pathogenic
bacteria and its relation to proteins
and carbohydrates, 673.
Bacterial nutrition, 672.
Bacterial toxins, complex nitrogenous,
composition of, 679.
Bacteriology, intestinal, adolescent and
adult, 696.
— exogenous intestinal infections,
bromatherapy, 706.
general history and development,
690.
of normal nurslings, 691.
INDEX
917
Bacteriology, intestinal, of normal
nursling, effects of sugars upon in-
testinal flora, experimental evidence
of, 694.
— relation between diet and mi-
crobic response, 691.
— sour milk therapy and intestinal
metabolism, 700.
Bag method of Kegnard, for measuring
respiratory exchange, 537.
Barium, in intravenous infusion, 800.
Barral (1819-1884), experiments of, on
metabolism of human beings, 38.
Basal metabolic rate, determination of,
Boothby and Sandiford, 611.
Basal metabolism, 607.
— in anemia, 822.
— of children, up to puberty, 649.
awake and sleeping, table, 658.
— of fat and thin boys, table,
658.
— influence on, of muscular ac-
tivity, 654.
— of sex, 652.
— influence on, of puberty, 654.
— comparison of, per kgm. and per sq.
meter, of surface, table, 610.
Basal metabolism, of infant, new-born,
632.
influence on, of crying, 637.
— of food and external tem-
perature, 638.
— of sex, 635.
— from two weeks to one year of
age, 642.
— influence on, of age, 646.
— influence on, of age, 612.
— of blood transfusion, 828.
of physical characteristics, 608.
— of radiation, 883.
of sex, 614.
Basedow's disease, treatment of, by
roentgen rays, 887.
Baths, cold, and cold douches, 863.
effects of, 856.
— extra energy, 858.
— fever reduction, 856.
on heat production, Ignatow-
ski, 857.
Lusk, 858.
-Matthes, 857.
-Kubner, 858.
— redistribution of blood, 859.
— refreshing, 860.
— friction in, 863.
— effervescent, 865.
— hot, effects of, on metabolism, 860,
861.
Baths, hot, effects of, on oxygen con-
sumption, 860, 861.
— on pulse and blood pressure,
862.
— on respiratory quotient, 861.
— on temperature of body, 860,
861.
- with sand, 863.
— influence of mechanical and chemi-
cal stimulation accompanying, 862.
— mustard, 863.
— peat and mud, 867.
— radioactive, 867.
— salt, effects of, 863.
— on blood pressure, 865.
— on metabolism, 863, 864.
— and sweat secretion, 867.
Beeswax, 185.
Benedict's method of measuring respir-
atory exchange, 544.
Benzoates, effect of, on metabolism,
726.
Benzol poisoning, blood transfusion in,
832.
Berthelot (1827-1907), work of, on me-
tabolism, 77.
Berzelius (1779-1848), experiments of,
in history of metabolism, 33.
Bidder, F. W. (1810-1894) and
Schmidt, C. (born 1822), combined
work of, on metabolism, 57.
— basal metabolism described by, 60.
— bile, excretion of, in relation to
the total ingesta and excreta of body,
58.
— carbon metabolism, 61.
— respiratory quotient, 63.
— total metabolism computed by, 60.
— "typical food minimum" of, 63.
— weight of feces following meat in-
gestion, 58.
Bile, absorption of, 49.
— character of, 464.
— • considered as both a secretion and
excretion, 464.
— constituents of, 465.
- table of, 465.
— • digestive action of, in making mate-
rials more fluid, 59.
— excretion of, its relation to total
ingesta and excreta of body, 58.
— as factor in fat digestion and absorp-
tion, 198.
— function of, 464.
— pigments of, 465.
— urobilin in, 165.
— clinical significance of increased
elimination of, 168.
918
IXDEX
Bile, urobilin in, determination of, 167.
— diagnostic value of, 169.
Bile salts, Pettenkofer reaction for, 65.
Biliary calculi or gallstones, composi-
tion and character of, 466.
Bilirubin, structural formula of, 163.
Bitter waters, effect of, on gastric se-
cretion, 850.
Biuret reaction of proteins, 96.
Black (1728-1799), on carbonic acid
gas, or "fixed air," 15.
Blood, acetone bodies in, 449.
— action on, of light, 892.
— amino-acids of, 442.
— ammonia in, 442.
— amount of, per kilogram of body
weight, effect on, of temperature and
humidity, .901.
— as a body fluid, 788.
— calcium in, 321.
— during pregnancy, and lactation,
322.
— coagulation of, effect on factors of,
of blood transfusion, 825..
— composition of, 423.
- table of 425.
— creatin of, 441.
— creatin metabolism, 175.
— creatinin of, 440.
— creatinin metabolism in, 177.
— diastatic activity of, method of esti-
mating, 445.
— effect on, of roentgen rays and radio-
active substances, 875.
— fat in, alimentary lipemia, 201.
— lipoids, 204.
— fat in, of amino acids, 104.
— fibrinogen in, 429.
— gas constituents of, in history of
metabolism, 33.
— hemoglobin of, 429.
— character and functions, 429.
— estimation of, 429, 431.
in normal males and females dur-
ing different age periods, table of,
430.
— in normal and pathological sub-
jects, table, 430.
— hydrogen ion concentration of, 427.
— mineral constituents of, calcium,
450.
— chlorids, 451.
— iron, 451.
— magnesium, 451.
— phosphates, 453.
— potassium, 450.
— sodium, 450.
— sulphates, 454.
Blood, mineral constituents of, table
of, 307.
— nitrogen of, rest, 442.
— effect on, of blood transfusion,
823.
— reaction and hydrogen ion concen-
tration, 427.
— redistribution, of, by cold baths,
859.
— rest nitrogen of, 442.
— significance of, 423.
— sodium chlorid in, 314.
— specific gravity of, 427.
— total solids in, 426.
— transfusion of, in hemorrhage, 790.
— reactions in, 800.
— water content of, 311.
Blood adaptive changes to high alti-
tude, 908.
Blood cells, 431.
Blood-forming organs, effect on, of
roentgen rays and radio-active sub-
stances, 875.
Blood gases, 454.
— carbon dioxid, 457.
— acidosis, 458.
— effect on, of carbon monoxid, 742.
— oxygen, 455.
— content of, 455.
— arterial, 456.
— in pathological conditions, 456,
457.
Blood groups, 835.
Blood lipoids, abnormalities in, and
anemia, 446.
— characteristic feature of pathologi-
cal conditions, 446.
— cholesterol, 448.
— . — percentage of, in normal and
pathological conditions, table, 448.
— content of, in normal and pathologi-
cal bloods, Bloor's table, 447.
— in diabetes, 446.
— and fat metabolism, 445.
- fats comprised in, 445.
-lecithin, 448.
— in nephritis, 446.
— study of, during fat assimilation,
445.
— total fat (plasma lipoids), 448.
Blood nitrogen, non-protein, 432.
— urea, 435.
-total, 432.
— urea, 435.
— uric acid, 437.
Blood poisons, effects of, on metabo-
lism, acid-base equilibrium, 744.
— carbohydrate metabolism, 744.
INDEX
919
Blood poisons, effects of, on metabolism,
carbon dioxid. See Carbon Dioxid.
carbon monoxid. See Carbon
Monoxid.
— chlorid excretion, 745.
— methemoglobinemia, 744.
— protein metabolism, 744.
— synthesis, 745.
Blood pressure, effect on, of hot baths,
862.
— of salt baths, 865.
— influence on, of water, 291.
Blood proteins, 427.
Blood regeneration, effect on, of blood
transfusion, 826.
Blood serum proteins, 428.
Blood sugar, 250.
— concentration of, effect on, of tem-
perature and humidity, 901.
— glucose, absorption of, 250.
— behavior of, 253.
concentration of, 250.
conversion of, into fat, 251.
oxidation of, 251.
— history of, 443.
— hyperglycemia and hypoglyeemia,
444.
— influence on, of adrenalin, 258.
— normal threshold of sugar excretion,
444.
— percentage of, in normal blood,
443.
— relation between calcium and, 338.
— in salt glycosuria, 722.
Blood sugar curves of normal indi-
viduals, table of, 256.
Blood transfusion, amount of, 834.
Blood transfusion, in anemia, 821.
— beneficial effects of, 823.
— upon basal and nitrogen metabo-
lism, 828.
— upon blood regeneration, 826.
— on blood volume, 825.
— upon factors of coagulation, 825.
— • — upon immune bodies, 828.
upon oxygen capacity of blood,
823.
— symptomatic, 829.
— choice of donor for, blood groups,
835.
— compatibility, 835.
— general, 835.
— indications for, 830.
— as desirable, 831.
— in anemia from blood loss,
832.
in anemia before operation, 833.
in benzol poisoning, 832.
Blood transfusion, indications for, in
anemia before operation, in carbon
monoxid poisoning, 833.
— in chronic hemolytic anemia,
832.
— in idiopathic aplastic anemia,
832.
in idiopathic purpura hemor-
rhagica, 833.
— in nitrobenzene poisoning, 833.
in other forms of chronic ane-
mia, 832.
— in pernicious anemia, 831.
— in sepsis and toxemias, 833.
— as necessary, hemorrhage, 830.
- shock, 830.
— introduction to, 821.
— methods of, 842.
— reactions from, 839.
— associated with instability of
blood when removed from body, 840.
— due to recognized incompatibility,
839.
not due to recognized incompati-
bility, 840.
that resemble those due to recog-
nized iso-hemolysis, 840.
Blood volume, 425.
— effect on, of blood transfusion, 825.
— influence on, of water, 291.
Boerhaave (1668-1738), on air, on his-
tory of metabolism, 11.
Bone deficiency, calcium in, disease of,
727.
Bones, magnesium in, 323.
Boracic acid, effect of, on metabolism,
740.
Borax, effect of, on metabolism, 740.
Boussingault (1802-1887), experiments
of, on calorimetry, 37.
^-oxidation, in fat metabolism, 208.
Boyle, Kobert, (1621-1679), in history
of metabolism, 8.
Brain, changes in composition of, dur-
ing growth, 468.
— constituents of, solid, 467.
cerebrosids, 470.
cholesterol, 470.
diamino - monophosphatids,
amidomyelin, 470.
sphingomyelin, 470.
extractives, 471.
lipoids, 467.
monominophosphatids, myelin,
470.
— - — paramyelin, 470.
phosphatids, 468.
— cephalin, 468, 469.
920
IXDEX
Brain, constituents of, solid, phos-
phatids, lecithin, 468, 469.
— proteins, 467.
relative proportion of, at dif-
ferent ages in albino rate, table, 469.
— sulphatids, 470.
- table of, 468.
— weight of, 467.
Bromatherapy, 706.
Bromids, effect of, on metabolism, 724.
Cadaverin, 685.
Calcium, adult normal requirement for,
317.
-of the blood, 321, 450.
— during pregnancy and lactation,
322.
— in diseases of bone deficiency, 727.
— effect of, on absorption, 318.
— on body temperature, 730.
on carbohydrate metabolism, 731.
on growth and reproduction, 732.
on mineral metabolism, 726.
calcium in diseases of bone de-
ficiency, 727.
— calcium deprivation, 727.
— in leprosy, 728.
in tetany, 728.
— on purin metabolism, 732.
on water metabolism, 730.
— in the feces, 511.
-in the food, 317.
— in leprosy, 728.
— relation between blood sugar and,
338.
— solution of, in intravenous infusion,
800.
— in tetany, 728.
— in the urine, 503.
— in urine and feces, 316.
Calcium deprivation, 727.
Calcium equilibrium, 318.
Caloric value of meat, von Liebig, 49.
Calorific requirements of body, intra-
venous injections of fluids to assist
in providing for, 795.
— glucose, 795.
Calorimeters, control tests of, 578.
— alcohol check, 580.
— heat check, 578.
— forms of, 570.
bath calorimeter of Lefevre,
572.
— compensation calorimeter, of Le-
fevre, 572.
— depending on warming of fixed
quantity of water, Dulong and Lau-
lanie, 570, 571.
Calorimeters, forms of, distillation
calorimeter of d'Arsonval, 570.
— obsolete, 571.
— emission calorimeters, anemo-
calorimeter of d'Arsonval, 581.
— respiration calorimeter of
Kubner, 582.
siphon calorimeter of Richet,
582.
ice calorimeter of Lavoisier, 570.
— obsolete, 571.
respiration calorimeter of At-
water-Rosa-Benedict, 573.
— for measuring heat production of
man, constructed by Voit, 75.
Calorimetry, alimentary, 554.
— animal, 570.
— computations of, foundations of,
laid by Rubner, 75.
conservation of, Lavoisier, 23.
Crawford's experiments on, in
history of metabolism, 17.
— direct, 570.
— forms of, 570.
— basic principles of energy metabo-
lism, basal metabolism. See Basal
Metabolism.
conservation of energy in the ani-
mal organism, 584.
determination in part by environ-
ing temperature, 593.
— heat production as affected by
external temperature, 601.
— energy of muscular work defi-
nitely related to potential energy of
food, 586.
indigestion of food increased the
metabolism, 604.
— beginnings of, 34.
— Berthelot's observations on, 77.
-direct, 76, 567.
— animal, 570.
— heat of combustion, 568.
— direct and indirect, heat production
of dogs by, 584.
— heat production of human sub-
jects by, 585.
— experiments on, of Barral (1819-
1884), 38, 39.
— of Boussingault (1802-1887), 37.
- of Despretz (1792-1863), 34.
-of Dulong (1785-1838), 35.
-of Dumas (1800-1884), 36.
-of Magendie (1783-1855), 37.
— of Regnault and Reiset, 40-44.
— factors determining level of energy
metabolism, 607.
— how heat is lost from body, 593.
INDEX
921
Calorimetry, indirect, 76.
— advantages of, 515.
— von Liebig's observations on, 46.
— methods of calculating the heat
production from respiratory ex-
change. See Respiratory Exchange.
— methods of measuring the respir-
atory exchange. See Respiratory
Exchange.
— Richet's observations on, 77.
— surface area, law of, 594.
— criticism of, 597.
— measurement of, 595.
— relation of, to body weight, 598.
Camphor, effect of, on metabolism, 776.
Caprin, of the brain, 471.
Carbohydrate metabolism, absorption,
249.
— sugar of the blood, 250.
— antiketogenesis, 271.
— digestion, 248.
— action of ptyalin, 248.
— gastric, 249.
— intestinal, 249.
— salivary, 248.
— effect on, of acids and alkalies, 737.
— of alcohol, 764.
— of anesthetics, general, chloro-
form and ether, 761.
— of antipyretics, 770.
— of arsenic, 754.
of atropin, pilocarpin, etc., 774.
— of blood poisons, 744.
of calcium, 731.
of carbon monoxid, 743.
— of cocain, 777.
— of cyanids, 748.
of epinephrin, 781.
— of mercury, 756.
of opiates, 766.
— of phlorizin, 759.
of phosphorus, 749.
— of pituitary substances, 785.
of purins, 780.
of roentgen rays and radioactive
substances, 883.
— of saline cathartics, 719.
— of strychnine, 775.
— of thyroid gland substances, 783.
— of uranium, 757.
— endocrin and nerve control of gly-
cogenesis, glycogenolysis and glu-
colysis, 257.
— adrenals, 257.
— pancreas, 258.
— pituitary, 261.
— sympathetic nervous system, 257.
- thyroid, 260.
Carbohydrate metabolism, fat forma-
tion, 268.
— functions of carbohydrates in diet,
271.
— influence of carbohydrates on inter-
mediary metabolism of fat, 271.
— intermediary, 261.
- introduction to, 213.
. — of rectal feeding, 811.
— tolerance, 254.
glucolysis and, 256.
— glycogenesis and, 255.
— standard of, 255.
Carbohydrate minimum, 411.
Carbohydrate residues, in the urine,
508.
Carbohydrate tolerance, 254.
— glucolysis and, 256.
— glycogenesis and, 255.
— standard of, 255.
Carbohydrates, chemical reactions of,
225.
action of alkalies, 227.
— conversion of glucose into fruc-
tose and mannose, 231.
— conversion of a higher to a lower
monosaccharose, 227.
isolation, 234.
— isolation of glutose, 232.
— melting points of hydrazones, 235.
— oxidation, 227.
— polymerization (aldol condensa-
tion) of simple sugars by action of
dilute alkali, 225.
reactions of sugars with substi-
tuted hydrazines, 232.
reduction, 230.
synthesis of higher forms from a
lower monosaccharose, 226.
— chemistry of, 214.
