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THE ADRENAL SYSTEM,

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TOBQEIO.

THE INTERNAL SECRETIONS

AND THE

PRINCIPLES OF MEDICINE

CHARLES E. DE M. SAJOUS, M.D.

FELLOW or THE COLLEGE or PHYSICIANS or PHILADELPHIA ;
MEMBER or THE AMERICAN PHILOSOPHICAL SOCIETY, THE ACADEMY or NATURAL SCIENCES

OF PHILADELPHIA, ETC.;

KNIGHT or THE LEGION or HONOR AND OFFICER OF THE ACADEMY or FRANCE;
KNIQHT or THE ORDER OF LEOPOLD OF BELGIUM, ETC.

FORMERLY LECTURER ON LARYNGOLOGY IN JEFFERSON MEDICAL COLLEGE AND PROFESSOR
or LARYNGOLOGY AND DEAN OF THE FACULTY IN THE MEDICO-CHIRUHGIOAL
COLLEGE ; FORMERLY PROFESSOR or ANATOMY AND PHYSI-
OLOGY IN THE WAGNER INSTITUTE or SCIENCE.

VOLUME FIRST

WITH FORTY-TWO ILLUSTRATIONS

PHILADELPHIA

F. A. DAVIS COMPANY, PUBLISHERS
1904

COPYRIGHT, 190S.

BT

F. A. DAVIS COMPANY.
[Registered at Stationers' Hall. London, Eng.J

Philadelphia, Pa., U. 8. A.:

The Medical Bulletin Printing-honte,

1914-16 Cherry Street

DEDICATED TO THE MEMORY OF
BROWN-SEQUARD

PREFACE AND SUMMARY OP CONTENTS.

THE late Professor Virchow once remarked with his char-
acteristic frankness: "We must not deceive ourselves or one
another in respect to the present condition of medical science.
Unmistakably, medical men are tired of the many new hypo-
thetical systems that are thrown aside as rubbish only to be re-
placed by similar ones. We shall soon see that observation and
experiments alone have permanent value/7 Two years ago, Prof.
William Osier expressed kindred views in a general summary
of the progress of medicine during the nineteenth century, and
radical expressions of a similar kind are not infrequently met
with in current medical literature.

When, early in the year 1888, we wrote the first "Preface"
of the "Annual of the Universal Medical Sciences," the purpose
of the work was denned in the following words: "It is expected
to become a helpmate to the practitioner in his efforts to relieve
suffering, and to assist the investigator by correlating facts,
thus enabling him to better compare." The successor of the
"Annual," the "Analytical Cyclopaedia of Practical Medicine,"
was framed with the same underlying thought as guide. It is
not within our power to state whether these purposes have at
all been attained, or whether, apart from their immediate use-
fulness to the practicing physician, these works have ever
opened new channels of thought; we can say, however, that
we have always deemed it our duty to closely follow the de-
velopment of the various branches of medical science as the
yearly panorama passed before our eyes, in the hope that we
might eventually collate the necessary elements for a more
solid foundation than Medicine now possesses. The present
volume is submitted to the profession as the result of our efforts
in this direction.

The pre-eminent impression which has been our beacon
in the preparation of this work differs somewhat from the in-
terpretation of the status of medical science published by the
distinguished authors mentioned, in that we have been led to

w

VI PREFACE AND SUMMARY OF CONTEXTS.

regard the majority of hypothetical conceptions now interspersed
throughout the many subdivisions of medical science as tem-
porary, though artificial, factors. Our knowledge of a given
disease, for example, might, as viewed from our standpoint, be
compared to a chain in which the majority of links are of gold
and the rest of lead, pending the acquisition of sufficient gold
to replace the lead. Thus construed, Medicine seems to us to
acquire its proper position among allied sciences, while the
many investigators who have devoted their life to its welfare
and progress also find their labors fitly represented in its annals.
Indeed, the list of these patient workers should be greatly
increased if the views submitted in this volume are sound, for
the data contained therein — the very ones that have presented
the strongest claims to recognition — were found in literature
of the kind that often lies dormant many years before its true
worth is brought to light. That thousands of such contribu-
tions exist we were able to ascertain: an auspicious feature of
our earlier work, which showed that we were not dependent
upon the "observations and experiments" the future alone
would contribute to begin the elimination of "theoretical sys-
tems" and replace them, if possible, with others of a more
durable kind.

Our earlier investigations included a careful review of
prevailing doctrines concerning the nature of vital processes,
particularly in respect to the physiological chemistry of cellular
metabolism. Notwithstanding our intense desire to acquire
elucidative data from the existing literature of the subject, we
found it impossible to advance one step beyond the position
taken by Professor Foster in 1895 when he wrote: "We cannot
trace the oxygen through its sojourn in the tissues. We only
know that sooner or later it comes back combined in carbonic
acid (and other matters not now under consideration)." To
us, this meant a closed door precisely where we hoped to find
the information required to fill numerous gaps in our knowl-
edge of the majority of diseases. Tissue-respiration being ob-
viously the dominant factor of all the problems we hoped to
solve, we thought it advisable to leave the beaten paths and
seek clues among subjects which had never been associated
with this physiological function.

PREFACE AND SUMMARY OF CONTENTS. VU

Among the subjects which had received attention during
our preliminary inquiry was the physiology of the ductless
glands. Although the thyroid body had been studied by a
larger number of investigators than the adrenals, the latter
seemed to us to present a feature directly connected with the
problem: i.e., the marked affinity of adrenal extractives for
oxygen. We therefore determined to follow the clue this af-
forded as far as recorded facts would permit, and to trace its
connections beyond the field of physiology if possible.

Still, we had little else at our disposal than experiments
performed in animals to elucidate the intrinsic functions of
these organs. Could such experiments be considered as safe
guides in our inquiry? We deemed it advisable to ascertain,
first of all, whether the physiological functions of the adrenals
were sufficiently similar in all vertebrates to warrant the use
of experimental data obtained with lower animals in the study
of these organs in man. Such proved undoubtedly to be the
case, and we cannot but feel that the results of our investiga-
tions— those we will now submit — are based upon solid prem-
ises. Indeed, the importance of this fact asserted itself when
we were brought to realize that the adrenals could be considered
as the key not only to tissue-respiration, but also to the func-
tions of all other organs now classed as "ductless glands." And
even these developments assumed secondary positions when it
became evident that the better-known organs, such as the heart,
lungs, liver, etc., were, so to say, subsidiary structures, the
instruments, in a measure, of the smaller "ductless glands," and
destined to fulfill the mandates of the latter.

The secretion of the adrenals was traced as far as the
pulmonary alveoli, but not beyond. Here it was found to hold
in combination the various constituents of haemoglobin, and to
endow both the latter and the plasma with their affinity for
oxygen. Prevailing views as to the chemistry of respiration
were thus radically transformed, and our knowledge of the
manner in which the blood-pigments were held together, like-
wise. We likewise ascertained that methasmoglobin (haematin)
and haematoporphyrm (haematoidin) were the component bodies
of haemoglobin thus held in association, and that hsemoglobi-
nuria, methaemoglobinuria, and haematoporphyrinuria indicated

Vlll PREFACE AND SUMMARY OP CONTENTS.

successive stages of haemoglobin dissociation incident upon ad-
renal insufficiency. Again, this portion of the inquiry revealed
that, while haemoglobin absorbed its share of adrenal secretion
and oxygen, the plasma did likewise. It thus became evident
that the red corpuscles were not the only carriers of oxygen,
and that the blood-plasma played an important part in the
distribution of this gas. Indeed, we subsequently ascertained
that the red corpuscles were secondary factors in this important
function, i.e., mere carriers, pack-mules, as it were, and that
it was the oxygen-laden adrenal secretion dissolved in the
plasma itself which carried on all the oxidation processes of the
organism.

Of course, it became necessary to control this assertion.
Physiological chemistry was found to afford ample confirma-
tory evidence, the investigations of Schmiedeberg, Jaquet,
Abelous and Biarnes, Salkowski, and others having shown the
presence in the plasma of an "oxidation ferment." Claude
Bernard had also, many years before, discovered a "ferment"
in the blood: the identical substance which Lepine subse-
quently termed the "glycolytic ferment." These bodies we also
found to correspond with our oxygen-laden adrenal secretion
— for which, by the way, we would venture to suggest the name
adrenoxin, though in the body of the present work it is termed
everywhere "oxidizing substance."

The many physiological problems awaiting solution then
appeared to us in quite a new light. The ease with which the
oxygen carried by the plasma could penetrate the minute vas-
cular net-works of all cellular elements not only furnished a
clue to the physiological chemistry of the latter, but it also led
to the discovery that various structures the functions of which
were unknown were in reality blood-channels, or rather plasma-
channels. Thus, the axis-cylinders of all nerves and the den-
drites of neurons were found to contain a fluid identical to
blood-plasma in its reactions to staining fluids. Even the
neuroglia-fibrils asserted their identity as plasma-capillaries, the
neuroglia felt-work of the substance of the brain and cord
representing the intrinsic circulation of these organs. The
muscular contractile structures, the various glandular organs,
including the liver, pancreas, and spleen, the gastric and in-

PREFACE AND SUMMARY OP CONTENTS. IX

testinal glandular elements, etc., were all found to be so dis-
posed as to allow the free circulation of this oxidizing plasma,
the red corpuscles passing on in the larger channels. An
exception to this rule was found, however, in the heart-muscle:
Oliver and Schafer, as is well known, ascribed to the adrenal
secretion the power to contract muscular tissue, and particu-
larly cardiac muscle. We found that contraction of the heart-
walls was, in great part, due to this secretion, and that the
latter penetrated the heart-substance by way of the Thebesian
foramina. The coronary arteries did not lose their functional
importance, however; they also were found to supply the car-
diac muscle-fibers with oxidizing substance.

Still, the mere presence of oxygen in organic combination
in cellular elements did not account, of course, for the physical
phenomena witnessed, and it became necessary to ascertain the
identity of the agencies with which the oxygen of the plasma
combined. In the muscular elements myosinogen proved to be
the primary source of residual energy. When combined with
the oxidizing substance of the plasma, this organic body lib-
erated, we ascertained, the mechanical energy required for a
given contraction, the nerves serving only to incite and govern
muscular function. The blood was also found to be supplied
with a body similar to myosinogen, i.e., fibrinogen, which like-
wise combined, but in fixed quantities, with a corresponding
proportion of the plasma's oxygen. The fluctuations of the
blood's temperature were traced to corresponding variations in
the quantities of fibrinogen supplied to the plasma. In the
nervous system the immanent source of functional energy was
found to be the myelin, or white substance of Schwann, its
active constituent being lecithin, composed mainly of hydro-
carbons and containing considerable phosphorus. This myelin
was not only found to surround the axis-cylinders of all nerves,
but also to line the inner surface of the dendrites of neurons
and to form the ground-substance of their cell-body. It thus
became apparent that the entire nervous system was built upon
the same plan: i.e., cylinders containing oxygen-laden plasma
surrounded by a layer of myelin, and that the reaction between
these two bodies served to form and liberate nervous energy.

The overwhelming importance of the internal secretion

X PREFACE AND SUMMARY OF CONTENTS.

of the adrenals having been determined., the functions of the
other ductless glands were studied. Our investigation then
showed that the adrenals were directly connected with the
anterior pituitary body through the solar plexus, the splanchnic
nerves, and the cervico-thoracic ganglia of the sympathetic.
Indeed, this diminutive organ, hardly as large as a pea, and
now thought to be practically functionless, proved to be the
most important organ of the body, as governing center of the
adrenals, and, therefore, of all oxidation processes.

In general diseases what has been termed the patient's
"vitality," or "vital resistance," thus became ascribable to fluct-
uations in the anterior pituitary body's functional efficiency.
In other words, overactivity of this organ, by correspondingly
enhancing the production of adrenal secretion, was found to
increase metabolism and the activity of all functions in pro-
portion; while depression of its normal activity, by inhibiting
the production of adrenal secretion and thus reducing the quan-
tity of oxygen distributed throughout the entire organism, pro-
portionally lowered the activity of all vital processes. But the
manner in which the functional efficiency of this organ was
maintained had also to be elucidated. This led us to the thyroid
gland, whose physiological purpose, we found, was to sustain
the functional efficiency of the anterior pituitary body up to
a certain standard by means of its secretion: iodine in organic
combination. Excessive production of this secretion, by causing
overstimulation of the anterior pituitary body, gave rise, when
prolonged, to "exophthalmic goiter"; while reduced produc-
tion of thyroid secretion, by inhibiting the functions of the
anterior pituitary body, caused myxcedema. The thyroid gland,
the anterior pituitary, and the adrenals were thus found to be
functionally united: i.e., to form an autonomous system, which
we termed the "adrenal system."

Further investigation in this direction showed that the
action of thyro-iodine upon the anterior pituitary body rep-
resented that of any poison introduced into the blood-stream.
In other words, it became evident that, instead of acting
directly upon the blood or cellular elements, poisons either
stimulated or depressed the functional activity of the adrenal
system, thus increasing or reducing the production of adrenal

PREFACE AND SUMMARY OF CONTENTS. XI

secretion, and, therefore, of oxidizing substance in the plasma.
Eadical changes in prevailing doctrines as to the manner in
which general infections, or other forms of poisoning, produced
their effects on the organism thus seemed to impose them-
selves. In fact, the mass of confirmatory evidence found on all
sides (including the effects of removal of the adrenals, the
thyroid, or the anterior pituitary body, and of the use of ad-
renal and thyroid extracts) proved to be incontrovertible. We
were thus led to conclude that what are now considered as
symptoms of infection or poisoning are all manifestations, more
or less severe, of overactivity or insufficiency of the adrenal system.
Indeed, the physiological action of remedies was also traced to the
anterior pituitary body, the governing center of this system.

The bearing of this discovery upon the prevailing inter-
pretation of the pathogenesis and treatment of disease is well
shown by the manner in which it at once elucidated our knowl-
edge of even the greater scourges of humanity. The symp-
tomatology of Asiatic cholera, for example, was found to be a
counterpart of the symptom-complex of advanced adrenal in-
sufficiency, and due to the effects of cholera-toxins upon the
anterior pituitary body. The only treatment of any value
whatever, as is well known, is early and active stimulation: i.e.,
the use of agents which, as does the thyroid's active principle,
reawaken the functional activity of this organ. Cholera in-
fantum, arsenic poisoning, various toxalbumins, and other in-
toxications produce identical symptoms; all these proved like-
wise to be syndromes due primarily to adrenal insufficiency.
Pulmonary tuberculosis also asserted its identity as a disease
due to lowered functional activity of the adrenal system:
either inherited or acquired. While "lowered vitality" had
become the result of such a state; here it meant, besides,
impaired cardiac activity and a corresponding malnutrition of
the pulmonary tissues, the underlying factor of vulnerability to
the effects of the tubercle bacillus. Our main resource, a
high altitude, enhances, we well know, the heart's activity
and simultaneously the nutrition of the lungs themselves, as
well as that of all other organs, including those of the adrenal
system. A multitude of agents have been found helpful in this
dread disease, including Koch's tuberculin. All proved to be

Xli PREFACE AND SUMMARY OP CONTENTS.

adrenal stimulants. Syphilis likewise revealed itself as due to
adrenal insufficiency. Here, however, it was of gradual devel-
opment, the terminal stages being attended with actual death
of circumscribed areas of the peripheral tissues: those, indeed,
most liable to succumb to denutrition. In "secondary" syphilis
a powerful stimulant of the adrenal system, mercury, is effi-
cacious; later on, in the "tertiary" form, a still more powerful
agent is required, i.e., Nature's own stimulant: iodine.

We were also led to conclude, in this connection, that the
majority of drugs, toxins, physiological toxalbumins, etc., stim-
ulated the adrenal system, when the proportion of these agents
in the blood did not exceed a certain limit, and that when this
limit was exceeded, i.e., when the dose administered, or the
amount of toxins secreted by bacteria, etc., was excessive, it
either inhibited or arrested the functions of this system. A
large dose of quinine may, for instance, cause adrenal over-
activity, a flushed face, a bounding pulse, etc.; but, if the dose
is excessive, it will overwhelm the adrenal system, the signs
of which are always similar, i.e., pallor, a weak and rapid pulse,
etc. Pneumonia illustrates a similar course of events, but due
to toxins; the erethic stage exemplifies excessive functional
activity of the adrenal system: a protective process, "fever,"
having for its purpose the conversion of pathogenic elements
into benign waste-products by cleavage and oxidation. When
the proportion of toxins increases notwithstanding this pro-
tective function, the adrenal system lapses into insufficiency,
that stage during which active stimulation — of the adrenal
center, the anterior pituitary body — is our sheet-anchor.

This brought to light a number of diseases: tetanus, epi-
lepsy, hydrophobia, septicaemia, eclampsia, and kindred disor-
ders, in which symptomatic treatment could prove harmful. In
tetanus, for example, the convulsions normally suggest the use
of cannabis Indica, the bromides, etc., as sedatives or depresso-
motors. In the light of our views, precisely the opposite course
is indicated, i.e., active stimulation of the adrenal system, be-
cause the convulsions are not due to the tetanus toxins, but to
accumulated waste-products. Indeed, the effect of this toxin
is to gradually reduce the efficiency of the adrenal system and
of all oxidation processes accordingly. The present mortality

PREFACE AND SUMMARY OF CONTENTS. xlH

of tetanus sustains us, especially when compared with the re-
sults of Baccelli's carbolic-acid treatment. As interpreted from
our standpoint, this agent powerfully stimulates the adrenal
system, and simultaneously causes prompt oxidation of the
waste-products. Baecelli, we know, saves almost all of his
cases. The same may be said of hydrophobia; here again the
method of treatment employed in the various Pasteur Insti-
tutes insures precisely what Baccelli does with the aid of car-
bolic acid: in suitable doses, the extract of desiccated cord in-
jected raises the anterior pituitary body's functions to their
normal standard and sustains them until all danger is past.

The element of specificity would seem to be lost with the
anterior pituitary body as the source of all symptomatic phe-
nomena. But such was not found to be the case by any means.
The adrenal system showed itself as the source of a large num-
ber of symptoms, but not of all. Each pathogenic agent, a
toxin, a vegetable poison, a venom, for example, influences the
adrenal center in its own way. Some drugs — quinine, for in-
stance— are able to raise the adrenal system's functional ac-
tivity to a very high state before they cause it to lapse into
insufficiency; others, such as hydrocyanic acid, almost at once
overwhelm it. Between these two extremes are many degrees
of functional activity, each of which gives rise to symptoms
essentially ascribable not only to the adrenal system itself, but
also to other organs which are gradually awakened to inordi-
nate activity as the oxidation processes become more active.
Among these other organs, the posterior pituitary body (or in-
fundibular lobe of the hypophysis), the spleen, and the pan-
creas, require special mention in this connection, since we found
them to be endowed with functions which had not so far been
discerned.

The posterior pituitary body, far from being the insig-
nificant vestigial organ it is generally thought to be, was found
by us, thanks mainly to the investigations of Berkley, An-
driezen, Howell, and de Cyon, to stand second in importance
only to its mate, the anterior pituitary body. Indeed, it proved
to be the chief functional center of the nervous system, its numer-
ous groups of neurons forming the starting-point, or highly
specialized center, of a single class of nerves. The various

XIV PREFACE AND SUMMARY OF CONTENTS.

medullary centers thus became mere connecting nuclei, which,
stimulated or injured, however, could become the source of all
the morbid phenomena recorded by physiologists. The poste-
rior pituitary body also proved to be the center upon which all
emotions, shock, — psychical or traumatic, — and kindred sources
of excitement or depression react, impairment of its functions
accounting for the pathological phenomena now ascribed to
such causes. Again, as the general center of the nervous sys-
tem, it was found to be the anterior pituitary body's co-center
in sustaining the cellular metabolism of all organs. While the
anterior pituitary body insured oxygenation of the blood
through the adrenal secretion, the posterior pituitary body
adjusted and governed the functional activity of all organs
through the nervous system. This accounts for the fact that
both cerebral hemispheres can be removed from various ani-
mals without materially impairing the functions of their motor,
vascular, respiratory, and nutritive systems. But it also sug-
gests that an organ so sensitive to external impressions should
likewise be easily influenced, directly or indirectly, whenever
pathogenic agencies, poisons, drugs, etc., are present in the
blood. Indeed, we ascertained that the posterior pituitary was
an important feature of the morbid process in influenza, hay
fever, hysteria, catalepsy, and other obscure affections.

The pancreas and spleen may be considered jointly, since,
as long ago asserted by Schiff, the secretions of these two organs
unite in the formation of a powerful proteolytic ferment, a
process subsequently defined by Herzen as the one leading to
the conversion of trypsinogen into trypsin: the albumin-solving
constituent of the pancreatic juice. While confirming this
view, our own analysis led to the conclusion that, in addition
to the trypsin supplied to the intestinal canal, a portion of this
ferment passed into the splenic vein as an internal secretion and
thence into the portal vein. We also ascertained that this fer-
ment played a leading part in all immunizing processes, its main
function in the blood-stream being to destroy toxic albuminoids.
These, as is well known, include all toxins and diastases secreted
by bacteria, proteids, toxalbumins, vegetable poisons, and
venoms.

Immunity, or rather the various subjects usually grouped

PREFACE AND SUMMARY OF CONTENTS. XV

under this heading, seems to us to have also acquired a number
of elucidative factors. The investigations of Metchnikoff, Ehr-
lich, Bordet, Pfeiffer, and others were not only sustained in
many particulars, but the solidity of many of their deductions
was shown by the fact that the addition of considerable new
evidence only served to harmonize their views. Phagocytosis
proved to be the preponderating factor of immunizing processes;
but the spleno-pancreatic internal secretion, trypsin, to which
we have just referred as the organic body which reduced toxic
albuminoids to inert cleavage products, was found to be the
agency which digested bacteria in the digestive vacuoles of
phagocytic leucocytes. Indeed, Metchnikoff had found this
body to be a trypsin.

The multiplicity of antitoxins, cytolysins, and haptophore
groups which Ehrlich connected with his side-chain theory no
longer seemed necessary in the light of our views, the diversity
of effects due to toxins, as in the case of poisons, drugs, etc.,
being ascribable to sundry factors, and especially to variations
in their toxicity. Rid of these confusing elements, Ehrlich's
labors appeared to us in a new light. His amboceptor (Bordet's
sensitizing substance) proved to be our oxidizing substance, and
his complement (Buchner's alexins, Metchnikoff's cytases) be-
came our spleno-pancreatic internal secretion: trypsin. But
we were led, in addition, to ascribe to an organic body which
we have already mentioned, fibrinogen, a preponderating part
in the process through which all albuminoid poisons (including
toxins) and bacteria are converted into benign products in the
blood. Indeed, we found that this process required the simul-
taneous co-operation of the three agencies named, trypsin only
becoming sufficiently active as a proteolytic agent in the pres-
ence of given proportions of oxidizing substance and fibrinogen.
Insufficiency of either of these three bodies was found to
compromise the issue of the disease in which it occurred. In
typhoid fever, for instance, fibrinogen was shown by our in-
vestigation to be the missing agency; in diphtheria it was
trypsin which was found absent from the blood-stream. In-
deed, the dominant active principle of antitoxin proved to be
trypsin.

The white corpuscles of the blood were found to be en-

XVI PREFACE AND SUMMARY OP CONTENTS.

dowed with functions greatly exceeding in importance any as
yet ascribed to them even hypothetically. Our researches
showed that these cells supplied the organism with the agencies
that combine with the oxidizing substance to insure the con-
tinuation of life and the efficiency of all organic functions.
The neutrophiles, Metchnikoff's wandering phagocytes, were
traced from the solitary and agminated follicles to the cavity of
the intestine, where they ingested proteids; then through the
villi, mesenteric veins, and portal veins, where they absorbed
the spleno-pancreatic secretion, i.e., the trypsin which Metch-
nikoff found them to contain. These cells formed, we ascer-
tained, peptones, myosinogen, and fibrinogen — all globulins — from
the proteids ingested by them and distributed these products
to all tissues, the muscles, and the blood itself. Ehrlich's
eosinophiles, non-phagocytic leucocytes, asserted their identity
as daughter-cells, the separation from their parent-cells, the
neutrophiles, occurring in the liver by mitosis. They were
traced to the pulmonary alveoli, where they participated in the
formation of the nucleated epithelium. Their product proved
to be haemoglobin. The basophiles were found to take up fats
derived from foodstuffs which penetrated the lacteals and lym-
phatic ducts, to convert them into myelin granules, and to dis-
tribute them throughout the entire nervous system.

As these three varieties of leucocytes (all other varieties
being probably immature cells) were traced to the right auricle,
either through the inferior or superior vena cava, the presence
of all three in the lungs appeared necessary as controlling evi-
dence. Indeed, Virchow, Wagner, Cohnheim, Lenhartz, and
others had referred to their presence in sputum without know-
ing their original source. The "myelin droplets" of Virchow, or
"crushed nerve-substance" of Lenhartz, are familiar features of
this subdivision of pathology.

Briefly, our inquiry seems to us to have shown that the
adrenal system is the source of the secretion which, with the
oxygen of the air, forms the oxidizing substance of the blood-
plasma. It has also revealed, we believe, the origin and mode
of distribution of the bodies with which this oxygen directly
or indirectly combines: i.e., peptones, myosinogen, fibrinogen,
haemoglobin, and myelin, to insure the continuation of life and

PREFACE AND SUMMARY OF CONTENTS. XV11

the efficiency of all organic functions. Finally, it has suggested
that in addition to these agencies, all leucocytes and, under
certain circumstances, the plasma, contain a protective agency,
trypsin, which, with Metchnikoff's phagocytic cells, serves to
destroy micro-organisms and convert their toxins and other
albuminoid poisons into harmless products. Considered jointly,
these various factors seem to us to represent the aggregate of
vital phenomena.

We have termed "Immunizing Medication" the use of
remedies to arrest diseases during their incipiency by stimu-
lating the functional activity of the adrenal system. Indeed,
in the light of our views, it becomes evident that during epi-
demics, after injuries received in places thought to contain tet-
anus saprophytes, after bites of presumably rabid animals or
venomous animals, or after infections of any sort, we can cause
in our blood-stream a sufficient accumulation of phagocytes,
trypsin, fibrinogen, and oxidizing substance to offset the lethal
tendency of these pathogenic elements. But it is not only in
acute affections that protection can thus be acquired. Inherited
vulnerability to tuberculosis, for example, is, in truth, nothing
but congenital adrenal insufficiency, a low grade of general
nutrition, which it is within our power to correct by the appro-
priate use of the many remedial agents which science has placed
in our hands.

The main cause of death during acute diseases was also
studied. Not only were the classical teachings regarding the
importance of the blood's alkaline reaction emphasized; but
the very fact that the various leucocytes were found to dis-
tribute their peptones, myosinogen, fibrinogen, etc., by migrat-
ing in every direction, raised the need of an adequate propor-
tion of alkaline salts in the blood-stream to the position of a
sine qua non as regards the continuation of life, especially in
febrile disorders. Indeed, the rapid utilization of alkaline salts,
especially sodium chloride, in the organism, and the fact that
they are inadequately, if at all, replaced through their normal
channel, the digestive tract, during disease, proved to be the
predominating cause of death.

The foregoing summary can only be said to include some
of the more important processes, physiological and pathological,

XV111 PREFACE AND SUMMARY OF CONTENTS.

studied in this volume. A comprehensive study of the nerv-
ous system and of the functional processes in the various organs,
as modified by the presence of previously unrecognized struct-
ures, the formation of glycogen, urea, etc., the protective proc-
esses in the intestinal canal and respiratory surfaces, could not
be satisfactorily summarized. The same may be said of Addi-
son's disease, acromegalia and chlorosis, the pathogenesis of
fever, the identity of the Widal reaction, the so-called gouty
diathesis, glycosuria, cancer, the causes of the predilection of
children to certain infectious diseases, the action of a large
number of remedies upon the adrenal system, etc.

Can we pretend that, owing to the care with which our
investigations have been conducted, our deductions are invul-
nerable? We only formulate this question to answer it nega-
tively. The working methods adopted, however, do not seem
to us to have rendered any serious deviation from the straight
path possible. All theories, even those advanced by all the
greatest authorities of the nineteenth century, were totally
ignored. Our purpose being to treat each question as if it had
been a mathematical problem, positive data were alone used as
factors. Preconceived conclusions were under no circumstance
allowed to prevail, and the solutions were only formulated after
each question had first been submitted to analysis, then to a
reconstructive, or synthetic, process.