— classification, 214, 216.
— constitution, 214.
disaccharides, 243.
fructose, 239.
— gelactose, 238.
— glucose, 214.
— glucosides, 235.
- methyl, 237.
— hexoses, 237.
— isomerism, of the aldohexoses,
222.
— and asymmetry, 218.
of glucose, 221.
— mannose, 238.
— methyl glucosides, 237.
— monosaccharids, special proper-
ties, 237.
— mutarotatin, 221.
922
INDEX
Carbohydrates, chemistry of, nomen-
clature, 214.
— pentoses, 240.
poly saccha rides, 247.
— classification of, 214, 216.
— constitution of, 214.
glucose, 214, 215.
— conversion of glucose into fructose
and mannose, 231.
— disaccharides, 243.
— lactose, 245.
— formula for, 244.
— maltose, 246.
— formula for, 244.
— sucrose, 245.
— formula for, 244.
— effects of, in liver poisoning, 689.
- fructose, 239.
— functions of, in animal world, 213.
- in the diet, 271.
— in plant world, 213.
- — galactose, 238.
— general nature of products of bac-
terial growth, arising from utiliza-
tion of proteins and, for energy, 669.
— glucose, 214, 215.
— aldehydic properties of, 217,
218.
— compounds of, 215.
— conversion of, into fructose and
mannose, 231.
- formulae for, 214, 215, 217, 218.
— isomerism of, 221 .
— oxidation of, 217.
reduction of, 215.
specific rotation of sugars, table
of, 225.
— glucosides, 235.
-methyl, 237.
— heat value of, 553.
— hexoses, 237.
— intravenous feeding of, 817.
— in liver, stored in form of glycogen,
463.
— mannose, 238.
— methyl glucosides, 237.
— monosaccharides, Arabinose, 241.
— dioses, 242.
— fructose, 239.
— galactose, 238.
— glucosides, 235.
— hexoses, 237.
— mannose, 238.
— methyl glucosides, 237.
— methyl pentoses, 242.
— pentoses, 240.
— rhamnose, 242.
— d-ribose, 242.
Carbohydrates, monosaccharides, special
properties of, 237.
tetroses, 242.
trioses, 242.
— xylose, 241.
— nomenclature of, 214.
— oxidation of, 227.
— pentoses, 240.
aldopentoses, table of, 241.
1-Arabinose, 241.
methyl, 242.
d-ribose, 242.
— polysaccharides, 247.
cellulose, 247.
gums, 247.
inulin, 247.
— starch, 247'.
— reduction of, 230.
— relation to, of pathogenetic bacteria,
673.
— subcutaneous feeding of, 816.
— synthesis of, 226.
— terminology of, 213.
— thermal quotient for, 556.
— utilizable, effects of, upon formation
of phenols, indol and amins, 685.
— upon general metabolism,
674.
Carbon, and hydrogen, calculation of
heat production from combustion of,
548.
Carbon dioxid, in the blood, 457.
— acidosis, 458.
— conclusions on, of Edwards, 32.
— effect of, on metabolism, 741.
— acapnia, 741.
Carbon monoxid, effect of, on lactic
acid excretion, 743.
— on metabolism, 742.
— blood gases, 742.
— carbohydrates, 743.
— mineral metabolism, 743.
— protein metabolism, 743.
— total metabolism, 742.
Carbon monoxid poisoning, blood trans-
fusion in, 833.
Carbonated waters, effect of, on gastric
mucosa, 848.
Carbonic acid gas, Black on, 15.
- first discovery of, 8.
— and oxygen, Spallanzani's experi-
ments, 32.
Carcinoma, treatment of, by radium,
887.
Carnosin, in muscle tissue, 461.
Cartilage, 466, 467.
Catalase, effect on, of epinephrin, 781.
— of purins, 780.
INDEX
923
Cathartics, effect of, on metabolism,
aloin, 719.
— saline, 718.
Cavendish (1731-1810), discovery of
water by, in history of metabolism,
15.
Cell proteins, action on, of light, 891.
Cellular fluid, 788.
Cellulose, 247.
Cephalins, 187.
— of brain, 468, 469.
Cereal protein, heat value of, 552.
Cereals, importance of, in diet, 421.
— as food, 365.
Cerebrosids, of brain, 470.
Cerebrospinal fluid, composition of,
metallic elements, 473.
— mineral, 473.
— non-protein nitrogen, 472.
— protein, 472.
— sugar, 473.
-table of, 472.
— mineral constituents of, chlorid,
473.
— phosphates, 473.
— non-protein nitrogen of, 472.
— protein content of, 471.
Cetin, 185.
Chemical development, bacterial re-
quirements for, 668.
— energy, 669.
— structural, 669.
Children, basal metabolism of, 649.
up to puberty, awake and sleep-
ing, table, 658.
— of fat and thin boys, table, 658.
— influence on, of muscular ac-
tivity, 654.
influence on, of puberty, 654.
of sex, 652.
— energy metabolism of, up to pu-
berty, 647.
basal, 649.
gaseous exchange, tables of,
648.
— gaseous exchange of, 648.
Chittenden's experiments, on protein
minimum and optimum, 402.
Chloral, effect of, on metabolism, 763.
Chlorid excretion, in carbon monoxid
poisoning, 745.
Chlorids, in the blood, 451.
high, pathological conditions
causing, 452.
— in cerebrospinal fluid, 473.
— in the feces, 511.
— in sweat, 513.
— in the urine, 500.
Chloroform, effects of, on metabolism.
See Anesthetics, general.
Chlorosis, iron waters in, therapeutic
value of, 851.
Cholesterol, 448.
— of brain, 470.
— in human milk, 478.
- of the liver, 463.
— percentage of, in normal and patho-
logical conditions, 448.
Chondrosamine, of connective tissue,
467.
Chondroitin, 466.
Chondrosin, 466.
Chromates, effects of, on metabolism,
758.
Cinchophen (atophan), effect of, 011
metabolism, 772.
Circulatory mechanism and high alti^
tude, 910.
Circulatory system, effect on, of tem-
perature and humidity, 900.
Citrates, effect of, on metabolism, 726.
Climate, air movement and winds,
902.
— altitude, blood adaptive change, 908.
— circulatory mechanism, 9101.
— high, dangers of, 911.
- effects of, 906.
— altitude sickness, 907.
and metabolism, 910.
— process of acclimatization, 907.
— respiratory adaptation to, 908.
— comparative value of good hygiene
and, 899.
— definition of, 899.
— general considerations in choice of,
905.
— influence of, 899.
— on food consumption, 387.
- light, effects of, 903.
— physical influences causing physio-
logical changes, 899.
— temperature and humidity, 900.
— effect of, on amount of blood per
kilogram of body weight, 901.
— on capacity for physical work,
901.
— on circulatory system, 900.
on concentration of sugar in
blood, 901.
— on metabolism, 902.
on nasal mucosa, 901.
— - — on respiration, 901.
— radiation and conduction, 900.
— temperature of body in relation
to, 900.
— variety of, 905.
INDEX
Climatotherapy, psychological factor
in, 904.
Coagulation of proteins, 100.
Cocain, effect of, on metabolism, 777.
Cod liver oil, as vehicle for phosphorus,
753.
Cold baths and cold douches, 863.
— effects of, 856.
— extra energy, 858.
and fever reduction, 857.
on heat production, Ignatowski,
857.
Lusk, 858.
Matthes, 857.
- Kubner, 858.
— redistribution of blood, 859.
— refreshing, 860.
- - friction in, 863.
Collagen, of connective tissue, 466.
Collecting apparatus, for measuring
respiratory exchange, 534.
Color reaction of proteins, 96.
Combustion, of alcohol, 300.
— of carbon and hydrogen, calculation
of heat production from, 548.
— heat of, in calorimetry, direct, 568.
— in history of metabolism, Boyle,
Eobert (1621-1679), 8.
-Mayow, John (1640-1679), 9.
-Stahl (16601734), phlogiston
theory of, 11.
— Leonardo da Vinci, 6.
— of organic foodstuffs, calculation of
heat production from, 549.
Connective tissues, constituents of, 466.
-table of, 467.
— types of, 466.
Copper, effect of, on metabolism, 758.
Crawford (1748-1795), on animal
calorimetry, 17.
Creatin, administered, fate of, 179.
— of the blood, 441.
— of the brain, 471.
— crystals of, 171.
— excretion of, after menstruation,
176.
— in pregnancy, 176.
— isolation of, 171.
— of the muscle, 493.
— origin of creatinin of the urine,
492, 493, 494.
— in muscle tissue, 460.
— origin of, 173.
— oxidation of, successive steps of,
172.
— preparation of, chemically, 172.
— resume of, 179.
— transformed into creatinin, 171.
Creatin, of the urine, 493.
and arginin, as source of, 494.
-excretion of, 493, 494.
Creatin content of muscle and other
tissues, 172.
Creatin metabolism, in blood, 175.
— muscle, 174.
— in urine, 176.
Creatinin, administered, fate of, 179.
— of the blood, amount of, in normal
individuals, 440.
increase of, 441.
in nephritis, chronic, table of,
439.
— creatin transformed into, 171.
— excretion of, clinical significance of,
178.
during starvation, 178.
— relative, in men and women, 178.
— preparation of, chemically, 172.
— resume of, 179.
— of the urine, 490.
— elimination of, 490.
origin of, in creatin of the mus-
cle, 492, 493, 494.
Creatinin metabolism, in blood, 177.
— in muscles, 177.
— in urine. 177.
Creatinuria, accompanying undernutri-
tion, 177.
— after menstruation, 176.
Crop failures and famine, 360.
Crying, influence of, on basal metabo-
lism of new-born, 637.
Crystalline structure, Pasteur's studies
on, 219.
Cuorin, 186.
Curare, effect of, on metabolism, 776.
Cyanids, effects of, on metabolism,
745.
Cystein, 88, 111.
Cystin, 88, 111.
Cytosine, 137.
— and uracil, 137.
Davy, Humphrey (1778-1829), oxygen
obtained from arterial blood by, 31.
— "phosoxygen" of, 31.
Decomposition, enzymatic, of combined
purins, 158.
— of phenyl alanin, by bacteria, 684.
— physiological, of nucleic acid, 148.
— of proteins by bacteria, decomposi-
tion of tryptophan, 682.
— decomposition of tyrosin, 681.
Decomposition products, partial, of
thymus nucleic acid, 147.
Denaturalization of proteins; 100.
INDEX
925
Dennstedt and Kumpf s table of min-
eral constituents of different organs,
304.
Dephlogisted air, 16.
Despretz (1792-1863), experiments of,
on calorimetry, 34.
Dextro-ribose, 136.
Dextrose, administration of, in intra-
venous feeding, 818.
— rectal feeding, 812.
— in subcutaneous feeding, 816.
Diabetes, alcohol in, 301.
- alkali therapy in, 316, 734.
— blood lipoids in, 446.
— effect on, of opiates, 766.
— hyperglycemia of, 444.
— threshold of sugar excretion in, 444.
Diamino-monophosphatides, of brain,
470.
Diarrhea, in infants, acidosis accom-
panying, alkaline treatment for, 735.
Diet, acid, 413.
— adequacy of, criteria of, 361.
— cereals, 421.
— changes of, its advantages, 408.
— conclusions on, of Stark, 12.
— crop failures and famine, 360.
— energy content of food, 407.
— experiments on, of Stark, 13, 14.
— functions of carbohydrates in, 271.
of proteins in, 121.
— of infants, artificial feeding with
cow's milk, 320.
fat, 320.
vegetable, 319.
—'milk, 421.
— normal, conclusions on, 420.
definition of, 361.
— ordinary, ash constituents of, 396.
— of primitive peoples, 359.
— protein, question of optimum versus
minimum, 119.
— relation between microbic response
and, in normal nurslings, 691.
— relative importance of certain foods,
362.
cereals, 365.
meat, 363.
per capita consumption of, ta-
ble of, 364.
— value of flavor in, Voit, 74.
— value of protein in, 408.
— vegetarian, 399.
basal metabolism of, 400.
— disadvantages of, 400.
Dietary constituent, water as, 275.
drinking of, with meals, 280, 283,
287, 288, 294.
Dietary constituent, water as, influence
on metabolism of diminished intake,
279.
influence on metabolism of in-
creased ingestion of, 277.
Dietary studies, according to weight
and age, normal and below normal,
416.
Symond's table of based on ac-
cepted applicants for life insurance,
419, 420.
— amount and nature of food con-
sumed in different countries, 370,
371.
— carbohydrate minimum, 411.
— changes in food habits within recent
times, 395.
— choice of factor for calculating food
consumed per man, 367.
— per woman, 367.
— energy content and bulk, 418.
— energy requirements for children,
367.
— of entire countries and cities, 371.
- tables, Belgium, 372, 373.
-Denmark, 374, 375.
- Finland, 374, 375.
-France, 374, 375.
Germany, 376, 377.
Great Britain, 378, 379.
Greenland, 376, 377.
-India, 380, 381.
- Italy, 380, 381.
— Japan, 382, 383.
— Java, 380, 381.
-Eussia, 382, 383.
- Sweden, 384, 385.
- Switzerland, 384, 385.
-United States, 384, 385, 386,
387.
— fat minimum, 410.
— food requirements, amount of ash,
394.
— amount of fat, 393.
— amount of protein, 392.
— importance of bread and flour, 418.
— influence on food consumption of
climate and season, 387.
— of economic status, 391.
— in amount of protein, 392.
— of work, 391.
— in amount of protein, 392.
- level of nutrition, 416.
— manner of conducting and of calcu-
lating results, 366.
— minimum of ash constituents, 411.
— Neumann's observations on himself
of reduced war diet, chart, 417.
926
Dietary studies, nitrogen minimum,
401.
— protein minimum and optimum, 401.
experiments on, of Chittenden,
402.
of Fisher, 405.
- of McCay, 406.
of Neumann, 402.
— results reported as food consumed
not that supposed to be absorbed,
369.
— scales for converting food require-
ment of women and children into
"man's equivalents," 368.
— undernutrition, 414, 415.
war edema, 415.
— war time foods, in Russia and Ger-
many, 418..
Digestion, of carbohydrates, 248.
action of ptyalin, 248.
gastric, 249.
• intestinal, 249.
— salivary, 248.
— in fat metabolism in the intestines,
193.
— of stomach, 189.
— of fats in the intestines, bile, 198.
— emulsification, 200.
factors in, pancreatic secretion,
197.
— gastric, influence on, of water, 281.
— pancreatic, influence on, of water,
289.
— of the protein, 101.
— salivary, influence on, of water, 281.
— of vitamines, 347.
Dioses, 242.
Diphtheria toxin, 669.
Disaccharides, 243.
— lactose, 245.
— formula for, 244.
— maltose, 246.
formula for, 244.
— sucrose, 245.
— formula for, 244.
Distilled water, 292.
Diuretic property of mineral waters,
847.
Drugs, epinephrinemia due to, 782.
— theory of reduction of fever by,
771.
Dulong (1785-1838), experiments of, on
calorimetry, 35.
Dumas (1800-1884), experiments of, on
calorimetry, 36.
Duodenal contents, urobilin in, 165.
— clinical significance of, 168.
— determination of, 167.
Duodenal feeding, Einhorn's routine,
808.
— indications for, 807.
— metabolism of, 807.
— method of introducing duodenal
tube, 807.
Dynamic action, of foods, in infants
from two weeks to one year of age,
643.
Economic status, influence of, on food
consumption, 391.
Edema, as a water retention, 311.
— war, or hunger, 415.
Edwards, William F. (1776-1842), car-
bon dioxid, his conclusions on, 32.
Effervescent baths, 865.
Eggs, in rectal feeding, 813.
Einhorn's duodenal feeding, 808.
Elastin, of connective tissue, 466.
Electricity, contraction of muscles by,
894.
— effects of, on body, 894, 895.
— stimulation of nerves by, 894.
— as a therapeutic agent, 894.
— use of, in, pathological condition,
895.
Electrolysis, salting out of proteins by,
99.
Embryonic growth, and energy metabo-
lism, 616.
Endocrin drugs, effect of, on metabo-
lism, epinephrin, 780.
thyroid gland substance, 782.
Endocrin glands, and mineral metabo-
lism, 336.
Endocrin and nerve control of glyco
genesis, glycogenolysis and glucoly-
sis, 257.
Energy, effect on, of temperature and
humidity, 901.
— extra, called out by cold baths, 858.
— general nature of products of bac-
terial growth, arising from utiliza-
tion of proteins and carbohydrates
for, 669.
— measurement of, Zuntz, 77.
Energy chemical requirements, for
bacterial development, 669.
Energy content of food, 406.
Energy metabolism, basic principles of,
583.
— basal metabolism. See Basal
Metabolism.
conservation of energy in the ani-
mal organism, 584.
determination in part by environ-
ing temperature, 593.
INDEX
927
Energy, metabolism, basic principle of,
determination in part by environing
temperature, heat production as af-
fected by external temperature, 601.
— energy of muscular work defi-
nitely related to potential energy of
food, 586.
ingestion of food increases me-
tabolism, 604.
— calorimetry, direct, 567. See also
Calorimetry.
— indirect, 515. See also Calorime-
try.
— of children, up to puberty, 647,
— basal, 649.
— gaseous exchange, tables of,
648.
— determined in part by environing
temperature, how heat is lost from
body, 59?.
law of surface area, 594.
— effect on, of acids and alkalies, 736.
of saline cathartics, 718.
of sodium chlorid, 720.
— and embryonic growth, 616.
— factors determining level of, 607.
— and growth, differences between
growth and maintenance, 615.
— embryonic, 616.
post-embryonic, 619.
— of infant, new-born, 627.
of parturition, before and
after, 634.
per unit of body surface, 633.
— respiratory quotient, 627.
See also Basal Metabolism, of
infants.
total energy requirement, 639.
from two weks to one year of
age, 640.
basal, 642.
dynamic action of foods in,
643.
influence of age on basal me-
tabolism, 646.
respiratory quotient, 640.
— mechanical efficiency of muscular
work, 586.
— methods of measuring heat produc-
tion from respiratory exchange.
See Kespiratory Exchange.
— methods of measuring .respiratory
exchange. See Respiratory Exchange.
— normal process of, 515.
— of old age, 658.
— origin of, in non-nitrogenous food,
586.
— and post-embryonic growth, 619.
Energy metabolism, of pregnancy, 621.
— comparison of energy metabolism
in pregnant and non-pregnant women,
table, 625.
relative value of different food
stuffs as a source of energy in mus-
cular work, 590.
- - surface area, law of, 594.
— criticism of, 597.
— measurement of, 595.
relation of, to body weight, 598.
— See also Muscular Energy.
Energy production, von Liebig's ob-
servations on, 47.
Energy relations, Rubner's insistence
on importance of, 76.
Enzymatic decomposition of combined
purins, 158.
Enzymes, action on, of light, 892.
— effect on. of roentgen rays and ra-
dioactive substances, 878.
--protein-liquefying, formation of,
670.
Epinephrin, effect of, on metabolism,
body temperature, 781.
— carbohydrate, 781.
catalase, 781.
growth, 782.
mineral, 782.
— protein, 782.
total, 780.
water, 781.
Epinephrinemia, due to drugs, 782.
Ether, effect of, on metabolism. See
Anesthetics, general.
Ethereal extract in the urine, 508.
Ethylenediamin, effect of, on metabo-
lism, 773.
Ethylhydrocuprein, effect of, on me-
tabolism, 772.
Excretion of alcohol, 298.
- of fat, 210.
— of iron, 328.
— of nitrogen in urine, 405.
— of phosphorus, 326.
Excretions, feces. See Feces.
— mediums for, 481.
— paths for. 481.
— sweat, 512.
— Wprine. See Urine.
Excretory channels, comparative im-
portance of intestines and kidneys
as, 511.
Exogenous intestinal infections, bro-
matherapy, 706.
Extractives, of brain, 471.
— of muscles, 460.
See also Muscles, extractives of.
928
Famine and crop failures, 360.
Fasting, metabolism during, 309.
protein. 116, 117.
Fat, amount of, required in diet, <39d.
— in the blood, alimentary lipemia,
201.
lipoids,. 204.
— conversion into, of glucose, 251.
— of starch, Voit, 73.
— of protein, 73.
— in diet of infants, 320.
— formation of, von Liebig on, 49.
from carbohydrate, 268.
— heat value of, 553.
Fat or fatty infiltration of liver, 463.
Fat excretion, 210.
Fat ingestion, contents of feces fol-
lowing, 64.-
Fat metabolism, absorption, in the in-
testines, 194.
— factors in, 197.
— paths of, 196.
— from the intestines, changes in
fats during, 196.
emulsification, 200.
in stomach, 190.
— in the blood, alimentary lipemia,
201.
-lipoids of the blood, 204.
— digestion, in the intestines, 193.
emulsification, 200.
factors in, 197.
in stomach, 189.
— effect on, of alcohol, 765.
of anesthetics, general, chloro-
form and ether, 762.
of cocain, 777.
of mercury, 756.
of opiates, 766.
of phlorizin, 759.
— of phosphorus, 748.
of saline cathartics, 718.
of thyroid gland substance, 784.
— of uranium, 758.
— excretion of fat, 210.
— intermediary, influence on, of carbo-
hydrates, 271.
absorption of fat, 194.
changes in fats during, 196.
-paths of, 196.
— bile, 198.
digestion, 193.
— emulsification in fat digestion
and absorption, 200.
— factors in fat digestion and ab
sorption, 197.
— lipases of intestinal tract and di
gestion, 192.
?at metabolism, bile, nature of food
fat, 199.
— pancreatic juice, 192.
pancreatic secretion, 197.
— passage from the stomach, 191.
— summary of, 200.
synthesis of fats during absorp-
tion from, 196.
— introduction to, 183.
— later stages of, ^-oxidation, 208.
— lipases of the intestinal tract and
digestion, 192.
— lipoids, compound, cephalins, 187.
— glycolipoids, 187.
lecithins, 186.
phospholipoids, 185.
— derived, fatty acids, 187.
sterols, 188.
— simple, fats, 184.
waxes, 185.
- liver in, 207.
— passage from the stomach to intes-
tines, 191.
— of .rectal feeding, 811.
— in stomach, absorption, 190.
— digestion, 199.
— synthesis of fat during absorption
from the intestines, 196.
— in the tissues, changes in fat, 206.
— storing of fat, 205.
Fat minimum, 410.
Fat-soluble vitamins, 345.
— sources of, 346.
Fats, intravenous feeding of, 817.
— respiratory quotient of, 561.
— as simple lipoids, 184.
— in subcutaneous feeding, 815.
— thermal quotient for, 556.
— in the tissues, changes in, 206.
storing of, 205.
— total, in blood lipoids, 448.
Fatty acids, 187.
Feces, amount of, normal, 505.
— calcium in, 316.
— carbohydrate residues in, 508.
— color of, normal, 506.
— composition of, 503.
— ash, 510.
bacteria, 504.
— - — carbohydrate residue, 508.
ethereal extracts, 508.
— nitrogen content, 504.
nitrogenous substances, 507.
in pellagra, daily average, table,
509.
— consistency of, normal, 506.
— contents of, following fat ingestion,
64.
INDEX
929
Feces, ethereal extracts in, 508.
— formation of, von Liebig, 49.
— nitrogen content of, 504.
— nitrogenous substances in, 507.
— odor of, normal, 506.
— a true secretion, 504.
— weight of, following meat ingestion,
58.
Feeding, artificial methods of, 805.
duodenal, 807.
— gavage, 806.
— intravenous, 817.
rectal, 809.
— subcutaneous, 814.
— duodenal. See Duodenal Feeding.
— intravenous. See Intravenous Feed-
ing.
— rectal. See Rectal Feeding.
— subcutaneous. See Subcutaneous
Feeding.
Ferments, effect on, of anesthetics,
general, chloroform and ether, 763.
— of arsenic, 755.
of cyanids, 747.
Fever, effect on, of antipyretics, 768.
— salt, 720.
— theory of reduction of, by drugs, 771.
Fevers, disturbances of mineral me-
tabolism in, 336.
Fibrinogen, 429.
"Fire air" of Scheele, 17.
Fisher's experiments on protein mini-
mum and optimum, 405.
"Fixed air," or carbonic acid gas,
Black on, in history of metabolism,
15.
— Lavoisier, 22.
Fluids, intravenous injections of, in
acidosis, of sodiumt bicarbonate, 792.
— to assist in providing for the
calorific requirements of the body,
795.
glucose, 795.
to combat toxemia, 794.
— for dehydration of tissues, 792.
— fluids used for, calcium and
barium, 800.
gelatin solutions, 791, 798.
glucose solutions, 795, 799.
. — gum acacia or gum-saline solu-
tions, 798.
magnesium sulphate, 800
saline solutions, 796.
sodium bicarbonate, 792, 793,
799.
in hemorrhage, 790.
blood, 790.
substitutes for blood, 791.
Fluids, intravenous injections of, to in-
crease buffer action of blood in
acidosis, 792.
— in nephritis, 793.
— reaction of urine in, 793.
— 3s routine measure in surgical
procedures, 793.
— to increase volume of blood and
tissue fluid, 789.
introduction to, 787.
in nephritis, of sodium bicarbo-
nate, 793.
— preparation of infusion solutions
and technic of administration, 801.
— purposes of, 789.
— reactions due to, 800.
— as routine measure before and
after surgical procedures, sodium bi-
carbonate, 793.
of sodium bicarbonate, in acido-
sis, 792.
in nephritis, 793.
reaction of urine in, 793.
— as routine measure before and
after surgical procedures, 793.
— solutions used for, 796.
Fluids of the body, bile. See Bile.
- blood, 788. See also Blood.
— cellular, 788.
— conditions depleting to store of, 789.
— content of, 787.
- intake of, 789.
— loss of, 789.
— lymphatic, 788.
- milk, 476.
— role of, 787.
— saliva, 474.
— tissue, 788.
— variety of adjustments to local con-
ditions, 787.
— cerebrospinal, 471.
Food, calcium in, 317.
— and civilization, 359.
— crop failures and famine, 360.
— influence of, on basal metabolism of
newborn infants, 638.
— on composition of urine, 64.
— on respiratory quotient of new-
born infant, 630.
- object of, 121.
— potential energy of, energy of mus-
cular work definitely related to, 586.
— and progressive civilization, 3.
-Voit's definition of, 74.
Food consumption, influence of climate
and season on, 387.
— of economic status, 391.
of work, 391.
930
INDEX
Food fat, nature of, in fat metabo-
lism, 199.
Food habits, changes in, within recent
times, 395.
Food minimum, typical, of Bidder and
Schmidt, 63.
Foods, acids, or acid-forming, pro-
longed administration of, 334.
— distribution of vitamins in, 346.
— dynamic action of, in infants from
two weeks to one year of age, 643.
— extract of meat, v. Liebig's, his de-
fense of the use of, 54, 55.
— oxidation of, various, von Liebig, 49.
— oxygen requirement for combustion
of, von Liebig, 50.
— relative importance of, 362.
cereals, 365.
meat, 363.
per capita consumption of, ta-
ble of, 364.
— used in gavage, 806.
Foodstuffs, classification of, Bischoffs
and Voit'? suggestions, 71..
von Liebig, nitrogenous or plas-
tic, 50.
non-nitrogenous or respiratory,
50.
— combustion of, calculation of heat
production from, 549.
— heat values of, cereal protein, 552.
-*- heat values of, fat and carbohydrate,
553.
— lean meat, 550.
— relative value of, as a source of
energy in muscular work, 590.
Fructose, 239.
— conversion of glucose into mannose
and, 231.
Galactose, 238.
Galen, on food, 5.
Gallstones, composition and character
of, 466.
Gaseous exchange, of children, up to
puberty, 648.
Gaseous metabolism, effect on, of hot
baths, 861.
Gases, blood. See Blood Gases.
Gastric digestion, of carbohydrates,
249.
— influence on, of water, 281.
Gastric lipase, 189, 190.
Gastric secretion, effect on, of alkaline-
saline waters, 848.
— of alkaline waters, 848.
— of bitter waters, 850.
of saline waters, 846.
Gastro-intestinal canal, protein diges-
tion in, 101.
— absorption, 103.
— schematic illustration of, 103.
Gavage, definition of, 806.
— foods used in, 806.
— indications for, 806.
— metabolism in, 806.
— method of performing, 806.
— number of feedings performed in,
807.
Gay-Lussac (1778-1850), gas constitu-
ents of blood determined by, 33.
Gelatin, as a substitute for blood in
intravenous infusion during hemor-
rhage, 791.
Gelatin solutions for intravenous in-
fusion, 791, 798.
Globulin, 428.
Globulins, 83.
Glucolysis, and carbohydrate tolerance,
256.
' — endocrin and nerve control of,
adrenals, 257.
— pancreas, 258.
— pituitary, 261.
— sympathetic nervous system, 257.
- thyroid, 260.
Glucose, administration of, in intra-
venous feeding, 818.
— aldehydic properties of, 217, 218.
— as blood sugar, 250.
— absorption of, 250.
— behavior of, in blood, 253.
concentration of, 250.
— conversion of, into fat, 251.
kidney threshold for sugar, 253.
— oxidation of, 251.
— compounds of, 215.
— conversion of, into fructose and
mannose, 231.
- formulas for, 214, 215, 217, 218.
— isolation of, 232.
— isomerism of, 221.
— in muscle tissue, 460.
— oxidation of, 217, 227, 228.
— reactions of sugars with substituted
hydrazines, 232.
— reduction of, 215.
— specific rotation of sugars, 225.
— transformation into of lactic acid,
108.
Glucose solutions, for intravenous in-
fusion, 795, 599.
— constituents of, 236.
— definition of, 235.
— formula of, 235.
-hydrolysis of, 236.
IXDEX
931
Glucose solutions, methyl, 237.
— preparation of, 236.
— table of, 236.
Glucosuria, 253.
-renal, 253.
Glucuronic acid, of connective tissue,
467.
Glutamic acid, 87, 110.
Glutelins, 83.
Glycocoll, 84, 107.
Glycogen, in the liver, 463.
— in muscle tissue, 460.
— storing of, by liver, 251.
Glycogenesis, and carbohydrate toler-
ance, 255.
— endocrin and nerve control of,
adrenals, 257.
— pancreas, 258.
— pituitary, 261.
— sympathetic nervous system, 257.
— thyroid, 260.
Glycogenolysis, endocrin and nerve
control of, adrenals, 257.
— pancreas, 258.
— pituitary, 261.
— sympathetic nervous system, 257.
- thyroid, 260.
Glycolipoids, 187.
Glycosuria, 444.
— asphyxial, 740.
— salt, 722.
Goiter, treatment and prevention of,
by iodin, 725.
Gout, treatment of, alkaline, 739.
by radium, 885.
— uric acid in, 438.
Grafe's apparatus for measuring respir-
atory exchange, 519.
Growth, embryonic, and energy me-
tabolism, 616.
— energy metabolism and differences
between growth and • maintenance,
615.
— embryonic growth, 616.
— metabolism of, effect on, of alcohol,
765.
of antipyretics, 769.
of calcium, 732.
of epinephrin, 782.
of purins, 780.
of thyroid gland substance,
784.
Guanase, distribution of, 156.
Guanidin bases, effect on, of purins,
780.
Guanine, 137, 138.
— in muscle tissue, 461.
Guanylic acid, 141, 142.
Gum acacia or gum-saline solutions for
intravenous infusion, 798.
— reactions in, 800.
Gums, 247.
Haldane's apparatus for measuring
respiratory exchange, 520.
Hales, Stephen (1677-1761), on respira-
tion and blood, in history of metabo-
lism, 11.
Hanroit and Richet's apparatus for
measuring respiratory exchange, 543.
Heat, animal. See Calorimetry.
— of combustion. See Calorimetry.
— lost from body, manner of, 593.
— surface area of, law of, 594.
— criticism of, 597.
— measurement of, 595.
— relation of, to body weight, 598.
Heat equivalent of COz, variation in
(Atwater and Benedict), 559.
Heat production, actual, 554.
— as effected by external temperature,
in cold-blooded animals, Yan't Hoff's
law, 601.
cooling power of air currents at
different velocities, 604.
— in warm-blooded animals, 602.
— of dogs by direct and indirect
calorimetry, 584.
— effect on, of cocain, 777.
— of cold baths, Ignatowski, 857.
-Lusk, 858.
-Matthes, 857.
- Rubner, 858.
— of human subjects, by direct and in-
direct calorimetry, 585.
— increase of, by indigestion of food,
604.
— in incubation period of hens' eggs,
617.
— of infants, per square meter of body
surface, 646.
— methods of calculating from respir-
atory exchange, 548.
— alimentary calorimetry, 554.