We fully realize, however, that our factors were necessarily
drawn from a mere fraction of existing literature, — though a
vast amount of the latter had to be scrutinized, — and that the
balance of recorded data and future work of the galaxy of
brilliant workers which our profession contains in all lands may
eventually completely transform our views. Again, we do not
lose sight of the fact that our short-comings may have caused
us to present distorted images simply through our limited
knowledge of several of the branches of science — physiological
chemistry, for instance — to which we have had recourse for
light. Yet, if our aim is properly interpreted, it will become
apparent that we have encompassed the whole field of medical
science in our labors, in the hope that a broad horizon would
enable us to discover its weaker parts.

We found, we may say, that the back-bone of Medicine was

PREFACE AND SUMMARY OP CONTENTS. XIX

the absent factor, and that if the patient labors of so many
great minds had not proven as useful in the development of
practical medicine as they should, it was because they lacked
such a fundamental frame-work to afford a fixed nidus for each
discovery, wherein its true relation to other discoveries would
at once become evident. What details we have introduced,
therefore, only had for their purpose to show that the newer
organic substances described — the oxygen-laden adrenal secre-
tion of the plasma, for example — were inherent parts of the
organism as a whole. What we have said of the physiological
chemistry of glycogen, myosinogen, urea, and many other
bodies, may not stand the scrutiny of an Ehrlich, a Gautier, an
Abel, a Chittenden, a Vaughan; but the fact that such men are
available to promptly correct what errors we might have made
gave us the confidence to proceed with our work without undue
anxiety. We did our utmost, with what limited knowledge we
possessed of these various auxiliary branches of medicine, to
clearly set forth our views, and will accept with gratitude any
warranted correction which our fellow-workers may deem
necessary.

That our conception of the functions of the ductless glands
is well grounded seems probable. Had it been otherwise, the
existing concordance between the various parts of the work
could not have been obtained; nor would solidly established
data have fallen normally into line without requiring hypo-
thetical functions to establish their usefulness in the elucida-
tion of the many questions which our investigation awakened.
If we are not mistaken, this affords in itself the kind of evi-
dence which betokens sound premises.

We may also venture the opinion that, if our views are
based on a firm foundation, our labors have served to illustrate
the dangers of promiscuous self-medication indulged in by the
general public. Indeed, we will have occasion to show, in the
second volume, that vulnerability to disease may not only be
thus acquired, but that the adrenal system, when debilitated
through injudicious stimulation, is unable to protect the or-
ganism when disease is initiated.

In addition to periodical literature, a large number of
books were consulted. Among these, however, two have been

XX PREFACE AND SUMMARY OF CONTENTS.

quoted very frequently in this volume, namely: Prof. Michael
Foster's "Physiology" and Prof. Horatio C. Wood's "Therapeu-
tics/' two masterpieces of their kind. Experimental therapeu-
tics, with which Professor Wood's name is so intimately asso-
ciated, afforded information which not only proved invaluable
in the course of our inquiries, but without which several of the
more important conclusions submitted could hardly have been
reached. Indeed, while foreign countries, especially France,
Germany, Great Britain, Italy, and Kussia, have contributed
the greater part of the evidence which has formed the ground-
work of our deductions, much of the best and soundest work
quoted, we are pleased to state, originated in our own country.

The subjects treated in this volume appear in the order
in which they were studied. The many new lines of thought
discussed could thus be made to start with familiar facts and
be gradually developed. The earlier data and deductions sub-
mitted, therefore, should only be considered by the reader as
inherent factors of conclusions to be reached later on.

Brown-Sequard's labors may be said to have laid the
foundation of this work. We little thought, when we met him
last, at the Institute of France, that the only expression of
gratitude available to us when this volume would be finished,
would be a dedication to his memory!

Special pharmacodynamics and physiological pathology,
both subdivisions of Applied Therapeutics (a department of
Medicine to which we expect to devote our special attention,
henceforth, both in our practice and in research work), will be
considered in the second volume, which will appear a few
months after the present one. The latter will also contain
an Analytical Index, in which the modifications in prevailing
doctrines that our labors may have suggested will be system-
atically arranged.

Our thanks are due to our publishers, the F. A. Davis
Company, and to the manager of their printing department,
Mr. Van Horn, for the care given to the mechanical prepara-
tion of this work.

C. E. DE M. SAJOUS.
PHILADELPHIA,
January 1, 1903.

TABLE OF CONTENTS OF VOLUME FIRST.

CHAPTER I.

THE PHYSIOLOGY OF THE ADRENALS AS VIEWED FROM THE STAND-
POINT OF CLINICAL PATHOLOGY 3

Similarity of the Effects of Removal of the Adrenals in all Ver-
tebrates, Including Man 3

Functions of the Adrenals that are Suppressed when these Or-
gans are Removed 9

Effects of the Adrenal Secretion on the Cardio-Vascular System. 11

The Adrenal Secretion and the Inhibitory Centers 11

The Adrenal Secretion and the Vasomotor System 14

Action of the Adrenal Secretion upon the Heart 17

Functional Relationship between Arteries and their Capil-
laries under the Influence of Adrenal Secretion 18

Variations in the Functional Activity of the Adrenals 19

Adrenal Insufficiency and its Causes 19

Poisons and Variations of the Functional Activity of the

Adrenals 23

Mechanical Phenomena that Attend Variations in the Func-
tional Activity of the Adrenals 29

The Adrenals in their Relations to Disease and Poisoning 33

Effects of Toxins on the Adrenals 33

Effects of Venoms, Vegetable and Mineral Poisons on the

Adrenals 39

Muscular Weakness 40

Vascular Pressure 44

Temperature 50

Cerebral Activity 55

Polyuria and Anuria 58

Chemico-Physiological Properties of the Adrenal Secretion 62

CHAPTER II.

THE INTERNAL SECRETION OF THE ADRENALS IN ITS RELATIONS
TO THE RESPIRATORY PROCESSES AND THE COMPOSI-
TION OF THE BLOOD 77

The Pathogenesis of Bronzing and Addison's Disease 77

The Adrenals in their Relation to Chlorosis 87

The Adrenals in their Relation to Blood-disintegration under

the Influence of Poisons 95

Insufficiency of the Adrenals as a Source of Blood-disintegration. 102

Methsemoglobin . . . : 102

Hsematoporphyrin 100

The Secretion of the Adrenals and the Respiratory Process.... 120

CHAPTER III.

THE INTERNAL SECRETION OF THE ADRENALS IN ITS RELATIONS

TO THE GENERAL OXIDATION PROCESSES 130

The Adrenal Secretion and the Oxidizing Substance of the

Blood 130

(xxi)

XX11 TABLE OP CONTENTS.

CHAPTER IV.

THE INTERNAL SECRETIONS OF THE THYROID AND THYMUS GLANDS

IN THEIR RELATIONS TO THE ADRENALS 146

The Thyroid Gland and the Adrenals 146

Exophthalmic Goiter and Impaired Functional Activity of the

Adrenals 152

Adrenal Overactivity 13 2

Adrenal Insufficiency 153

Myxoedema and Cretinism and Insufficiency of the Adrenals... 165

The Thymus Gland and the Adrenals 171

CHAPTER V.

THE ANTERIOR PITUITARY BODY, THE THYROID GLAND, AND THE

ADRENALS AS PARTS OF AN AUTONOMOUS SYSTEM . . 186

The Pathogenesis of Acromegaly 192

The Functional Relations between the Anterior and Posterior

Pituitary Bodies 207

The Anterior Pituitary Body as the Adrenal Center 215

CHAPTER VI.

THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS 233

The Oxidizing Substance and the Motor Nerves in their Rela-
tion to Muscular Contraction 233

The Oxidizing Substance and Myosinogen 234

The Motor Nerves and their Role in Muscular Contraction. . 247
The Oxidizing Substance and the Motor Nerves in their Rela-
tion to Glandular Secretion 262

Lacrymal Glands :»(><>

Salivary Glands 270

Sudoriferous Glands 276

Mammary Gland 285

General Conclusions as to the Mechanism of Functional

Activity 293

CHAPTER VII.

THE ADRENAL SYSTEM, THE GENERAL MOTOR SYSTEM, AND THE

PNEUMOGASTRIC NERVE 296

The Oxidizing Substance and the Dual Nervous Supply of the

Organs of Digestion 296

The Stomach and its Physico-Chemical Functions 296

The Gastric Nervous Supply and the Formation of Gastric

Juice 297

The Intestines and their Prophylactic Functions 310

Secreting Glands 312

Villi and Lymph-follicles 315

The Liver and its Physico-Chemical Functions 326

Hepatic Blood-pigments 334

The Hepatic Tissues in their Relations to Bacteria 341

Urea and its Formation 342

Glycogen and its Formation 347

General Functions of the Liver, Spleen, and Pancreas. . . . 359

TABLE OF CONTENTS. XX111

CHAPTER VIII. pAQE

THE INTERNAL SECRETIONS OF THE PANCREAS AND SPLEEN 362

Glycosuria and Overactivity of the Adrenal System 362

The Functional Relationship between the Pancreas and Spleen . . 367

The Functional Mechanism of the Pancreas 381

Functional Mechanism of the Spleen 386

The Spleno-Pancreatic Internal Secretion 392

CHAPTER IX.

THE ADRENAL AND VAGAL SYSTEMS IN THEIR RELATIONS TO

CARDIAC AND PULMONARY FUNCTIONS 421

The Adrenal Secretion as the Source of the Functional Activity

of the Right Heart 421

The Action of the Adrenal Secretion and the Oxidizing Sub-
stance upon the Cardiac Muscle 433

The Innervation of the Heart 444

"Augmentor," or "Accelerator," Phenomena 446

"Inhibitor" Phenomena 449

The Adrenal and Vagal Systems in their Relations to Respira-
tory Functions 454

The Innervation of the Respiratory System 455

The Identity of the Respiratory Center 455

The Innervation of the Respiratory Muscles 464

The Nervo-Vascular Mechanism of the Lungs 468

CHAPTER X.

THE POSTERIOR PITUITARY AS THE FUNCTIONAL CENTER OF THE
NERVOUS SYSTEM, AND AS THE ANTERIOR PITUI-
TARY'S CO-CENTER IN SUSTAINING THE VITAL PROC-
ESSES 483

The Identity of the Lower Brain, or Central Nervous System . . 483
The Histology and Physiology of the Posterior Pituitary Body. 493
The Histology and Physiological Chemistry of the Neuron.... 518

The Physiological Chemistry of Nerves 532

The Circulation of the Neuron 539

The Physiological Chemistry of the Neuron 552

The Minute Circulation of the Cerebro- spinal Substance.... 562
The Posterior Pituitary Body as the Chief Center of the Nervous

System 591

The Posterior Pituitary as the Central Sensorium 598

Efferent (Motor) Impulses 601

Afferent (Sensory) Impulses 603

The Pituitary Bodies as the Governing Centers of the Vital

Processes . 606

CHAPTER XL

THE INTERNAL SECRETIONS IN THEIR RELATIONS TO IMMUNITY. .. . 609

The Unity of Cellular Life 609

The Adrenals in their Relations to Phagocytosis and Leuco-

cytosis 610

Buchner's Bactericidal Alexins . . . 625

XXIV TABLE OF CONTENTS.

PAGE

The Adrenal System and the Vulnerability of Children to In-
fectious Diseases 632

The Adrenal System and the Tuberculin Test 635

The Adrenal System and Antitoxic Serum 637

Identity of the Prophylactic Agency through which Toxins are

Antagonized in the Blood 652

Trypsin as the Toxin-Destroying Agent 055

The Composition of Antitoxin 665

CHAPTER XII.

THE INTERNAL SECRETIONS AND THE PRESERVATION OF LIFE.... 667

The Leucocyte in its Relations to Life and Organic Functions. . 668

The Mitoma 668

Functional Mechanism of the Leucocyte 674

The Granules as Secretory Products 679

The Physiological Chemistry of Leucocytes 682

Classification of Leucocytes 686

Lymphocytes and Hyaline Cells 688

Neutrophile Leucocytes ; 688

Ehrlich's Eosinophile Leucocytes 703

The Basophile Leucocytes 717

Leucocytes and their Relations to Vital and Functional

Processes 727

The Functions of Leucocytes in Immunity 728

The Physiological Action of Antitoxic Serum 745

The Active Principle of Antitoxin 746

The Uniformity of all Antitoxic Sera 749

The Limits of Serum-therapy 751

Typhoid Fever and the Typhoid State 751

Diphtheria 757

Tetanus 7(50

Artificially-Produced Immunity 7(53

Vaccination against Small-pox 765

Immunizing Medication 767

Pulmonary Tuberculosis 772

Pneumonia 775

Insanity 776

Syphilis 777

Alkalinity of the Blood and the Preservation of Life during

778

ILLUSTKATIONS IN VOLUME FIRST.

PAGE

The Adrenal System (Sajous) Frontispiece

Circulation of the Adrenals in the Dog (J. M. Flint) 32

Vascular Supply of the Thyroid Gland (Pocket- Johnson) 148

Nervous Path from the Anterior Pituitary Body to the Adrenals (Sajous).. 218
Diagrammatic Representation of the Submaxillary Gland of the Dog, with

its Nerves and Blood-vessels (Foster) 273

Histological Section of the Wall of a Sebaceous Cyst (Cornil and Ranvier).. 286
The Mammary Lobule near the Resting Stage (Upper) and during Func-
tional Activity (Creignton) 287

Expanded Mammary Acinus, showing the Arrangement of Epithelial Mosaic

(Creiyhton) 288

Intestinal Villus (Cadiat) 316

Intestinal Villi; Injected Lacteals in the Middle of Each Villus (Cadiat).... 317
Section of Liver, showing the Lobules, Cells, and the Blood-supply (Piersol).. 329

Biliary Canaliculi (Mathias Duval) 330

Liver of Rabbit Injected from the Portal Vein (E. A. ScMfer) 340

Camera-Lucida Tracing of the Lobule Boundaries in One of a Series of Sec-
tions from the Splenic End of a Cat's Pancreas (Eugene L. Opic) 398

Termination of Small Blood-vessels in the Spleen (Gray) 401

Circulation of the Human Heart (Arthur V. Meigs) 436

Mechanism of Cardiac Action (Sajous) 440

Diagrammatic Representation of the Course of Cardiac Augmentor Fibers

in the Frog (Foster) 447

Median and Vertical Section of a Three Months' Embryo (Dejerine) 490

Vertical Section of the Posterior Pituitary Body (Berkley) 494

Various Types of Cells in the Posterior Pituitary Body (Berkley) 496

Various Types of Cells in the Posterior Pituitary Body. Portion of Gland-
ular Elements of the Anterior Pituitary Body (Berkley) 498

Median and Vertical Section of a Two and One-half Months' Embryo (His).. 510
Diagram of Relation between Longitudinal and Transverse Sections, show-
ing Cones Cut Across at Different Levels (W. H. Wynn) 537

Nerve-fibers from a Frog Injected with Methylene-blue (Kolliker) 541

Sensory Nerve-ending. Stained with Methylene-blue in the Exocardium of the

Left Auricle of a Gray Rat (Bmirnow) 542

Lesions in the Neurons of Animals after Ricin Poisoning (Berkley) 550

Lesions in the Neurons of Animals after Ricin Poisoning (Berkley) 552

Schematic Representation of the Lower Motor Neuron (Barker) 558

A Protoplasmic Glia-cell from a Human Brain (First Layer of Cortex)

(Andriezen) 564

Leucocytes in the Perivascular Spaces and in Vessels, as a Result of Acute

Alcoholic Poisoning (Berkley) 572

A Protoplasmic Neuroglia-cell from the Human Brain (Fourth Layer of
Cortex), showing Two Expanded Conical Disk-like Attachments to a
Vessel (Andriezen) 584

(xxv)

XXVI ILLUSTRATIONS IN VOLUME FIRST.

PAGH

Relationship of the Vascular and Lymph Channels in the Brain (Andriezen) . . 586
Blood-vessel of the Human Brain, showing Several Neuroglia Fiber-cells

Surrounding it and Forming a Felt-work (Perivascular System)

(Andriezen) 587

Seven Caudate Fiber-cells from the Human Brain-cortex (First Layer)

(Andriezen) 589

Terminal Tufts and Endings of the Protoplasmic Apical Processes in the

First Layer (Human Brain-cortex) (Andriezen) 590

Semidiagrammatic Transverse Vertical Section of the Infundibular Region

of the Brain (Berkley) 594

The Posterior Pituitary Body as General Center of the Nervous System

(Sajous) 598

Intraphagocytic Destruction of Bacteria (Metclinikoff) 628

Coincident Drop in Fever and in the Number of Leucocytes (Osier) 651

Leucocytes: their Mitoma and Microsomes (Ghilland) .. 668

CHAPTER I.

THE PHYSIOLOGY OF THE ADKENALS AS VIEWED

FROM THE STANDPOINT OF CLINICAL

PATHOLOGY.

SIMILARITY OF THE EFFECTS OF REMOVAL OF THE ADRENALS
IN ALL VERTEBRATES, INCLUDING MAN.

in 1856, demonstrated the physiolog-
ical importance of the suprarenal capsules by showing that
removal of these organs from animals was soon followed by
death. To offset the conclusions of Phillipeaux and Gratiolet,
who ascribed death to secondary involvement of the central
nervous system, he extended his researches,2 and showed, first,
that transfusion of blood taken from a normal animal into a
dying, decapsulated animal brought the latter to life, and,
second, that the blood of a dying, decapsulated animal was
poisonous to another decapsulated animal, the life of the latter
being shortened by eight hours as compared to the average
longevity of other animals similarly mutilated.

A certain degree of antagonism to Brown-Sequard's con-
clusions still prevails among a limited number of investigators,
who ascribe death in animals from which both adrenals have
been extirpated to surgical shock: a view apparently sustained
by the close relationship that exists between these organs and
the sympathetic system. That such may be the case under some
circumstances: i.e., the use of an animal debilitated by starva-
tion or rough handling, lack of dexterity in the extirpation of
the organs, is to be surmised; but when all features that tend
to compromise the issue are absent, there appears to be no
ground for the view that shock is the cause of death in decap-
sulated animals. As shown by Langlois,3 no marked symptoms
usually occur during the first twenty-four hours. The fatal

1 Brown-Sequard: Comptes-Rendus de 1'Academie des Sciences, vol. xviii,
1856.

2 Brown-Sequard: Journal de Physiologic, vol. i, 1858.
•Langlois: Archives de Physiologie norm, et path., vol., 1897.

i (3)

4 THE PHYSIOLOGY OF THE ADRENALS.

issue is not immediate; and in frogs, rabbits, guinea-pigs, and
dogs the post-operative life varies from an average of forty
hours in mild weather to twelve or thirteen days in the hiber-
nating frog in winter. In a series of fifty-nine rats from which
Boinet4 removed both adrenals, four lived several months.
Some evidence of shock should have appeared in at least a
small proportion of the operated animals. Not only was this
not the case, but the fact that in four of them the prolongation
of -life was found to have been due to accessory or compensa-
tory organs demonstrates the weakness of the shock hypothesis
as the main cause of death in decapsulated animals. Further-
more, the average symptomatology of post-operative life in
various species — inco-ordination, muscular weakness or excite-
ment, and tremors; then paralysis of the hind-quarters, with
gradual involvement of the trunk and upper extremities, con-
traction of the pupil, gradual and steady slowing of the cardio-
vascular rhythm, convulsions, hasmaturia, epistaxis, etc. — in no
way resembles that of shock.

Finally, complete removal of but one organ seems to affect
animals so slightly that they appear to suffer no inconvenience;
they continue to live month after month, "quite well and
active"; i.e., until the experimenter removes the second adrenal,
when death occurs within thirty-six hours. This fact, added
to many others elucidated by the labors of Abelous and Lan-
glois,6 Oliver and Schafer,6 Cybulski,7 Szymonowicz,8 Gourfein,9
Langlois,10 Swale Vincent,11 Boinet,12 A. G. Auld,13 among
others, suggests that there is no legitimate ground — after elim-
inating all factors that obviously tend to disguise the source of
physiological phenomena and pervert their meaning — to doubt
that, as Brown-Sequard was first to show, extirpation of both

Boinet: Marseille Medical, Sept. 1, 1899.

Abelous and Langlois: Archives de Physiologic norm, et path., vol. xiii
p. 267.

Oliver and Schafer: Journal of Physiology, vol. xviii, 1895

Cybulski : Gazeta Lekarska, March 23, 1895.

Szymonowicz: Archiv f. d. Gesam. Phys., vol. Ixiv, 1896.

Gourfein: Revue MSdicale de la Suisse Romande, March, 1896.
1 Langlois: Loc. cit., 1898.

1 Swale Vincent: Journal of Physiology, Sept. 11, 1897; Feb. 17 1898' Apr
25, 1898.

12 Boinet: Loc. cit.

13 A. G. Auld: British Medical Journal, June 3, 1899.

EFFECTS OF REMOVAL SIMILAR IN ALL VERTEBRATES. 5

suprarenals is followed by death, and that these organs fulfill
in the organism a role of great physiological importance.

Are the suprarenal glands functionally as important in
man as they are in the lower vertebrates? The clinical field
alone offers the necessary elements for the study of this ques-
tion; but it is strewn with obstacles. The various kinds of
neoplasms which develop in these organs, with the possible
exception of sarcoma, are of slow growth; the sufferer passes
through various phases that are more or less influenced by
concomitant conditions and by the pressure which the tumor
exerts upon important neighboring structures. In carcinoma
there may also be involvement of other viscera by continuity
of tissue or metastasis. We therefore obtain, in relation to the
symptom-complex of pure suprarenal origin, a transformed
picture, one that precludes all certainty as to the relations
between cause and effect. Addison's disease affords, if any-
thing, less opportunity for solid analysis; it may be associated
with suprarenal lesions and it may not; in some cases but one
organ is involved; in others, both; if it is due to suprarenal
tuberculosis, this process may be secondary or primary, thus
furnishing a series of misleading symptoms due to the extrinsic
lesions; finally, we may at a post-mortem find the organs com-
pletely destroyed and obtain an ante-mortem history in which
the Addisonian syndrome is conspicuously absent.

What is required for a fruitful analysis of this question is
a condition in which the adrenals are alone the seat of a mortal
lesion: a lesion capable of suddenly annihilating the functions
of both organs precisely as does their experimental removal
in animals. A single disorder of the adrenals, among the few
that have been so far described, fulfills these requirements in
some of its manifestations, namely: haemorrhage. The litera-
ture of this subject is, however, exceedingly meager: hardly
one hundred cases having been reported. We are therefore
fortunate in having at our disposal an able and exhaustive re-
view of eighty of these cases, including several of his own, by
Frangois Arnaud,14 of Marseilles, which afford the necessary
data. While some of the cases are very briefly reviewed, the

Frangois Arnaud: Archives Generates de Medecine, p. 64, July, 1900.

6 THE PHYSIOLOGY OF THE ADRENALS.

details furnished are at least sufficient to enable us to obtain
what appears to be strong evidence to the effect that, precisely
as it does in the lower animals, destruction of the adrenals in
man causes death within a very brief period.

Indeed, out of the eighty cases collected by this investiga-
tor, death occurred within a period ranging from a few hours
to three days in fifteen. In all of these the pathological data
given show that both glands had been the seat of the hemor-
rhagic process: of "suprarenal apoplexy," as he terms it. Ten
of these cases, however, lose some of their value as testimony
because no allusion is made to the condition of the other or-
gans. In the other five, including details that we have obtained
from the original reports, it is specifically stated that lesions
were found nowhere else in the organism. To the following tabu-
lated list of these cases we have added two recently reported
(Andrewes and Colman): —

CASE 1 (Arnaud15). — Male, 36 years. Death occurred 48
hours after entrance. Both glands were apoplectic and greatly
enlarged. One weighed 28 1/2 grammes; the other 48 grammes.
Both when cut resembled flesh, and were studded with hem-
orrhagic foci and spots of haematomatous organization indi-
cating a progressive lesion of long standing. A small amount
of medullary substance was still present in the right capsule,
but otherwise the organs were structurally destroyed.

CASE 2 (Arnaud16).— Female, 17 years. Death occurred
suddenly on the eleventh day after the receipt of a burn on
the arm; the symptoms suggested acute poisoning, but the
autopsy revealed hemorrhage into the right capsule and con-
gestion of the left.

CASE 3 (Andrewes17). — Female, 15 months. Death 36
hours after onset of symptoms. Both capsules showed inter-
stitial hemorrhage. All cultures were sterile, or, if any or-
ganisms were present, not one grew on ordinary media or
stained with ordinary reagents.

CASE 4 (Mattei18).— Male, aged 60 years. Death in 24

16 Arnaud: Archives Generates de M6decine, pp. 16 and 53, July, 1900.
18 Arnaud: Archives G§n6rales de Mgdecine, p. 50, July, 1900.

17 Andrewes: Lancet, May 7, 1898.

18 Mattei: Lo Sperimentale, 1863. Case I in Trans. Gaz. hebdom Paris
No. 35, p. 380.

EFFECTS OP REMOVAL SIMILAR IN ALL VERTEBRATES. 7

hours after onset of acute symptoms. Both capsules were en-
larged, and transformed into bags containing clots surrounded
by the cortex, which had thus been forcibly detached from the
medullary substance.

CASE 5 (Garrod and Drysdale19). — Case, aged 4 months.
Brought into hospital dead. Both glands dark-purplish red,
though not enlarged; meshes of stroma filled with red corpus-
cles.

CASE 6 (Droubaix20). — Case, 11 hours old at onset of symp-
toms. Death in 3 days. Hemorrhage into both organs, with
infiltration into the pericapsular cellular tissue.

CASE 7 (Colman21).— Case, 11 months. Death in about
25 hours. Both capsules showed diffuse interstitial haemor-
rhage, and cultures proved sterile.

Strongly suggestive, also, is the fact that, of the seventeen
cases of comparatively sudden death, fifteen showed suprarenal
apoplexy in both organs, while two only showed involvement of
but one organ. These two instances might invalidate the evi-
dence adduced, could the sudden death in them not be shown
to have been due to other causes. But such is the case: In
the one (Parrot's22 case No. 11) the hemorrhagic adrenal had
ruptured, and the patient died of hemorrhage into the peri-
toneal cavity; in the other (Droubaix's23 case No. 9) death
had resulted from uraemia, due mainly to granular and cystic
kidneys.

Additional evidence is afforded by the fact that complete
destruction of but one adrenal proves harmless to man, as it
does in animals. The results of operative procedures insti-
tuted for the removal of suprarenal neoplasms prove this to
be the case. A liponiatous capsule, for instance, was removed,
along with a wedge-shaped piece of underlying kidney, by Mayo
Eobson24 in 1897. "The wound healed by first intention and
the patient rapidly regained her lost flesh and strength. She
remains well, and had had no return of the trouble." This

19 Garrod and Drysdale: Lancet, May 7, 1898.

20 Droubaix: These de Paris, Case I, p. 26.

21 Colman: Lancet, May 7, 1898.

22 Parrot: Archives Generales de Medecine, vol. xcix, 1872.

23 Droubaix: These de Paris, 1887

«* Mayo Robson: British Medical Journal, Oct. 21, 1899.

8 THE PHYSIOLOGY OP THE ADRENALS.

report was published almost two years after the operation. A
fibromyxosarcomatous adrenal was removed, along with the
entire right kidney, by Howard A. Kelly.25 The case proceeded
to full recovery notwithstanding the malignant nature of the
growth. A tuberculous adrenal and the right kidney were also
removed by A. F. Jonas.26 The patient was discharged six
weeks later in full convalescence. Finally, Knowsley Thorn-
ton27 removed a sarcomatous gland from a woman aged 56
years. The patient was seen six years later and found in good
health.

This does not mean, however, that a diseased gland may
not cause death. In this particular the adrenals are similar
to any other organ. A rapidly growing sarcoma or a carcinoma
may start in one of the organs, develop by metastasis elsewhere,
and cause death. Tuberculosis frequently finds a nidus in
either adrenal or both simultaneously; this process, along with
the asthenia engendered by the suprarenal disease, may rapidly
end in death. Again, when we consider the frequency with
which fatty degeneration is found in these organs when micro-
scopically examined, — thirty-six times out of one hundred
autopsies taken at random, according to Arnaud,28 — it would
certainly be unwise to establish such limits.