— combustion of carbon and hydro-
gen, 548.
combustion of organic foodstuffs,
549.
non-protein respiratory quotient,
566.
respiratory quotient and its sig-
nificance, 559.
— thermal quotients of Oa and COz,
555.
and from urinary nitrogen, 563.
932
INDEX
Heat production, methods of calculat-
ing from respiratory exchange, and
from urinary nitrogen, method of
successive thermal quotients, 563.
— method of Zuntz and Schum-
berg, 565.
Heat radiation, relation of, to surface
of animal body, table, 610.
Heat value, of one gram of different
substances in large calories, 571.
Hemoglobin, character and function of,
429.
— estimation of, 429, 431.
— in males and females during differ-
ent age periods, table of, 430.
Hemoglobin content of blood in nor-
mal and pathological subjects, 430.
Hemophilia, typical hereditary, disturb-
ances in mineral metabolism in,
336.
Hemorrhage, indications for blood
• transfusion in, 830.
— intravenous injection of fluids for,
790.
Hexoses, 237.
Hippocrates, on food, 4.
Ilippuric acid, of urine, 498.
Histamin, action of, 687.
— formation of, 686.
Histidin, 91, 114, 686.
Histones, 83.
Hopkins and Willcock's experiments,
on nitrogen balance and incomplete
proteins, 325, 126.
Hoppe-Seyler's apparatus for measur-
ing respiratory exchange, 522.
Hot baths, effects of, on metabolism,
860, 861.
on oxygen consumption, 860, 861.
on pulse and blood pressure, 862.
— on respiratory quotient, 861.
— on temperature of the body, 860,
861.
— sand, 863.
Humidity. See Temperature of Air,
and humidity.
Hydrazin, effect of, on metabolism,
773.
Hydrazones, 235.
— melting point of, 235.
— substituted, reactions of sugars
with, 232.
Hydrogen, and carbon, calculation of
heat production from combustion of,
548.
— discovery of, 15.
Hydrotherapy, baths and sweat secre-
tion, 867.
Hydrotherapy, cold baths, effects of,
856.
— extra energy, 858.
— fever reduction, 857.
— on heat production, Ignatow-
ski, 857.
Lusk, 858.
Matthes', 857.
Eubner, 858.
redistribution of blood, 859.
— refreshing, 860.
— with friction, 863.
— cold douches, 863.
— effervescent baths, 866.
— foundation of, in functions and ac-
tivity of skin, 855.
— historical, 855.
— hot baths, effects of, on metabolism,
860, 861.
— on oxygen consumption, 860,
861.
on pulse and blood pressure,
862.
— on respiratory quotient, 861.
— on temperature of body, 860,
861.
-with sand, 863.
— influence of mechanical and chem-
ical stimulation accompanying baths,
862.
— mustard baths, 863.
— peat and mud baths, 867.
— radioactive baths, 867.
— and regulation of temperature of
body, 855.
— salt baths, effects of, 863.
— on blood pressure, 865.
— on metabolism, 863, 864.
£-hydroxyglutamie acid, 88, 110.
Hyperglycemia, 253.
— conditions causing, 444.
— of diabetes, 444.
Hypnotics, effect of, on metabolism, of
amylen hydrate, 764.
chloral, 763.
— paraldehyde, 764.
— sulphonal, 764.
urethan, 764.
Hypoglycemia, conditions causing, 444.
Hypoxanthin, 137, 138.
— of the brain, 471.
— in muscle tissue, 461.
Ice water, 293.
Immune bodies, effect on, of blood
transfusion, 828.
Immunity, effect on, of roentgen rays
and .radioactive substances, 876.
INDEX
933
Incubation period of hen's eggs, heat
production during, 617.
Indican, excretion of, 684.
— formation of, 680.
Indigestion of food, metabolism . in-
creased by, 604.
Indol acetic acid, 684.
Indol ethylamin, change of, 688.
Indol formation, 670, 680, 683.
— effects on, of utilizable carbohy-
drates, 685.
Indol toxemia, 683.
Indol, toxicity of, 683.
Infants, acidosis of diarrheal attacks
in, alkaline treatment for, 735.
— diet of, artificial feeding with cows'
milk, 320.
— fat, 320.
— vegetables, 319.
— feeding of vegetables to, 319.
— heat-production per square meter of
body surface for, 646.
— new-born, basal metabolism of,
632.
influence on, of crying, 637.
of food and external tem-
perature, 638.
of sex, 635.
— energy metabolism of, basal, 632.
per unit of body surface, 633.
— respiratory quotient, 627.
— total energy requirement, 639.
intestinal bacteria of, effects of
sugars upon intestinal flora, 694.
— relation between diet and mi-
crobic response, 691.
respiratory quotient of, 627.
— Bailey and Murlin, 628.
Benedict and Talbot, 630.
— for first eight days, 631.
-Hasselbach, 627.
— influence of food on, 630.
-table, 629.
— two days of age, mineral metabolism
of, 636.
— from two weeks to one year of age,
basal metabolism of, 642.
influence on, of age, 646.
dynamic action of foods in, 643.
energy metabolism of, 640.
- basal, 642.
— dynamic action of foods in,
643.
— respiratory quotient, 640.
Inflammable air, or hydrogen, 23.
— discovery of, 15.
Inosinic acid, 141.
Inositol, in the brain, 471.
Inositol, in muscle tissue, 460.
"Insensible perspiration" and food,
Hippocrates on, 4.
-Sanctorius (1561-1636), 7.
Intestinal bacteriology, adolescent and
adult, 696.
— development of, 690.
— exogenous intestinal infections,
bromatherapy, 706.
— general history of, 690.
— of normal nurslings, 691.
— effects of sugars upon intestinal
flora, experimental evidence of, 694.
— relation between diet and mi-
crobic response, 691.
— sour milk therapy and intestinal
metabolism, 700.
Intestinal digestion of carbohydrates,
249.
Intestinal elimination of iron, 328.
Intestinal flora and putrefaction, in-
fluence on, of water, 291.
Intestinal infections, exogenous, bro-
matherapy, 706.
Intestines, comparative importance of
kidneys and, as excretory channels,
511.
— • fat metabolism in, absorption of fat,
194.
-paths of, 196.
changes in fats during, 196.
— digestion, 193.
• emulsification in fat digestion
and absorption, 200.
— factors in absorption and diges-
tion, bile, 198.
— pancreatic secretion, 197.
— lipases of, 192.
— pancreatic juice, 192.
— passage from stomach, 191.
— summary of, 200.
— synthesis of fats during absorp-
tion from, 196.
Intravenous feeding, 817.
— of carbohydrates, 817.
— dangers of, 817.
-of fats, 817.
— indications for, 817.
— of proteins, 817.
Intravenous injection of fluids. See
Fluids.
Inulin, 247.
lodids, effect of, on metabolism, 724.
lodin, content of, in thyroid of man
and animals, 332.
— effect of, on metabolism, 724.
— lack of, in food and drinking water,
333.
934
IXDEX
lodin, treatment and prevention of
goiter by, 725.
lodin compounds, 333.
Ionic substances, important role of in
life processes, 335.
Iron, effect of, on metabolism, 755.
— in human body, in the blood, 451.
-course of, 327, 328.
— distribution of, 326.
— excretion of, 328.
- function of, 326, 327.
— intestinal elimination of, 328.
in liver, 463.
— metabolism of, 329.
urinary elimination of, 329.
— in the urine, 503.
Iron-containing foods, 327.
Iron metabolism, 329.
— role of spleen in, 331.
Iron waters, in anemia, 851.
— in chlorosis, 851.
— and metabolism, 851.
Iso-amylamin, effect of, on metabolism,
773.
Isodynamic equivalents, von Liebig, 49.
- table of, 50.
Iso-leucin, 85, 109.
Isomerism, 218.
— of the aldohexoses, 222.
— of glucose, 221.
Jaquet's apparatus for measuring re-
spiratory exchange, 519.
Kidney secretion, mechanism of, 482.
Kidney threshold for sugar, 253.
Kidneys, comparative importance of
intestines and, as excretory channels,
511.
Krogh's apparatus for measuring re-
spiratory exchange, 531.
Lactation, calcium in blood during,
322.
Lactic acid, in the brain, 471.
— excretion of, in carbon monoxid
poisoning, 743.
increased, in oxygen deficiency,
741.
— in muscle tissue, 460.
— transformation of, into glucose, 108.
Lactose, 245.
— feeding of, 707.
— formula for, 244.
— hydrolysis of, 708.
— methods of administration of, 707.
Lactose-protein solutions, feeding with,
709.
Lanolin, 185.
Lavoisier, accurate measuring instru-
ments of, 20, 21.
— "air eminently respirable" of, 22.
— experiments of, animal heat, con-
servation of, 23.
— on nature of water, 19.
— respiration, 25.
on man, 25.
basic facts regarding metab-
olism, 25.
— respiratory quotient, 22.
— history of, 19.
outside his laboratory, 28, 29.
— phlogiston theory of combustion de-
molished by (1783), 23.
Lead, effects of, on metabolism, 758.
Lecithin, 448.
- of brain, 468, 469.
— in the liver, 463.
Lecithins, 186.
Lefevre, Nicholas (died 1674), and me-
tabolism, 8.
Leprosy, calcium in, 728.
— disturbances in mineral metabolism
in, 336.
— uric acid in, 437.
— increased elimination of, 498.
Leucin, 85.
— of the brain, 471.
- fate of, 109.
Leukemia, chronic lymphatic, treat-
ment of, by x-rays and radium, 884.
— myeloid, treated by x-rays, 884.
Levulinic acid, 240.
v. Liebig, Justus, activity of yeast
cells discussed by, 54.
v. Liebig's extract of meat, v. Liebig's
defense of the use of, 54.
Light, action of, 903.
— on blood, 892.
— on cell proteins, 891.
— on enzymes, 892.
— on metabolism, 893.
— on tissues and skin, 891.
— chemical changes brought about by,
891.
— rays of, 890.
— effective, 891.
— as a therapeutic agent, 890.
— waves of, 890.
Lime metabolism, in infancy and child-
hood, 318.
Lipase, gastric, 189, 190.
Lipases, of intestinal tract and diges-
tion, 192.
— pancreatic, 192.
Lipemia, alimentary, 201.
INDEX
935
Lipoids, 184.
-of the blood, 204. See also Blood
Lipoids.
— of brain, 467.
— compound, cephalins, 187.
glycolipoids, 187.
lecithins, 186.
— phospholipoids, 185.
— derived, fatty acids, 187.
— sterols, 188.
— simple, fats, 184.
Lithium, effect of, on metabolism, 724.
Liver, capacity of, to store glycogen,
251.
— cholesterol of, 463.
-fat of, 463.
— in fat metabolism, 207.
— functions of, 463.
— glycogen in, 463.
• — iron in, 463.
— lecithin of, 463.
• — normal constituents of, 463.
— phosphatids of, 463.
— proteins of, 463.
— secretion of. See Bile.
— storing in, of carbohydrate, in form
of glycogen, 463.
— urea formation in, 464.
Liver poisoning, effects of carbohydrate
in, 689.
Lusk's experiments on protein metab-
olism, 131.
Lymphatic fluid, 788.
Lysin, 88, 112.
Magendie (1783-1855), exxperiments
of, on calorimetry, 37.
Magnesium, absorption of, 323.
— in the blood, 451.
— effect of, on mineral metabolism,
727.
— in the feces, 511.
— in human body, 323.
— in metabolism, 323.
— in the urine, 503.
Magnesium sulphate, intravenous in-
fusion of, in tetanus, 800.
Magnus (1802-1870), experiments of,
in history of metabolism, 33.
Magnus-Levy's table of mineral con-
stituents of different organs, 305.
Maltose, 246.
— formula for, 244.
Mannose, 238.
— conversion of glucose into fructose
and, 231.
Masks, for measuring respiratory ex-
change, 532.
Mayow, John (1640-1679), on respira-
tion, in history of metabolism, 9, 10.
McCay's experiments on protein mini-
mum and optimum, 406.
Meals, water drinking with, 280, 283,
287, 288, 294.
Meat, caloric value of, von Liebig, 49.
— dry, free from ash, elementary anal-
ysis of, 60.
— extract of, v. Liebig's, his defense of
the use of, 54, 55.
— heat value of, 550.
— importance of, as food, 363.
per capita consumption of, table
of, 364.
— metabolism of, von Voit, 68.
— place of, in diet, 400.
— weight of feces following ingestion
of, 58.
Meat protein, metabolism of, 61.
Mechanical efficiency, on different
diets, 591.
— of muscular work, 586.
Menstruation, creatinuria after, 176.
Mercury, effect of, on metabolism, 755.
acid-alkali, 756.
body temperature, 756.
carbohydrate, 756.
fat, 756.
mineral, 756.
protein, 756.
total, 756.
water, 756.
Metabolism, acid-alkali, effect on, of
anesthetics, general, chloroform and
ether, 762.
of antipyretics, 773
of mercury, 756.
of opiates, 766.
— acid-base, effect on, of arsenic, 754.
of phosphorus, 750.
— action on, of light, 893.
— activity of yeast cells, von Liebig's
discussion of, 54.
— of alcohol, 297.
distribution of, after absorption,
299.
excretion of, 298.
— von Liebig, 49.
and muscular work, 301.
— nutritive value of, 297.
— alkalinity, effect on, of purins, 780.
— analysis of, in human beings, by
Barral, 38, 39.
— bacterial, chemical requirements for
bacterial development, 668.
— energy, 669.
— structural, 669.
— chemistry of, 678.
936
INDEX
Metabolism, bacterial, chemistry of,
phases of, 678.
— reactions, 680.
— general nature of products of bac-
terial growth, arising from utiliza-
tion of proteins and of carbohydrates
for energy, diphtherial toxin, 669.
indol formation, 670.
protein-liquefying enzymes,
formation of, 670.
general relations between surface
and volume of bacteria and the gen-
eral energy requirements of bacteria,
665.
— influence on, of saprophytism,
parasitism, and pathogenism, 666.
— intestinal bacteriology, 690.
adolescent and adult, 696.
exogenous intestinal infec-
tions, 706.
— of normal nurslings, 691.
sour milk therapy and, 700.
nitrogenous, illustrative date, «
676.
quantitative measures' of, 674.
— significance of, 663.
— sour milk therapy and, 700.
— specificity of action of pathogenic
bacteria, and its relation to proteins
and carbohydrates, 673.
-basal, 130, 607.
— in anemia, 822.
— basal metabolic .rate, Boothby and
Sandiford, 610.
— of children, up to puberty, 649.
awake and sleeping, 658.
of fat and thin boys, table,
658.
influence on, of muscular
activity, 654.
— of sex, 652.
influence on, of puberty,
654.
— comparison of, per kgm. and per
sq. meter, of surface, table, 610.
— described by Bidder and Schmidt,
60. '
— effect on, of blood transfusion,
828.
— of radiation, 883.
— facts regarding, from Lavoisier's
respiration experiments, 25.
— of infants, new-born, 632.
influence of crying, 637.
of sex, 635.
from two weeks to one year of
age, 642.
— influence of age, 645.
— influence on, of age, 612.
Metabolism, basal, influence on, of in-
creased water ingestion, 279.
— of physical characteristics, 608.
— of sex, 614.
in vegetarian diet, 400.
— basal level, 130.
— bile, digestive action of, in making
materials more fluid, 59.
relation of excretion of to total
ingesta and excreta of body, Bidder
and Schmidt, 58.
— body temperature, effect on, of epi-
nephrin, 781.
of narcotics, 760.
of opiates, 765.
of purins, 779.
of uranium, 758.
and heat production, effect on,
of cocaih, 777.
— calculation of, Bischoff and Voit,
69.
its difficulties, von Liebig on, 48.
— caloric value of meat, von Liebig,
49.
— carbohydrate, absorption, 249.
sugar of the blood, 250.
antiketogenesis, 271.
digestion, 248.
action of ptyalin, 248.
gastric, 249.
intestinal, 249.
salivary, 248.
of anesthetics, general, chloro-
form and ether, 761.
of antipyretics, 770.
of arsenic, 754.
of blood poisons, 744.
of calcium, 731.
of carbon monoxid, 743.
effect on, of acids and alkalies,
737.
of alcohol, 764.
of cocain, 777.
of cyanids, 748.
of epinephrin, 781.
of mercury, 756.
of opiates, 766.
of phlorizin, 759.
of phosphorus, 749.
of pituitary substances, 785.
of purins, 780.
of roentgen rays and radioac-
tive substances, 883.
of saline cathartics, 719.
of sodium chlorid, 722.
of strychnin, 775.
of thyroid gland substance,
783.
— of uranium, 757.
IXDEX
937
Metabolism, carbohydrate, endocrin and
nerve control of glycogenesis, glyco-
genolysis and glucolysis, 257.
— adrenals, 257.
— pancreas, 258.
— pituitary, 261.
— sympathetic nervous system,
257.
— thyroid, 260.
— fat formation from carbohydrate,
268.
— functions of carbohydrates in the
diet, 271.
— influence of carbohydrates on in-
termediary metabolism of fat, 271.
— intermediary, 261.
— introduction to, 213.
— minimum, 411.
— of rectal feeding, 811.
— tolerance, 254.
— glucolysis and, 256.
— glycogenesis and, 255.
— standard of, 255.
— carbon, quantity of computed by
Bidder and Schmidt, 61.
— catalase, effect on, of epinephrin,
781.
— of purins, 780.
— classification of, foodstuffs, von Lie-
big's nitrogenous or plastic, 50.
— non-nitrogenous or respiratory,
50.
— conversion of protein into fat and
into sugar, Voit, 73.
— conversion of starch into fat, Voit,
73.
— creatin, in blood, 175.
— muscle, 174.
— in urine, 176.
— creatinin, in blood, 177.
— in muscles, 177.
— in urine, 177.
— in diabetes, effect on, of opiates, 766.
— in disease, influence on, of roentgen
rays and radioactive substances,
884.
- — of duodenal feeding, 807.
— effect on, of acids, 733.
of acids and alkalies, 732.
— of alcohol, 764.
— of alkaline earths, calcium, 726.
— magnesium, 727.
— of alkaline waters, 849.
— of aluminum, 732.
— of amino-acids, 774.
— of ammonia, 773.
— of anesthetics, general, chloro-
form and ether, 760.
— of antimony, 753,
Metabolism, effect on, of antipyretics,
767.
— of arsenic, 753.
— of asphyxiants, 740.
— of atropin, pilocarpin, etc., 774.
— of blood poisons, 744.
of blood transfusion, basal metab-
olism, 828.
— nitrogen metabolism, 828.
of boracic acid and borax, 740.
— of bromids, 724.
— of calcium, 727.
— of camphor, 776.
— of carbon dioxid, 741.
— of carbon monoxid, 742.
of chloroform, 760.
— of chromates, 758.
— of cinchophen (atophan), 772.
— of cocain, 777.
— of copper, 758.
— of curare, 776.
— of cyanids, 745.
— of endocrin drugs, epinephrin,
780.
— parathyroid gland substances,
785.
— pineal gland, 785.
— pituitary, 784.
— prostate gland, 785.
— spleen, 785.
-testis, 785.
— thymus gland, 785.
— thyroid gland substance, 782.
— epinephrin, 780.
— of ether, 760.
— of ethylenediamin, 773.
— of ethylhydrocurpein, 772.
— of high altitude, 910.
— of hot baths, 860, 861.
— of hydrazin, 773.
— of hypnotics, 763.
— of iodin and iodids, 724.
— of iron, 755.
— of iron waters, 851.
— of iso-amylamin, 773.
- of lead, 758.
-of light, 893.
— of magnesium, 727.
— of mercury, 755.
— of narcotics, 760.
— of opiates, 765.
— of oxygen, 740.
— of parathyroid gland substances,
785.
— of phenylethylamin, 773.
— of phlorizin, 759.
— of phosphorus, 748.
— of pilocarpin, atropin, etc., 774.
of pineal gland feeding, 785.
938
IXDEX
Metabolism, effect on, of pituitary sub-
stances, 784.
— of pituitary substances, anterior
lobe, 785.
of platinum, 758.
— of prostate gland substances, 785.
— of purins, 778.
— of quinin and its congeners, 772.
of radium, 758.
of salt baths, 863, 864.
— of salts, 718.
— of santonin, 776.
. of sodium chlorid, 719.
— salt fever, 720.
— salt glycosuria, 722.
salt starvation, 723.
— of spleen, 785.
of strychnin, 775.
of temperature and humidity,
902.
— of testis feeding, 785.
— of thymus gland substances, 785.
— of thyroid gland substance, 782.
— of tyramin, 773.
— of water, 717.
— deficiency of water, 717.
— mineral waters, 718.
— of zinc, 758.
— energy, basic principles of, 583.
— basal metabolism. See Metab-
olism, basal.
— conservation of energy in ani-
mal organism, 584.
— determination in part by en-
vironing temperature, 593.
— heat production as affected
by external temperature, 601.
— energy of muscular work defi-
nitely related to potential energy of
food, 586.
— indigestion of food increases
metabolism, 604.
— calorimetry, direct, 567. See also
Calorimetry.
— indirect, 515. See also Cal-
orimetry.
— of children, up to puberty, 647.
— determined in part by environing
temperature, how heat is lost from
body, 593.
— law of surface area, 594.
— effect on, of acids and alkalies,
736.
of calcium, 730.
— of saline cathartics, 718.
— of sodium chlorid, 720.
— and embryonic growth, 616.
— factors determining level of,
607.
Metabolism, energy, and growth, 615.
— differences between growth and
maintenance, 615.
— embryonic, 616.
— post-embryonic, 619.
— of infant, new-born, 627.
— from two weeks to one year of
age, 640.
mechanical efficiency of muscular
work, 586.
— methods of measuring heat pro-
duction from respiratory exchange.
See Respiratory Exchange.
— methods of measuring respiratory
exchange. See Respiratory Ex-
change.
— normal processes of, 515.
-of old age, 658.
— origin of, in non-nitrogenous
food, 586.
— of parturition, before and after,
table, 634.
— and post-embryonic growth, 619.
— of pregnancy, 621.
— comparison of energy metab-
olism in pregnant and non-pregnant
women, table, 625.
— relative value of different food-
stuffs as source of energy in mus-
cular work, 590.
— surface area, law of, 594.
— law of, criticism of, 597.
— measurement of, 595.
— relation of, to body weight, 598.
— See also Muscular Energy.
— energy relations, importance of in-
sisted on by Rubner, 76.
— in fasting, 309.
— von Liebig's observations on, 46.
— fat, absorption, from the intestine,
194.
— changes in fats during, 196.
— emulsification, 200.
— factors in, 197.
-paths of, 196.
— stomach, 190.
— in the blood, alimentary lipemia,
201.
-lipoids of, 204.
— and blood lipoids, 445.
— digestion, in the intestines, 193.
— emulsification, 200.
factors in, 197.
in stomach, 189.
— effect on, of alcohol, 765.
of anesthetics, general chloro-
form and ether, 762.
of cocain, 777.
of mercury, 756.
I^DEX
939
Metabolism, fat, effect on, of opiates,
766.
— of phlorizin, 759.
— of phosphorus, 748.
— of saline cathartics, 718.
— of thyroid gland substance,
784.
— of uranium, 758.
— fat excretion, 210.
— intermediary, influence of carbo-
hydrates on, 271.
— in the intestines, absorption,
changes in fats during, 196.
— absorption of fat, 194.
paths of, 196.
bile, 198.
digestion, 193.
— emulsification in fat digestion
and absorption, 200.
— factors in digestion and ab-
sorption, 197.
— lipases of intestinal tract and
digestion, 192.
— nature of food fat, 199.
— pancreatic juice, 192.
— pancreatic secretion, 197.
passage from the stomach, 191.
— summary of, 200.
— synthesis of fats during ab-
sorption from, 196.
— introduction to, 183.
— later stages of, /2-oxidation, 208.
— lipoids, compound, cephalins, 187.
— glycolipoids, 187.
lecithins, 186.
— phospholipoids, 185.
— derived, fatty acids, 187.
— sterols, 188.
simple, fats, 184.
waxes, 185.
— liver in, 207.
— minimum, 410.
— passage from the stomach to in-
testines, 191.
— of rectal feeding, 811.
— — stomach, absorption, 190.
— digestion, 189.
— synthesis of fats during absorp-
tion, from the intestines, 196.
— in the tissues, changes in fat, 206.
— storing of fat, 205.
— fat ingestion, contents of feces fol-
lowing, 64.
— ferments, effect of anesthetics, gen-
eral, chloroform and ether, 763.
- effect on, of arsenic, 755.
— in fever, effect on, of antipyretics,
768.
— final stage of, oxidation, 130.
Metabolism, formation of fat, von Lie-
big on, 49.
— formation of feces and absorption
of bile, von Liebig on, 49.
— gaseous, effect on of hot baths, 861.
— in gavage, 806.
— of growth, effect on, of epinephrin,
782.
— of purins, 780.
of thyroid gland substance,
784.
and reproduction, effect on, of
calcium, 732.
— guanidin bases, effect on, of purins,
780.
— heat production of body, Berthelot's
observations on, 77.
— history of, 3.
— air, its combustion and respira-
tion, 8, 9.
beginnings of calorimetry, 4.
— Barral (1819-1884), 38.
- Boussingault (1802-1887), 37.
Despretz (1792-1863), 34.
-Dulong (1785-1838), 35.
-Dumas (1800-1884), 36.
-Magendie (1783-1855), 37.
-Regnault (1810-1878), 40.
— carbonic acid gas, 8.
— chemical revolution, 14.
-Black (1728-1799), 15.
— Cavendish (1731-1810), 15.
-Crawford (1748-1795), 17.
-Lavoisier (1743-1794), 19.
-resume of, 29, 30.
-Entherford, Daniel (1749-
1819), 16.
-Scheele (1742-1786), 17.
— classical period, 4.
— Aristotle, 5.
— Galen, 5.
— Hippocrates, 4.
— Socrates, 4.
conclusions on, 78.
dark ages, 5. Voit, Carl, 5.
— dawn of, 3.
"insensible perspiration," 4, 7.
— introduction to, 3.
— late French work, 77.
Berthelot (1827-1907), 77.
Richet, Charles (1850 ),
77.
— renaissance, 6.
- Boerhaave (1668-1738), 11.
Boyle, Robert (1621-1679), 8.
-Hales Stephen (1677-1761), 11.
von Haller, Albrecht (1708-
1777), 11.
Van Helmont (1577-1644), 8.
INDEX
Metabolism, history of, renaissance,
Jean Key (1645), 8.
-Lefevre, Nicholas (died 1674),
8.
-Leonardo da Vinci (1452-
1519), 6.
Mayow, John (1640-1679), 9.
Paracelsus (1493-1591), 7.
Sanctorius (1561-1636), 7.
Stahl (1660-1734), 11.
Stark, William (1740-1770),
12.
-Willis (1621-1675), 11.
— respiration, 8, 9, 10.
— rise of German science, Bidder,
F. W. (1810-1894) and Schmidt, C.
(born 1822), 57.
- von Liebig, Justus (1803-1873),
44.
— von Liebig, Justus, Munich
period of, 53.
— von Pettenkofer, Max (1818-
1901), 64.
-Rubner, Max (1854 ), 75.
-von Voit, Carl (183-1-1908), 65.
-Zuntz, Nathan (1847-1920), 76.
— science after the French Revolu-
tion, 30.
-Berzelius (1779-1848), 33.
-Davy,. Humphrey (1778-1829),
31.
-Edwards, William F. (1776-
1842), 32.
-Gay-Lussac (1778-1850), 33.
-Magnus (1802-1870), 33.
-Spallanzani (1729-1799) 32.
— of a horse, von Liebig's observations
on, 48.
— influence on, of carbohydrates, 130.
— of fat, 130.
— of diminished water intake, 279.
— of increased water ingestion, 277.
— on basal metabolism, 279.
— of protein, 130.
— of roentgen rays and .radioactive
substances, introduction to, 871.
— in metabolism in disease, 884.
— in normal metabolism, 880.
— influence of food on composition of
urine, 64.
— ingestion of meat, weight of feces
following, 58.
— isodynamic equivalents, 49.
— table of, von Liebig's, 50.
— lime, in infancy and childhood, 318.
— measurement of, Zuntz, 76.
— measurement of energy, Zuntz, 77.
— meat, dry, free from ash, elementary
analysis of, 60.
Metabolism, meat protein, fate of, Bid-
der and Schmidt, 61.
-v. Voit, 68.
— mineral, 303.
— alkalies, 315.
— ash minimum, 411.
— calcium, 316.
— disturbances in, accompanying
pathological conditions, 336.
— effect on, of acids and alkalies,
736.
— of anesthetics, general, chloro-
form and ether, 763.
— of calcium, 726.
— of carbon monoxid, 743.
— of epinenephrin, 782.
•— of mercury, 756.
— of phosphorus, 750.
— of purins, 780.
— of saline cathartics, 719.
— of sodium chlorid, 719.
— of uranium, 757.
— and endocrin glands, 336.
— of infants two days of age, table,
636.
- iodin, 332.
-iron, 326.
— magnesium, 323.
— neutrality regulation, 333.
— phosphorus, 323.
— salt and salt-poor diet, 308.
— sodium chlorid, 312.
-sulphur, 332.
— water, 311.
— in nephritic conditions, effect on, of
purins, 778.
— nitrogen, determination of, in urine,
titration method of Liebig, 67.
-Voit's method, 68.
— effect on, of antimony, 754.
— of arsenic, 754.
— of blood transfusion, 828.
— of cocain, 777.
— of purins, 779.
— of sodium chlorid, 721.
— nitrogen elimination, 67.
— non-nitrogenous constituents of
blood, original and role of, 433.
— nutrition and energy relations in-
volved, as they concern the animal
organism, 69.
— oxidation of various foods, von' Lie-
big, 49.
— oxygen as cause of, passing of con-
ception, 71.
— oxygen requirement for combustion
of foods, von Liebig, 50.
— percentage of, taking place in mus-
cles during rest and activity, 459.
INDEX
941
Metabolism, protein, coagulation and
denaturalization, 100.
continuance of, in body, irrespec-
tive of any ingestion of protein, 116,
117.
— digestion, 101.
— absorption of products of, from
the gastro-intestinal canal, 103.
— schematic illustration of, in
the gastro-intestinal canal, 103.
effect on, of acids and alkalies,
739.
— of alcohol, 300, 764.
of anesthetics, general, chloro-
form and ether, 760.
— of antipyretics, 769.
of blood poisons, 744.
of carbon monoxid, 743.
of cyanids, 748.
— of epinephrin, 782.
on hot baths, 861.
— of mercury, 756.
— of opiates, 766.
— of phlorizin, 759.
of phosphorus, 750.
— of saline cathartics, 719.
of saline waters, 847.
of starvation, 116, 117.
of thyroid gland substances,
783.
of uranium, 757.
when fasting, tables of, 116,
117.
fate of amino acids in body, ab-
sorbed in the blood, 104.
— non-nitrogenous fraction of,
107.
table summarizing, 115.
— in the tissues, 105.
function of protein in diet, 121.
higher, when carbohydrate is ab-
sent from diet, 118.
incomplete, Hopkins and Will-
cock's experiments with, 125, 126.
incomplete proteins, 122.
— Abderhalden's experiments
with, 123, 124, 125.
Osborne and Mendel's experi-
ments with, 127, 128, 129.
introduction to, 81.
— • — Lusk's experiments with, 131.
minimum and optimum. See
P.rotein Minimum and Optimum.
nitrogen balance and body weight,
Hopkins and Willcock's experiments
on, 125, 126.
— nitrogenous equilibrium and hody
weight, experiments on, of Abder-
halden, 123, 124, 125.
Metabolism, protein, peptones in di-
gested protein, original views of,
121.
protein factor, obtaining of,
116.
— question of optimum versus min-
imum protein diet, 119.
of recital feeding, 810.
— salt formation of proteins, 100.
state of negative nitrogen bal-
ance, 116.
state of nitrogenous equilibrium,
116.
— state of positive nitrogen balance,
116.
— — synthesizing by animal body of
its own protein from elementary
amino acids, 121.
Abderhalden's experiment, 122.
urea formation, 105.
of Voit, 68, 69.
See also Proteins.
— purin, effect on, of acids and alka-
lies, 739.
— of alcohol, 300.
— of calcium, 732.
of cinchophen (atophan), 772.
— of purins, 779.
— of rectal feeding, 810.
— of reproduction and growth, effect
on, of alcohol, 765.
effect on, of antipyretics, 769.
— respiratory quotient of Bidder and
Schmidt, 63.
— salt, of rectal feeding, 812.
— source of muscle power in, 53.
— total, computation of, Bidder and
Schmidt, 60.
— effect on, of acids and alkalies,
736.
— of alcohol, 764.
— of alcohol, 299.
— of antipyretics, 767.