But this also suggests that death may thus follow any
destructive process (haemorrhage included) of a single adrenal,
if the functions of its mate are sufficiently inhibited through
a local lesion or by a morbid condition involving its peripheral
vascular or nervous supply. Indeed, the anatomical relations
of these glands indicate that their functions are primarily de-
pendent upon the integrity of these trophic structures. The
multitude of nerves distributed to them include medullated
fibers from the solar plexus, the sympathetic's densest net-
work. Dogiel29 states that the internal zone of the cortex is
surrounded -by a more or less dense fibrillary plexus, and that
the medullary substance is supplied with an extraordinary sup-

28 Howard A. Kelly: Quoted by Ramsay, Johns Hopkins Hosp. Bull., Jan.,
Feb., Mar., 1899.

26 A. F. Jonas: Annals of Surgery, April, 1898.

27 Knowsley Thornton: Harveian Lectures.

28 Arnaud: Loc. cit., p. 6.

29 Dogiel: Archiv f. Anatomie u. Physiologie, p. 90, 1894.

FUNCTIONS SUPPRESSED BY ADRENALECTOMY.

ply of nerves. He likewise found the aggregate of these nerve-
fibrils to be greater than that of the glandular elements proper.
It seems evident, therefore, that any organic lesion affecting
or involving the peripheral nerve-structures of one organ —
tuberculosis, cancer, etc. — can so compromise its functions as
to make it practically useless if suddenly called upon by haem-
orrhage into its mate to assume the physiological role of both.
All these facts appear to demonstrate that in man, as well
as in the lower vertebrates, life continues as long as one of the
adrenals is normal, or, at least, as long as any morbid condition
affecting this organ intrinsically or extrinsically is not suffi-
ciently advanced to materially compromise its physiological
functions. But, as is also the case in lower vertebrates, man
soon dies if the physiological functions of both organs are ar-
rested through any intrinsic or extrinsic disorder, unless some
compensating organ or condition be vicariously active. It
seems evident, therefore, that the physiological functions of the
adrenals are sufficiently similar in all vertebrates to warrant the
use of experimental data obtained with lower animals in the study
of these organs in man.

FUNCTIONS OF THE ADRENALS THAT ARE SUPPRESSED
WHEN THESE ORGANS ARE REMOVED.

Cybulski and Szymonowicz30 found that blood drawn from
the suprarenal vein gave rise, when injected into the blood-
stream of normal animals, to manifestations similar to those
observed after the injection of suprarenal extract. As a con-
trolling experiment, these observers also injected blood taken
from veins other than the suprarenal, but with negative results.
Langlois31 corroborated these observations as regards the ef-
fects of blood obtained from the suprarenal vein. Dreyer32
reached the same results, though not in all animals: a feature
of his experiments easily accounted for by the known fact, re-
ferred to by Howell, that the amount of substance produced
by the organs may vary at different times and under different

80 Cybulski and Szymonowicz: LOG. cit.

81 Langlois: Archives de Phys. norm, et path., p. 152, 1897.

82 Dreyer: Cited by Howell, loc. cit.

10 THE PHYSIOLOGY OF THE ADRENALS.

circumstances. This obviously suggests that the morbid phe-
nomena witnessed after extirpation of the adrenals are due to
the absence of a substance produced by these organs and se-
creted into the suprarenal veins.

Not only do the adrenals produce the blood-pressure-rais-
ing substance the lack of which accounts for the symptoms that
follow bilateral removal, but the secretion of these organs alone
possesses the property of arresting these symptoms. Cybulski33
experimentally found that the increase of blood-pressure and
other cardio-vascular manifestations, etc., could not be ob-
tained from similar preparations from the brain, spinal ganglia,
lymph-glands, liver, spleen, kidney, testicle, or thyroid. Man-
kowsky34 corroborated these observations and noted that the
blood-pressure-raising power was peculiar to the suprarenal
extract, his experiments having also shown that this action
could not be obtained from the fresh thyroid gland, pancreas,
lymphatic glands, parotid, kidneys, liver, spleen, cerebrum,
heart, or skeletal muscles.

An extract obtained from human adrenals possesses similar
properties to the preparations -in general use. This important
fact was ascertained by Guinard and Martin, of Lyons,35 who
conducted a series of experiments with the adrenals of a
healthy executed criminal. Expressed juice of these glands
"produced physiological phenomena similar to those noted with
the extracts from organs obtained from other animals. The
nature of the poisons contained in them did not appear to
differ."

The following conclusions therefore appear to be war-
ranted:—

1. Removal of both adrenals arrests the supply of a secretion
which these organs pour into the suprarenal veins.

2. The secretion of the adrenals gives rise to physiological
phenomena which are not aivaltened by the active principles of
other organs.

83 Cybulski: Loc. cit.

MMankowsky: Russian Archives of Physiology and Bact., March, 18£
36 Guinard and Martin: Journal de Physiologie et de path, gener.,
Archives Generates de M6decine, Oct., 1899.

EFFECTS OF SECRETION ON THE HEART AND VESSELS.

11

EFFECTS OF THE ADRENAL SECRETION ON THE CARDIO-
VASCULAR SYSTEM.

THE ADRENAL SECRETION AND THE INHIBITORY CENTERS.
— While removal of both adrenals is followed by a great fall of
blood-pressure and very feeble and rapid cardiac action, intra-
venous injections of suprarenal extract invariably cause marked
increase of the blood-pressure and equally marked slowing of
the heart-beat. The blood-pressure increase thus appears to be
due to the direct effect of the specific suprarenal principle;
but to account for the slowing of cardiac action we are led to
implicate the inhibitory action of the vagus. If the bulbar
center of this nerve be paralyzed by atropine, however, or the
vagus itself be cut, this inhibition ceases and quickening of
the heart-beat follows, accompanied by a still greater increase
of blood-pressure. Oliver and Schafer found36 that the inhib-
itory action was exerted mainly upon the auricles, their beats
becoming gradually weaker; while the ventricular contractions,
though slower, were, in reality, stronger.

Mooted points have arisen in this connection that have
entailed considerable divergence among physiologists; and,
curiously enough, when the various views entertained are
analyzed, none of them seem to harmonize with available ex-
perimental data.

Cybulski,37 after a series of careful experiments, reached
the conclusion that suprarenal extract acted upon the vaso-
motor centers of the medulla and spinal cord, first stimulating,
then paralyzing, them. Oliver and Schafer,38 after equally
careful experiments, concluded that the extract induced reflex
stimulation of the inhibitory center by first causing powerful
constriction of the arterioles. This they thought accounted
for the slowing of the heart observed before the vagi were cut,
and physiologists have generally accepted the conclusion that
the inhibitory center is stimulated. Indeed, even the more
recent — and carefully conducted — physiological researches have
sustained this opinion; Wallace and Mogt,39 for instance, were

36 Oliver and Schafer: Journal of Physiology, xviii, 1895.

87 Cybulski: Gazeta Lekarska, March 23, 1895.

38 Oliver and Schafer: Journal of Physiology, vol. xviii, p. 230.

89 Wallace and Mogt: American Physiological Society Proc., Dec. 28, 1898.

12 THE PHYSIOLOGY OF THE ADRENALS.

led by unquestionable experiments to conclude that the su-
prarenal extract stimulated the vagus center, thus inhibiting
the heart.

A second set of divergent views refers to the nervous
structures involved when the heart is separated from its in-
hibitory center by section of the vagus. The influence of the
extract, in this connection, is ascribed by Mankowsky40 to
stimulation of the cardiac and respiratory centers; by Gott-
lieb,41 to the direct stimulating effects of the substance upon
the intrinsic cardiac ganglia; by de Cyon,42 to some action upon
the vasoconstrictor nerves and simultaneously upon the central
and peripheral ends of the cardiac accelerators; by Velich,43
to stimulation of the vasoconstrictors; and finally by other
observers to various more or less complicated combinations
which all include some part of the nervous system as the seat
of primary effect. By inference, therefore, we are led to look
upon this system as the one upon which the specific principle
of the adrenals acts physiologically.

The first question, which embodies the divergent views of
Cybulski, on the one side, and Oliver and Schafer, on the other,
resolves itself into this: Does the suprarenal active principle
act at all upon the inhibitory centers?

It may prove useful in this connection to recall that, ac-
cording to prevailing doctrines, the functions of the heart are
governed by two sets of nerve-fibers. The one set, derived from
the splanchnic, increases the vigor of the heart-beat and tends
to quicken the number of beats in a given time. The other
set, which arises from the vagus, inhibits the vigor of the
heart-beats and their rate or rhythm. Both these "augmentor"
and "inhibitor" fibers receive their impulses from the medulla
oblongata and from a limited area of the upper portion of the
cord, and represent the external, or extrinsic, motor-supply of
the organ. Again, the medulla and the spinal area referred to
receive impulses — including reflex impulses — from all parts of
the organism, including the heart proper, and there is thus

40 Mankowsky: Russian Archives of Pathology, Clinical Med., and Bact., vol.
v, No. 3, March, 1898.

« Gottlieb: Archiv fur exp. Path., Bd. xxxviii, 1896.

*2De Cyon: Pfliiger's Archiv fur Physiol., vol. Ixii, p. 370, 1898.

"Velich: Wiener med. Blatter, Nov. 11, 1897.

EFFECTS OF SECRETION ON THE HEART AND VESSELS. 13

established a cycle of afferent and efferent impulses of which
the medulla and the portion of the cord immediately below it
represent the center. The effects of destruction of these
structures can easily be foretold. As shown by Strieker nearly
thirty years ago and by other physiologists since, extirpation
of the cervical and dorsal portions of the cord causes arrest
of the heart's action. When to this is added destruction of
the medulla, the certainty of immediate death is but enhanced.
Again, certain agents — chloral hydrate, for instance — are
known to abolish the functional activity of the cord and to
affect the heart as if the vagus had been severed.

Applying these classical data to the question in point, it
becomes evident that, if the inhibitor or augmentor centers
were directly or reflexly stimulated by suprarenal extract, the
effects of extirpation of these centers or of the cord would
not be counteracted by its use since there would be no center to
receive and transmit impulses. The arrest of the heart's action
would therefore be permanent.

But experiments have shown that the injection of supra-
renal extract at once causes this organ to resume its beats not-
withstanding total extirpation of the entire cord. Thus, Biedl44
cut the medulla oblongata and removed the entire cord of
mammals; and, when the blood-pressure had become reduced
to 9 millimeters, injected suprarenal extract. This at once
brought up the pressure to 160 millimeters. Gottlieb45 chlo-
ralized rabbits until the heart-beats became irregular and ex-
cessively slow. An injection of suprarenal extract at once
restored the regularity and volume of the pulse. He tried
the same experiment when the pulse was no longer registrable
by the manometer; a similar result was obtained, and the heart
almost immediately resumed its normal action. Isaac Ott46
etherized a rabbit, cut the cord above the atlas, severed all
the cardiac nerves in the neck, and verified the section of the
cord post-mortem. Injections of suprarenal extract were then
used repeatedly as soon as the pressure became greatly lowered.
They brought it up from 24 to 144 the first time, from 17 to

"Biedl: Wiener klin. Wochenschrift, Bd. ix, 1896.

48 Gottlieb: Archiv fur exp. Path, und Phar., Bd. xxxviii,

46 Isaac Ott: Experiment No. 11, Medical Bulletin, Jan., II

14 THE PHYSIOLOGY OF THE ADRENALS.

134 the second, and from 24 to 124 the third time, the interval
between the injections of extract and the highest-pressure
marks ranging from fifteen to thirty seconds.

These experiments, to which others of a similar kind
could be added, speak for themselves. They distinctly show
that the inhibitory centers are not directly stimulated ~by the supra-
renal extract, as thought by Cybulski, Wallace and Mogt, Man-
kowsky, Gottlieb, and other careful observers.

And, indeed, their conclusion is apparently justified, if
removal of the medulla and cord is left out of consideration,
and with injections of suprarenal extract as an only guide. In
other words, to the question — does suprarenal extract directly
affect the cardio-inhibitory centers? — an affirmative experi-
mental result on injecting it into mammals — slowing of the
heart — would always be obtained, while the crucial test — sec-
tion of the vagus — would at once confirm the conclusions pre-
viously reached by causing great increase in the rapidity of
the heart's action. But removal of the vagal centers and the
cord in no way preventing the action of the extract, the only
logical deduction that imposes itself is that the suprarenal ex-
tract exercises a stimulating action directly upon the cardiac
muscle.

THE ADRENAL SECRETION AND THE VASOMOTOR SYSTEM.
— The last deduction submitted necessarily implicates other
phases of the question. Prominent among these is the effect
ascribed to suprarenal extract upon the vasomotor system by
various physiologists and clinicians. Is there any such action?
Veins — which are but little, if at all, influenced by the cardiac
impulse in respect to their rhythmical changes of caliber, the
blood before reaching them having to penetrate the capillary
system — are distinctly contractile. This may be clearly seen
by examining the larger veins, especially those near the heart,
in bats' wings. While, to use Foster's47 words, "similar rhyth-
mical variations, also possibly due to rhythmical contractions,
but possibly also of an entirely passive nature, have been ob-
served, very little is known of any nervous arrangements gov-
erning the veins." Granting, for the time being, that veins

47 Foster: "Text-book of Physiology," 1895.

EFFECTS OF SECRETION ON THE HEART AND VESSELS.

15

are not endowed with a vasomotor supply, we find that they
nevertheless contract under the influence of suprarenal extract.
Szymonowicz48 observed that the pressure rose and fell in the
external jugular vein, along with the pressure caused in the
arteries by injections of this substance. Auld,49 in the course
of a series of experiments which had in view the influence of
suprarenal extract on the blood, states that when it was in-
jected into a vein "which had been clamped as high up as prac-
ticable, on releasing the vein after a few minutes a marked
diminution of pressure was recorded as compared with that
produced by injection into the free vein." While it is difficult
to account for the general increase of vascular pressure caused
by the extract without including vasomotor nerves in the
process, a direct action upon the vascular muscles themselves
might underlie the result attained: a question which can only
be elucidated by stripping the vessels of all their nervous con-
nections and then watching the effects of the extract. This
procedure has been resorted to by Oliver and Schiifer,50 and
these physiologists have shown that a vessel will contract after
all the nerves to it are cut. Even a freshly-excised vessel —
one, therefore, obviously freed of all nervous influence — will
respond to the contracting effects of an aqueous solution of
suprarenal extract, and, if a large vessel be used for the ex-
periment to render the change of caliber more appreciable, the
diameter will be found reduced nearly one-sixth. Furthermore,
these investigators51 have found that it acts directly on the
muscles of the blood-vessels, and that this action occurs equally
well after section of the cord. As we have seen, destruction of
the adrenals or annihilation of their functions is followed by
extreme muscular weakness; this normally led them to the
conclusion that all varieties of muscle — the striated, non-
striated, and the cardiac muscle (which histologically partakes
of both kinds of muscular tissue) — are stimulated by the ex-
tract. Having further observed that the blood-pressure in-
creased rapidly, giving a steep rise to the kymograph-curve,

48 Szymonowicz: Archiv fiir die gesam. Physiol., Bd. Ixiv, 1896.
"Auld: British Medical Journal, June 3, 1899.
60 Oliver and Schafer: Journal of Physiology, vol. xviii, p. 426.
« Ibid., p. 230.

16 THE PHYSIOLOGY OP THE ADRENALS.

they concluded that there had been a strong constriction of
the small arteries: strong in their sense, meaning the relative
constriction as compared to that of other vessels. This is fully
accounted for by the greater relative supply of muscular tissue
in these peripheral vessels. As is well known, arteries are
endowed with a coat of muscular fibers, which assumes in-
creased thickness and relatively greater mechanical power as
the capillaries are approached; so that in the smaller arteries
the muscular layer is relatively quite thick. Isaac Ott52 re-
peated the test with a Ludwig kymograph and reached the
same conclusion.

That all organs are similarly affected owing to their vas-
cular supply was also shown by Oliver and Schafer by means
of the plethysmograph, not alone the limbs, but such organs as
the spleen and the kidney being contracted from 20 to 25 per
cent, after intravenous injections of the extract. These ex-
periments also showed that great vascular constriction in the
splanchnic area was caused. Veins, we have seen, are likewise
constricted by suprarenal extract; they also contain muscular
fibers in their thinner walls. Although the supply of muscular
elements is less important than in the arteries, this is, to a
degree, compensated by the greater lumen. That the entire
vascular system of the organism is thus acted upon by the
suprarenal specific principle, owing to the muscular tissues
which it contains, is beyond question.

Can we conclude from these data that the vasomotor sys-
tem is never influenced by the suprarenal extract, in view of
the fact that the blood-pressure is as actively increased by it
when the bulb and the cord have been removed or severed?
Such a deduction is hardly warranted, since the vasomotor sys-
tem as a source of stimuli (unlike the inhibitory action referred
to, which must obviously withhold stimuli) might, in a normal
animal, contribute to the general vascular contraction and
perhaps be its main source. Indeed, it is probable that the
injected extract does, in an animal deprived of its cord, what
it would not do in a normal animal: i.e., find its way into
the blood-vessels, owing to the general vascular dilation caused

62 Isaac Ott: Medical Bulletin, Jan., 1898.

EFFECTS OF SECRETION ON THE HEART AND VESSELS. 17

by the loss of the vasomotor center, and cause contraction
of the vascular walls by a direct action upon them. For the
time being, therefore, we can only conclude that, while injections
of suprarenal extract may cause cardiac and vascular contraction
by directly stimulating the muscular elements of these organs in
an animal from which the vasomotor center has been removed, it
probably stimulates the vasomotor center in a normal animal.

ACTION OF THE ADRENAL SECRETION UPON THE HEART.
— We have seen that destruction of the medulla and cord and
section of the cardiac nerves in the neck does not prevent
the rise of blood-pressure; the vasomotor center being thus func-
tionally eliminated, it is clear that constriction of the vessels
does not occur under these conditions, as a result of impulses
transmitted through them. Such being the case, it becomes a
question whether Oliver and Schafer's explanation in respect
to slowing of the heart by suprarenal extract — namely: that
it is due to reflex inhibition of this organ through the constric-
tion of the arterioles induced — still holds. We must not over-
look, in this connection, the fact that the active agency through
which the heart is slowed, according to their view, is not the
suprarenal extract, but the impulses from the center to which
the reflex inhibition is attributed, and it is plain that in the
absence of this center "inhibition" cannot occur. Hence, as
slowing of the heart takes place when this center has been re-
moved, it must be due to some other cause.

Suprarenal extract, if its action is similar to that of the
secretion of the adrenals, should, it seems to us, be regarded
as a physiological agency, and not be confounded with toxics
which pervert normal conditions, nor with elements foreign to
existing structures. Considered from this standpoint, the ad-
dition of a given proportion of glandular substance to the sum-
total of that contained in the organism, or the removal of some
by any method, should involve a corresponding augmentation
or a diminution of the normal manifestations that represent
suprarenal functions, whatever these may be. The injection
of suprarenal extract, we have seen, produces a rapid and
marked increase of blood-pressure by stimulating the cardiac
and vascular muscles. When, therefore, we speak of stimulating
these structures we imply contraction of the muscular fibers

18 THE PHYSIOLOGY OF THE ADRENALS.

and approximation of the vascular walls toward the center of
the blood-stream. Where is the need of "reflex inhibition,"
therefore, to account for slowing of the heart's action, when
it is combined with increased power of the heart-muscle? The
increase of contractile energy normally implicates a slower
action in virtue of familiar mechanical principles. As we have
seen, the secretion of the adrenals first appears in the supra-
renal veins; it must thence flow into the inferior vena cava
and penetrate the heart. It seems apparent — to us at least —
that we need seek no farther for the source of the slowing of
the heart, and that it is the result of a direct action of the adrenal
secretion upon the cardiac muscle.

FUNCTIONAL KELATIONSHIP BETWEEN ARTERIES AND
THEIR CAPILLARIES UNDER THE INFLUENCE OF ADRENAL
SECRETION. — The very marked contractile power that supra-
renal extract also possesses over the muscular coat of vessels
plays an important indirect role in the organism which seems
to have been overlooked so far: i.e., that, as capillaries are not
supplied with muscles, their walls consisting of endothelial plates,
they are not contracted as are arteries and arterioles.

This embodies two kindred prominent features of pathol-
ogy: i.e., the fact that when vessels supplied with a muscular coat
contract their capillaries dilate owing to the increased pressure
to which the arterial contraction gives rise within the latter,
while the opposite relative mechanism — when vessels supplied
with a muscular coat dilate their capillaries contract — prevails
owing to the resiliency of the latter when the blood in them
recedes. In other words, while, in the first case, the blood is
crowded outwardly, in the second it is crowded inwardly.

The physiological importance of these propositions will be
shown in subsequent chapters, but their bearing and soundness
seem sustained by the fact that they alone, of all solutions so
far advanced, can satisfactorily explain an experimental phe-
nomenon— a true suprarenal paradox — encountered by Lan-
glois and Charrin in the course of their earlier laboratory
work.63 These observers, in order to study the action of su-
prarenal substance upon toxic agents and toxins, injected equal

53 Langlois and Charrin: Comptes-Rendus de la Societe de Biologie, July 10,
1896.

VARIATIONS IN ADRENAL FUNCTIONAL ACTIVITY. 19

doses of virulent cultures into two groups of guinea-pigs, the
animals constituting one of the groups having each been de-
prived of one suprarenal gland. The group of normal animals
lived altogether 138 hours; that of mutilated animals 150
hours. Several experiments of the same kind were performed;
invariably did they find that the animals from which one gland
had been extirpated lived longer than those left in their nor-
mal condition. The differential contractility of vessels and
capillaries referred to render this phenomenon a normal con-
sequence under the circumstances: The caliber of the muscular
vessels, veins, and arteries of the mutilated animals having be-
come enlarged and their walls relaxed by the loss of supra-
renal stimulus, engorgement of the larger trunks occurred, and
caused depletion of the remote capillaries, including those of the
bulbar and other neighboring centers. The toxics injected
producing their main primary effects upon the latter, and, the
quantity of toxic blood transported to them in a given time
being smaller than in a normal animal, the longevity of the
latter was prolonged in proportion.

We will frequently refer in subsequent chapters to this
relative behavior of vessels under the effects of suprarenal
secretion or extract; the view, therefore, that vessels supplied
with a muscular coat and capillaries are antagonistic in con-
traction and dilation is only submitted as a postulate for the
time being.

VARIATIONS IN THE FUNCTIONAL ACTIVITY OF THE
ADRENALS.

ADKENAL INSUFFICIENCY AND ITS CAUSES. — Analogy sug-
gests that, besides the normal standard of suprarenal activity,
there must be excessive and inadequate activity, both physio-
logical to a certain extent, but pathological when extremes are
approached. Haemorrhage into the adrenals under such con-
ditions would seem, at least, to represent one of the extremes,
but which extreme: overactivity or insufficiency? In other
words, acute intoxication is attended, we have seen, by an
overwhelming increase of blood in the organs, and death seems .
to follow through cessation of adrenal functions. Is this
arrest of action due to the haemorrhage, or is the haemorrhage

20 THE PHYSIOLOGY OF THE ADRENALS.

the result of the impairment by the toxic elements of the
functional activity of the organs? If the increase of blood is
primary, we would have over activity ; if the toxics first paralyze
the glandular tissues and haemorrhage occurs as a result, we
would have insufficiency.

This question may perhaps be elucidated by tracing to
their origin, the symptoms that appear in various cases in
which the haemorrhage occurs as a complication of local chronic
disease. These at first seem to afford a ready answer, since the
vast majority of them are traceable to organic lesions of the
glands that practically annul their efficiency by destroying the
greater part of their substance. Partial destruction of the
organs and corresponding loss of activity follow each other so
logically that any conclusion other than that hemorrhage oc-
curs as a result of glandular insufficiency seems unwarranted.
And yet the opposite might be true, since partial organic de-
struction of the organs might cause their physiological func-
tions to become concentrated upon what normal structures are
left. Both arguments are equally strong, therefore, and fur-
nish but little light. Yet they afford a clue by suggesting the
question: Can the normal suprarenal substance left assume the
additional functional power represented by that lost through
destruction of a part of the organ?

While studying the pathological histology of suprarenal
haemorrhage, Arnaud found that it was not in the medulla
proper, as generally believed, that these haemorrhages occurred,
but in the tissues of the internal cortical zone. In emphasizing
this fact, he states: "It is at this point that the capillaries tear
under the influence of a powerful congestion. When the
haemorrhage is important, it is due to rupture of one of the
branches of the capsular vein at any point of its walls, and
occurs into the medullary substance or into the central con-
junctivo-vascular sheath." The medulla proper is thus re-
spected to the last, either a capillary peripheral to it, or some
part of the intrinsic portion of the vein — probably weakened
liy the local disease — constituting the yielding structure.
Furthermore, Nature seems to protect the last vestiges of the
medullary substance even after a localized haemorrhage. This
is suggested by the fact that Arnaud found in such areas evi-

VARIATIONS IN ADRENAL FUNCTIONAL ACTIVITY. 21

dent signs of organization, at times indicating a local inter-
stitial inflammatory process, at others a retrogressive meta-
morphosis recalling that observed in hgematomata. Finally,
using his words: "The normal anatomical elements of the
suprarenal gland may be found in a more or less perfect state
of integrity, either in the periphery of the growth or at one
of its extremities."

This not only typifies the gradual progress of disease in
the medullary substance and the steady and certain submission
of its structure to the destructive agency, but it also indicates
— if we recall the fact that mammals continue to live,, as shown
by Gourfein, when over nine-tenths of either of their adrenals —
that is to say, nineteen-twentieths of both — has been removed
— that, unless some compensative action or some accessory
organ be present, death occurs when this limit of normal ad-
renal substance is reached. This is well shown in Andrewes's
case, previously alluded to, in which a small strip of normal
substance was found post-mortem in the adrenals, the only
organs of the body presenting any indication of disease. Again,
it becomes evident that Nature supplies mammals with twenty
times the amount of medullary substance required under nor-
mal circumstances: a proportion probably far exceeded in man,
as a result of development incident upon his varied diet. Were
the medulla itself capable of 'assuming compensatory activity,
so large a supply for emergencies (the nature of which will be
described later on) would hardly have been provided. If
analogy be again accepted as guide, other organs do not com-
pensate for what insufficiency organic disease may produce in
them by overtaxing remaining normal structures; collateral
kindred tissues, supernumerary or accessory organs, vicarious
functions, and hypertrophy being all added elements, thus con-
stituting either auxiliary resources per se or auxiliary resources
plus compensative growth. Even in the case of the organs
of special sense, where the loss of one organ imposes all the
physiological labor upon the other, the existing tissues are not
overtaxed; they are brought to their highest proficiency by the
increase of nutrition which the additional functional use in-
volves. Whatever evidence we have, therefore, tends to show
that the remaining normal structures of a diseased adrenal do

22 THE PHYSIOLOGY OF THE ADRENALS.

not assume the physiological functions of the areas destroyed,
and it seems clear that the first line of argument — i.e., that
haemorrhage is the result of glandular insufficiency — should
prevail.

Further analysis of this question elicits the fact that the
symptoms which characterize the progress of the primary or-
ganic disease of the adrenals differ totally from those attending
the haemorrhage proper. While the former may hardly cause
suffering or be totally obscured by the signs of any concomitant
disorder present, the symptoms attending haemorrhage are par-
ticularly violent and sudden, the patient abruptly screaming
from excruciatingly intense pain in the abdomen, or dropping
at once into apoplectiform coma from which he never rallies.
Cerebral apoplexy does not furnish a more vivid picture of the
overwhelming effects of haemorrhage. Yet haemorrhagic foci
in various stages of organization are found at autopsies. Thus,
one of Arnaud's cases suddenly fell into apoplectiform coma,
and died in 48 hours; the only organs found diseased after
death were the adrenals, which contained old haematomata,
and various more or less organized haemorrhagic foci which
showed that local haemorrhages into them had repeatedly oc-
curred. The suprarenal substance was entirely destroyed ex-
cepting a narrow zone toward the inferior edge of the right
organ. The urine, during life, and the kidneys, after death,
were found normal. Obviously we cannot well ascribe the
acute symptoms to the primary organic lesion, since they appear
suddenly, practically without warning, and promptly lead to a
fatal issue. Must we, therefore, as in cerebral apoplexy, ascribe
them to the haemorrhage per se? Evidently not, since, as we
have seen, haemorrhagic foci of old standing have frequently
been found in the organs post-mortem, while the acute. symp-
toms had only appeared when death was near. The following
conclusions, therefore, seem to conciliate all the data at
hand: —

1. The acute symptoms and death which follow hcemorrhage
into the adrenals are due to the sudden and complete cessation of
adrenal functions.

2. The causes of haemorrhage into the adrenals are also those
of insufficiency of these organs.

VARIATIONS IN ADRENAL FUNCTIONAL ACTIVITY. 23

POISONS AND VARIATIONS OF THE FUNCTIONAL ACTIVITY
OF THE ADRENALS. — We have only considered so far the haem-
orrhages that follow a gradual destruction of the adrenals
and which appear only when the fragment of medulla left can
no longer fulfill the organ's functions. But there are cases in
which, independently of any such a slow destructive local
process, the sudden accumulation of one or more toxics sud-
denly overpowers the adrenals and through the insufficiency
thus brought about engender secondary fatal hyperaBmia, or
hcTmorrhage attended with fully as violent symptoms as those
observed in Arnaud's case in which sudden death followed a
burn of the arm. Andrewes's case, in which death occurred 36
hours after the first symptoms of an acute disease which he
thought bore some points of resemblance to haBmorrhagic small-
pox, also illustrates this class. In fact, instances such as
Andrewes's have so often been noticed by clinicians that Still54
has proposed a distinct category of cases in which "after an
acute illness lasting only two or three days, usually with a
purpuric or bullous eruption," death occurs, "and the supra-
renal lesion appears to be a part of the fatal issue."

That general intoxication can thus act as an original cause
of hemorrhage has been shown experimentally. Thus, Roger55
found that inoculation of the guinea-pig with a culture of the
pneumobacillus of Friedlander was followed by profuse hem-
orrhage into both capsules, the blood actually bursting through
the great capsular vein, or causing necrosis of the surrounding
elements by mechanical compression. Langlois56 also demon-
strated that suprarenal haemorrhage could be brought on by
the bacillus pyocyaneus. Charrin57 found that, by injecting
diphtheria toxins into guinea-pigs, congestion — which in some
instances reached the hemorrhagic stage — was not alone
caused, but he also observed that small doses used repeatedly
and during prolonged periods caused hypertrophy of the or-
gans. Petit58 also noted, after introducing Loffler bacilli in

54 Still: Lancet, May 7, 1898.

K Roger: Berliner klin. Wochenschrift, Jan. 21, 1894.

58 Langlois: Le Bulletin Medical, Feb. 7, 1894.

57 Charrin: La Semaine Medicale, June 3, 1896.

68 Petit: La Semaine Medicale, June 3, 1895.

24 THE PHYSIOLOGY OF THE ADRENALS.

fishes in which the suprarenal structure is clearly glandular,
that all the phases of excessive reaction could be brought on.
Hemorrhagic foci were found by Wybauw59 in the adrenals of
a child which had died of broncho-pneumonia the result of a
tracheotomy for croup. Even drugs may bring on hyperemia,
congestion, and hemorrhage of the suprarenal glands, as shown
by Pilliet,60 who observed these phenomena after the use of
the essence and nitrate of uranium. Essence of cloves has also
been found capable of stimulating them to such a degree as to
bring on macroscopically-visible lesions.

The next step in our analysis is to ascertain by what proc-
ess toxic elements can bring on, not haemorrhage, but the in-
sufficiency of the organs which gives rise to this condition.

The few allusions to this feature in the literature upon
suprarenal hemorrhage refer to this condition as a direct result
of various intoxications.

One prominent investigator, for example, writes: "Ex-
periments have shown that certain poisons, essence of cloves,
Friedlander's bacillus, diphtheric toxin given by the mouth
or by injection to guinea-pigs produce acute congestion or haem-
orrhage in the suprarenals," thus relegating, with all other
writers on the subject, glandular insufficiency to the position
of a consequence of congestion or hemorrhage. We, therefore,
have no direct data to fall back on for our investigation in this
direction.

The view that the suprarenal specific principle itself pos-
sesses antitoxic powers, has suggested to those who have ac-
cepted it the conclusion that a high degree of toxosmia, by over-
taxing the organs, caused congestion, and, if this reached be-
yond certain limits, haemorrhage. This conception was mainly
based on the view of Brown-Sequard, who was led, by the toxic
effects of blood taken from decapsulated animals upon normal
ones, to ascribe to the glands themselves a direct antitoxic
function. It met with further support in the fact that violent
toxemia invariably follows the removal of both organs, and
was therefore accepted by many investigators. It was also

69 Wybauw: Annalos de la Soci6t§ Royale des Sciences M6d. et Nat. de Bel-
gique, vol. vi, Nos. 2 and 3, 1897.

w Pilliet: Le Bulletin Medical, Feb. 7, 1894.

VARIATIONS IN ADRENAL FUNCTIONAL ACTIVITY. 25

maintained by Dubois,61 who, having isolated toxic alkaloids
from adrenal substance identical in some of their reactions
with muscle-toxins, concluded that the adrenals occluded prod-
ucts of organic waste and modified them in situ, but that they
did not seem to secrete any special substance destined to enter
the circulation.

This hypothesis does not seem to us to be able to stand
close scrutiny. The destruction of poisons within the adrenals
themselves involves the passage of the systemic blood through
their cellular elements. When in the cadaver we note the
relative dimensions of all the vessels within a narrow radius
of the adrenals, it becomes apparent that the conditions are
not such as to indicate a provision for the passage of the blood
through these organs. The arteries, derived from branches of
the phrenic, the renal and often directly from the aorta, are
relatively insignificant vessels and totally inadequate to allow
the passage through them of enough blood to represent the
three hundred and sixty grammes which the cardiac ventricles
send into the arteries at each systole, their total sectional area
being but a small fraction of that of the aorta, their source of
supply. The utter impossibility for the whole volume of blood
in the organism to pass through the adrenals in 24 seconds,
the length of time required to complete the entire systemic
circulation, hardly needs to be emphasized. Again were the
blood-stream to traverse the organs, their veins would, to a
degree at least, correspond, in diameter, with their arteries.
But such is not the case; they are disproportionately large: a
fact which in itself shows that the efferent blood must be the
carrier of some added product obtained from the glandular
structure. It also seems obvious that, if the adrenals were
intended to asepticise blood in transit through them, the
afferent channels would normally contain blood from all parts
of the organism and charged with toxic elements, while the
efferent channels would convey the purified blood charged with
the suprarenal secretion to the heart, ready for redistribution.
Instead of this the afferent vessels receive their blood from the
aorta, — arterial blood, — while the efferent vessels pour their

61 Dubois: Archives de Pathologic norm, et path., vol. viii, 1896.

26 THE PHYSIOLOGY OP THE ADRENALS.

blood into the vena cava. But, as shown by Alezais and
Arnaud62 in 1890, this blood is also arterial. We thus have a
short arterial circuit, or loop, which, besides furnishing the
adrenals their intrinsic and functional blood-supply, evidently
has for its purpose the immediate return to the general cir-
culation of a small quantity of arterial blood charged with what
Claude Bernard (1867) has well termed an "internal secretion."

More in keeping with experimentally-established facts are
the views which attribute to the secretion itself, when in the
blood-stream, the antitoxic functions referred to. Thus,
Abelous and Langlois,63 after a series of careful experiments,
reached the conclusion that their normal function was to
elaborate an internal secretion capable of neutralizing or de-
stroying the poisonous substances resulting from muscular
contractions: a fact further demonstrated to them by the
mitigating effects of injected suprarenal extract. More re-
cently these observers64 amplified their views and concluded
that, after removal of both adrenals, there was a true auto-
intoxication, the animals generating poisons which were nor-
mally either destroyed or changed in the interior of the glands
or by material formed by the organs and poured into the blood.
The poisons, they thought, were probably products of muscular
activity and also of bacterial origin, and exerted a special in-
fluence on the heart and circulatory system. Mosse65 also be-
lieved that the adrenals produced a stimulating substance and
that they could simultaneously neutralize poisons formed in
various parts of the organism.

Reasoning by analogy, we can surmise that the metabolism
of the organs is principally maintained by the passage of blood
through them and that the internal secretion represents the
physiological product of their metabolism. Under these cir-
cumstances, the quantity of blood in them at a given time
would stand as the controlling factor, the quantity of active
principle secreted into the general circulation being propor-
tionate to this quantity. Have we any ground for the belief

82 Alezais and Arnaud: Quoted by Arnaud, loc. cit., p. 34.

83 Abelous and Langlois: Archives de Physiologic norm, et path., vol. iii, p.
267, 1892.

8* Abelous and Langlois: "Travaux de Laboratoire," Lancet, Aug. 20, 1898.
M Mosse: Fortschritte der Medicin, No. 21, 1897.

VARIATIONS IN ADRENAL FUNCTIONAL ACTIVITY. 27

that the circulation alone may keep up the suprarenal func-
tions? The experiments of Soddu66 seem to throw light upon
this question. In order to ascertain the role of the suprarenal
peripheral nerves, this investigator isolated the glands of sev-
eral dogs from their external connections, leaving only the
blood-vessels. Although eight animals were submitted to this
operation, none died, and all, after a few days, were in their
normal health. It is evident that, if the blood alone can thus
sustain the life of the organs, an increased flow into them —
under, perhaps, the influence of toxic blood upon the centers
of their nerve-supply — will involve a corresponding increase
of functional activity. That very large or overwhelming doses
of any poisonous agency should produce the contrary effect and
arrest the functions of the adrenals by annihilating those of
their center is suggested by the pathogenesis of suprarenal
hemorrhage.

Still, this involves the existence of an intrinsic nervous
supply capable of producing an increased flow of blood into
the glands under the stress of an acute toxaemia and a corre-
sponding increase of vascular tension. By suddenly calling the
suprarenal functions into violent activity, an excessive dose
would thus paralyze them or cause what Arnaud has termed
"suprarenal apoplexy": i.e., intrinsic hemorrhage. To ascer-
tain whether such a nervous influence can exist, and, if it does,
whether a poison can stimulate the glands through the latter's
nerve-supply, is necessary before further progress can be made.

Biedl67 studied the effects of various poisons, particularly
atropine, to ascertain whether they influenced the character
or quantity of suprarenal secretion, and obtained negative re-
sults. But can this be said to apply to all poisons? A close
analysis of this physiologist's work has led us to interpret his
experiments in a manner that is not in accord with his con-
clusion. He states that he found blood-pressure to be increased
in the organ by the interruption of artificial respiration. This
interruption appears to us to point to an accumulation in the
organism of products of metabolism, and therefore of poisons of
a class which stand out prominently as the basis of phenomena

66 Soddu : Lo Sperimentale, No. 2, 1898.

« Biedl: Pfluger's Archiv, vol. Ixvii, H. 9 and 10, 1897.

28 THE PHYSIOLOGY OF THE ADRENALS.

that promptly end in death. That products of metabolism may
with justice be considered as toxic is shown by a detail in
Langlois's work, the importance of which does not seem to
have attracted sufficient attention: While decapsulated frogs
died in 48 hours during summer months, they lived 12 days
in the winter: i.e., during hibernation, when metabolic proc-
esses are at their lowest ebb. It required a certain ratio of
toxic elements to the body-weight to bring on the culminating
phenomena; the "fatal dose" was made up in 48 hours, in
summer, — i.e., when the full activity and proportionate catab-
oiism prevailed; the same relative dose could only be made
up in six times 48 hours when hibernal lethargy reduced tissue-
waste in proportion. Thus, Biedl's experiments are not nega-
tive in this direction, as he deemed them to be. They appear
to us to suggest that, as will be shown in these pages, all toxics
do not influence the adrenals with equally marked activity.

Biedl also found that, when the splanchnic nerve was cut
and the suprarenal branches were stimulated, hypergcmia ap-
peared in the organs. Howell refers to the striking evidence
afforded by the effects of electrical stimulation. If, after cut-
ting the splanchnic nerve and introducing a cannula into the
suprarenal vein, the blood is collected and the peripheral end
of the cut nerve is stimulated, the quantity of blood obtained
in a definite time is not increased, but it is found to contain
more of the blood-pressure-raising substance: a fact which indi-
cates that its secretory activity is increased. He therefore con-
cludes that the adrenals act as true glands, and that they are
provided with a reflex mechanism corresponding to that of the
latter. Biedl also expressed his conviction that secretory
fibers as well as vasodilator fibers are present in the splanchnic
nerves. Dogiel68 likewise found that the medullary nerves
form complicated plexiform arrangements which terminate
upon the surface of the glandular elements; and, furthermore,
that the nerve-cells in no way differ from those of any sym-
pathetic ganglion.

All these facts seem to us to warrant the conclusions
that:—

88 Dogiel: Archiv f. Anatomie und Physiologic, p. 90, 1894.

THE DYNAMICS OF ADRENAL FUNCTIONAL ACTIVITY. 29

1. The functions of the adrenals are actively enhanced by
stimulation of the splanchnic nerve, and appear to be increased
in the same manner by poisons.

2. The functions of the adrenals appear to undergo over-
stimulation when a sufficiently active toxic is present in the blood,
the result being either haemorrhage into the adrenals per se, or
inhibition of their functions.

MECHANICAL PHENOMENA THAT ATTEND VARIATIONS IN
THE FUNCTIONAL ACTIVITY OF THE ADRENALS.

In cases of suprarenal haemorrhage, as we have seen, two
entirely distinct forms of this condition prevail. The first of
these occurs when, after a destructive disease, the vestige of
medulla left suddenly ceases to secrete enough active principle
to continue the physiological functions over which the adrenals
preside. The second form is that due to general intoxication.

The symptoms observed in these cases include the follow-
ing, which may be considered as standard signs: (1) extreme
weakness due to gradual decline of muscular power; (2) violent
abdominal pain; (3) great reduction of vascular pressure; (4)
subnormal temperature; (5) liquid stools; (6) scanty urine or
anuria; (7) syncope or convulsions — the whole ending in death
in from 20 minutes to 3 days. The sudden annihilation of
suprarenal functions obviously involves cessation of secretion.
We have seen that the latter maintains the tone of the vascular
muscles; the first effect produced, therefore, is suddenly to
relax the entire vascular system, as shown by the marked re-
duction of vascular pressure. As a consequence, the great cen-
tral trunks — the aorta, the vena cava, etc. — become, by reason
of their size and their situation, the main centers of engorge-
ment: an assertion not only demonstrable by clinical signs, but
indirectly also by the experiments of Oliver and Schafer, who
found, by plethysmographic observations upon the limbs and
spleen, that injections of suprarenal extract produced great
vascular constriction chiefly in the splanchnic area. That ab-
sence of suprarenal secretion in the organism should produce
the opposite result in the same region is obvious.

This central engorgement of suprarenal origin — greatly
accentuated through the fact that "vessels supplied with a mus-

30 THE PHYSIOLOGY OF THE ADRENALS.

cular coat and capillaries are antagonistic in contraction and
dilation" — appears to us to be far reaching in its application.
Indeed, if the phenomena observed in Asiatic cholera, arsenic
poisoning, and other kindred conditions are recalled, the truth
of this assertion will appear.

As a result of the central accumulation of blood, the ex-
tremities and peripheral tissues, more or less depleted of theirs,
are cold; the muscles, also deprived of the greater part of
their blood, lose their power; the tension upon the abdominal
vessels and neighboring structures, including the unusually
rich nervous net-works, produces the intense abdominal pain;
engorgement of the intestinal vessels gives rise to copious
diarrhoea, which by causing reduction of liquids tends to reduce
the renal secretion and sometimes to cause anuria. The de-
pletion of the cerebral vessels accounts for the syncope, and
the auto-intoxication, through accumulation of waste-products,
for the convulsions. All the symptoms of this terrible disease
thus seem to be accounted for — and, we believe, for the first
time. They are precisely those that follow removal of both
adrenals.

Still, while the various morbid conditions outlined account
for the symptoms recorded, closer investigation soon shows that
they are only satisfactory as far as they go, and that some
features of the symptom-complex are not fully met. Thus,
general relaxation of the vascular system means sudden in-
crease of caliber of all vessels, and, therefore, a corresponding
increase of area for the blood. Why should it, under these
circumstances, accumulate in the larger trunks? Why should
it not merely lie dormant in the relaxed vessels evenly dis-
tributed throughout them all? Again, gravitation prevails in
our body precisely as it does elsewhere. Why should the blood
not fill the vessels of the lowest levels of the organism and the
back, the nates, the calves, and the heels of the recumbent
patient become hypostatically congested, red, and hot, while
his toes, knees, abdomen, and face, blanched and cold, reveal
by their pallor and coldness the total absence of blood, which
has gone to find its level? Instead of this the entire surface is
frigid and blanched; the lowest portions of the body as well
as the uppermost show that all the peripheral capillaries are

THE DYNAMICS OF ADRENAL FUNCTIONAL ACTIVITY. 31

depleted and collapsed, the blood in them having been drawn
internally: i.e., toward the great abdominal trunks. Again,
the intensity of the pain seems to indicate not mere engorge-
ment, but inordinate, disruptive, centrifugal, pressure, for
which mere relaxation of the vascular walls cannot account.

On the whole, we are forced to conclude that there must
be an overpowering display of centripetal energy from the pe-
ripheral capillaries, arterial and venous, as soon as the supra-
renal secretion fails to indirectly hold the central vascular walls
up to their normal tone. That it is mechanical is suggested by
its mode; that it enters into the domain of hydrokinetics is
evident; and that loss of the normal equipoise between two
forces forms the basis of the process affirms itself on all sides.
The solution of the problem suggests itself when we recall,
besides the fact that the total sectional area of the capillaries
is seven hundred times that of the aorta, the manner in which
the capillaries are affected when muscular vessels are dilated.
The blood in them, as we have seen, is compressed by the
resiliency of their walls and the surrounding tissue, neuroglia,
etc., and literally floods the abdominal organs. Indeed, the
peripheral system contains as many sources of pressure as there
are capillary tubes in it — enough many times to account for
all the mooted points just reviewed.

To illustrate the violence of the power exerted in this con-
nection, we may refer to the principle of hydrokinetics, — Pas-
cal's principle, — which underlies the whole mechanical process.
This physicist completely filled a strong cask with water, closed
it hermetically, then inserted the end of a long, narrow, and
close-fitting glass tube through a hole in one of the staves.
Into the upper end of the tube, which stood upright, he then
slowly poured water. Long before the tube had been filled the
cask burst, owing to the excessive pressure within its walls.
How was this pressure exercised? "The pressure of a fluid
being due to its weight," the pressure in the upper layers of
the water in the tube was slight, while that in its lower layers
had increased in proportion with its distance from the top,
since "pressure at any point in a liquid varies as its depth/'
"A pressure exerted on a fluid inclosed in a receptacle" being
"transmitted undiminished to every part of that receptacle,

32 THE PHYSIOLOGY OF THE ADRENALS.

and the total pressure exerted on the interior of the latter"
being "equal to the area multiplied by the pressure per unit
of area," a centrifugal display of force occurred — which far
surpassed the resistance of the cask, and it had to yield. The
hydraulic press, by means of which the hand of a child can
break a steel rail, is based upon this principle.

These principles prevail in the human organism precisely
as they do elsewhere in Nature. In the large vascular trunks
of the abdomen, abdominal and thoracic viscera, etc., we have
closed channels typifying the cask; in the narrow muscular
vessels leading to them we have a multitude of conduits por-
traying the glass tube. Finally, we have the aggregate of press-
ure of millions of contractile, resilient capillary vessels con-
taining a mass of blood (so great in comparison to the larger
vascular structures that these have been considered as sub-
sidiaries to the capillary system) to represent the gobletful
of water with which Pascal indirectly caused explosion of his
cask. That we have ample power to account for the symptoms
mentioned is evident. It also accounts for suprarenal haem-
orrhage when violent toxaemia is present. The rich vascular
supply of the organs is well shown in the annexed colored plate
prepared by J. M. Flint in the course of an exhaustive study
of their anatomy, and published in the Johns Hopkins Hospital
Reports, two years ago.

Obviously the application of this principle is subject to
limitations which the volume of blood accumulated in the ves-
sels of the trunk impose. Admitting, for purposes of illustra-
tion, that all the blood of the organism has been forced into
the interior of the body, its mass represents a fixed area which
the various internal structures must furnish. Thus, while the
large vascular trunks bear the brunt of the pressure, all the
neighboring organs, including their capillaries, become en-
gorged in proportion as the quantity of blood added to their
normal contents is great. In other words, the blood accom-
datcs itself to any room it can find after the larger vascular
trunks are engorged, whether it be in a blood-vessel or a viscus.
Thus, Boinet,69 in 45 of his 59 decapsulated rats, found hacm-

69 Boinet: Gazette des H6pitaux, July 20, 1899.

CJ]

n

n

H

e

B I

w <?
J *

U

?i

n I
«J 1

H I

w k

PH

n

%

n

THE ADRENALS IN DISEASE AND POISONING. 33

orrhage in the lungs in 16, in the spleen in 41, in the thyroid
in 13, in the thymus in 11, in the kidneys in 8, in the liver in
5, and in the spinal cord in 5. All this further emphasizes the
practical bearing of the postulate: "Vessels supplied with a
muscular coat and capillaries are antagonistic in contraction
and dilation."

On the whole, it appears to us that the mechanical phe-
nomena that attend fluctuations of suprarenal functional ac-
tivity are of surpassing importance in pathology — as will be
shown in subsequent chapters. For the present it seems per-
missible to submit the following conclusions: —

1. Insufficiency of the adrenals is followed by engorgement
of the central vascular trunks and depletion of the peripheral capil-
laries, as indicated ~by general pallor.

2. Overactivity of the adrenals causes contraction of the cen-
tral vascular trunks and engorgement of the peripheral capillaries,
as indicated ~by general peripheral hypercemia, which assumes the
stage of "fever" when toxics accumulate in the blood-stream.

THE ADRENALS IN THEIR RELATIONS TO DISEASE AND
POISONING.

EFFECTS OF TOXINS ON THE ADRENALS. — Do poisons of
various kinds, venoms, or bacterial toxins cause primary in-
sufficiency by a direct action upon the suprarenal structures
or do they cause it indirectly through an influence upon the
nervous centers of these organs? We have seen that experi-
mental physiology conclusively shows that the adrenals are
provided with a reflex mechanism corresponding to that of true
glands, and that electrical stimulation of the suprarenal branch
of the splanchnic nerve can cause increase of secretory activity.
These facts, considered simultaneously, suggest that the pres-
ence of an unusual proportion of toxic elements in the blood
may, physiologically, so affect the nervous centers of the ad-
renals as to increase the functional activity of the latter. On
the other hand, ample post-mortem evidence is available to
show that tubercular, cancerous, and other morbid processes
may find in the organs a soil of activity. It is evident, there-
fore, that their structure is vulnerable from both directions:
i.e., that disease, poisons, etc., can assail them indirectly

34 THE PHYSIOLOGY OF THE ADRENALS.

through their nervous supply, and directly by invasion of
pathogenic elements of various kinds.

What is the nature of the pathological process that follows
infection or the ingestion of poisons? The relation between
the class of cases previously described and this is well shown
by the reports of several observers, who not only refer to the
invariable presence of hyperaemia, but also to local haemorrhagic
processes. Rene Wybauw, for example,70 injected diphtheria
toxin into the peritoneal cavity of a large number of guinea-
pigs, causing death within three days. In all these animals the
adrenals had become somewhat enlarged and showed intense
hyperaemia, the central vein being particularly engorged. In
one of them, a guinea-pig, the disease followed an acute course;
the vascular epithelium had yielded to the pressure and the
organs showed abundant haemorrhages. The reticular and
medullary zones, in which capillaries are especially abundant,
presented the most marked lesions.

We have already seen that Abelous and Langlois also
found that the injection of various bacterial cultures caused
vascular lesions varying from slight congestion to severe haam-
orrhage. Two cases, reported by different observers, are par-
ticularly interesting in this connection: In the one, a case of
acute toxaemia reported by Andrewes,71 death occurred in 36
hours, and the adrenals alone showed lesions — interstitial haem-
orrhage. In the other, reported by W. S. Colman,72 the symp-
toms also indicated a general infection; death occurred in
about 25 hours, and no lesion other than suprarenal inter-
stitial haemorrhage was found. The interesting feature of these
cases, however, is that both observers submitted blood taken
from the haemorrhagic foci in the organs to bacteriological
examination. Andrewes invariably obtained sterile cultures,
and he states that, if any organisms were present, "there were
none that grew upon ordinary media or stained with ordinary
reagents." Colman not only reached the same result with
blood from the adrenals proper, but with blood taken from

70 Ren6 Wybauw: Annales de la Societe1 Royale des Sciences M6d. et Nat. de
Bruxelles, vol. vi, p. 134, Nos. 2 and 3, 1897.

71 Andrewes: Lancet, May 7, 1898.

« W. S. Colman: Lancet, May 7, 1898.

THE ADRENALS IN DISEASE AND POISONING. 35

other organs. The cases had doubtless been caused by a spe-
cific toxin, but with the ever-present hypersemia as a terminal
feature.

Does a specific organism or its toxin produce its own char-
acteristic lesion in the adrenals? Wybauw73 states that he has
invariably found in these organs, after the injection of diph-
theric toxins in rabbits, the histological lesions found else-
where in this disease. He further noted that the point of
union of the reticular and medullary zones, where the capil-
laries are especially numerous, presented the well-known type
of degeneration, while the slides also clearly showed all the
stages of cellular destruction, with more or less disintegration
of the nuclei. The latter were also undergoing retrogressive
stages, gradual loss of regular outline., irregular perimetric
retraction, etc. He likewise examined microscopically the ad-
renals of a guinea-pig killed with cholera germs, but in this
connection he says: "The adrenals are the seat of much less
pronounced changes than those of the diphtheric guinea-pig.
They are redder than normal. But the examination shows
lesions which must certainly le produced by the same mechanism.
The cells are irregular, the nucleus having lost in places its
characteristic structure," etc. In a case of broncho-pneumonia
following tracheotomy for diphtheria, he was able to .note the
same changes that he had observed in the diphtheric rabbits
and choleraic guinea-pigs, but less marked, the patient having
died of the concomitant disease before the diphtheric process
had become far advanced. Arnaud,74 in a case of suprarenal
hemorrhage associated with liver-abscess, also found lesions in
the suprarenal medulla characterized by cellular degeneration,
granular disintegration, etc.: i.e., a general necrobiosis of sep-
tic origin. If to these results we add those of Andrewes and
Colman, referred to above, it seems clear that we can, with
Wybauw, conclude that bacterial toxins as a class possess a
direct destructive action upon adrenal tissue.

But this observer ascribes to the adrenals a special sen-
sitiveness to the influence of diphtheric toxins. While this may
be the case, it seems to us that, inasmuch as a specific toxin

73 Wybauw: Loc. cit., pp. 134 and 165.
'* Arnaud: Loc. cit., p. 15.

3

36 THE PHYSIOLOGY OF THE ADRENALS.

does not produce a characteristic lesion in them, the phe-
nomena witnessed, histological and symptomatic, should rather
be considered as expressions of excessive stimulation or ex-
haustion of these organs. The various toxins differ in potency
precisely as do other poisons; why their mode of action should
differ would be difficult to show. On the other hand, it may
easily be demonstrated that all poisons affect the adrenals in
a similar way, and in proportion to their virulence and dose.
In curare poisoning, for example, the symptoms produced so
exactly portray those that follow extirpation of both organs in
mammals that Abelous and Langlois75 were led to conclude
that there were in the blood various substances possibly orig-
inating in the chemical changes of muscular contraction, which
produced curare-like symptoms, and which were destroyed or
neutralized by the internal secretion of the adrenals. Tillie,76
after a series of experiments (which did not refer to the
adrenals), thus describes the physiological effects of curare:
"With larger doses there is dilation of the abdominal vessels,11
and, hence, accumulation of blood, little or nothing of this
fluid entering the empty ventricle notwithstanding that the
heart may continue to beat. Curarine causes an almost imme-
diate fall of blood-pressure in mammals; it occurs even after
section of the vagi, after a paralyzing dose of atropine, after
division of all the cardiac nerves, after section of the spinal
cord, and after paralysis of the central reflexes by urethane.
The cause, therefore, of the fall of pressure must be due to a
direct action upon the peripheral nerves or upon the muscles
of the blood-vessel walls." Probably stronger evidence to show
the direct paralyzing action of curare upon the adrenals could
not be found.

The common action of various toxins may be as clearly
demonstrated. Thus, Langlois and Charrin78 invariably noted
hypertrophy of the suprarenal tissues after the prolonged use
of diphtheric toxins in small quantities, in guinea-pigs. In one
of the animals the organs had increased to over four times

76 Abelous and Langlois: Archives de Physiologic norm, et path., vol. xili, p.
267.

79 Tillie: Medical Chronicle, March, 1891.

77 The italics are our own.

78 Langlois and Charrin: La M6decine Moderne, Feb. 6, 1896.

THE ADRENALS IN DISEASE AND POISONING. 37

their normal size. The same phenomena followed injections
of bacillus pyocyaneus. Petit70, also found hypertrophy to fol-
low filtered cultures of the Loffler bacillus in fishes. That the
hypertrophic process is compensative is shown by the fact that
hypertrophy also occurs in the remaining gland when one has
been extirpated. Stilling80 observed that in young rabbits the
remaining adrenal sometimes attained very large size; Auld81
also reported several instances in cats. In the presence of
these facts it is evident that the adrenals are submitted to
excessive activity when toxics are introduced into the organism,
and that the local lesions are the expression of a physiological
function utilized beyond its normal limits. The histological
lesions found post-mortem are no longer pathological mani-
festations of the toxins introduced; they are those of overuse
and common to all.