— of arsenic, 754.
— of carbon monoxid, 742.
— of epinephrin, 780.
— of mercury, 756.
— of narcotics, 760.
— of opiates, 765.
— of phlorizin, 760.
— of phosphorus, 748.
— of pituitary substances, 784.
— of purins, 779.
— of saline cathartics, 718.
— of sodium chlorid, 721.
— of thyroid substances, 783.
— of uranium, 758.
— "typical food minimum," of Bidder
and Schmidt, 63.
942
INDEX
Metabolism, ultimate disposal of
products of, von Liebig s, 51.
— undernutrition, 414.
war edema, 415.
-uric acid excretion, effect on, of
arsenic and antimony 754.
— value of flavor in diet, Voit, 74.
— of vitamins, 341.
end, 350.
digestion and absorption of,
347
intermediary, and physiological
action, 347.
special features of, 451.
— Voit's and Pfliiger's controversy, 72,
73
— Voit's theory of "organized protein"
and "circulating protein, 72.
— water, effects on, of acids and al-
kalies, 736.
— of anesthetics, general chloro-
form and ether, 763.
— of antipyretics, 770.
— of arsenic, 755. j%
— of calcium, 730.
of epinephrin, 781.
of mercury, 756.
of opiates, 767.
— of pituitary substances, 784.
of purins, 778.
of sodium chlorid, 720.
— of uranium, 757.
of rectal feeding, 812.
— work on, of Bidder, F. W. (1810-
1894) and Schmidt, C. (born 1822),
57.
— of Kubner, 75.
of yon Voit, Carl, 65.
— of Zuntz, 76.
Metchnikoff hypothesis, 700.
Methemoglobinemia, 744.
Methylglucosides, 237.
Methylpentoses, 242.
Microbic response, relation between
diet and, in normal nurslings, 691.
Milk, composition of, 476.
— percentage of, of human milk by
periods, 477.
— rate of growth and, in different
species, 477.
— variation in as between human
and cow's milk, 478.
— constituents of, mineral, 478.
table of, 479.
nonprotein nitrogenous, table of
i. 478.
-table of, 476.
— cow's, artificial feeding of, to in
fants, 320.
Milk, of different species of animals,
difference in, 476.
human, mineral constituents of, 319.
— importance of, in diet, 421.
— mineral content of, 478.
— physical appearance of, 476.
— reaction of, 476.
-in rectal feeding, 812.
Millon's reaction, 98.
Mineral constituents of adult human*
body, 303.
— alkalies, 315.
— arsenic, 308.
-of the blood, 306.
— calcium, 450.
chlorids, 451.
iron, 451.
— magnesium, 451.
phosphates, 453.
potassium, 450.
sodium, 450.
sulphates, 454.
-table of, 307.
— calcium, 316.
— of cerebrospinal fluid, 473.
— of different organs, 303.
Dennstedt and Kumpfs table of,
304.
Magnus-Levy's table, 305.
of milk, 319, 478.
table of, 479.
iodin, 332.
— iron, 326.
— magnesium, 323.
— of muscles, 305.
table of, 462.
— of nervous tissue, Weil's table, 306.
— phosphorus, 323.
— salt, nutritive value of, 308.
— salt-poor diet, effect of, 309.
-silica, 308.
— sodium chlorid, 312.
-sulphur, 332.
— water, 311.
Mineral metabolism, alkalies, 315.
— calcium, 316.
— disturbances in, accompanying
pathological conditions, 336.
— effect on, of acids and alkalies, 73fi.
— of aluminum, 732.
— of anesthetics, general, chlo--
form and ether, 763.
— of calcium, 726.
of carbon monoxid, 743.
of epinephrin, 782.
of magnesium, 727.
of mercury, .756.
of phosphorus, 750.
of purins, 780.
1XDEX
Mineral metabolism, effect on, of saline
cathartics, 719.
— of sodium chlorid, 719.
— of uranium, 757.
— and endocriii glands, 336.
— of infants two days of age, table,
636.
- iodin, 332.
— iron, 326.
— magnesium, 323.
— neutrality regulation, 333.
— phosphorus, 323.
— sodium chlorid, 312.
— sulphur, 332.
— water, 311.
Mineral requirements, of adult organ-
ism, 310.
— for calcium, 317.
— magnesium, 323.
— phosphorus, 324, 325.
— for sodium chlorid, 312.
-for water, 312.
— of childhood and adolescence, 321.
— in infants, 318.
Mineral waters, 845.
— alkaline waters, including carbon-
ated, 848.
— arsenic, 851.
bitter waters, 850.
— carbonated, 848.
— classification of, 845.
— diuretic property of, 847.
— effect of, on metabolism, 718.
— iron, 851.
— radioactive, 852.
— saline waters, 846.
— sulphur, 851.
Molisch reaction, 98.
Monominophosphatids of brain, 470.
Monosaccharids, special properties of,
237.
Monosaccharose, conversion of higher
to lower, 227.
— synthesis of higher forms from, 226.
Mouth-pieces for measuring respira-
tory exchange, 531.
Mud baths, 867.
Muscle power, Frankland's comparison
of, with steam engine, von Liebig's
criticism of, 54.
— source of, 53.
Muscles, contraction of, by electricity,
894.
— creatin content of, 172.
— creatin metabolism, 174.
• — creatinin metabolism in, 177.
— extractives of, 460.
— nitrogenous, carnosin, 461.
creatin, 460.
Muscles, extractives of, nitrogenous,
purin bases, 461.
-table of, 462.
— uric acid, 461.
non-nitrogenous,, glucose, 460.
glycogen, 450.
lactic acid, 460.
inositol, 460.
— magnesium in, 323.
— metabolism percentage taking place
in, during rest and activity, 459.
— mineral constituents of, 305.
— mineral content of muscles, table,
462.
— percentage of body weight com-
prised in, 459.
— proteins of, 459.
• voluntary and involuntary, 459.
Muscular activity, influence of, on
basal metabolism of children, 654.
— comparison of fat and carbohydrate
as a source of, 592.
— alcohol and, 301.
— energy of, definitely related to po-
tential energy of food, 586.
— energy production of, on different
diets, 590.
— mechanical energy of, 586.
— relative value of different food-
stuffs, as a source of energy in, 590.
Mustard baths, 863.
Mutarotatin, 221.
Myelin, in brain, 470.
Narcotics, effect of, on metabolism,
760.
body temperature, 760.
— total metabolism, 760.
Nasal mucosa, effect on, of temperature
and humidity, 901.
Nephritic conditions, effect on, of
purins, 778.
Nephritis, blood lipoids in, 446.
— chronic, urea nitrogen, urin acid,
and creatinin of blood in, 439.
uric acid, urea nitrogen and
creatinin of blood in, 439.
— disturbances of mineral metabolism
in, 336.
— injections into blood of sodium bi-
carbonate, 793.
— uranium, alkaline treatment in, 735.
— uric acid in, 437.
Nerve and endocrin control of gly-
cogenesis, glycogenolysis and glu-
colysis, 257.
Nerves, magnesium in, 323.
— stimulation of, by electricity, 894.
944
IXDEX
Nervous tissue, mineral constituents of,
306.
Neumann's experiments on protein
minimum and optimum, 402.
Neutrality regulation, 732.
New-born infant, See Infant, new-
born.
Nitrobenzene poisoning, blood trans-
fusion in, 833.
Nitrogen, amount of, excreted in urine,
table of, 405;
— blood, comparative nitrogen parti-
tion of urine and, in per cent of
total non-protein nitrogen, table,
434.
— non-protein, 432.
— urea, 435.
-rest, 442.
total, 432.
— uric acid, 437.
— determination of, in urine, titra-
tion method of Liebig for, 67.
- Voit's- method, 68.
— elimination of, 67.
— in the feces, 504.
— non-protein, of cerebrospinal fluid,
472.
— in the sweat, 513.
— urea, in nephritis, fable of, 439.
— of the urine, 485.
— methods of calculating from re-
spiratory exchange and, 563.
— nitrogenous substances, 507.
Nitrogen balance, negative, 116.
— positive, 116.
Nitrogen gas, "residual air," discovery
of, by Rutherford, 16.
Nitrogen intake, lowest value for, with
maintenance of equilibrium, 407.
Nitrogen metabolism, effect on, of
antimony, 754.
of arsenic, 754.
— of blood transfusion, 828.
— of cocain, 777.
— of purins, 779.
of sodium chlorid, 721.
Nitrogen minimum, 401.
Nitrogen partition of urine and blood,
comparative, in per cent of total
non-protein nitrogen, table of, 434.
Nitrogenous constituents of milk, 478.
Nitrogenous equilibrium, 116.
— and body weight, Abderhalden's ex-
periments on, 123, 124, 125.
Nitrogenous substances, in the urine,
507.
Normal leucin, 86, 109.
Nose-pieces, for measuring respiratory
exchange, 532.
Nucleic acid, animal, 145.
— chemical part, 135.
— decomposition, enzymatic, of com-
bined purins, 158.
— distribution of, purin ferments, 154.
— formation of oxy-purins from
amino-purins, 151.
— formation of uric acid from, 150.
— from oxy-purins, 151.
— guanylic acid, 141, -142.
— inosinic acid, 141.
— physiological decomposition of, 148.
— physiological destruction of uric
acid, 153.
— plant, 135.
— thymus, partial decomposition
products of, 147.
— yeast, dextro-ribose, 136.
— yeast, fundamental groups of, 136.
nucleotides of, 143.
— nucleotides of, 139.
— nucleotide linkages of, 140.
— pentose, 136.
purin derivatives, 137.
— amino-purins, adenin, 137.
— -guanine, 137.
- — chemical relation of amino-
and oxy-purins, 138, 139.
— oxy-purins, hypoxanthin, 137,
138.
-uric acid, 137, 138, 139.
— zanthin, 137, 138.
— pyrimidin derivatives, 136.
— cytosin, 137.
— uracil, 137.
— six substances of, 136.
Nucleoprotein, formation of uric acid
in urine from, 495.
Nucleotides, yeast, 143.
Nucleotide linkages of yeast nucleic
acids, 140.
Nucleotides of yeast nucleic acid, 139.
Nurslings. See Infants.
Nutrition, level of, 416.
Nutrition, and energy relations in-
volved, as they concern the animal
organism, 69.
Nutritive value of alcohol, 297.
Old age, energy metabolism of, 658.
Opiates, effect of, on metabolism,
765.
— acid-alkali, 766.
— body temperature, 765.
— carbohydrate, 766.
— in diabetes, 766.
-fat, 766.
— protein, 766.
— temperature of the body, 765.
INDEX
945
Opiates, effect of, on metabolism, total,
765.
— water, 767.
Organic acids, salts of, effects of, on
metabolism, 725.
Organic phosphorus, 752.
Ornithin, 89, 113, 685.
Osazones, 235.
Osborne and Mendel's experiments il-
lustrating physiological value of
amino acids, 127, 128, 129.
Osones, 235.
Osteomalacia, and mineral metabolism,
339.
Oxalates, effects of, on metabolism, 725.
Oxalic acid, in urine, 499.
Oxyacids and derivatives, aromatic,
499.
Oxidation, of carbohydrates, 227.
— of glucose, 251.
Oxygen, from arterial blood, by
Humphrey Davy, 31.
— in the blood, 455.
— content of, 455.
— arterial, 456.
— in pathological conditions, 457.
— and carbonic acid gas, Spallanzani's
experiments, 32.
— as cause of metabolism, passing of
conception of, 71.
— discovery of, by Priestley, 16.
— by Scheele, 17.
— effect of, on metabolism, 740.
— oxygen deficiency, 740.
— relation between quantity exhaled
as carbon dioxid, and quantity con-
sumed, 41.
Oxygen capacity of blood, effect on, of
blood transfusion, 823.
Oxygen consumption, effects on, of
hot baths, 860, 861.
Oxygen deficiency, 740.
— blood alkalinity in, 741.
— lactic acid excretion in, 741.
Oxygen requirement for combustion of
foods, von Liebig, 50.
Oxyprolin, 90, 114.
Oxy-purins, chemical relation of, with
amino-purins, 138.
— formation of, from amino-purins, 151.
— formation of uric acid from, 151.
— hypoxanthin, 137, 138.
— uric acid, 137, 138, 139.
— xanthin, 137, 138.
Pancreas, influence of, on glycogenesis,
glycogenolysis and glucolysis, 257.
Pancreatic digestion, influence on, -of
water, 289.
Pancreatic juice, amount of, secreted,
in 24 hours, 192.
— excitants for secretion of, 192.
Pancreatic lipase, action of, 192.
— extraction of, from gland, 193.
— secretion and activity of, 193.
Pancreatic secretion, effect on, of al-
kaline waters, 849.
— of saline waters, 847.
— as factor in fat digestion and ab-
sorption, 197.
Paracelsus (1493-1591), on metabolism,
7.
Paraldehyde, effect of, on metabolism,
764.
Paramyelin, 470.
Parasitism, influence of, on bacterial
metabolism, 666.
Parathyroid gland substances, effect of,
on metabolism, 785.
Parturition, energy metabolism before
and after, table, 634.
Parasitism, influence of, on bacterial
metabolism, 666.
Peat baths, 867.
Pellagra, feces in, average daily com-
position of, 509.
Pentose, 136.
Pentoses, 240.
— aldopentoses, table of, 241.
— 1-arabinose, 241.
-methyl, 242.
— rhamnose, 242.
— d-ribose, 242.
— xylose, 241.
Pernicious anemia, blood transfusion
in, indications for, 831.
— treatment of, by x-rays, 886.
— urobilin excreted in, 168.
"Perspiration, insensible," Hippocrates
on, 4.
-Sanctorius (1561-1636), 7.
von Pettenkofer, Max (1818-1901),
contribution of, to study of meta-
bolism, 64, 65.
— apparatus of, for measuring respira-
tory exchange, 516.
Pettenkofer reaction for bile salts, 65.
Phenols, formation of, 680.
— effects on, of utilizable carbohy-
drates, 685.
Phenylalanin, decomposition of, 684.
Phenylamin, 89, 113.
Phenylethylamin, 686.
— effect of, on metabolism, 773.
Phlogiston theory of combustion, 11.
— demolished by Lavoisier <1783), 23.
Phlorizin, effect of, on metabolism, 759.
carbohydrate, 759.
94G
INDEX
Phlorizin, effect of, fat, 759.
— protein, 759.
- total, 760.
"Phosoxygen," of Humphrey Davy, 31.
Phosphates, in the blood, ^
— of cerebrospinal fluid, 473.
— of the urine, 501.
Phosphatids, of the grain, cephalin,
468.
-lecithin, 468.
— of the liver, 463.
Phospholipoids, 185.
— cuorin, 186.
Phosphorus, cod liver oil as vehicle for,
753.
— distribution of, in body, 324.
— effects of, on metabolism, 748.
— acid-base, 750.
— carbohydrate, 749.
fat, 748.
mineral, 750.
. — protein, 750.
— total metabolism, 748.
— on skeleton, 751.
— excretion of, in urine and feces,
326.
- in the feces, 511.
—.in human body, 323.
— inorganic, in animal and plant tis-
sues, 324.
— organic, 752.
— requirements for, in human body,
324.
Phosphorus deficiency, 751.
Phosphorus metabolism, 325.
Phosphorus poisoning, 748.
Pigments, bile, 465.
Pilocarpin, effect of, on metabolism,
774.
Pineal gland substances, effect of, on
metabolism, 785.
Pituitary gland, influence of, on gly-
cogenesis, glycogenolysis and glu-
colysis, 261.
Pituitary substances, anterior lobe, ef-
fect of, on metabolism, 785.
— effect of, on metabolism, 784.
Plant nucleic acid, 135.
Platinum, effect of, on metabolism,
758.
Pneumonia, treatment of, by x-rays,
886.
Polymerization of simple sugars, 225.
Polysaccharids, cellulose, 247.
— gums, 247.
— inulin, 247.
— starch, 247.
Potassium, in the blood, 450.
— in the brain, 471.
Potassium, in cerebrospinal fluid,
473.
— effect of, on metabolism, 724.
— in the urine, 502.
Potassium citrate, in milk, human and
cow's, 478.
Precipitating reactions of proteins,
99.
Pregnancy, calcium in blood during,
322.
— creatin excretion in, 176.
— energy metabolism of, 621.
— before and after parturition,
634.
comparison of, in pregnant and
non-pregnant women, table, 625.
Priestley (1733-1804), discovery of ox-
ygen by, 16.
Prolamins, 83.