That we are dealing with the effects of overactivity is
sustained by evidence from another direction. In the instances
in which hypertrophy was caused by injections of toxins these
were administered in small doses at frequent intervals, the
process extending over a period of many weeks. If we analyze
Wybauw's report, there are points which tend to indicate even
more than the direct effects of toxins noted. This author
refers to promiscuously-distributed swollen cells, the proto-
plasm of which is less clear than usual, and to other features
that recall the characteristics of cloudy swelling observed most
frequently in the liver and kidney and in the heart-muscle.
This we know may be caused not only by bacterial toxins, but
also, and with equal frequency, by nutritional disturbances
excited by nervous stimulation. We have evidence that the
excessive stimulation of the nervous center of the organs must
underlie the overactivity induced, in the fact that electrical
stimulation of the splanchnic nerve causes, as we have seen,
an increase of suprarenal secretion.

Of course, both processes — local lesions induced directly
by the toxins and those brought on through excessive func-
tional activity — may be simultaneously present in the organs.

79 Petit: Loc. cit.

80 Stilling: Virchow's Archiv, Dec., 1889.

81 Auld: British Medical Journal, June 3, 1899.

38 THE PHYSIOLOGY OF THE ADRENALS.

Thus, advanced' nuclear degeneration is rarely seen in cloudy
swelling, while in Wybauw's preparations it is marked, indi-
cating the destructive effects. It seems clear, therefore, that
we thus have simultaneously pictured, not only the direct
effects of the poison, but also the primary effects of excessive
activity, the physiological "spontaneous wearing out of living
parts" of Virchow having become pathological.

Cloudy swelling and its almost unfailing sequel, fatty
degeneration, represent the dominant processes, however: a
statement which suggests that the latter should show itself
even more frequently in the adrenals than elsewhere, in con-
sideration of the fact that agencies capable of inducing this
pathogenic overactivity not only include poisons, but also a
large number of diseases, particularly those of childhood.
Arnaud,82 alluding to the evidences of fatty degeneration in
the adrenals observed post-mortem, writes: "This lesion, which
is appreciable only by histological examination, is very com-
mon, as shown by my personal researches. It existed to a more
or less marked extent 36 times in 100 subjects whose adrenals
had been collected at random at autopsies." Rolleston83 refers
to this subject in the following words: "In the suprarenal
bodies of adults fatty change is so common as to be a physio-
logical condition. The fat occurs as large globules in the cells.
This change may be present throughout the whole of the cortex
or be best marked in the zona fasciculata. The medulla is
occasionally seen to be occupied by fat, but never to the same
extent as the cortex, while in children there is little fat nor-
mally. Attlee found, however, some, though slight, fatty
change in still-born children. In children dying from maras-
mus there was marked fatty change, which was more frequent
than in the liver. The cortex was affected in all, and the
medulla in 6 out of the 9. Experimentally he found that starva-
tion, suppuration, or poisoning, whether acute or chronic, gave
rise to fatty changes"84: further evidence that all intoxications
exercise the brunt of their action upon these organs. And yet
Rolleston but voices the present conception of the position

82 Arnaud: Loc. cit., p. 6.

83 Rolleston: Allbutt's "Practice," p. 567.
M The italics are our own.

THE ADRENALS IN DISEASE AND POISONING. 39

occupied by the adrenals in pathology when he adds: "Fatty
change does not give rise to any symptoms."

If the views herein recorded are not erroneous, it would
seem far more exact to state that fatty change of the adrenals
represents an end-result of almost all morbid processes attended
with the introduction into the blood of a toxic, whether this be a
vegetable or mineral poison, a toxin, a catabolic product, a venom,
etc., any agency in fact, extrinsic or intrinsic, capable of induc-
ing what we now term a "toxaemia." Another deduction which
logically suggests itself is that all the major symptoms now
ascribed to the direct action of all these toxics are primarily
ascribable to their morbid effects upon the adrenals, either
directly upon the organs themselves or indirectly upon them
through a primary action upon the centers of their nervous
supply. In other words, it would appear that all major symp-
toms witnessed in diseases in which the blood is invaded by a poison
are in reality manifestations of overactivity, insufficiency, or total
inactivity of the adrenals.

The latter conclusion, however, imposes as conditions that
all poisons give rise to similar symptoms, due allowance being
made for the differences in power as represented by the activity
of an agent plus the dose administered, and that these symp-
toms precisely coincide with those of suprarenal insufficiency
or those which follow removal of both adrenals. That such is
the case is shown below.

EFFECTS OF VENOMS, VEGETABLE AND MINERAL POISONS
ON THE ADRENALS. — Removal of both organs, as we have seen,
is followed by extreme muscular weakness, marked reduction
of blood-pressure, hypothermia, dyspnoea, and blood-changes.
All these phenomena should appear under the influence of suf-
ficiently active poisons if the above conclusion is warranted.

To strengthen the evidence adduced only works will be
used for comparison in which the observations given in no way
refer to the suprarenal glands. For the study of venoms we
are fortunate in having at our disposal a comprehensive and
admirable article by J. Noe,85 of Paris, which gives a complete
retrospect of all the main investigations upon this subject dur-

85 J. No6: Archives G6n6rales de M6decine, Jan., Feb., Sept., and Nov., 1899.

40 - THE PHYSIOLOGY OF THE ADRENALS.

ing the last fifty years, and in which the semeiological and
pathological effects of the various venoms, ranging from those
of insects to those of reptiles, are studied. For the study of
the toxic manifestations of drugs the excellent work on "Thera-
peutics," by Horatio C. Wood,88 of Philadelphia, will be util-
ized. The agents to be analyzed in this connection will not be
selected, however, among any special class — cardiac depressants,
depresso-motors, antipyretics, and 'the like to facilitate our
task; they will be taken in the promiscuous order afforded
by the index, in which the first letter of the name given each
drug is the only feature involving sequence. Obviously only
those subjects in which the cardinal symptoms referred to —
muscular weakness, variations of vascular pressure and tem-
perature, etc. — have been sufficiently studied by the author
will be considered. This includes a large proportion of the
best-known drugs, and may with all fairness be accepted as
representatives of all those capable of giving rise to toxic
symptoms.

Muscular Weakness. — The great muscular weakness attend-
ing insufficiency of the adrenals, as shown in Addison's disease
and so marked after removal of both organs, finds its counter-
part in the symptomatology of intoxication as well with venoms
as with vegetable and mineral poisons. Vulpian in 1869 called
attention to the progressive asthenia, followed by somnolence
with motor phenomena recalling those of curare poisoning,
caused by cobra-venom. Paul Bert noted that muscular activ-
ity disappeared after scorpion toxaemia, and that the muscles
failed to respond to strong induction currents. He also ob-
served that even bee-venom caused loss of motor activity, and
therefore concluded that this toxic acted on the muscular sys-
tem. Salamandrine was likewise found to cause progressive
weakness, the voluntary and spasmodic movements, particularly
those of the hind-quarters, being abolished. Phisalix and Ber-
trand also observed that the main effect of toad-venom was
paralysis of the lower extremities. Norris Wolfenden ascer-
tained that cobra-venom caused ascending paralysis, but that
this varied according to the species in which it occurred; in

••Wood: "Therapeutics," eleventh edition, 1900.

THE ADRENALS IN DISEASE AND POISONING. 41

man paraplegia was produced, while all four extremities were
finally paralyzed in animals. Finally, Valentin87 noted that
eel-venom, ichthyotoxin, caused absolute loss of conductivity of
sensation in the lower extremities.

Acetanilid is stated by Bokay88 to "paralyze motor nerve-
endings of the frogs' muscles in a manner similar to curare.
. . . In the poisoned animal just before death the muscles
respond actively": evidence that the muscular elements them-
selves were not affected by the poison, and that the "tonus,"
of which suprarenal secretion is the recognized source, alone
failed them. Aconite is said by Wood to give rise in thera-
peutic doses to "a sense of muscular inertia and weakness/' and
if the dose administered be larger "the muscular weakness is
extreme/' Alcoholic muscular relaxation hardly needs to be
insisted upon; the attitudes of drunkards speak for themselves.
Antimony in large doses is referred to as causing great mus-
cular relaxation, the exhaustion becoming extreme after toxic
doses. Antipyrin acts according to the dose administered,
causing rigidity in large doses (excessive momentary supra-
renal tonus), while "in overwhelming amount/' according to
Blumeneau,89 it causes in frogs "muscular relaxation with loss
of reflex activity deepening into complete paralysis and death."
Arsenic causes, even in small doses in the frog, cessation of
voluntary movement. The muscular weakness, lapsing into
complete exhaustion, that follows arsenic poisoning, is a famil-
iar clinical picture.

Belladonna — i.e., its alkaloid, atropine — is referred to as
follows: "When an enormous dose of the alkaloid has been
taken, a fatal stupor, with muscular relaxation, may develop
at once. . . . Probably, however, in all cases stupor and
muscular paralysis finally develop." . . . Bromism, accord-
ing to E. H. Clarke, is attended with "muscular weakness which
becomes paralysis." Camphor is referred to as giving rise in
large doses to a feeling of lassitude, while general paralysis
follows the ingestion of poisonous doses. Carbolic acid is stated
by Wood to give rise to muscular weakness, but a striking indi-

.* Valentin: Zeitschrift fur Biologic, 1877.

"Bdkay: Deutsche med. Wochenschrift, Oct., 1897.

••Blumeneau: St. Petersburger med. Wochenschrift, 1887.

42 THE PHYSIOLOGY OF THE ADRENALS.

cation of the relationship between the effects of carbolic-acid
poisoning and disturbed suprarenal functions is the reference
to the fact that in frogs and mammals "the paralyzing influ-
ences of carbolic acid are usually first manifested upon the
hind-legs." . . . Chloral is referred to as producing mus-
cular weakness and then paralysis. Labbee is stated to have
found that after death the muscles respond perfectly to gal-
vanism, thus eliminating organic alteration of the muscular
tissues as a factor in the paralytic phenomena.

The muscular relaxation witnessed in chloroform anes-
thesia needs only to be recalled. Cocaine is termed by Wood
"a muscle-poison, stimulating and afterward depressing the
functional activity." Copper is referred to as capable of caus-
ing progressive paralysis. Bokay90 found that the muscles were
affected very early by continuous doses, "cloudiness of their
protoplasm and disappearance of their cross-striation coming
on." This recalls the cloudy swelling previously referred to as
observed even in the adrenals themselves, the precursor of fatty
degeneration. Digitalis in toxic doses is said to cause lassitude,
prostration, and muscular tremors. Ether anaesthesia, and the
profound muscular relaxation produced, need only be men-
tioned. Hydrocyanic acid is termed a "paralyzant to the mus-
cles," general paralysis ensuing almost immediately after taking
a toxic dose. That the hind-extremities are first paralyzed in
animals we have ascertained. The effects of mercury in this
connection are well known, — "mercurial palsy," which occurs
within a few hours after the poison enters the organism; the
"peculiar brownish hue of the whole body" . . . "which
generally accompanies the disease," are easily accounted for
with suprarenal insufficiency as an element of the process.

Opium was found as long ago as 1826 by Charvet91 to
cause "progressive loss of power in the contractile tissue, end-
ing in death; in fishes, paralysis and convulsions; in birds and
mammals, paralysis, convulsions, and stupor." Interesting in
this connection is the observation credited to Albers92 that
"convulsive movements occur in limbs after section of their

» Bfikay: Pester med.-chir. Presse, 33, 1897.

91 Charvet: Perelra's "Materia Medica," 1035; Philadelphia, 1854.

•2 Albers: Virchow's Archiv, xxvi, 229.

THE ADRENALS IN DISEASE AND POISONING. 43

nerves." In man "alarming depression" also occurs. Oxalic-
acid poisoning is stated to be attended with "entire prostration
of strength." Phosphorus poisoning also produces "a sense of
weakness and general wretchedness." Physostigma gives rise,
after the full therapeutic dose, to "slight weakness and dislike
for muscular exertion" and in large doses to "great muscular
weakness." "When an animal receives a small fatal dose of
Calabar bean, after a time muscular tremors appear, and al-
most immediately the victim falls to the ground or lies down
in a state of perfect muscular flaccidity." Santonin poisoning
is attended with trembling, which increases in severity until
convulsions occur.

Silver was observed by Charcot and Ball93 to cause, when
injected directly into the blood, sudden paralysis of the hind-
extremities. Strychnine in large doses produces "muscular
twitchings and startings and formications" while toxic doses
induce spasm, opisthotonos, etc. Muscular relaxation other
than that occurring between convulsions is not referred to,
though death during these periods of exhaustion are stated to
sometimes occur. Asphyxia caused by the "unyielding, spas-
modically-contracted muscles" doubtless occurs before the
stage of suprarenal insufficiency is reached, strychnine, of all
agents, standing prominently as the most active suprarenal
stimulant. Tobacco poisoning is stated to cause "absolute loss
of muscular strength" and finally complete collapse. Veratrine
is referred to as primarily a muscle-poison, a stage of hyper-
excitability preceding the stage of paralysis. Zinc poisoning
is attended with prostration. As to chronic poisoning by this
metal, Wood refers to the experiments of Sacher,94 who found
that intravenous injections of very large doses of zinc salts
produced paralysis of the voluntary muscles.

We thus have typified in all these various poisonous agents
not only the typical muscular weakness observed in recognized
diseases of the adrenals and the total prostration following re-
moval of the organs, but we can also discern in the list a series
of grades or degrees in the loss of muscular function ranging

•» Charcot and Ball: Gazette Medicale, 1864.
M Sacher: Thesis, Dorpat, 1893.

44 THE PHYSIOLOGY OF THE ADRENALS.

from slight weakness to total paralysis. We not only behold
total loss of muscular power, therefore, as a result of supra-
renal-extract poisoning, but also as the result of absence of
secretion: i.e., of advanced suprarenal insufficiency. And what
is more simple than this cause of paralysis: the mere loss of
tone afforded by absence of secretion? That all remedies suffi-
ciently active to induce the phenomena outlined give rise to
both these phases of muscular activity through a primary effect
upon the adrenals — the source of the twitchings ascribed to
strychnine, for instance — will again be referred to.

Vascular Pressure. — The marked decrease of vascular
pressure accompanied by the still more evident cardiac weakness
which attends loss of suprarenal function has been emphasized.
We have also seen that the injection of suprarenal extract into
the circulation, besides enhancing vascular tone, slows the
heart. Both these phenomena appear under the influence of
venoms and poisons. In small doses these tend to increase
vascular pressure and slow the heart; in powerful doses they
reduce vascular pressure and weaken the heart.

Kauffmann is referred to by Noe as having observed that
viper-venom at once causes enormous reduction of arterial
pressure. "It is especially marked in the digestive tract/' says
this author, "a true gastro-intestinal apoplexy; it is the main
cause of death." Phisalix, on the other hand, observed that
viper-venom caused general vasodilation, congestion of all or-
gans, rapid lowering of blood-pressure, and weak pulse; and
found the blood to contain but a small amount of C02. Gouty
also observed vasodilation after injections of rattlesnake-poison.
Overactivity of the adrenals, typified by Swale Vincent's
injections into animals, and which caused hasmaturia, nose-
bleed, etc., soon followed by symptoms of marked insuffi-
ciency, is well illustrated by Fraser, who states that hasmor-
rhages are most marked in viper and rattlesnake intoxication,
and that hgematuria and haemoglobinuria were caused when
the full dose of venom has not entered the wound. Hsmaturia
attends, we shall see, overactivity; hgemoglobinuria, insuffi-
ciency. Fayrer observed that viper-venom caused intense hem-
orrhage and ha3maturia. Calmette also associates this symp-
tom with the cobra-venom. Scorpion-venom, according to

THE ADRENALS IN DISEASE AND POISONING. 45

Paul Bert, Phisalix, de Varigny, and others, sometimes gives
rise to intense congestion of certain viscera.

Are we really dealing, in this connection, with variations
of vascular tension and pressure? The presence of increased
vascular pressure is illustrated by the effects of smaller doses
or weaker poisons. Thus, Phisalix and Langlois95 are stated
to have found that salamandrine in small doses stimulated car-
diac action and greatly increased vascular pressure in dogs,
while large doses gave rise to ecchymotic spots and haemor-
rhages. So intense was the central depletion observed in frogs
that Dutartre hardly found a few drops of blood in the heart.
Mosso found that ichthyotoxin, the tissue-venom of the eel,
greatly increased blood-pressure, causing convulsions, while
small doses only caused slight and ephemeral increase of press-
ure, followed by a tendency toward diminution. He further
ascertained manometrically that the venom did not paralyze
the vessels (obviously since the poison had nothing to do with
it): a fact also sustained by the regular contractions of the
rabbit's auricles.

Intimately associated with the phenomena just outlined
are those connected with the heart. Do venoms affect this
organ as does adrenal extract? Weir Mitchell and Reichert
observed that snake-venom exercised a moderating action on
the heart. We now know that suprarenal extract acts directly
on the muscular elements of this organ. Vulpian called atten-
tion to the fact that toad-venom and triton-venom arrested the
heart by reducing the irritability of its walls. Kauffmann
found that viper-venom caused it to beat rapidly, but feebly,
the weakness increasing with the rapidity of the beats, but he
could find no moderator nerves. A weaker venom, on the other
hand, salamandrine, in small doses, was found by Phisalix and
Langlois96 to strengthen the weakened animal's heart and its
arterial tension. The correspondence between these effects
and those induced by suprarenal extract is thus further em-
phasized, since in all the venoms both actions are observable
according to the dose and the power brought into activity.

The same variations of pressure, cardiac and vascular, are

96 Phisalix and Langlois: Academie des Sciences, Sept. 6, 1899.
88 Ibid., Sept. 16, 1899.

46 THE PHYSIOLOGY OF THE ADRENALS.

observed in connection with poisons. Acetanilid in toxic doses
rapidly produces insufficiency. Even in repeated doses, accord-
ing to Wood, it may cause a peculiar cyanotic condition of
the face and extremities, while "the fall of temperature is ac-
companied by profuse sweating." . . . "In rare cases,"
says the author, "the lowering of the bodily temperature has
been coincident with the occurrence of collapse." The transi-
tion from overactivity to insufficiency would thus seem to
occur at the onset of hypothermia, deficiency of suprarenal
secretion being indicated by the diastolic heart found after
<leath from collapse. The sweating must obviously be due to
the loss of tone of the muscles of the sweat-glands. In aconite
we first have the characteristic picture of injections of supra-
renal extract indicating suprarenal activity, followed by the
characteristic signs of insufficiency. "In frogs," writes Wood,
"the phenomena caused by aconite are similar to those seen in
man, and consist of, at first, a reduction and afterward an in-
crease in the rate of the heart's beat, with a loss of power in
the circulation, and finally irregular systolic movements, with
marked prolonged diastolic pauses ending in diastolic arrest."
Alcohol is referred to as acting upon the heart as a stimulant
in small doses and as causing marked increase of arterial press-
ure. A large dose, on the other hand, is followed by a fall of
arterial pressure and acts as a depressant and paralyzant. The
stimulation is doubtless exercised upon the suprarenal glands,
and the reaction stage marks the onset of insufficiency whose
manifestations progress as more alcohol is imbibed. Antimony
is another agent which, like acetanilid, seems rapidly to induce
suprarenal insufficiency. "In the lower animals," writes Wood,
"all doses of antimony sufficient to cause any apparent effect
progressively lower the arterial pressure; the pulse is some-
times at first temporarily accelerated, but usually the slowing
of the pulse occurs from the beginning of the poisoning. Dur-
ing this period of slow pulse the diastolic pauses are extremely
long and the pulse-waves greatly augmented, it may be to five
times their original size. After a time the pulse usually be-
comes very rapid, the pulse-waves very small, the arterial
pressure almost extinguished, and in a few minutes diastolic
arrest occurs." The process referred to in these remarks,

THE ADRENALS IN DISEASE AND POISONING.

47

based on the experiments of Ackermann97 and Ernst Sentz,93
underlies -the clinical phenomena familiar to all as well as those
of Asiatic cholera, cholera infantum, and cholera morbus.

Antipyrin resembles acetanilid in its action. "Demme,
Arduin, Armand, H. Casimir,99 and Cerna and Carter100 have
separately determined by experiment that in moderate doses
antipyrin increases the arterial pressure, while toxic doses
lower the pressure." "The toxic dose of arsenic," says Pro-
fessor Wood, "greatly lessens the rate and force of the pulse-
beat and markedly lowers the blood-pressure." He refers to
the experiments of Unterberger,101 who "found that in an
animal under the influence of the poison neither galvanization
of a sensory nerve nor of the vasomotor center in the upp.-r
cord had any influence upon the force of the blood-current."
The reason for this is apparent with the adrenal secretion as
a factor of the process. Belladonna, or, better, its alkaloid,
atropine, it is stated, "may cause a primary slowing of the
pulse (very brief and only to be occasionally demonstrated),
followed by an extraordinarily rapid pulse, with a very great
rise in the arterial pressure; followed, after a time, if the dose
has been sufficient, by a progressive lowering of pressure until
death is reached, the rapidity of the pulse being maintained

until the end'

'in atropinized animals neither sec-

tion nor galvanization of the vagi affects the pulse-rate."

Bromides, these apparently benign agents, stand in this
connection as actively toxic as many of the more virulent drugs
reviewed. They seem to inhibit suprarenal activity even in
small doses. Schouten102 found that, during the injection of
a 2-per-cent. solution into the vena cava of a rabbit, "the car-
diac systole grew slower, the diastolic pauses longer, and finally
the heart stood still." Wood considers it as "well established
that large, toxic doses of the bromides exert a direct paralyzing
action on the heart, lessening both the force and the frequency
of the beat, and finally causing diastolic arrest." The relation

97 Ackermann : Virchow's Archiv, xxv, 531.

98 Ernst Sentz: Inaugural Dissertation, Dorpat, 1853.
90 H. Casimir: ThSse de Lyon, 1886.

100 Cerna and Carter: "New Remedies," 1892.

101 Unterberger: Archiv fur exp. Path., etc., ii.

102 Schouten: Archiv fur Heilkunde, xii, 97, 1871.

48 THE PHYSIOLOGY OF THE ADRENALS.

between the suprarenal insufficiency induced and the arrest of
the heart is apparent. Camphor is referred to as acting directly
as a stimulant to the heart-muscle. Interesting, however, is
Professor Wood's reference to the contrary results reached by
Alexander Lewin,103 which he ascribes to "the use of over-
whelming doses, camphor first stimulating and then depressing
the heart-muscle." Carbolic acid he refers to in the following
words: "The prominent symptoms induced by lethal doses are
disturbance of respiration; stupor, deepening into coma; rapid,
feeble pulse; muscular weakness; abolished reflexes; collapse;
fall of temperature, and albuminous or bloody urine, etc." It
is perhaps necessary to point to these phenomena as the exact
counterpart of total suprarenal insufficiency. Chloral at first
causes slowing of the heart's action. "Very large doses," ac-
cording to both Andrews and Da Costa,104 "decidedly lessen
arterial pressure. The characteristic influence of therapeutic,
and still more of toxic, doses is to produce a fall in the blood-
pressure, usually accompanied by a lessening in the frequency
of the heart's action."

The preliminary stimulation of cardiac action induced by
chloroform is well known. "Putting all the evidence together,"
writes Wood, "it seems to us to have been completely demon-
strated by physiologists, first, that chloroform is a direct de-
pressant and paralyzant to the heart-muscle or its contained
ganglia; second, that the fall of blood-pressure which occurs
in chloroformization is in great part due to this direct depres-
sion of the heart." Cocaine, as shown by various investigators,
produces an increase of arterial pressure when given in mod-
erate doses. "The drift of the present evidence," says Wood,
"is to show that the small dose of cocaine moderately stim-
ulates the heart, and that the large, toxic dose finally depresses
it."

Copper is another agent the clinical phenomena of which
recall those of cholera: toxic doses paralyze the heart in lower
animals. Digitalis, in batrachians, raises blood-pressure and
depresses it in the last stage. "In most of the experiments of

108 Alexander Lewin: Archiv fiir exp. Path., etc., 1890.

104 Andrews and Da Costa: American Journal of the Medical Sciences, April,
1870.

THE ADRENALS IN DISEASE AND POISONING.

49

J. P. Arnold and H. C. Wood, Jr., upon dogs," writes Wood,
"the change from a slow to a rapid pulse has been abrupt and
usually accompanied by an enormous rise of the already ele-
vated blood-pressure. At the end, the fall of pressure is very
sudden and rapid, so that it has immediately preceded death."
. . . "It seems to be clearly established that in poisoning
of the mammal by digitalis the heart is arrested, not in sys-
tole, but in diastole." It also seems "very certain that the
proposition framed for the lower mammals applies also to
man."

Ether is referred to in the following terms: "Our present
evidences show that there is, during ether anaesthesia, a rise
of pressure, which is, at least in part, the result of cardiac
action. . . . This rise is followed by a fall." . . . Hy-
drocyanic acid is probably the most violent suprarenal paral-
yzant; it was found by Preyer, Lecorche, and Meuriot to pro-
duce, in sufficient amount and concentration, instantaneous
diastolic arrest. In large, though not enormous, doses Preyer
and Laschkewitsch noted that "it first produced a sudden pro-
longed arrest of the heart, followed by an augmentation in
the rapidity of the cardiac action, and after this a diminution
of the rate: to the normal number in cases of recovery, to
cardiac standstill in cases of death." Small, non-toxic doses
simply slow the heart's action.

Mercury, in the form of corrosive sublimate, also gives rise
to choleraic symptoms in toxic doses. "In the course of two
or three hours," says Wood, "very rarely in less than an hour,
collapse occurs, with small, frequent, irregular pulse." Opium
is referred to as follows: "In man the circulatory phenomena
are a slight primary evanescent acceleration of the pulse-rate
(Nothnagel105), succeeded by the characteristic slowing and
increased fullness and force of the pulse, which is followed by
a return to the normal pulse or a great increase of the rapidity
and loss of strength during the third stage." Experimentally
it was found to cause arrest of the heart in diastole. Oxalic-
acid poisoning is also attended by a small, irregular pulse.
Phosphorus, in the very acute cases of poisoning, may be at-

106 Nothnagel : "Handb. d. Arzeneimittellehre," 1870.

50 THE PHYSIOLOGY OF THE ADRENALS.

tended with pronounced cardiac weakness, even in the primary
stage. "The patient," says Wood, "may suddenly succumb to
collapse and cardiac paralysis." Physostigma, injected in poi-
sonous doses into the jugular vein, causes death from syncope
or from simultaneous "failure of the cardiac and respiratory
functions, and the heart is arrested in diastole. When smaller
doses are exhibited, there is slowing of the heart's action."
Santonin in toxic doses causes slowing of the pulse in dogs, and
rapid or slow, feeble pulse in children. Silver salts when in-
jected into the veins were found by Charcot and Ball, Rabuteau
and Mourier to cause instantaneous death, which is ascribed
by these investigators to "a direct paralyzing influence of the
drug upon the muscle of the heart." Strychnine is stated by
Wood to produce in full dose "a rise of the arterial pressure,
which is enormously increased during the convulsion, after
which there is a very pronounced fall in the arterial pressure."
Tobacco, or rather its alkaloid, nicotine, is referred to as hav-
ing "a very distinct influence" upon the circulation, "produc-
ing, first, rise, and afterward fall, of pressure." Veratrine, even
in small doses, causes slowing and weakening of the pulse, and
a toxic dose has produced collapse, with rapid, thready, and
irregular pulse. The toxic effects of zinc are similar to those
of copper referred to above.

This long list of toxics can be said to fully indicate, first,
that all poisons primarily induce a more or less marked period
of overactivity: i.e., increased vascular pressure and cardiac
energy. The central vascular trunks are suddenly contracted,
the heart is stimulated by the direct action of an unusual
amount of suprarenal secretion. Second, that at a given time
and when the dose and power of the toxic are sufficiently
great, this increase of activity ceases and is replaced by a more
or less marked decrease of vascular pressure and cardiac energy.
The central vascular trunks are then dilated and the heart-
action reduced through a corresponding reduction of suprarenal
secretion.

Temperature. — A marked reduction in the temperature,
we have seen, is a prominent symptom of advanced supra-
renal insufficiency. The symptomatology of all forms of
poisoning also includes this phenomenon. As to venoms,

THE ADRENALS IN DISEASE AND POISONING. 51

Phisalix106 refers to hypothermia as the most marked charac-
teristic of viper intoxication. He found it to occur rapidly
and to an intense degree, reaching in guinea-pigs as low as
22° C., though death usually occurred at 32° C. He also
observed that hypothermia prevailed after injections of ich-
thyotoxin, or eel-venom, while Bottard107 noted it in guinea-
pigs after injections of sea-dragon venom. Hutinel also ob-
served it in a case of cobra-bite, the temperature of the patient,
a man, reaching down to 31.2° C.