Prolin, 90, 114.
Prostate gland, effect of feeding of, on
metabolism, 785.
'Protamins, 83.
Protein diet, optimum versus mini-
mum, question of, 119.
Protein factor, obtaining of, 116.
Protein-liquefying enzymes, formation
of, 670. .
Protein metabolism, effect on, of acids
and alkalies, 739.
— of alcohol, 764.
— of anesthetics, general, chloro-
form and ether, 760.
— of antipyretics, 769.
of atropin, pilocarpin, etc., 774.
— of blood poisons, 744.
of carbon monoxid, 743.
— of cyanids, 748.
of epinephrin, 782.
of hot baths, 861.
— of mercury, 756.
of opiates, 766.
— of phlorizin, 759.
— of phosphorus, 750.
of saline cathartics, 718.
— of saline waters, 847.
— of thyroid substances, 783.
— of uranium, 757.
— of rectal feeding, 810.
Protein minimum and optimum, 401.
— experiments on, of Chittenden, 402.
-of Fisher, 405.
— of McCay, 406.
of Neumann, 402.
Protein molecule, role of amino acids
in structure of, 91.
— structure of, 84.
Proteins, alcohol soluble, 83.
— amino acid content of, 96."
INDEX
947
Proteins, amino acid content of, rela-
tive, table of, 97.
— absorbed, fate of, in blood, 104.
— amino acids or "building stones" of,
84.
— aromatic amino acids, 89.
— compounds of, 93, 94.
compounds of, possible, number
of, 95.
— diamino acids, 88.
dibasic mono-amino acids, 86.
fate of, in the body, table sum-
marizing, 115.
of non-nitrogenous fraction of,
107.
— in the tissues, 105.
— heterocyclic amino acids, 90.
hydroxy- and thio-a-amino acids,
87.
monobasic mono-amino acids, 84.
number of, 95..
role of in structure of protein
molecule, 91.
— amount of, required in diet, 392.
— blood, 427.
— blood serum, 428.
— of brain, 467.
— cell, action of light on, 891.
— in cerebrospinal fluid, 471.
— classification of, 81.
conjugated, 82.
derived, 82.
simple, 82.
— coagulation and denaturalization of,
100.
— conjugated, 82.
— decomposition of, by bacteria,
tryptophan, 682.
tyrosin, 681.
— denaturalization of, 100.
— derived, 82.
— digestion of, 101.
— digestion of, absorption of products
of, from the gastro-intestinal canal,
103.
— — schematic illustration of, in the
gastro-intestinal canal, 103.
— elementary composition of, 81.
— function of, in diet, 121.
— general nature of products of bac-
terial growth, arising from utiliza-
tion of carbohydrates and, for en-
ergy, 669.
— incomplete, 122.
Abderhalden's experiments on,
123, 124, 125.
— definition of, 125.
Hopkins and Willcock's experi-
ments with, 125, 126.
Proteins, incomplete, Osborne and
Mendel's experiments illustrating
physiological value of amino acids,
127, 128, 129.
- influence of, on metabolism, 130.
— intravenous feeding of, 817.
— of the liver, 463.
— and their metabolism. See Meta-
bolism, protein.
— of muscles, 459.
— precipitating reactions of, 99.
— precipitation of, relative influence
of anions and actions on, 100.
— reactions of, Adamkiewicz-Hopkins-
Cole, 98.
-Biuret, 96.
color, 96.
Millon's, 98.
- Molisch, 98.
precipitating, 99.
sulphur-lead, 98.
— triketohydrinden hydrat, 98.
xantho proteic, 98.
— relation to, of pathogenic bacteria,
673.
— respiratory quotient of, 561.
— salt formation of, 100.
— "salting out" of, by means of elec-
trolytes, 99.
— simple, albuminoids or scleropro-
teins, 83.
albumins, 82.
globulins, 83.
glutelins, 83.
histones, 83.
prolamins or alcohol soluble pro-
teins, 83.
protamins, 83.
— specific dynamic action of, 130.
— in subcutaneous feeding, 815.
— thermal quotient for, 555.
— urea formation, 105.
— value of, in diet, 408.
Ptomains, 685.
Ptyalin, action of, 248.
Puberty, influence of, on basal meta-
bolism of children, 654.
Pulse, effect on, of hot baths, 862.
Purin bases, of muscle tissue, 461
— of urine, 498.
Purin derivatives, amino-purins,
adenin, 137.
guanin, 137.
— chemical relation of amino- and
oxy-purins, 138, 139.
— oxy-purins, 138.
- hypozanthin, 137, 138.
uric acid, 137.
zanthin, 137.
948
INDEX
Purin fermentation, independent fac-
tors of, 153.
Purin ferments, distribution of, 154.
— adenase, 156.
guanase, 156.
uricase, 155.
— xanthin oxidase, 156.
Purin metabolism, effect on, of acids
and alkalies, 739.
— effect on, of atropin, pilocarpin, etc.,
774.
— of calcium, 732.
— of cinchophen (atophan), 772.
— of purins, 779.
Purin nucleotides, and hydrolysis, 140.
Purins, combined, enzymatic decom-
position of, 158.
— effect of, on metabolism, 778.
— in nephritic conditions, 778.
Purpura hemorrhagica, idiopathic,
blood transfusion for, 833.
Putrefaction, intestinal, influence on,
of water, 291.
Putrescin, 685.
Pyrimidin derivatives, 136. -
— cytosin, 137.
— uracil, 1.37.
Pyridimin nucleotides, and hydrolysis,
140.
Quinin, effect of, on metabolism, 772.
Quotients, respiratory. See Respira-
tory Quotient.
— thermal. See Thermal Quotients.
Rachitis, and mineral metabolism, 339.
Radiation and conduction in hot cli-
mates, 900.
Radioactive baths, 867.
Radioactive substances, distribution
and elimination of, 874.
— effect of, on blood and blood-form-
ing organs, 875.
— constitutional, 887.
— on enzymes, 878.
— on immunity, 876.
— on metabolism, in disease, 884.
— introduction to, 871.
-normal, 880.
— tissues, 874.
— measurement (standardization) of,
872.
— theories of action of, 889.
— treatment by, of arthritis, chronic,
886.
— .of carcinoma, 887.
- of gout, 885.
— of leukemia, chronic lymphatic,
884.
Radioactive substances, treatment by,
of sarcoma, 887.
Radioactive waters, effects and thera-
peutic value of, 852.
Radium, effect of, on metabolism, 758.
Radium emanation, therapeutic value
of, 852.
Reactions, in bacterial metabolism, de-
composition of proteins by bacteria,
681.
— effects of utilizable carbohy-
drates upon formation of phenols,
indols and amins, 685.
formation of phenols, indol and
indican, 680.
— physiological action of aromatic
amins, 687.
— due to infusions, 800.
— of sugars with substituted hydra-
zins, 232.
Rectal feeding, 809.
— formulae for, 812.
, — indications for, 809.
— length of time for employment of,
809.
— metabolism of, 810.
— carbohydrate, 811.
-fat, 811.
— protein, 810.
— salt and water, 812.
— physiology of, 810.
— precautions and technic in, 813.
— summary of results of, 814,
— of carbohydrates, 230.
Regnard's bag method for measuring
respiratory exchange, 537.
Regnault and Reiset's apparatus for
measuring respiratory exchange, 521.
— monograph of, on respiration of an-
imals, 40.
Renal glucosuria, 253.
Reproduction, effect on, of alcohol, 765.
— metabolism of, effect on, of. calcium,
732.
Reproduction and growth, metabolism
of, effect on, of antipyretics, 769.
Respiration, of animals,, monograph on,
of Regnault and Reiset (1849), 40.
— effect on, of temperature and hu-
midity, 901.
— in history of metabolism, Boerhaave
(1668-1738), 11.
-Hales, Stephen, on, (1677-1761),
11.
von Haller, Albrecht (1708-1777),
11.
- Mayow, John (1640-1679), 9.
Willis on (1621-1675), 11.
— von Liebig on, 46.
INDEX
949
Respiration experiments on man of
Lavoisier, 25.
Respiratory adaptation to high alti-
tudes, 908.
Respiratory exchange, methods of cal-
culating heat production from, 548.
— combustion of carbon and hydro-
gen, 54.
combustion of organic foodstuffs,
549.
non-protein respiratory quotient,
566.
respiratory quotient and its sig-
nificance, 559.
thermal quotients of 02 and
CO*, 555.
and from urinary nitrogen, 563.
method of successive thermal
quotients, 563.
method of Zuntz and Schum-
berg, 565.
— methods of measuring, by direct con-
nection with respiratory passages,
531.
closed circuit instruments, 544.
Benedict's, 544.
Krogh's modification of
Haldane & Douglas' instrument, 544.
— open-circuit instruments, air
analyzers, Haldane's, 540.
analysis of outdoor airr
541.
bag method of Regnard,
537.
collecting apparatus, 534.
of Hanroit and Richet, 543.
masks, 532.
. mouth-pieces, 531.
nose-pieces, 532.
spirometers, 534.
valves, 533.
Zuntz and Geppert's, 538.
by means of a respiration cham-
ber, 516.
closed circuit type of appar-
atus, 521.
— Atwater and Benedict's, 524.
of Hoppe-Seyler, 522.
of Regnault and Reiset, 521.
for very small animals, 529.
Krogh, 531.
Thumberg, 530.
Winterstein, 530.
open-circuit type of apparatus,
of Atwater and Rosa, 518.
of Grafe, B., 519.
Haldane's, 520.
of Jaquet, 519.
Pettenkofer, 516.
Respiratory exchange, methods of meas-
uring, by means of a respiration
chamber, open-circuit type of ap-
paratus, of Sonden and Tigerstedt,
518.
Respiratory quotient, of Bidder and
Schmidt, 63.
— calculation of thermal quotient for
oxygen from, 562.
— effect on, of hot baths, 861.
— of fats, 561.
— of infants, new-born, 627.
Bailey and Murlin, 628.
Benedict and Talbot, 630.
for first eight days, 631.
Hasselbach, 627.
influence of food on, 630.
prematurely born, 631.
table of, 629.
from two weeks to one year of
age, 640.
— Lavoisier and La Place (1780),
22.
— non-protein, 566.
— of proteins, 561.
— and its significance, 559.
Rest nitrogen of the blood, 442.
Retention acidosis, 735.
Rey, Jean, (1645), on metabolism, 8.
Rhamnose, 242.
Rheumatoid arthritis, treatment of, by
x-rays, 886.
Richet, Charles (1850- ) work of,
on metabolism, 77.
Rickets, calcium in, 727.
Roentgen rays, distribution and elimi-
nation of, 874.
— effect of, on blood and blood-forming
organs, 875.
constitutional, 887.- •
on enzymes, 878.
on immunity, 876.
— on metabolism, in disease, 884.
; introduction to, 871.
normal, 880.
-tissues, 874.
toxic constitutional reaction fol-
lowing exposure, 888.
— measurement (standardization) of,
872.
— theories of action of, 889.
— treatment by, of Basedow's disease,
887.
of chronic lymphatic leukemia,
884.
of myeloid leukemia, 884.
of pernicious anemia, 886.
of pneumonia, unresolved, 886.
of rheumatoid arthritis, 8§6.
950
INDEX
Kubner, Max (1854- ), work of, on
metabolism, 75.
Kutherford, Daniel, (1749-1819), on
"residual air" or nitrogen gas, 16.
Saline cathartics, effects of, on meta-
bolism, 718.
— body temperature, 718.
— carbohydrate metabolism, 719.
— fat metabolism, 718.
— mineral metabolism, 719.
— protein metabolism, 718.
— total metabolism, 718.
Saline solutions, for intravenous in-
jection, normal saline, 796.
— reactions, 801.
— sodium chlorid, 797.
Saline waters, diuretic property of,
847.
— effects of, 'on gastric secretion, 846.
— on pancreatic secretion, 847.
-on protein metabolism, 847.
Saliva, composition of, 474.
— constituents of, organic, 474.
— diastatic action of, 475.
— dilution of, effect of in concentrated
mixtures, 281.
— reaction of, 474.
— thiocyanate content of, 475.
Salivary digestion, of carbohydrates,
248.
— influence on, of water, 281.
Salivary factor, 475.
Salt, nutritive value of, 308.
— in rectal feeding, 812.
— relation of, to water retention, 311,
312.
— See also Sodium Chlorid.
Salt baths, 863.
Salt fever, 720.
Salt formation of proteins, 100.
Salt glycosuria, 722.
Salt metabolism, of rectal feeding, 812.
Salt-poor diet, effect of, 308, 313.
Salt-rich diet, effects of, 313.
Salt solution, introduction of, into
blood stream, for hemorrhage, 791.
Salt starvation, 723.
Salting out of proteins by electrolysis,
99.
Salts, aloin, effect of, on metabolism,
719.
— effects of, on metabolism, 718.
— alion, 719.
; of organic acids, acetates and
citrates, 726.
— benzoates, 726.
- — r — oxalates, 725.
tartrates, 726.
Salts, effects of, on metabolism, potas-
sium, lithium and others, 724.
saline cathartics, 718.
salt fever, 720.
salt glycosuria, 722.
salt starvation, 723.
sodium chlorid, 719.
— and water in subcutaneous feeding,
816.
Sanctorius, (1561-1636), on food and
perspiration, 7.
Sand baths, 863.
Santonin, effect of, on metabolism,
776.
Saprophytism, influence of, on bac-
terial metabolism, 666.
Sarcoma, treatment of, by radium, 887.
Scheele (1742-1786), discovery of ox-
ygen by, experiments of, 17, 18.
Scleroproteins, 83.
Schmidt, C. (born 1822), See Bidder,
F. W. and.
Schmidt test, 164.
•Season, influence of, on food consump-
tion, 387.
Sepsin, 685.
Sepsis, blood transfusion in, 833.
Serin, 87, 111.
Serum proteins, 428.
Sex, influence of, in basal metabolism,
614.
of children, 652.
new-born, 635.
Shock, indications for blood transfu-
sion in, 830.
Silica, distribution of, in human body,
308.
Skeleton, effect on, • of phosphorus,
751.
Skin, action on, of light energy, 891.
— foundations of hydrbtherapy in
functions and activity of, 855.
— loss of heat from, 603.
Socrates, on food, 4.
Sodium, in the blood, 450.
— in cerebrospinal fluid, 473.
— in the urine, 502.
Sodium bicarbonate^ intravenous in-
fusion of, in acidosis, 792.
reaction of urine in, attention to
793.
as routine measure before and
after surgical procedures, 793.
— solutions of, for intravenous infu-
sion, 792, 793, 799.
— reactions, 801.
Sodium chlorid, content of, in blood,
312.
— effects of, on body temperature, 700.
IXDEX
951
Sodium chlorid, effects of, on metab-
olism, 719.
— salt glycosuria, 722.
— salt starvation, 723.
mineral, 719.
— on nitrogen, 721.
-on total, 721.
water, 720.
— relation of, to diet, 312.
— See also Salt.
Sodium chlorid fever, 720.
Sodium salt, in milk, human and
cow's, 478.
Sonden and Tigerstedt's apparatus for
measuring respiratory exchange, 516.
Sour milk therapy, in bacillary dysen-
tery, 709.
— and bacterial metabolism, 700.
Spallanzani (1729-1799), experiments
relating to oxygen and carbonic acid
gas, 32.
Sphingomyelin, of brain, 470.
Spirometers, for measuring respiratory
exchange, Boothby's, 535.
-Speck's, 534.
- Tissot method, 535.
Spleen, effect of, on metabolism, 785.
-«— role of, in iron metabolism, 331.
Spoiled air, or nitrogen, of Scheele,
17.
Stahl (1660-1734), phlogiston theory of
combustion of, 11.
Starch, 247.
Starch, conversion of, into fat, Yoit,
73.
Stark, William, (1740-1770), on diet,
in history of metabolism, 12.
Starvation, creatinin excretion during,
178.
— metabolism during, protein, 116,
117.
-salt, 723.
Steapsin, 192.
Sterols, 188.
Stomach, fat metabolism in, absorp-
tion, 190.
— digestion, 189.
— in passage from, to intestines,
191.
— passage from, of water, 286.
Stools, urobilin in, 165.
— clinical significance of increased
amount of, 167, 168.
— determination of, 167.
— diagnostic value of, 169.
Structural chemical requirements for
bacterial development, 669.
Strychnin, effect of, on metabolism,
775.
Subcutaneous feeding, 814.
— of carbohydrates, 816.
— of fats, 815.
— of protein, 815.