Acetanilid affords a striking illustration of the proposition
that when the central vascular trunks are dilated the periph-
eral capillaries are contracted. Wood refers to the experiments
of Hare, subsequently confirmed by Evans, in which a distinct
fall of temperature was observed to have followed the use of
acetanilid in normal animals allowed to run free. In a criti-
cism of these observations he writes: "In examining the records
of the calorimetric experiments made by Hare and Evans on
the normal animal, we find that not only did the rectal tempera-
ture not fall under the influence of antifebrin, but in nearly
every instance there was a distinct rise, amounting in some
cases to over a degree. It is evident, therefore, that these
experiments cannot be used to explain how antifebrin reduces
temperature when it does cause a fall." In truth, they can be
used for this purpose, but only with dilation of the large
vascular trunks of the abdomen, and secondary contraction of
the peripheral capillaries as factors of the process. The in-
ternal congestion caused the rise of temperature observed by
Wood; the peripheral depletion caused the lowered tempera-
ture observed by Hare and Evans. And so it appears to be
with all drugs we term "antipyretics" whose main effects are
exercised by withdrawing blood from the surface through in-
sufficiency of the adrenals induced by them, and transferring
it to the abdominal vascular trunks. In other words, they
merely remove the excess of temperature from the surface and
transfer it to the internal organs.

The temperature in severe aconite poisoning is stated to
undergo "a very pronounced fall," though at the very start it

106 Phisalix: Archives de Physiologie, 1894.

107 Bottard : These de Paris, 1889.

4

52 THE PHYSIOLOGY OP THE ADRENALS.

may rise slightly: an effort of the adrenals to abnormal activity
before insufficiency prevails. Alcohol, a cardiac stimulant, was
found by Ruge108 to lower the temperature 3° C. when given
in sufficient quantity to animals to produce narcosis, while a
lethal dose reduced it 5° C. The flushed face of the drunkard
betokens adrenal overactivity with contraction of the abdom-
inal vascular trunks and congested capillaries, while the pallor
of the advanced stage typifies the contrary condition. Anti-
mony is also stated to perceptibly reduce animal heat. Wood
refers to the observation of Ackermann, who observed a fall
of 6.6° C. in rabbits that lived five hours. In fact, the term
"cardiac depressant" points to insufficiency of the adrenals.
Insufficiently supplied with its normal tone-giving element, the
suprarenal secretion, the heart is arrested in diastole. Anti-
pyrin likewise gives rise to a fall of bodily temperature, but
we have here a set of symptoms which emphasize the presence
of further advanced suprarenal insufficiency: an eruption fol-
lowed by a brown pigmentation. Bullae, which recall those
previously referred to as observed in children whose adrenals
were found heemorrhagic post-mortem, also follow the use of
this drug in some cases.

Arsenic poisoning has already been referred to as simulat-
ing cholera, for which, according to Wood, it has not only been
mistaken "during life, but also on the post-mortem table."
It is the intense suprarenal insufficiency, similar in degree,
brought on by arsenic as well as by the cholera toxin, that
gives rise to the phenomena witnessed, among which is "icy
coldness." Belladonna, with its alkaloid atropine, affords a
good example of the antagonistic effects that always prevail.
Stimulated to great activity by this drug, the central vascular
trunks are contracted and the surface capillaries engorged at
first. But, while a marked increase may be caused by large
doses, as is well known, poisonous doses will bring it down
below normal. In animals this reduction has reached 5.1°
C. The bromides in toxic doses, to use Wood's words, "lower
very decidedly the temperature." We have typified in the
effects of these agents continued insufficiency of adrenals, just

Ruge: Virchow's Archiv, xlix, 265.

THE ADRENALS IN DISEASE AND POISONING. 53

sufficient to keep up moderate peripheral capillary contraction,
with resulting impaired nutrition: the so-called "bromism."
Dougall's case,109 in which 1 V2 ounces of potassium bromide
was taken in 24 hours, affords a picture of total suprarenal
insufficiency, weak pulse, cold extremities, temperature of 96.8°
F., general cutaneous anaesthesia, coma, etc. Camphor, classed
as an antispasmodic, is referred to as giving rise to "cool,
pale, and livid skin" in poisonous doses. Carbolic acid, classed
as antipyretic, was found by Hare110 to produce a very distinct
fall of temperature in rabbits. Chloral, a somnifacient, is
referred to by Wood as follows: "A most remarkable action
of chloral is upon the temperature." In this particular all ob-
servers agree with Kichardson, of London, who has seen the
temperature fall 6° F. in a rabbit which recovered. Hammer-
sten observed a fall of 6° C. (Wood) in an hour in animals well
wrapped up and laid in a warm place.

Chloroform furnishes a typical picture of suprarenal ac-
tivity followed by insufficiency. The central trunks, at first
contracted, produce engorgement of the peripheral capillaries,
causing facial congestion and suffusion, accompanied by cere-
bral excitement. When the dangerous stage comes on, the
contrary occurs: dilation of the central trunks depletes the
peripheral capillaries. The heart-muscle, more or less rapidly
deprived of the suprarenal secretion, gradually or suddenly
fails, according to the quantity of secretion furnished its walls.
These phenomena coincide with the temperature changes.
Simonin111 "found that the temperature rises during the first
stage (1.1° to 0.9° C.), falls slightly during the second or re-
mains above normal, and falls decidedly during the third stage."
Cocaine, a "delirifacient," is stated to cause a "rise of rectal
temperature in cocaine poisoning, which sometimes amounts
to as much as 8° F." . . . "It is certainly not due to con-
vulsions," says Wood, "as it usually occurs before the motor
disturbance." Copper sulphate was found by Falck112 to cause
great depression of temperature. Digitalis also lowers the tem-

i°» Dougall: Glasgow Medical Journal, Feb., 1893.
«° Hare: Therapeutic Gazette, No. 519, 1887.
"i Simonin: Centralblatt fur Chirurgie, 234, 1877.
112 Falck: Deutsche Klinik, vol. xi, 1859.

54 THE PHYSIOLOGY OF THE ADRENALS.

perature several degrees in healthy men and animals, this
hypothermia being preceded by a temporary rise.

Ether was found by Angelesco113 to lower the temperature
to a greater extent than chloroform. Ether-pneumonia would
thus appear to be but a manifestation of the suprarenal insuf-
ficiency started by the anaesthetic when the recuperative powers
of the organs are impaired. Hydrocyanic acid acts with such
promptness that the distinction between hypothermia and the
increasing coldness of the extremities preceding death cannot
be differentiated. Mercury was found by Kuperwasser114 to
lower the temperature 2° C., in some instances, when admin-
istered in injudicious doses. Opium and its alkaloids are re-
ferred to as causing the skin to become cold and moist when
given in toxic doses. Oxalic acid in poisonous doses also gives
rise to livid surface and cold skin. Phosphorus is often at-
tended, when ingested in toxic doses, with what Wood terms
"a remarkable fall in the temperature/' the lowest point re-
corded some hours before death being 31.2° C. (88.2° F.).
Physostigma brought the temperature of a strong man down
to 96.6° F. Santonin poisoning is also attended with great
coldness of the surface. Silver salts have likewise been found
to lower the temperature of animals.

Strychnine is another agent which enables us to verify the
correctness of the contention that a low peripheral temperature
means an increased central temperature. Wood refers to the
observations of Kionka, who showed that "the primary eleva-
tion of temperature which occurs in strychnine poisoning, both
in man and the lower animals, is in animals followed by a
pronounced fall, which takes place even if the convulsions per-
sist," and to the affirmations of Mosso,115 that "even in cura-
rized dogs a very pronounced rise of rectal temperature may be
produced by strychnine." Very suggestive in this connection
is the denial credited to Delezenne,116 "who states that in
curarized animals the exhibition of strychnine is always fol-
lowed by an abatement of the central temperature, which is

118 Angelesco: La Semaine Medicale, Dec. 14, 1894.

u* Kuperwasser: Archives des Sciences Biologiques de St. Petersburg, No. 6,
1898.

115 Mosso: Archives italiennes de Biologic, 1886.

118 Delezenne: Bulletin Medical du Nord, xxxiv, 1895.

THE ADRENALS IN DISEASE AND POISONING.

55

often, but not always, followed by an increase of the tempera-
ture of the surface/' This increase Delezenne explains by "the
supposition that the drug has the power of dilating the periph-
eral vessels." It now becomes evident that the only discrepancy
between the observations of Mosso and Delezenne is that the
latter used smaller doses of strychnine than the former, thus
producing central contraction and peripheral dilation, instead
of central dilation and peripheral contraction. Tobacco,
veratrum, and zinc show corresponding effects, and close the
list of agents whose temperature variations are considered
along with other toxic effects. All present a reduction of
peripheral temperature as a sign of advanced poisoning; none
show simultaneous central and peripheral hypothermia; sev-
eral incidentally prove that, when peripheral hypothermia is
present, there is simultaneous internal hyperthermia, thus
further sustaining the view that the effects on temperature
ascribed directly to drugs are of suprarenal origin.

The symptoms just reviewed and with which those asso-
ciated with functional disturbances of the suprarenal glands
so accurately coincide, represent the most prominent ones
witnessed. There are several others, however, that are directly
traceable to these organs. Of these, dyspnoea seems to point
to so important a modification in the prevailing views respect-
ing the physiology of respiration that it will be treated in con-
junction with the latter function.

Cerebral Activity. — The reduction of cerebral activity —
indicated by drowsiness, apathy, vertigo, coma, etc. — seems
also to be — at least partly — of suprarenal origin. All drugs
capable of acting as toxics apparently produce effects in this
particular, corresponding exactly with those that follow re-
moval of both adrenals or advanced Addison's disease, after
giving rise to a period of excitement which also reproduces
that caused by injections of suprarenal extract. We thus have
again exemplified a period of suprarenal activity, followed by
one of insufficiency. Four drugs taken at random — atropine,
alcohol, opium, and cannabis Indica — will serve to illustrate
these facts.

In atropine poisoning, the patient who, in the primary
stage was talkative, perhaps violent, and showed marked evi-

56 THE PHYSIOLOGY OF THE ADRENALS.

dence of increased vascular pressure, including cerebral hyper-
aBmia, — a pathological condition often observed at autopsies, —
more or less suddenly lapses into a period of quietude which
recalls the critical stage of many diseases. Drowsiness, con-
fusion of thought, and coma then appear in quick succession.
That we are dealing with suprarenal insufficiency is shown by
the concomitant loss of muscular power beginning in the lower
extremities and which may reach the stage of paralysis. Is
this condition due to cerebral exsanguination? Paralysis of
one of the extremities of a frog poisoned with atropine may
be interfered with, according to Wood, by tying the member.
This demonstrates that peripheral vascular depletion under-
lies the production of paralysis as well as the reduction of
cerebral activity, since tying the frog's leg can have but one
result: i.e., prevent the return to the dilated abdominal trunks
of at least a part of the blood in the limb.

Acute alcoholism probably typifies better than any con-
dition brought on by poisons the fall from a primary intense
erethism of the cerebral circulation to the opposite state
through suprarenal insufficiency. The cheerfulness and the
gestures of the inebriate often reach a stage of inco-ordinate
excitement, mental and physical. Epileptic seizures are
brought on not only in epileptics, but also, at times, in indi-
viduals that are not subject to the disease. If deterioration
of the cerebral cellular elements have occurred through pre-
vious excesses and delirium tremens appear, the delirium is
attended with terrors and frightful vision; if mania a potu
prevail, the patient — perhaps gentle and kindly disposed nor-
mally— becomes furious, wild, shouts and strikes, often with
homicidal intent, him or her whom he probably .most cherishes.

Here, again, the suprarenal glands are shown to be pri-
mary factors of the process by the excessive muscular activity.
But is the action of the secretion exerted directly upon the
muscular tissues or upon the nervous structures themselves,
including the centers? The action of alcohol "would seem to
be due," according to Wood, "to a direct action upon the
heart itself or upon the walls of the arterioles." By inserting
"suprarenal secretion" instead of the word "alcohol" the proc-
ess becomes clear, since it is the former which would cause

THE ADRENALS IN DISEASE AND POISONING. ~>~

contraction of the walls of all muscular vessels and of the
heart-muscle, followed by centrifugal pressure in the cerebral
capillaries almost to bursting-point: the source of the intense
hyperaemia found post-mortem.

In mania a potu, in which the most violent mania pre-
vails, the pulse is strong, bounding, and tumultuous: an indi-
cation of correspondingly excessive suprarenal activity. When
the critical stage is reached, — the first sign that the organism's
protective organs, the adrenals, are losing their hold, — reason,
will, and consciousness fail, and insensibility soon follows.
That these organs are concerned in the production of these
effects is demonstrated by the marked fall of the blood-pressure,
and the rapid, thin, and compressible pulse. The lower limbs,
early in this stage, have first shown their inability to support
the body. "In the majority of carefully examined cases the
lower limbs are affected before the upper" wrote Norman Kerr
several years ago, though not aware that in this statement he
pointed to a primary sign of suprarenal insufficiency.

Opium, we know, first stimulates mental activity and
procures sensations of well-being. Simultaneously, muscular
activity is increased — slightly in man, markedly in animals.
In the latter, particularly, tremors and cramp-like contractions
— true tetany — are sometimes witnessed. The vascular press-
ure is raised, the face is congested, suffused, and sometimes
cyanosed, the skin being dry and warm. The heart's power is
increased and the pulse is correspondingly full and strong.
"No phenomenon of human poisoning by opium can be at-
tributed to its action on nerve-trunks," says Wood.117 The
effects must also, therefore, be exerted upon muscular ele-
ments alone. When the crisis is reached, drowsiness lapses
into deep sleep, from which the patient is roused with diffi-
culty. If he is awakened, weakness and general prostration
are more or less noticeable. The vascular pressure is lowered;
pallor and cyanosis attest to imperfect oxidation; and respira-
tion has become distant, feeble, and shallow. The heart's
action is depressed and weak, the temperature low, and the
skin cold and moist — all signs of suprarenal failure.

117 Wood: Loc. cit., p. 125.

58 THE PHYSIOLOGY OF THE ADRENALS.

Cannabis Indica is an interesting drug in this connection,
in that it seems to stimulate the adrenals just sufficiently to
awaken purely psychical phenomena. This does not prevent,
however, the most commonplace evidences of organic disturb-
ance. Exhilaration, revery, ecstasy, hilarity, visions, exalta-
tion, etc., account for the attraction possessed by some Hindoos
for their hashish. But an overdose soon asserts the physical
nature of all these phenomena. Tonic contractions, local
spasms, a flushed and warm surface, heightened reflex activity,
a full and strong pulse appear here as well as after poisonous
doses of other drugs. When the crisis occurs, unconsciousness,
paresis — beginning also in the lower extremities — a feeble and
rapid pulse, attest to the effects of cannabis Indica or hashish
upon the adrenals.

The list of agents in which such phenomena occur includes
all those capable of causing intoxication. They all with more
or less emphasis confirm the existence of a direct relationship
between morbid cerebral phenomena and the suprarenal glands.

Polyuria and Anuria. — Anuria is commonly observed in
animals deprived of both capsules. On the other hand, injec-
tions of suprarenal extract, as shown by Swale Vincent,118
cause marked thirst and abundant micturition. This author
also observed that the subcutaneous tissues simultaneously
became distinctly cedematous. The causes of these manifesta-
tions seem clear. The reduced or arrested flow of urine re-
sulted, in the decapsulated animals, from the immediate con-
centration, in the visceral vascular trunks, of blood drawn from
the peripheral capillaries; the increased flow was caused by
the intense increase of vascular pressure, which brought on
capillary engorgement, not only of the urinary apparatus, but
also of the skin. That inordinate capillary pressure underlies
such a process is evident, since we not only have the ha3maturia
to sustain the assertion, but also the fact, noted by Swale
Vincent, that the "subcutaneous tissues were cedematous and
blood-stained."

If we now turn to drugs, an interesting point suggests
itself, namely: that the same effects of suprarenal overactivity

118 Swale Vincent: Journal of Physiologie, Feb. 17,

THE ADRENALS IN DISEASE AND POISONING. 59

and insufficiency are observed whenever the agent administered
is not one which tends to inhibit metabolism of the renal cellular
elements or to cause renal irritation in moderate doses.

Opium, for instance, markedly inhibits metabolism; dur-
ing the primary stage of suprarenal activity the quantity of
urine is not only reduced, but complete cessation of the flow
is often witnessed. We simultaneously have diminished elim-
ination of urea and other waste-products. Copper is poisonous
to all forms of protoplasm; it either gives rise to suppression
or, if the dose be less active and anuria does not occur, it causes
haematuria, and the tissues, as in Swale Vincent's animals, are
blood-stained. Quinine occasions similar phenomena; hsama-
turia is brought on in some cases; methsemoglobinuria — a
sign of suprarenal insufficiency, as will be shown — in others.
Judging by the ratio of waste-elimination, however, urea, uric
acid, phosphoric acid, etc., quinine must also inhibit tissue-
metabolism, and as the signs of suprarenal insufficiency only
appear after very large doses, the anuria must be an attendant
symptom of suprarenal activity. The anuria due to irritation
may be illustrated by the effects of iodoform: a drug which
readily induces inflammation of the glomeruli. Iodine also
irritates the kidneys and causes nephritis when given in large
doses; but these need not be such as to cause suprarenal in-
sufficiency. Anuria, therefore, may appear along with violent
cerebral excitement, a markedly increased vascular pressure
and cardiac power — all evident signs of suprarenal overactivity.
In two of our own cases iodide of potassium administered for
syphilis gave rise to oedema of the glottis: a localized oedema
of suprarenal origin. The oedema brought on by arsenic is
of the same kind. In large doses it reduces the excretion of
urea, and increases that of phosphoric acid and also1 — an im-
portant point in this connection — that of sodium chloride.

Alkalinity of the plasma, due mainly to the alkaline phos-
phates and carbonates it contains, is an all-important factor of
the blood's physiological functions; and the sodium chloride
also present serves not only to facilitate osmosis, but also to
preserve the solubility of the globulins. While the water and
possibly the other constituents of the urine are separated from
the blood by the glomerular epithelial cells, and not by filtra-

60 THE PHYSIOLOGY OF THE ADRENALS.

tion resulting from blood-pressure, the fact remains that, when
the quantity of blood passed through the glomeruli is aug-
mented, the formation of urine can be correspondingly in-
creased. The enhanced blood-pressure incident upon supra-
renal overactivity may, therefore, become directly responsible
for the diuresis observed when agents other than those capable
of causing irritation of renal structures or of inhibiting the
metabolic process of their cellular elements are employed.

These facts, collectively considered, account for the pres-
ence of many diuretics among alkaline salts, but they cannot
be included among the agents capable of causing diuresis
through suprarenal overactivity, because they belong to a class
of remedies which do not stimulate the adrenals before inducing
insufficiency of these organs, and the first signs of poisoning,
therefore, are those attended by general depression. "No dose
of a potash ever calls forth symptoms of circulatory stimulation
from the human body/' says Wood, referring to the diuretic
salts; and, indeed, if they do, the signs are hardly perceptible.
An overdose of the potassium nitrate for instance, is soon fol-
lowed by a symptom complex including "collapse, great mus-
cular weakness" . ... "with or without paralysis of the
lower limbs," and "suppression of the urine in some cases" —
doubtless those in which the dose was sufficiently large. A
dangerous salt in this connection is potassium chlorate, which
suddenly brings on most violent symptoms of poisoning: the
exact symptom-complex following removal of both adrenals.

It thus becomes apparent that there are two classes of
diuretics: i.e., those that increase micturition through stim-
ulation of the suprarenal glands and those that act independ-
ently of these organs — probably, in the case of alkaline diu-
retics, through the increased alkalinity they bring about, and
liquefaction of the blood-serum they enhance. That the latter
factor also comes into play when the adrenals take part in the
process is probable. The supposed oxidizing power of potas-
sium salts is probably due also, though indirectly, to the in-
creased alkalinity which their introduction into the blood
causes.

Among the true alkaline diuretics, the strontium salts
alone seem to cause preliminary suprarenal overactivity. The

THE ADRENALS IN DISEASE AND POISONING. 61

vegetable diuretics, buchu and uva ursi, undoubtedly do so,
and it seems probable that it is only with toxic doses of their
active principles — hydrochinone in the case of uva ursi, for
instance — that the stage of suprarenal insufficiency can at all
be reached. Digitalis gives rise to very marked symptoms of
suprarenal overactivity, followed, when excessive doses are ad-
ministered, by the typical signs of insufficiency.119 Huchard
aptly ascribes Petresco's remarkable results in pneumonia, in
this connection, to the fact that the digitalis-leaves employed
by him were rich in alkaline salts. The diuretic effect and
the continued alkalinity of the plasma thus insured must cer-
tainly have done much to enable him to obtain the remarkably
low death-rate reported: i.e., 2.06 per cent, of 825 cases
treated. The bearing of a reduced sodium-chloride ratio upon
the prognosis of this disease is well known.

Among general remedies, the coal-tar products — anti-
pyrin, acetanilid, sulphonal, etc. — may be classed with those
which give rise to a short stage of excitement, attended some-
times, in the case of acetanilid, with copious urination. Here,
again, all the signs observed after removal of both adrenals
occur, and when anuria is absent methaemoglobinuria or haema-
toporphyrinuria sometimes appears. Yet the bladder must
always be taken into account in such conditions. Wood says,
for example, that this organ is completely paralyzed in ad-
vanced atropine poisoning. While forcible expulsion of urine
occurs in the primary stage, — that of suprarenal activity, — the
flow steadily decreases and finally ceases. "It rises and falls
with the arterial pressure," observed Meuriot120: a strong hint
that the adrenal functions are involved.

All these facts seem to us to show that what are now con-
sidered as the cardinal symptoms of poisoning are, in reality,
manifestations of overactivity or of insufficiency of the adrenals,
and that the functions of these organs may le stimulated, inhibited,
or arrested in two ways: —

1. By a direct action of the toxic agent upon their cellular

119 This gives us a clue to the meaning of the supposed "cumulative" property
of digitalis. Continued stimulation finally overtaxes the adrenals.
1*0 Meuriot: Quoted by Wood, loc. cit., p. 174.

62 THE PHYSIOLOGY OF THE ADRENALS.

elements and most liable to occur in acute infectious and chronic
diseases and intoxications.

2. By an indirect action upon the vascular supply of the or-
gans through a primary action upon the centers of the nervous
elements that control the adrenal secretion and most liable to occur
in acute intoxications by toxins, venoms, vegetable and mineral
poisons.

That a simultaneous action upon both the suprarenal ele-
ments and the centers of their nervous supply may occur, how-
ever, is probable.

3. The period between the two general stages, stimulation and
depression, seems to coincide with that considered in the course of
acute disease as the crisis.

As toxic effects are alone involved in the foregoing proc-
esses, it is probable that: —

4. The adrenals are potent factors in the efforts of the or-
ganism to prevent the destructive effects which this selective affinity
engenders, when poisons, in sufficient doses to do harm, are intro-
duced into the circulation. This subject will again be considered
in the chapter on "Immunity."

CHEMICO-PHYSIOLOGICAL PROPERTIES OF THE ADRENAL
SECRETION.

Digitalis, notwithstanding its apparent predilection for the
heart, affects this organ through its action upon the adrenals.
But the heart-muscle is not alone stimulated by this drug; the
entire muscular system responds to its action precisely as it
does to that of other sufficiently active agents. Muscular over-
activity, tremors, increased response to electrical stimulation,
and other signs of erethism prevail. The vascular pressure is
raised to such an extent in the web of frogs and in the mesen-
tery of rabbits that the lumina -oi the arterioles are almost
completely obliterated. The heart's action is slowed and the
diastole prolonged, and when in the laboratory the behavior
of the ventricles can be watched, they actually become white
through the intensity of their contraction. That this is at-
tributable to the powerful contracting effect of suprarenal
extract upon muscular tissue and its constricting influence upon
vessels supplied with muscular fibers, as demonstrated by

CHEMICAL PROPERTIES OF ADRENAL SECRETION.

Co
O

Oliver and Schafer, seems evident. And yet, notwithstanding
these effects, — those for instance which are so marked in the
arterioles of the frog's web, — if we remove blood from an in-
jected animal's peripheral vessels, even the larger ones, or
blood from those of any animal, or even of a human being, a
puzzling fact asserts itself, namely: this blood shows no sign
of the presence of suprarenal secretion. How then does it give
rise in these remote regions to the phenomena which are un-
questionably of suprarenal origin?

From what has already been stated of the nervous relations
of the structures directly influenced by suprarenal extract and
its effects upon isolated tissues, the intervention of the nerves
as a factor of the process does not even bear a superficial
analysis. Another source of inquiry is available, however: i.e.,
the possibility that the suprarenal secretion has undergone a
chemical reaction in the blood, through which it has conveyed
to the latter its physiological properties, while losing its own
identity. This question can only be elucidated by inquiring into
the chemical nature of the suprarenal active principle and the
manner in which its biochemical functions are performed.

One of the first investigators to clearly define the nature
of the suprarenal secretion was G-ottschau,121 who observed,
in some of his preparations, projections of the medullary cells
into the lumen of the central vein; he was also able to obtain,
by slight pressure of the glands, blood which contained proto-
plasmic masses. Manasse122 also found in man masses of
medullary cells and even buds of the substance of the supra-
renal capsules in the interior of veins, more frequently in the
medullary than in the cortical substance. The same peculiari-
ties were noted in the horse, the ox, the pig, and the sheep.
Medullary tubes, the central portion of which was filled with
brown, hyaline masses secreted by a double row of cells seen
in their interior, projected into the lumen of the veins, those
situated at this point being deprived of their endothelial cov-
ering. The brown, hyaline masses were thus secreted by the
adrenals and carried into the circulatory stream. A. G. Auld123

121 Gottschau: Archiv fur Anatomie und Physiologie, 1883.

122 Manasse: Revue des Sciences Med. en France et a l'6tranger, July 15, 1894.
128 A. G. Auld: British Medical Journal, Oct. 4, 1894.

64 THE PHYSIOLOGY OF THE ADRENALS.

characterized this secretion as "colloid." Biedl124 subsequently
found these masses to consist of clear, yellow, bright granules,
resembling blood-plaques or fragments of red blood-cells,
though the ratio of white and red corpuscles in the vessels was
normal.

The earliest chemical investigations in this connection
were probably those of Vulpian,126 of Paris, who found that
the juice expressed from the suprarenal glands of various ani-
mals contained a powerful reducing substance which gave
color-reactions obtainable with no other tissue of the organism.
Thus, with ferric chloride, this suprarenal juice gave an
emerald-green color, and with iodine solutions, a rose-carmine
tint. Attempts to isolate the chromogenic substances were
made by several investigators, including Virchow, Arnold, and
Holm, but without success. Krukenberg126 many years later
concluded that the suprarenal chromogen was a non-volatile,
nitrogenous, and ferruginous organic acid, the green color-
giving substance being "more likely pyrocatechin accompany-
ing the chromogen." An alcoholic extract prepared by Brun-
ner127 gave nearly all the pyrocatechin reactions, while the
addition of an alkali caused it to assume a brown color. Miihl-
mann128 ascribed the blood-pressure-raising power to a pyro-
catechin derivative . taken up with ether from the residue of
fresh adrenals boiled with dilute hydrochloric acid, and which
became brown on exposure to light or contact with alkaline
solutions. The principal substance entering into its formation,
mainly derived from vegetable foodstuffs, were, he thought,
present in the blood and supposedly built up in the cortex.
Eecent investigations, however, have not sustained Miihlmann's
views. Giirber129 not only found it impossible to establish the
relationship thought by Miihlmann to exist between the active
principle and pyrocatechin, but the latter substance did not,

124 Biedl: Pflliger's Archiv, vol. Ixvii, H. 9 and 10, 1897.

128 Vulpian: Comptes-Rendus, vol. xliii, pp. 663-665. Quoted by J. J. Abel and
A. C. Crawford, Johns Hopkins Hosp. Bull., July, 1897.