— of salts and water, 816.
Sucrose, 245.
— formula for, 244.
Sugar, of blood. See Blood Sugar.
— in cerebrospinal fluid, 473.
— cleavage of, von Liebig's observa-
tions on, 47.
— conversion of protein into fat and,
73.
— of the urine, 499.
Sugars, effects of, upon intestinal flora
of nurslings, experimental evidence
of, 694.
— polymerization of, 225.
— reactions of, with substituted hydra-
zins, 232.
— reduction of, 230.
— specific rotations of, table of, 225.
— terminology of, 213.
Sulphates, in the blood, 454.
— in the urine, 502.
Sulphatids, of brain, 470.
Sulphonal, effect of, on metabolism.
764.
— in metabolism, 332.
Sulphur waters, 851.
Sulphur lead reaction, 98.
Surface area of body, heat production
in infants per square meter of, 646.
— law of, 594.
criticism of, 597.
— measurement of, 595.
— relation of, to body weight, table,
598.
— relation of heat radiation to, table,
610.
Sweat, composition of, 512.
table of, 513.
— diastatic ferment in, 513.
— methods employed to collect, 512.
— nitrogen content of, 513.
— substances excreted in, 512.
— total solids in, 513.
— urea in, 513.
— uric acid, in, 513.
— volume eliminated, 512.
Sweat secretion, baths and, 867.
Sympathetic system and adrenals, in-
fluence of, on glycogeriesis, glyco-
genolysis and glucolysis, 257.
Syntheses, in blood poisons, 745.
Synthesis, of carbohydrates, 226.
Tartaric acid, Pasteur's studies on,
219.
952
INDEX
Tartrates, effect of, on metabolism,
726.
Temperature, of air, heat production
as affected by, in coldblooded ani-
mals, Van't Hoff's law, 601.
cooling power of air currents
at different velocities, 604.
in warm-blooded animals, 602.
— and humidity, effect of, on
amount of blood per kilogram of
body weight, 901.
— on capacity for physical
work, 901.
— on circulatory system, 900.
on concentration of sugar in
blood, 901.
— on metabolism, 902.
on nasal mucosa, 901.
— on respiration, 901.
— radiation and conduction,
900.
— relation of, to temperature of
body, 900.
— influence of, on basal metabolism
of new born infants, 638. .
Temperature, of the body, effect on,
of acids and alkalies, 736.
— of arsenic, 755.
of atropin, pilocarpin, etc.,
775.
— of calcium, 730.
— of cocain, 777.
— of curare, 777.
— of cyanids, 747.
— of epinephrin, 781.
— of hot baths, 860, 861.
— of mercury, 756.
— of narcotics, 760.
— of opiates, 765.
— of purins, 779.
— of saline cathartics, 718.
— of santonin, 776.
— of sodium chlorid, 720.
— of uranium, 758.
— regulation of, as related to hy-
drotherapy, 855.
— relation to, of temperature of the
air, 900.
Testis, effect of, on metabolism, 785.
Tetany, calcium in, 728.
— as a condition of alkalosis treat-
ment for, 739.
— and mineral metabolism, 337.
Tetroses, 242.
Thermal quotient, of CO2, 558.
— variation in heat equivalent of
CO*, (Atwater and Benedict), 559.
— of Oz, based upon experiments on
man, (Atwater and Benedict), 557.
Thermal quotient, of Oz, calculation of,
from respiratory quotient, 562. .
— of Oz during muscular work (At-
water and Benedict), 558.
— Oz and COz for carbohydrate, 556.
for fat, 556.
in a lacto-vegetarian diet, 557.
for mixed diet, 556.
— for protein, 555.
Thermal quotients, successive, 663.
Thumberg's apparatus for measuring
respiratory exchange, 530.
Thymus gland substances, effect of, on
metabolism, 785.
Thymus nucleic acids, partial decom-
position products of, 147.
Thyroid gland, influence of, on glyco-
genesis, glycogenolysis and glu-
colysis, 260.
Thyroid gland substance, effect of, on
metabolism, 782.
Tissue fluid, 788.
Tissues, action on, of light energy,
891.
— brain, 467.
— connective, 466.
— liver. See Liver.
— muscles. See Muscles.
— creatin content of, 172.
— effect on, of roentgen rays and radio-
active substances, 874.
— fat in, changes in, 206.
— storing of, 205. .
Tissues, fate in, of amino acids, 105.
Tolerance, carbohydrate, 254.
— glucolysis and, 256.
— glycogenesis and, 255.
Total metabolism, effect on, of acids
and alkalies, 736.
— of alcohol, 764.
— of antipyretics, 767s.
of arsenic,. 754.
of atropin, pilocarpin, etc., 774.
of carbon monoxid, 742.
of epinephrin, 780.
of mercury, 756.
— of narcotics, 760.
of opiates, 765.
of phlorhizin, 760.
of phosphorus, 748.
of pituitary substances, 784.
— of purins, 779.
of thyroid substances, 783.
— of uranium, 758.
Toxemia, intravenous injection of
fluids in, 794.
— blood transfusion in, 833.
Toxic constitutional reaction follow-
ing exposure to x-rays, 888.
INDEX
955
Toxin, diphtheria, 669.
Transfusion of blood. See Blood
Transfusion.
Triketohydrindeh hydrat reaction of
proteins, 98.
Trioses, 242.
Tryptophan, 91, 115.
Tryptophan decomposition by bacteria,
682.
Tuberculosis, disturbances in mineral
metabolism in, 336.
Tyramin, 686.
— change of, 688.
— effect of, on metabolism, 773.
Tyrosin, 90, 113.
— in the brain, 471.
— change of, 685.
— decomposition of, by bacteria, 681.
Undernutrition, 414.
— creatinuria accompanying, 177.
Uracil, 137.
— and cytosin, 137.
Uranium, effects of, on metabolism,
757.
— carbohydrate, 757.
- — — fat, 758.
— - —mineral, 757.
— protein, 757.
-total, 758.
water, 757.
Uranium nephritis, alkaline treatment
in, 735.
Urea, in blood, 435.
— conditions with significant urea
nitrogen findings, 436.
— origin of, 675.
— as principal end product of metabol-
ism, 675.
— in sweat, 513.
-of the urine, 486, 487, 488.
Urea formation in liver, 464.
— in protein metabolism, 105.
Urea nitrogen, in nephritis, chronic,
table of, 439.
Urethan, effect of, on metabolism, 764.
Uric acid, 137, 138, 139.
— content of, in human blood, 437.
— acids affecting, 438.
Uric acid, elimination of, acids affect-
ing, 438.
— fate of, in man and in animals,
497.
— formation of, from nucleic acid, 150.
— from oxy-purins, 151.
— in gout, 438.
— increased elimination of, 498.
— in leucemia, 437.
— in muscle tissue, 461.
Uric acid, in nephritis, 437.
chronic, table of, 439.
— physiological destruction of, 153.
— precursors of, 497.
— in sweat, 513.
— of urine, 495.
formation of, 495.
Uric acid eliminants, 498.
Uric acid excretion, eifect on, of ar-
senic and antimony, 754.
Uricase, distribution of, 155.
Uricolysis, 496.
Urinary elimination of iron, 329.
Urinary nitrogen, calculation of heat
production from the respiratory ex-
change and, 563.
Urine, 481.
— alkalinization of, 849.
— amino-acids of, 490.
— ammonia of, 489.
— amount of nitrogen excreted in,
405.
— aromatic oxyacids and derivatives,
499.
— calcium in, 316, 503.
-chlorids of, 500.
— composition of, influence of food on,
64.
— creatin of, 493.
— and arginin, as source of, 494.
— excretion of, 493, 494.
— creatin metabolism in, 176.
— ceatinin of, 490.
— elimination of, 490.
origin of, in creatir, of the mus-
cle, 492, 493, 494.
— creatinin metabolism in, 177.
— endogenous and exogenous origin of
different waste products, 486.
— hippuric acid of, 498.
— inorganic constituents of, 500.
calcium, 503.
-chlorids, 500.
iron, 503.
magnesium, 503.
phosphates, 501.
potassium of, 502.
— sodium, 502.
— sulphates, 502.
— iron of, 503.
— magnesium of, 503.
— mechanism of kidney secretion, 482.
— nitrogen of, 485.
— amino-acids, 490.
ammonia, 489.
components of, 486.
creatin, 493.
creatinin, 490.
distribution of, 486.
954
INDEX
Urine, nitrogen of, urea, 486, 487, 488.
uric acid, 495.
— organic constituents of, amino-
acids, 490.
aromatic oxyaeids and deriva-
tives, 499.
ammonia, 489.
creatin, 493.
— creatinin, 490.
— hippuric acid, 498.
— nitrogen, 485.
— oxalic acid, 499.
— purin bases, 498.
— sugar, 499.
urea, 486, 487, 488.
— uric acid, 495.
— oxalic acid of, 499.
— phosphates of, 501.
— physical .properties of, color, 483.
- odor, 483.
— reaction and acidity, 483.
— specific gravity, 483.
— titratable acidity, and true
acidity, 484.
— transparency of, 485. .
— volume, 482.
. — potassium of, 502.
— purin bases of, 498.
— sodium of, 502.
— sugar of, 499.
— sulphates of, 502.
- urea of, 486, 487, 488.
— uric acid of, 495.
fate of, in man and in animals,
497.
— formation of, 495.
— increased elimination of, 498.
— precursors of, 497.
— urobilin in, 165.
— clinical significance of increased
amount of, 167, 168.
— determination of, 167.
— diagnostic value of, 169.
Urobilin, in the bile, 165.
— clinical significance of increased
amount of, 168.
— determination of, 168.
— diagnostic value of, 169.
— chemistry of, 163.
— clinical significance of, in urine, in-
creased amount, 167, 168.
— derivation of, 169.
— description of, by Jaffe, 163.
— determination of, 165.
— diagnostic value of, 168.
— in duodenal contents, clinical sig-
nificance of, 168.
— determination of, 167.
— formation of, mechanism of, 165.
Urobilin, mechanism of formation of,
165.
: — obtained from urobilinogen, 164.
— occurrence of, 164.-
in bile, 165.
in blood, 165.
in serum, 165.
in stools, 165.
in urine, 165.
— in pernicious anemia, 168.
— Schmidt test with, 164.
— in stools, 165.
— clinical significance of increased
amount of, 167, 168.
determination of, 167.
diagnostic value of, 169.
— in urine, 165.
clinical significance of increased
amount of, 167, 168.
determination of, 167.
diagnostic value of, 169.
Urobilinogen, chemistry of, 163.
— description of, 164.
— empirical formula of, 163.
— structural formula of, 163.
— synthesization of, Fischer, H., 164.
— treated with para-dimethylamino-
benzaldehyd, 164.
— urobilin obtained from, 164.
— See also Urobilin.
Urobilinuria, 167.
Urorosein, mother substance of, 684.
Valin, 85.
- fate of, 109.
Valves, for measuring respiratory ex-
change, 533.
Van Helmont (1577-1744), on metabo-
lism and carbonic .acid gas, 8.
Van't Hoff s law of heat production as
affected by external temperature, in
cold-blooded animals, 601.
Vegetables, feeding of, to young babies,
319.
Vegetarianism, 399.
— basal metabolism in, 400.
— disadvantages of, 400.
Da Vinci, Leonardo, on nourishment,
6.
Vitamins, antineuritic (water-soluble
B), 342.
distribution of, in food, 346.
— antiscorbutic (C Factor), 345.
sources of, 346.
— chemical nature and physical prop-
erties of, 342.
antineuritic vitamin (water-solu-
ble B), 342.
antiscorbutic (C factor), 345.
INDEX
955
Vitamins, chemical nature and physical
properties of, fat-soluble vitamin
(fat-soluble A), 345.
— discovery of, 341.
— distribution of, in food, 346.
-fat-soluble (fat-soluble A), 345.
— distribution of, in food, 346.
— metabolism of, 341.
digestion and absorption, 347.
end, 350.
intermediary, and physiological
action, 347.
— special features of, 351.
- table of, 352, 355.
Voit, Carl, on metabolism, 5, 65.
von Haller, Albrecht (1708-1777), on
respiration, in history of metabolism,
11.
von Liebig, Justus (1803-1873), 44.
— caloric value of meat, 49.
— classes of foodstuffs according to, 50.
— isodynamic equivalents, 49.
— table of, 50.
— Munich period of, 53.
— on alcohol, comments, 49.
— on energy production, 47.
— on formation of fat, 49.
— on formation of feces and absorption
of bile, 49.
— on metabolism, difficulties of cal-
culating, 48.
— on metabolism in fasting, 46.
— on metabolism of a horse, 48.
— ; on muscle power, criticism of
Frankland's comparison of with
steam engine, 54.
source of, 53.
— on respiration, 46.
— on sugar, cleavage of, 47.
— on oxidation of various foods, 49.
— oxygen requirement for combustion
of foods, 50.
— plagiarism of ideas of, 51, 52.
— ultimate disposal of products of me-
tabolism according to, 51.
— Voit's description of services of, 46.
War edema, 415.
Water, content of, in blood, 311.
in body, 311.
— deficiency of, effect of, on metabo-
lism, 717.
— as a dietary constituent, 275.
drinking with meals, 280.
influence of diminished water in-
take on metabolism, 279.
influence of increased water in-
gestion on metabolism, 277.
on basal metabolism, 279.
Water, discovery of composition of, by
Cavendish, 15.
— distilled, 292.
— drinking of, with meals, 280, 283,
287, 288, 294.
— effect of, on metabolism, 717.
deficiency of, 717.
mineral waters, 718.
— experiments of Lavoisier on nature
of, 19.
— external use of, for therapeutic
measures. See Hydrotherapy.
— ice, 293.
— importance of, to human body, 276.
— influence of, on absorption, 291.
on blood pressure and blood vol-
ume, 291.
on gastric digestion, 281.
on intestinal flora and putrefac-
tion, 291.
on pancreatic digestion, 289.
on salivary digestion, 281.
— influence of diminished water in-
take on metabolism, 279.
— influence of increased ingestion of,
on metabolism, 277.
on basal metabolism, 279.
— passage of, from stomach, 286.
— percentage of, in organs, tissues and
secretions of body, 275.
— regulation of intake of, in certain
conditions, 294.
— requirement of body for, 312.
— and salts, subcutaneous feeding of,
816.
— stimulatory power of, 281.
Water metabolism, effect on, of acids
and alkalies, 736.
of anesthetics, general, chloro-
form and ether, 763.
— of antipyretics, 770.
of arsenic, 755.
of atropin, pilocarpin, etc., 774.
of calcium, 730.
of epinephrin, 781.
of mercury, 756.
of opiates, 767.
of pituitary substances, 784.
of purins, 778.
of sodium chlorid, 720.
of uranium, 757.
— of rectal feeding, 812.
Water retention, edema due to, 311.
- relation of salt to, 311, 312.
Waters, mineral, 845.
alkaline waters, including carbo-
nated, 848.
arsenic, 851.
bitter waters, 850.
D56
IXDEX
Waters, mineral, carbonated, 848.
classification of, 845.
diuretic property of, 847.
iron, 851.
radioactive, 852.
saline waters, 846.
— sulphur, 851.
Waxes, as simple lipoids, 185.
beeswax, 185.
cetin, 185.
— wool wax (lanolin), 185.
Weight, relation of, to surface area,
598.
Willis (1621-1675), on respiration, in
history of metabolism, 11.
Winds, effects of, 902.
Winterstein's apparatus for measuring
respiratory exchange, 530.
Wool wax, 385.
Work, influence of, on food consump-
tion, 391.
Xanthin, in muscle tissue, 461.
Xanthin oxidase, distribution of, 156.
Xantho proteic reaction, 98.
Xylose, 241.
Yeast cells, activity of, von Liebig's
discussion of, 54.
Yeast nucleic acid, fundamental
groups of, 136.
Zanthin, 137, 138.
Zinc, effect of, on metabolism, 758.
Zuntz, Nathan (1847-1920), work of,
on metabolism, 76.
Zuntz and Gepperfs method of measur-
ing respiratory exchange, 538.
*
OS
1
University of Toronto
Library
DO NOT
REMOVE!
THE
CARD
FROM
THIS
POCKET
Acme Library Card Pocket
Under Pat. "Ref. Index File"
Made by LIBRARY BUREAU
Live Music Archive
Librivox Free Audio
Metropolitan Museum
Cleveland Museum of Art
Internet Arcade
Console Living Room
Books to Borrow
Open Library
TV News
Understanding 9/11