128 Krukenberg: Virchow's Archiv, ci, 542-591, 1885. Quoted by Abel and
Crawford, loc. cit.

127 Brunner: Schweizer Wochenschrift fur Pharmacie, xxx, 121-123.

128 Muhlmann: Deutsche med. Wochenschrift, June 25, 1896.

129 Giirber: Sitzungs. d. physik. med. Gesellschaft Wurzburg, 1897.

CHEMICAL PROPERTIES OF ADRENAL SECRETION. 65

when injected, cause a rise of blood-pressure. Abel and Craw-
ford130 noted that it could not be isolated from the active com-
pound by boiling with acids: a conclusion further corroborated
by von Fiirth.131

Moore132 studied the chemical reactions noted by Vulpian
from another standpoint. Having noticed that the blood-
pressure-raising properties of a previously active substance dis-
appeared after the color-reactions were destroyed by oxidizing
the reducing agent, he was led to conclude that the color-giving
constituent of the suprarenal substance was the same as the
blood-pressure-raising constituent. The solubilities of both
were similar, while both, also, were found only in the medulla
or in the suprarenal vein. Manasse133 obtained from the supra-
renal medulla a substance resembling greatly in chemical prop-
erties Drechsel's jecorin, but its reducing power was found to
differ in several particulars from that described by Vulpian
and Moore. Friinkel,134 by utilizing the more advanced meth-
ods of organic chemistry, also reached the conclusion that Vul-
pian's chromogen and the blood-pressure-raising constituent
were identical, and called it "sphygmogenin" : a nitrogenous
derivative of the orthodioxybenzine series. He succeeded in
isolating the jecorin-like body obtained by Manasse and Vul-
pian's reducing substance, and attributed to the latter the
blood-pressure-raising attributes.

A closer investigation of the whole subject was then un-
dertaken by J. J. Abel and A. C. Crawford,135 of Johns Hop-
kins University, who recalled that all previous work had
brought forth conclusions based on reactions made with aqueous,
alcoholic, or acetonic extracts only, and that so far no definite
chemical compound had been isolated. They found, by isolat-
ing the blood-pressure-raising constituent, Vulpian's chromo-
gen, in the form of a benzoate, and, decomposing it, that the
active principle was a substance which could, in all probability,
be classed with the pyridine bases or alkaloids, or the pyrrol

30 Abel and Crawford: Johns Hopkins Hosp. Bull., July, 1897.

31 Hoppe-Seyler: Zeitschrift fur Physiol. Chemie, vol. xxiv.

32 Moore: Journal of Physiology, vol. xviii, p. 230.

33 Manasse: Zeitschrift fur Physiol. Chemie, vol. xx, p. 478, 1895.
8*Frankel: Wiener med. Blatter, Nos. 14, 15, and 16, 1896.

86 J. J. Abel and A. C. Crawford: Johns Hopkins Hosp. Bull., July, 1897.

60 THE PHYSIOLOGY OF THE ADRENALS.

compounds. In a subsequent paper Abel136 announced that he
had isolated the active principle of the suprarenal capsule in
the form of a light-gray or brownish powder whose percentage
composition could be expressed by the formula C17H15N04.
This approaches in elementary composition several alkaloids,
namely: pseudomorphine, represented by C17H19N04; cocaine,
the formula of which is C17H21N04; while sanguinarine, whose
power to raise blood-pressure is noteworthy, is represented by
C20H15N04. Again, in the course of previous work, Abel and
Crawford had noticed that suprarenal extract, entirely free
of proteids and physiologically active, gave a pyrrol reaction
on dry distillation, as evidenced by the odor and various tests.
Alkaloids — morphine, "for instance — also give pyrrol on dry
distillation; while, on the other hand, pyrrol compounds, to
which Abel's active principle — called by him "epinephrin" —
belongs, are known to possess marked blood-pressure-raising
properties. While the free base prepared at high pressure, or
its salts, is not active in this particular, the free base prepared
at low pressure is very active, and, of its salts, — the benzoate,
picrate, hydrochlorate, hydrobromate, and sulphate, — the latter
is most particularly so. Its identity is also demonstrated by
the fact that, as is the case with suprarenal extract, its effects
are ephemeral; small doses intravenously injected at first ex-
cite, then centrally depress, respiration, heart-failure following
the use of large doses. Again, its kinship to chromogens be-
comes apparent through the fact that uroerythrin, the normal
pigment principle of the urine, exhibits properties very similar
to epinephrin. Finally, active suprarenal extractives are known
to be very prone to become oxidized; this tendency is so marked
in the case of epinephrin that it is a source of great incon-
venience. Von Fiirth, of Strassburg,137 has also produced an
active principle which he has termed "suprarenin," but this
product does not seem to show properties superior to those of
epinephrin. J. Takamine138 has more recently contributed a
preparation which he has named "adrenalin," the physiological
activity of which is said to be remarkably powerful, a fraction

138 Abel: Johns Hopkins Hosp. Bull., Sept.-Oct., 1898.

137 Von Fiirth: Journal fur prakt. Chemie, Bd. xxix, S. 105.

iM j. Takamine: Therapeutic Gazette, April 15, 1901.

CHEMICAL PROPERTIES OP ADRENAL SECRETION. G7

of a drop of a solution of 1 to 10,000 being sufficient to blanch
the conjunctiva. It was found to be equally active as a blood-
pressure-raising substance, Vaooooo gramme intravenously in-
jected into an adult man being sufficient to produce a distinct
effect.

A striking feature that a review of the biochemical work
done in this direction discloses is the peculiar property shown
by the various preparations of suprarenal gland and its ex-
tractives to become oxidized. Abel has found this feature so
marked, for example, that it caused him, as we have seen, con-
siderable inconvenience. Takamine states that the colorless,
aqueous solution of adrenalin is easily oxidized by contact with
the air, its color changing from pink to red and eventually to
brown. Cybulski also observed that the addition of weak doses
of permanganate of potassium destroyed the activity of the
suprarenal extract, and held that the office of the active prin-
ciple was to sustain the activity of the vasomotor and respira-
tory centers, the vagi and accelerator nerves, and probably also
the center which maintains the muscular tonus. He also
thought that oxidation might account for the temporary effects
which injected suprarenal extract produced. His views were
shown to be erroneous by Oliver and Schafer, however, and
indirectly by other physiologists. Yet, while Cybulski's hypoth-
esis is untenable, the remarkable affinity for oxygen shown
by suprarenal extractives remains and affords a solid chemical
foundation upon which our inquiry can be based.

By what process could this property to become oxidized en-
able adrenal extractives to induce the contraction of muscular
tissues which underlies blood-pressure-raising power? Besides
their pressure-raising power, these extractives also possess a
property which may elucidate some phases of the problem be-
fore us, namely: the fact that injections of suprarenal extract
counteract, at least for a time, the morbid phenomena wit-
nessed after removal of both adrenals. This, in a measure,
refers us to the liver, and it may prove profitable to first study
the relations of this organ with the toxic phenomena which
removal of both adrenals awakens. Especially is this probable
since we have control evidence in the fact that a large number
of investigators have observed that the toxic symptoms thus

5

68 THE PHYSIOLOGY OF THE ADRENALS.

caused could be counteracted by injections of suprarenal secre-
tion. Thus, Abelous and Langlois139 found that the fatal
effects of removal of both organs in frogs could be delayed by
the insertion of small pieces of the removed gland into the
dorsal lymph-sac, and also by injections of suprarenal extract.
Cybulski140 also noted that intravenous injections of 1 cubic
centimeter of a 10-per-cent. solution of suprarenal extract
caused all the toxic phenomena to disappear after the extirpa-
tion of both adrenals, the effect lasting from a few minutes to
one-half hour. In normal animals the extract merely increased
pressure, lowered the pulse-rate, and accelerated respiration.

The oxygen-ratio of hepatic tissue first claims our atten-
tion, since it is possible that the suprarenal secretion might
lose its identity as such by yielding to the liver some of its
own molecular constituents: i.e., constituents endowed with
less affinity for the remaining suprarenal components than for
structures containing, as does the liver, a high ratio of fixed
oxygen. The labors of Schmiedeberg, Jaquet, and Salkowski141
may advantageously be used to ascertain this point.

Schmiedeberg, to study the oxidation of living tissues,
used benzilic alcohol and salicylic aldehyde, because these sub-
stances do not burn in air, while they are easily consumed in
the organism. Their oxidation products could only, therefore,
originate in the latter. Jaquet142 also demonstrated the cor-
rectness of Schmiedeberg's observation that the blood alone
caused but an extremely small quantity of benzilic alcohol to
become oxidized into benzoic acid, while salicylic aldehyde
was in no way influenced. His researches further confirmed
Schmiedeberg's discovery that, when these agents were simply
dissolved in the blood, they were easily oxidized into benzoic
acid by living tissues. The blood, as a whole, seemed to retard
oxidation, since the process occurred with greater rapidity
when blood-plasma alone — i.e., serum devoid of all its cor-
puscular elements — was used as a solvent. Not only was lung-
tissue, for instance, found to act perfectly as an oxidizant, but

189 Abelous and Langlois: Archives de Physiologic, vol. xlli, p. 267, 1892.

140 Cybulski : Gazette Lekarska, March 23, 1895.

141 Schmiedeberg, Jaquet, and Salkowski: Archives G6n6rales de M6decine,
March, 1898.

142 Jaquet: Archiv fur exp. Path., 1892.

CHEMICAL PROPERTIES OF ADRENAL SECRETION. 69

frozen lung-tissue, as hard as wood, as well. Horse-lungs and
kidneys kept from twelve to fourteen days in alcohol at sev-
enty-five degrees, even after having become sodden with physio-
logical saline solution, etc., were found fully active. Abelous
and Biarnes143 successfully used blood alone as an oxidizant,
but only tulien a continuous current of air traversed the blood
treated with salicylic aldehyde. Schafer and subsequently Auld
also observed that the activity of suprarenal extract was not
in the least impaired when blood and the extract were mixed
in vitro even when allowed to stand some time.

Salkowski144 repeated the experiments of Schmiedeberg
and Jaquet, in order to ascertain the differential oxidizing
powers of various viscera. The following proportions of sali-
cylic acid were obtained from salicylic aldehyde placed in
contact a definite time with 100 grammes of the following
organic tissues: Liver, 138 milligrammes; spleen, 110 milli-
grammes; kidneys, 22 milligrammes; pancreas, 2.8 milli-
grammes; and muscle, 1.4 milligrammes. This clearly demon-
strates, at least, that the liver and spleen are by far the organs
that take up and fix the greatest proportion of oxygen, and
that, of all organs, the liver is the most active oxidizing agent.
Now, Langlois found that maceration of hepatic tissue with
suprarenal extract greatly decreased the activity of the latter.
The remarkable affinity for oxygen possessed by the extract
normally suggests that, like salicylic acid, it must have become
oxidized at the expense of the liver-tissue and that it is through
this reaction that its' activity became impaired. Still, the con-
trary might be the case and the liver acquire its own oxygen-
storing properties from the secretion of the adrenals and take
it up from the blood while the latter is in transit through it.
Under these circumstances it would also acquire the blood-
pressure-raising power of the secretion. That such is not the
case, however, is evident. Swale Vincent could not obtain the
effects of suprarenal extract with either liver or spleen extracts;
neither could Mankowsky145 from extracts of liver, pancreas,
thyroid, lymphatic glands, parotid, kidney, spleen, cerebrum,

148 Abelous and Biarn6s: Archives de Physiologic, 1895.

144 Salkowski: Virchow's Archiv, Jan. 4, 1897.

145 Mankowsky: Russian Arch., March, 1898.

70 THE PHYSIOLOGY OF THE ADRENALS.

heart, or even of muscle. Evidently, therefore, the great
affinity of the suprarenal extractive for oxygen caused it, as
had the salicylic aldehyde, to take up and fix the hepatic oxygen,
and the fact that in doing so it lost its activity appears to us to
indicate that its physiological functions are in some way con-
nected with this property.

If the affinity of the suprarenal secretion for oxygen is the
source of its physiological activity, where would the useful
reaction occur? The first important vessel reached by the se-
cretion is the inferior vena cava. As veins contain blood which
has served its purpose in the organism, it is not likely that this
blood should be utilized otherwise than as a vehicle. Again,
that it is not in the blood of the vena cava that the secretion
undergoes a reaction is obvious; it enters the blood-stream
near the heart: i.e., where the proportion of oxygen is normally
at its lowest ebb. That this acts only as a carrier for the secre-
tion, therefore, is evident. Yet there is a very interesting and
suggestive feature connected with the itinerary of the secretion
and which bears directly upon the question in point. Biedl
and Szymonowicz undoubtedly found the secretion in the ves-
sels near the adrenals, but not in other veins of the organism.
Blood drawn from the suprarenal vein gave rise, when injected
into the blood-stream of a normal animal, to manifestations
similar to those observed after the injection of suprarenal ex-
tract, while injections of blood taken from other veins were
followed by negative results. The suggestive feature referred
to is that the limits of the organs in which the reaction must
occur become restricted to the neighborhood, as it were, of the
channels in which the secretion first appears. What are the
limits of this "neighborhood?"

The inferior vena cava supplying nothing capable of sug-
gesting a reaction in its blood, the secretion must reach the
heart, and, if it does, its presence must in some way become
manifest, since we have seen how powerfully this organ re-
sponds to the action of suprarenal extract. But, of course, it
is necessary to ascertain whether it reaches the heart under
normal conditions. Digitalis, owing to its well-known action
upon the heart-muscle, suggests itself as a ready means for
this purpose. Indeed, its toxicology not only associates it di-

CHEMICAL PROPERTIES OF ADRENAL SECRETION. 71

rectly with suprarenal functions, but it constitutes one of the
most active suprarenal stimulants, judging from the character
of the symptoms to which it gives rise. Striking, for instance,
is the fact that its action is greatest on the right side of the
heart: a fact emphasized by many authorities, including Ringer,
Frangois Franck, Hale White, Germain See, and Openkowski.
As this is the side which the suprarenal secretion would first
reach, a strong indication is afforded that the stimulation we
ascribe to digitalis itself is really induced by the secretion of
the adrenals. It is evident, however, that the myocardium can-
not supply the required oxygen, since it only stands 1.4 milli-
grammes as a muscular structure to the liver's 138 in Salkow-
ski's series. Again, its structure and physiological functions in
no way indicate a connection with any chemical change in the
fluids that pass through it.

The next organs are the lungs, the tissues of which, ac-
cording to Abelous and Biarnes, occupy a third place as oxidiz-
ing agents in the experimental series: i.e., immediately after
the spleen and liver. Yet, the reaction cannot occur in the
parenchyma to which these experiments refer, since, judging
by the effects of the suprarenal secretion throughout the entire
body, the whole volume of blood submitted to the respiratory
process must be utilized. May the suprarenal secretion be a
physiological factor of the respiratory gaseous interchanges?

Among the symptoms observed after the extirpation of
both adrenals is dyspnoea. When the physiological and patho-
logical origin of this symptom is analyzed in the light of the
views submitted in the foregoing pages, the possibility that the
respiratory process may in some way be connected with the
suprarenal glands imposes itself. This can be illustrated by
what appears to us to be a sudden awakening of suprarenal
activity by one of our best agents for this purpose, strychnine.
"It produces in the dog," says Wood, "an extraordinary increase
in the respiratory movements"; his experiments have shown
that this "never amounted to less than 75 per cent., and some-
times rose to 300 per cent." He refers to Kionka's observation,
confirmed by Obermeier,146 that "in the rabbit there is a

146 Obermeier: Inaugural Dissertation; Erlangen, 1891.

72 THE PHYSIOLOGY OF THE ADRENALS.

notable increase in the production of carbonic acid: i.e., of
oxidation/' Kionka147 is also stated to have found that "blood
taken from the strychninized animal did not absorb oxygen
with the avidity of normal blood, although no spectroscopic
changes could be discovered in it. We are evidently in the
presence of an inordinate and excessive functional manifesta-
tion: i.e., an extraordinary increase in the respiratory move-
ments, of oxidation, and of C02 production. That such is the
case is sustained by the fact that this oxygen-laden blood does
not absorb in vitro as much 0 as would normal blood. It is
further branded as a result of excessive function by the ab-
sence of spectroscopic changes.

The corresponding effect of toxic doses of suprarenal ex-
tract is well shown by Swale Vincent,148 who states: "In cats,
by far the most noticeable feature was an enormous rapidity
of the respiratory movements in the early stage. ... In
one frog the condition induced appeared to resemble that of
strychnine or veratrine poisoning. On touching the animal
a short series of spasms set in. But that the effects were not
due to the spinal cord was shown by its destruction, when the
condition of the animal was apparently the same as in another
with cord intact." In rats he found that doses of 0.25 to 0.5
gramme of dried suprarenal gland produced "quick and shallow
respiration." It seems clear that toxic doses of suprarenal
extract give rise to increased respiratory activity, and further-
more that these effects did not originate in respiratory centers.
Neither can the effects of strychnine be asserted to be of cen-
tral origin. "On chloralized dogs the respiratory effects of the
alkaloid were even more pronounced," writes Wood. The
paralyzing effects of chloral upon the medulla are well known.
All these facts, collectively considered, seem to strongly sug-
gest that dyspnoea and other respiratory phenomena are due to
variations, qualitative and quantitative, of the suprarenal se-
cretion, and directly associated with the functions of the glands
themselves.

This conflicts with the generally-accepted teachings con-
cerning the effects of poisonous blood upon the respiratory

147 Kionka: Archives de Pharm. Inter., vol. iii, 1898.

i« Swale Vincent: Journal of Physiology, vol. xxii, No. 4, Feb. 17, 1898.

CHEMICAL PROPERTIES OF ADRENAL SECRETION.

73

centers, and particularly with the view that these centers "may
be excited both by blood that is rich in carbon dioxide and by
blood that is poor in oxygen." And yet there probably does
not exist in the whole domain of physiology a question ad-
mittedly more obscure, and in which ingenious theories have
proven more sterile. A reduction of the oxygen in the blood
is thought to impair central functions, although there is
ample experimental evidence to prove that such is not the
case. The blood of an animal may in great part be removed
and replaced by saline solution and its breathing continue as
quietly and regularly as before the procedure. The same re-
sults have been obtained even in frogs from which the heart
had been removed. As elsewhere in the organism, the func-
tions of the medullary centers occur in virtue of the molecular
changes, which must normally be enhanced, if at all, by an
excess of oxygen and inhibited by an excess of carbonic acid.
How can, therefore, the latter give rise to increased respiratory
activity?

That considerable uncertainty prevails in this connection
is shown by the following lines by Professor Foster149: "A
lack of oxygen in the blood, or a nervous impulse along an
afferent fiber, both affect the center by modifying its metab-
olism; but each probably affects it in a different way. It is
beyond our present knowledge to explain how either the one
or the other acts. We may imagine that a lack of oxygen, on
the other hand, has a more profound effect in modifying the
whole complex series of metabolic changes, the whole chain of
building-up and breaking-down processes, thus in some way or
other rendering the whole edifice, so to speak, more unstable;
and that an afferent augmenting impulse (and possibly an
excess of carbonic acid) acts rather after the fashion of what
we are accustomed to call a stimulus, and fires off a larger
amount of the already stored up explosive compounds. And
we may further imagine that the special feature of the sub-
stance of the respiratory center is that the metabolism is so
arranged as to be thus, unlike that of other living substances,
rendered unstable and more explosive, not simply diminished

149 Foster: "Text-book of Physiology," p. 383.

74 THE PHYSIOLOGY OF THE ADRENALS.

or deadened by a lack of oxygen. But these, as yet, are matters
of speculation."

The clinical evidence which could be adduced to emphasize
a relationship between the respiratory functions and the ad-
renals is very great. Several of the more prominent symptoms
of the algid stage of Asiatic cholera, for instance, when con-
sidered collectively, — cyanosis of the extremities and face, in-
creased frequency of the respiratory movements and dyspnoea,
etc., — point to the lungs as the seat of morbid phenomena.
Cyanosis obviously denotes insufficient oxygenation whatever
be its cause, while imperfect oxygenation in turn implies an
increase of the carbonic-acid ratio. That this gas accumulates
in the organism during cholera has been demonstrated. The
connection is further suggested by the symptoms that follow
extirpation of suprarenal glands in mammals; so closely do
they resemble those of Asiatic cholera as to suggest that we
have in this disease the characteristic symptom-complex of
arrested suprarenal function. Besides the general manifesta-
tions, which will be reviewed later on, those pertaining to gen-
eral vital processes, oxygenation, temperature, etc., are similar
in both conditions. Both show great reduction of vascular
pressure, with consequent small and rapid pulse, while both
are alike attended by "increased frequency of the respiratory
movements, dyspnoea, and often cyanosis and subnormal tem-
perature" during what might be termed the algid stage of both
morbid states, which are also similar in this particular. If,
then, the symptoms referred to are traceable to the lungs in
cholera, we are warranted, we think, in ascribing those that
occur after extirpation of the adrenals also to the lungs. Espe-
cially is this permissible since we are led to the lungs for a
reaction which the chemical properties of the adrenal secretion
render possible, and since they are so anatomically disposed as
to make it possible to distribute the charged blood, through the
agency of the heart, to all the tissues of the organism.

Indeed, the more the inquiry progresses in this direction,
the more does it become evident that an important relation-
ship exists between the suprarenal and the pulmonary func-
tions. A striking feature is the apparent exemption of the
pulmonary tissues to the effects of suprarenal secretion. Wai-

CHEMICAL PROPERTIES OF ADRENAL, SECRETION. 75

lace and Mogt,150 of Ann Arbor, found that, while suprarenal
extract caused a rise in the systemic blood-pressure due to the
contraction of the arterioles, the pressure in the pulmonary
arteries was not raised, these vessels, in their opinion, not being
acted upon as are the others. Velich,151 on the other hand,
found, by a series of experiments instituted to ascertain whether
vasoconstrictor fibers exkted for the pulmonary vessels, that
suprarenal extract gave rise to but a slight rise of pressure:
a result which led him to conclude that the existence of a spe-
cial vasoconstrictor mechanism, either central or peripheral,
for the pulmonary circulation, could not be considered as estab-
lished. Warm suprarenal extract, which, when applied even to
the skin, causes pallor, was found by him to exercise no such
effect upon the surface of the lungs. Briefly, upon all other
tissues the effects of suprarenal extract are strongly marked;
as soon as the pulmonary structures — where the conversion of
venous blood into arterial blood occurs — are reached, its powers
practically cease.

True, the physiology of respiration as at present interpreted
in text-books and as generally taught would not be sustained.
This does not mean, however, that all physiologists have finally
accepted the prevailing doctrine based on the diffusion of gases.
Indeed, there is considerable experimental evidence based on
the labors of Eobin, Bohr, Miiller, and others to show that it
is by no means invulnerable. "When," says Prof. Mathias
Duval,152 of Paris, "an animal is caused to breathe in the
smallest possible space — the air imprisoned in its lung by
strangling — it uses up all the oxygen of this air. This is be-
cause hemoglobin, in virtue of its chemical affinity, takes up
the oxygen as fast as this gas is dissolved in the serum, so that
the latter, always despoiled, is never able to satisfy its absorp-
tion coefficient for oxygen, however low be this coefficient, and
however slight be the tension of the oxygen in the surrounding
air. As to the exhalation of carbonic acid, it is not produced
in so simple a manner as would a priori seem, by mere gaseous
diffusion or by the mere giving off of a gas in solution, because

160 Wallace and Mogt: Transactions of the Physiological Society, Dec. 28-30,
1898.

151 Velich: Wiener med. Wochenschrift, No. 26, 1898.

152 Mathias Duval: Cours de Physiologic, Ed., 1892..

76 THE PHYSIOLOGY OF THE ADRENALS.

of the scarcity of the gas in the surrounding atmosphere. In-
deed, the air in the pulmonary vesicles contains 8 per cent,
of carbonic acid, hardly a favorable condition for the escape of
carbonic acid from the blood, especially since a portion of this
gas is not dissolved, but combined with the serum salts. It is
therefore probable that the pulmonary tissues are the seat of
an action having for its object to rapidly dislodge the carbonic
acid. This action is probably of a chemical nature.153 . . .
Whenever oxygen is mixed with venous blood, even in vitro
during experiments, the carbonic acid is immediately given off.
One is led to admit, therefore, that the combination of oxygen
with the blood-corpuscles (oxyhaemoglobulin) plays a role
analogous to that of an acid, and involving the elimination of
carbonic acid from venous blood." He refers to Eobin and
Verdeil's view in respect to the existence of a hypothetic
"pneumonic acid" and to the experiments of Gamier,154 who
observed that ultramarine blue sprayed into the lungs of living
guinea-pigs lost its color: a phenomenon which could only
occur through the presence of a strong acid, neither taurin
nor carbonic acid being capable of producing it. "Chemical
analysis of the lung has not disclosed a specific acid, however."
. . . "It is, perhaps, wrong," adds Professor Duval, "for
physiologists to continue to only see in these phenomena mere
results of endosmosis of liquids and of diffusion of gases
through an inert membrane."

To study this question satisfactorily, however, and place
the deductions reached upon a strong footing, it is necessary
to clearly define the relations between the various bodies con-
cerned in the process. All the phases of the problem, physio-
logical and pathologi2al, must therefore be analyzed. The fol-
lowing facts, however, seem to afford a firm foundation for the
inquiry: —

1. The adrenals secrete a colloid substance which penetrates
the lungs with the venous blood and cannot be traced beyond these
organs.

2. The secretion of the adrenals possesses a marked affinity
for oxygen.

163 The italics are our own.

"" Gamier: Comptes-Rendus de 1' Academic des Sciences, July 26, 1886.

CHAPTEK II.

THE INTERNAL SECRETION OF THE ADRENALS

IN ITS RELATIONS TO THE RESPIRATORY

PROCESSES AND THE COMPOSITION

OF THE BLOOD.

THE PATHOGENESIS OF BRONZING AND ADDISON'S DISEASE.

BoiNET1 found a large proportion of black pigment and
hgematoidin crystals in the blood of a decapsulated rat which
had lived several months after removal of its capsules. This
pigment proved on analysis to be similar to that obtained from
the skin, mucous membrane, and other structures of two fatal
cases of Addison's disease. The identical black pigment was
also found by him in more or less great quantities in 75 per
cent, of 109 decapsulated rats. It was distributed practically
everywhere, including the lungs. In several of these animals
and in a number out of another series of 20 in which the ad-
renals had been experimentally cauterized with tincture of
iodine, silver nitrate, ferric chloride, or zinc chloride, or irri-
tated with pus from inflammatory or tuberculous lesions, the
pigment had permeated the subcutaneous cellular tissue besides
the other structures. In 3 animals in which the pigment in-
filtration had been abundant, the adrenals had not only been
removed, but excessive fatigue had been induced by rotation
or frequently repeated electric shocks. All the rats from which
the glands had been removed sooner or later presented the
characteristic signs that follow this operation. Some of those
in which the organs had been cauterized showed "marked mus-
cular paresis with tardy asthenia: features that gave them the
aspect of incompletely curarized animals and which further
completed the analogy between the pigmentary infiltration and
a sort of Addison's disease."

The liberation of this pigment through removal of the
adrenals suggests as a working hypothesis that the secretion of

i Boinet: Marseille Medical, April 15, 1896.

(77)

78 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

these organs serves to keep united or hold together various bodies
entering into the formation of hcemoglobin and that it is concerned
with the affinity of this compound for oxygen.

In man the blood-pigment is more soluble than in animals,
and the likelihood of observing similar effects in human blood
to those witnessed in that of Boinct's rats is slight. Cutaneous
pigmentation and the pigments observed will, therefore, have
to form the basis of our inquiry. The first affection to present
itself, Addison's disease, will serve a double purpose; it will
not only enable us to trace a closer connection between the
respiratory blood-changes and suprarenal secretion, but also
the manner in which the adrenals exercise their prophylactic
mission notwithstanding the inroads of local organic disease.

Bronze spots have been observed in connection with a
variety of disorders in which the adrenals were apparently
normal: abdominal growths, diabetes, exophthalmic goiter,
tuberculosis, chronic gastric and hepatic disorders, hysteria,
pulmonary sarcoma, cholangitis, etc. To conclude, however,
as some authors have done, that the adrenals are not involved
in Addison's disease or in any other disorder is doubtless in-
judicious, since any disease may directly or indirectly implicate
the central or extrinsic nervous structures of the organs, in-
hibit their nutrition, disturb their metabolism, and in this
manner give rise to organic lesions only appreciable micro-
scopically. Indeed, it must be admitted that much of the work
reported in this connection is quite valueless and, in fact, mis-
leading. Arnaud, as already stated, found, in one hundred
adrenals picked up at random at autopsies, thirty-six which
microscopically showed more or less marked lesions. What can
the statement that "the suprarenal glands were found normal"
based upon a macroscopical inspection of the organs be worth
under these circumstances?

A single perfectly normal adrenal, we have seen, can com-
pensate for an inactive or extirpated mate, and, as no bronzing
seems to follow unilateral adrenalectomy, we can at least sur-
mise that this symptom will not appear unless the functions
of both organs are simultaneously compromised. This is sus-
tained by the six cases of adrenal haemorrhage out of the eighty
collected by Arnaud, in which true bronzing was present. A

THE PATHOGENESIS OP BRONZING; ADDISON'S DISEASE. /9

review of each of these will prove interesting. In a case cred-
ited to Mattei2 the skin of the face, neck, forearms, and hands
was bronze-like, while marked muscular debility was com-
plained of. The accompanying broncho-pulmonary congestion
with emphysema and valvular disorder did not account for the
bronzing. At the autopsy both adrenals were found hsemor-
rhagic. In Carrington's3 case the bronzing was especially
marked over the mammary glands, the penis, and scrotum, and
the patient died of progressive asthenia. Both lungs were
found oedematous and dark, and both adrenals diseased and
probably cancerous. In Murray's4 case the skin was described
as brown; there was dyspnoea, cough, and asthenia, but the
patient's illness only lasted four days. Both capsules were
hasmorrhagic. Less clearly defined is a case reported by
Northrup,5 in which an "abnormal color" was associated with
haemorrhage into both capsules. In Leconte's case the dis-
coloration is termed "swarthy," with large sepia-like spots,
discovered after death. The case was one of pulmonary tuber-
culosis, but unusually cachectic. No tubercular foci were
found in the adrenals; one of these was atrophied and the
other was studded with hgemorrhagic puncta the size of a millet-
seed. In Eayner's6 case a "marked olive hue" is referred to,
the patient suffering from bilateral bronchitis and pain in the
lumbar region. Death occurred suddenly and both adrenals
were found haemorrhagic. The interesting feature of these six
cases is that they are all associated with organic lesions of
both adrenals, while all cases (excepting two in which the dis-
coloration is obviously ascribable to other disorders) with only
one organ diseased show no discoloration. This does not mean,
however, that bilateral organic lesions always cause bronzing,
inasmuch as there were twenty-seven of such cases in which no
discoloration appeared, but it emphasizes the fact that, when
bronzing occurs, both adrenals are diseased or functionally insuffi-
cient.

2 Mattel: Lo Sperimentale, p. 386, Case III, 1883.

3 Carrington: Transactions of the Pathological Society of London, 1885.

* Murray: Transactions of the Pathological Society of London, vol. xxi, p.
396, 1870.

s Northrup: Proceedings of the New York Pathological Society, p. 161, 1889.
8 Rayner: Cited by Roger in 1'Experience, May 10, 1837.

80 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

But why does bronzing not occur in all cases of bilateral
organic lesion? To study this feature of the problem we must
first eliminate all cases in which the cutaneous changes could
not have Lad time to develop. Burns, traumatisms (including
compression of the funis or of the body at birth), asphyxia, and
toxic processes of various kinds can suddenly produce haemor-
rhage into both organs simultaneously and cause death long
before any such symptom as bronzing can at all be produced.
Almost all hemorrhages observed, in fact, appear to be of
recent date. To ascertain the point in question we must, there-
fore, not only utilize cases in which very clear post-mortem data
are furnished, but also cases in which both glands can be shown
to have been diseased sufficiently long to have involved both
the parenchyma and the cortex and to have caused bronzing
through complete structural disorganization.

Of the eighty cases collected by Arnaud, but two appear
in which both suprarenal capsules seem to have been suffi-
ciently diseased to lead us to expect the appearance of bronzing
if complete structural disorganization of these organs in its
evolution can give rise to this symptom. In Goolden's case7
all the symptoms of Addison's disease were present except
bronzing. The autopsy revealed that both organs were prac-
tically destroyed. Yet the left organ still contained a small
quantity of medullary substance, and the acute symptoms had
come on suddenly a few months before with as suddenly devel-
oped ancemia. The second case is one of Arnaud's, in which
both organs were transformed into large organized hgema-
tomata. The patient having been brought into the hospital
in a comatose condition, his history could not be traced; but
there was no bronzing. The histological data of the neoplasms
clearly indicate that they were not of recent formation, while
no other visceral lesion could be detected. But again do we
find a small area of normal parenchyma in the right capsule.
Can we attribute the continuation of the organ's functions and
the absence of bronzing to the presence in both cases of these
remnants of suprarenal medulla? We probably can, since the
work of various investigators — Gourfein particularly, as pre-

Goolden: Lancet, p. 266, vol. ii, 1857.

THE PATHOGENESIS OF BRONZING; ADDISON'S DISEASE.

81

viously stated — tends to show that one-twentieth of both glands
suffices for the continuation of those functions for a given time.

In the light of all that has been incorporated in this work
so far, these cases suggest an explanation of the causes of
bronzing which it might be well to outline before going any
farther. Collectively considered, the data alluded to suggest
that any case of suprarenal disease may proceed to death without
reaching the stage of bronzing, for, in all instances in which this
symptom occurs, the suprarenal insufficiency, whether due to
intrinsic or extrinsic disease, must have reached a correspond-
ingly advanced stage. Disease of any structure which directly
or indirectly nourishes or innervates the adrenals, or any or-
ganic lesion of the organs themselves, can thus inaugurate a
condition that will lead to their physiological insufficiency both
quantitative and qualitative. But, and this is the important
feature: the integrity of the organs must be greatly compromised
before their all-important functions become implicated in the mor-
bid process — so great is the supply of cellular reserve which
Nature has granted them, or so small perhaps, in proportion
to its potency, is the amount of secretion required to satisfy
the needs of the systemic functions which they normally sup-
ply. It is only when this minimum limit of normal activity is
passed that the stage of bronzing begins, preceded or soon fol-
lowed by the earlier symptoms of Addison's disease. The latter
would thus represent but an advanced stage of slowly pro-
gressive suprarenal insufficiency brought on by a pathogenic
cause of any kind.

The application of this conception to the many paradoxical
phases which Addison's disease presents in respect to its main
symptom, bronzing, singularly clears the field, besides afford-
ing a basis for all the theories, based on careful study, which
have been advanced so far concerning the origin of this
symptom.

If Lewin's proportion of caseous glands in Addison's dis-
ease, 74 per cent., and Oilman's, 80 per cent., are considered
collectively, — i.e., 77 per cent., — we are only obliged to account
for 23 out of 100 cases which do not present tuberculous
lesions of the adrenals. For this purpose we have at our dis-
posal all the diseases to which the nervous, vascular, and lym-

82 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

phatic supplies of the organs — including, of course, their
cerebro-spinal connections — are liable. The pericapsular
nerve-ganglia, for example, which, according to Alezais and
Arnaud,8 may be diseased without implicating the nerves and
ganglia of the solar plexus, have been so often found the seat
of lesions by these clinicians that, in their opinion, bronzing
only occurs when these structures are diseased. Lesions of the
sympathetic have so frequently been noted by Lancereaux9 when
bronzing is present that he ascribes this symptom only to ex-
tensive disease of the nerves and ganglia of the abdominal
sympathetic. That all nervous structures peripheral to the
adrenals are involved in the pathogenic process of bronzing
has been contended by Fenwick, Greenhow, Jurgens, Raymond
and other observers. At the origin of the nervous structures,
the spinal axis, Kalendero and Babes10 found chronic sclerosis
of the posterior roots, with marked swelling .of the axis-cylin-
ders of the spinal nerves, as main features of a typical case.
Bonardi11 noted in another instance spinal lesions exactly
similar to disseminated myelitis of toxic origin. Thus any
disease of the nervous supply including the cord may be etio-
logically associated with bronzing, but only when, as is the
case with local lesions, the morbid process is far advanced.
This is readily accounted for when we consider the wide mar-
gin of glandular substance present, which likewise insures the
continuation of physiological functions even under greatly im-
paired innervation. Disease of the semilunar ganglia or of any
other nervous structure might thus exist, as it often does,
without causing physiologically perceptible lesions of the ad-
renals. The vascular lesions are, briefly, those of the general
vascular supply, particularly atheroma.

A kinship to some cardiac valvular lesions is also suggested
by the presence of valves in the veins of the capsular plexus,
emptying into the lumbar vein, as shown by J. M. Flint,12 who
says: "Thus the circulation in the medulla depends somewhat
on the condition of pressure in the lumbar vein, and stagnation

8 Alezais and Arnaud: La Semaine Medicals, Oct. 7, 1891.

9 Lancereaux: Archives Generates de Medecine, Jan., 1890.

10 Kalendero and Babes: La Semaine M6dicale, Feb. 22, 1889.

11 Bonardi: Revue Neurologique, Aug., 1897.

12 J. M. Flint: Johns Hopkins Hosp. Reports, vol. ix, 1900.

THE PATHOGENESIS OP BRONZING; ADDISON'S DISEASE. 83

of the blood-current in the vena lumbaris would induce a con-
gestion in the venous tree of the medulla." If we recall the
puthogenesis of suprarenal hasmorrhage as reviewed in the
earlier portion of this work, the connection between this con-
dition and possible valvular lesions of the adrenals will appear.
The lymphatic glands bear the same relations to these organs
as the nervous system, and give rise to bronzing when in addi-
tion to tuberculous processes in distant chains, the peribron-
chial, cervical, etc., the abdominal lymphatics are sufficiently
diseased to seriously interfere with the suprarenal functions.
This sometimes occurs when the abdominal glands alone are
affected, as was the case in an instance recorded by Henry
Waldo.13 Their important connection with the diseases which
most frequently cause structural lesions of the organs — tuber-
culosis, cancer, etc. — obviously gives them a prominent posi-
tion in their pathology.

Under all these conditions, even with advanced peripheral
disease, the organs may appear normal macroscopically and
their functional integrity be so compromised as to give rise to
bronzing. Structural destruction of one adrenal and functional
inhibition of the other through peripheral lesions may also
occur simultaneously and thus lead to the belief, at the autopsy,
that one organ was normal. Again, the great margin of func-
tional power with which these organs are endowed places beyond
question the fact that long before a sufficiently extensive in-
volvement of both organs can have occurred the patient may die,
all the stages of organic lesion appearing post-mortem. Vul-
nerable in the extreme, these cases, if the general affection does
not carry them away before bronzing will have had time to
appear, sink rapidly under the effects of any intercurrent dis-
ease, a slight toxasmia, or any condition which spurs their
infirm adrenals into any degree of activity beyond the normal
needs of the organism.

All this does not necessarily mean that because pigmenta-
tion is present the case is nearing its end in every instance.
The causative disorder may become, so to say, latent, and the
diminished glandular activity suffice for the more or less per-

13 Henry Waldo: British Medical Journal, July 10, 1897.

84 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

feet performance of physiological functions, if the insufficiency
be not too far advanced. The bronzing of tuberculosis, syph-
ilis, and chronic arsenic poisoning offers many examples of this
kind. Syphilitic cases under specific treatment may sometimes
be brought to a condition suggesting recovery, for instance.
Oestreich14 witnessed such a result in a case of Addison's disease
in which a tuberculous adrenal was removed under the belief
that it was a malignant growth. All the typical symptoms of
the disease disappeared after the operation, and complete re-
covery ensued. This clearly indicates that the toxic process
caused by disease of the one gland induced insufficiency of the
other, and that as soon as the morbid source was removed what
was left normal of the other organ was sufficient for the con-
tinuation of life.

As already stated, hypertrophy of the glandular tissues to
meet an increase of physiological work has been brought on
experimentally by several investigators, Stilling,15 Charrin and
Langlois, and others, while, as shown below, compensation
through supernumerary organs undoubtedly occurs. The op-
posite condition to hypertrophy — atrophy — may, on the other
hand, bring the adrenals to the brink of total physiological
insufficiency, and thus induce bronzing. But under these cir-
cumstances the quality of the secretion may also play an im-
portant role in the production of this symptom, the causative
condition — impaired nutrition — being of a nature suggesting
such an effect. As the bronzing progresses with the advance
of the atrophic process, it may appear long before the severe
symptoms of suprarenal insufficiency assert themselves. This
type is well illustrated by a case described by Carlin Philips,16
in which bronzing began fourteen years before the onset of
the profound constitutional symptoms. Eolleston17 has em-
phasized the fact that atrophy of the adrenals occurs normally
in old age, and that it may occur earlier in life and give rise to
Addison's disease.

Total absence of the adrenals has been observed in autop-

i* Oestreich: Zeitsch. f. klin. Med., Nos. 1 and 2, 1896.

16 Stilling: Virchow's Archiv, Dec., 1889.

16 Carlin Philips: Journal of Experimental Medicine, vol. iv, 1900.

"Rolleston: Lancet, Mar. 23, 1895.

THE PATHOGENESIS OF BRONZING; ADDISON'S DISEASE. 85

sies of cases of Addison's disease. In RispalV8 case, notwith-
standing the presence of typical symptoms, including bronzing,
there was no evidence of tuberculosis, the abdominal sym-
pathetics were normal, and there was no evidence to show
that the adrenals had ever existed. He was only able to find
two similar instances in literature. In animals compensation
occurs in various ways. In four rats which survived bilateral
adrenalectomy several months Boinet found three or four red-
dish organs round the kidneys structurally similar to the cortex
of adrenals. He found the spleen enlarged and that its re-
moval rapidly caused death, thus strongly suggesting vicarious
function. Auld observed very great hypertrophy of the thy-
mus after one capsule had been removed two or three months.
In the human being accessory suprarenal bodies have been
found in the semilunar ganglion and in the midst of the solar
plexus by Jaboulay19 and by Stilling.20 Gottschalk21 found
accessory adrenals in the infundibulo-pelvic ligament close to
one of the ovaries. Eossa,22 in reporting a similar instance,
alluded to other well-authenticated cases. Wiesel23 examined
fifteen pairs of testicles and epididymes from the newborn and
found accessory suprarenal capsules connected with them 23
times: 5 times on each side and 13 times singly. The accessory
organs had the same structure that the gland usually shows.
They were usually situated in the connective tissue about the
vas deferens, and were surrounded by a mass of blood-vessels.
In older children or adults no fully developed accessory glands
were found, but there were remnants in the form of strings
and clumps of cells. Aichel,24 on the other hand, emphasizes
the importance of organs found by Marchand near the testes
in man and in the broad ligaments of woman, which organs
are homologous to the suprarenal bodies. These few examples
could be greatly multiplied were they not sufficient to show
that total absence, or complete, but slow, destruction of the

'SRispal: Le Progres Medical, Aug. 29, 1896.
^ Jaboulay: Lyon Medical, Nov. 2, 1890.

20 Stilling: Revue de Medecine, Oct., 1891.

21 Gottschalk: Centralblatt fur Gynakol., No. 15, 1898.
22Rossa: Centralblatt fur Gynakol., No. 25, 1897.

23 Wiesel: Wiener klin. Wochenschrift, May 5, 1898.
2*Aichel: Munchener med. Wochenschrlft, Sept. 4, 1900.

SO THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

organs, may not in some instances prove fatal, and that the
physiological functions of the adrenals can be fulfilled vicari-
ously.

Addison's disease with absence of adrenals only shows
that the compensation established was insufficient to carry the
subject through normal life. Nothnagel's inability to observe
pigmentation in 153 animals from which he had removed both
adrenals is often quoted to show that these organs are not
directly connected with this symptom. But death in all these
animals occurred long before bronzing could have appeared.
Boinet, on the other hand, who utilized animals in which com-
pensatory organs are often found, observed typical pigmenta-
tion in all animals that had lived several months after bilateral
adrenalectomy. Tizzoni noted the same results after crushing
the organs. Various investigators, beginning with Brown-
Sequard, had already noted that pigmentation appeared in ani-
mals in which the operation did not prove fatal for some
months, the symptoms present being analogous to those of
Addison's disease.

On the whole, there appears to be good ground for the
belief that: —

1. Addison's disease is a symptom-complex due to insuffi-
ciency of the adrenals.

2. Insufficiency of the adrenals only manifests itself by
bronzing when, from any cause, all but a small proportion of the
organs has been rendered physiologically inactive. Hence,

3. Bronzing is a symptom of advanced adrenal insufficiency
brought on by any local, peripheral, or general disease.

Its appearance depends upon the quantity of normal sub-
stance, whether this occupy a small area in one organ or be
disseminated amidst morbid foci, in one or both of them.

But how does the pigmentation originate, and why does
advanced insufficiency of the adrenals give rise to it? The
relation between this terminal stage and pigmentation is evi-
dent, while the occurrence of the latter imposes the conclusion
that the suprarenal secretion must serve to keep the pigment
within its precincts: the red corpuscle. We may ascertain this
by locating the seat of dissociation: i.e., the spot where the
absence of secretion causes the pigment to leave the corpuscle

THE ADRENALS AND CHLOROSIS. 87

or fail to be taken up by it. We already have reason to believe
that this occurs in the lungs, and, haemoglobin being the pre-
dominating factor in this connection, analysis of the conditions
that compromise the integrity of the haemoglobin molecule in
the lungs will doubtless furnish some clue to the nature of
the process involved.

THE ADRENALS IN THEIR RELATION TO CHLOROSIS.

Hemoglobin not only requires iron for its elaboration,
but this metal constitutes by far its most striking character-
istic. It cannot be formed without iron any more than the
chlorophyl of plants can be formed without it. Again, since
the power of haemoglobin to take up oxygen depends upon the
proportion of this ingredient, a sufficiently great ratio both of
iron and of the pigments with which it enters into association
must be present to insure normal functions, all other features of
the process being adequately carried out. The almost unfail-
ing beneficial effects of iron in chlorosis are well known. We
are led to believe, therefore, that chlorosis is mainly due to
a deficiency in the quantity of iron taken into the organism
or to the imperfect assimilation from animal foods, etc.

Yet there are many phenomena of chlorosis that are not
satisfactorily accounted for and which the known physiological
properties of the suprarenal secretion seem to readily explain.
Thus, the gastric symptoms, so marked in practically all cases,
are easily understood when the effects of suprarenal extract on
muscular tissue are recalled. Moreover, the close relationship
between the first artery of the cceliac axis and the stomach, on
the one hand, and the origin of the cceliac axis from the aorta
— which contains freshly adrenalized blood — on the other, all
previously referred to, show how direct is the connection be-
tween the adrenal secretion and the gastric muscular walls.
What is more clearly accounted for by this physio-anatomical
distribution than the gastric dilation and gastroptosis con-
stantly observed in these cases: i.e., when relaxation of the
muscular walls, due to deficiency of suprarenal secretion, is
introduced as a cause? That in all other diseases in which
suprarenal insufficiency prevails gastric disorders are more or
less marked further confirms this fact. Again, the cardiac

88 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

murmurs and venous hums that are practically always ob-
served represent a striking feature of chlorosis. That they are
functional cannot be denied, since they usually cease when the
blood's haemoglobin shows an increase, as noted by Richard-
son25 and others. That muscular relaxation of the cardiac walls
exists can also be shown. In a careful examination of 22
hearts Gautier26 found 20 enlarged; this organ, as we have
seen, is the first to receive perfect blood from the lungs di-
rectly from the aorta through the coronaries; is it not plain
that deficiency of suprarenal secretion also causes muscular
relaxation of this organ? The lassitude and indisposition to
exertion are obviously of muscular origin and traceable to the
same cause. When we come to the most striking symptom of
chlorosis, the extreme pallor, suprarenal insufficiency again
suggests itself, since we not only have the blood-changes to
account for it, but also the contraction of the capillaries of the
surface caused by the simultaneous dilation of the abdominal
vascular trunks which the reduction of adrenal secretion in-
volves. The applicability of the postulate — "Vessels supplied
with a muscular coat and capillaries are antagonistic in con-
traction and dilation" — in this connection seems to us to
greatly strengthen the position taken.

A review of the literature upon the absorption of iron
and particularly that bearing upon its intra vitam relations
with haemoglobin soon shows the correctness of Prof. H. C.
Wood's27 remark that, "although a great amount of work has
been done by chemists upon the absorption and elimination of
iron, the results have been so imperfect, contradictory, and
difficult of explanation that they are at present of very little
use to the clinician." Bunge's view that iron is not absorbed
has steadily lost ground, and there is considerable available
evidence to show that absorption occurs. A. B. Macallum,28
for instance, observed, in sections of intestines taken from ani-
mals first starved then fed upon a substance containing albu-
minate of iron, free leucocytes crowded with granules of iron

25 Richardson: Lancet, June 27, 1891.

*» Gautier: Deutsch Archiv f. klin. Med., Bd. Ixii, H. 1 and 2,

27 H. C. Wood: Loc. cit.

28 A. B. Macallum: Jour, of Physiol., vol. xvi, 1894.

THE ADRENALS AND CHLOROSIS. 89

pigments in the intestine, some appearing to pass out through
the epithelial cells, while others advanced into the subepithe-
lial elements. He also found them in the venules of the villi,
the capillaries of the liver, the spleen, etc.

If the question of absorption is still sub judice, what can
we say of the process through which iron combines with other
bodies to form hemoglobin? Yet there are general points of
a chemical nature which may assist us in determining the gross
lines of this process. Thus we know that when hemoglobin
is acted upon by acids in the presence of oxygen hsematin is
formed; and also that in the absence of oxygen a hcemochro-
mogen first appears which slowly loses its iron, the end-product
being hcematoporphyrin. In chlorosis the tissues probably play
in this connection the part of the acid usually employed in
laboratories to disintegrate hemoglobin: they abstract oxygen.
The imperfect condition of the blood involving reduced oxida-
tion, oxyhsemoglobin is not always formed, and arterial blood
fresh from the lungs, while still containing a large proportion
of this compound, — though just sufficient, in some cases, to
insure continuation of the vital processes, — also contains a
more or less great proportion of reduced hsemoglobin. Under
these conditions the avidity of the tissues for oxygen causes
them not only to absorb the one molecule of this gas from the
oxyhagmoglobin, but also to make up for the deficiency by
taking up oxygen from haemoglobin: i.e., the only remaining
source of supply. We thus have in the blood the precise con-
ditions required for the reaction outlined, namely: absence of
oxygen and a powerful deoxidizant, and therefore obtain as
end-results free iron and hematoporphyrin. But does free
hematoporphyrin appear in the blood when insufficiency of
the adrenals occurs? The urine alone can afford the desired
information, and the inquiry must therefore be turned in this
direction.

Haematoporphyrin was found in small quantities in normal
urine and practically always in pathological urine by Garrod29
and Stockvis,30 while various authors, including MacMunn,31

29 Garrod: Journal of Physiology, vol. xvii, No. 5.
*>Stoekvis: Jahresb. f. Therap. Chemie, vol. xxiii, 1893.
81 MacMunn: Journal of Physiology, vol., 1885.

90 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

D. Fraser Harris,32 Nakarai,33 and Ogden34 have collectively
found it in rheumatic fever, pericarditis, peritonitis, meningitis,
cirrhosis of the liver, croupous pneumonia, typhoid fever,
measles, Hodgkin's disease, exophthalmic goiter, pulmonary tu-
berculosis, pleurisy, leprosy, lead poisoning, and chronic poi-
soning with sulphonal, trional, and tetronal.

Another important feature of these reports is that they
also refer to the discovery of haBmatoporphyrin in several cases
of Addison's disease, while D. Fraser Harris35 alludes to a case
of exophthalmic goiter attended with haBmatoporphyrinuria in
which "some patchy pigmentation of the skin with bullae filled
with red, alkaline fluid" had been observed. Still another
point of association with suprarenal insufficiency is furnished
by several reported cases of peritoneal blood-effusion. If we
recall the various instances of suprarenal apoplexy (Arnaud),
followed by rupture of the organs previously alluded to, the
presence of adrenal disease can be surmised. Again, Stokvis
found that sulphotial caused punctiform hemorrhages into the
mucous membrane of the stomach and intestines, besides
haematoporphyrinuria, in rabbits. Capillary centrifugal dila-
tion, due to the protective overactivity of the adrenals, which
precedes insufficiency, and consequent constriction of the ab-
dominal trunks had obviously appeared: the counterpart of
other experiments already related in which hsematuria, epis-
taxis, etc., had been noticed after injections of suprarenal
extract.

As to the haemoglobin ratio in these cases, the sequence of
chemical reactions involved in the morbid process suggest that
a reduction should simultaneously appear. D. Fraser Harris36
refers to a case reported by Cant in which the ratio was 40
per cent, of normal with 2,250,000 red corpuscles — evidently a
case in which hgemogenesis was impaired. A case of McCall
Anderson's, on the other hand, showed a normal number of
red corpuscles, while the haemoglobin was only 60 per cent, of
normal. In a case referred to in Campbell's paper (Oswald's),

82 D. Fraser Harris: British Medical Journal, Feb. 5, 1898.
"Nakarai: Deutsches Archiv f. klin. Med., Nos. 2 and 3, 1897.
84 Ogden: Boston Med. and Surg. Jour., Feb. 24, 1898.
86 D. Fraser Harris: Loc. cit.
86 Ibid.

THE ADRENALS AND CHLOROSIS. 91

the percentage of haemoglobin was 49 per cent. We have seen
the close association between hasmoglobinuria and suprarenal
insufficiency; it is probable that we have in haamatoporphy-
rinuria, therefore, an advanced step in blood-disintegration
connected with correspondingly advanced suprarenal disease
bordering on total insufficiency. This view is sustained by the
practically general prognostic estimate of clinicians. Refer-
ring, for example, to McCall Anderson's case, in which haama-
toporphyrinuria had recurred for years, the man being still
living, Harris says: "Had I not seen Prof. McCall Anderson's
case ... I should say this red urohaamatoporphyrinuria
was a most grave symptom, a precursor of a fatal issue; such,
at any rate, it seems to be in the case of women."

A direct connection between haamatoporphyrinuria and
suprarenal insufficiency further asserts itself when the symp-
tomatology of cases in which the former occurs are studied from
this standpoint, and the morbid lesions are carefully sought
post-mortem. A case of haamatoporphyrinuria ably described
by Keith Campbell,37 of Perth, is especially valuable in this
connection. The abdominal pain, muscular paresis beginning
at the extremities and including the diaphragm, tendency to
diarrhoea, Cheyne-Stokes respiration, convulsions, and coma
interspersed among the symptoms of the major disease (mania
and pulmonary tuberculosis) typify the phase of overactivity
bordering on insufficiency which corresponds with the sequence
of events in the chemical reactions referred to above. The most
striking feature of this case, however, is the fact that by far
the most marked lesions found post-mortem were in the adre-
nals. The report of the pathologist, Dr. W. F. Eobertson, in
this connection was as follows: "Right adrenal shows in the
cortex numerous large areas in which the epithelial cells have
undergone a marked degenerative change, consisting of the
replacement of the protoplasm by clear globules. These glob-
ules, which vary considerably in size, do not (with an occa-
sional exception) give a fatty reaction with osmic acid. There
is no evidence of any tubercular disease in any part of the
organ. Left adrenal shows similar changes. There is no

87 Keith Campbell: Journal of Mental Science, April, 1898.

92 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

tubercular disease. The degenerative changes above noted are
evidently the same as those that are so commonly to be ob-
served in the adrenal epithelium in various diseases." This
is probably the only case of hgematoporphyrinuria in literature
in which the adrenals were carefully examined. That advanced
disease of these organs existed in others is shown by the fre-
quency of references to haemorrhage and intraperitoneal blood-
effusions associated with morbid phenomena distinctly of supra-
renal origin.

The last point to be determined is the relationship between
the haematoporphyrin obtained in laboratories from haemoglobin
and that found in the urine. This may be ascertained spectro-
scopically. D. Fraser Harris refers to the laboratory pigment
as follows: "The acid solution is two-banded, and very charac-
teristic; the pigment is iron-free." If we now compare this
with the spectroscopic findings of a case of haamatoporphy-
rinuria studied by J. B. Ogden38 the identity of both laboratory
and pathological pigments will appear. "The dark urine which
was collected on February 12th was examined with the spectro-
scope. At first the untreated urine (acid) was used, but with
unsatisfactory results, since the two spectral bands of each
hasmatoporphyrin could not be made out with certainty. The
pigment was then separated from the urine by Salkowski's
method and it was found that both the acid and alkaline solu-
tions gave the characteristic absorption-bands of haematopor-
phyrin." It is thus shown that the haematoporphyrin artificially
produced and haematoporphyrin of pathological origin are
identically the same.

What becomes of the free iron? The elimination of this
metal by the urine has been demonstrated by Robert and his
assistants, Damaskin, Kumberg, Busch, and Steuder,39 who
ascertained that, while the daily elimination in the urine was
hardly 1 milligramme in diseases attended by destruction of
the blood, this elimination not only increased, but the presence
of biliary coloring matter in the urine bore no influence
upon this increase. Various authors have demonstrated that
it was eliminated in great part by the intestinal tract, the

88 J. B. Ogden: Loc. cit.

88 Quoted by H. C. Wood, loc. cit.

THE ADRENALS AND CHLOROSIS. 93

liver, kidneys, etc., also assisting, while Macallum,40 Kunkel,41
Quincke,42 Hall,43 Hare,44 and others have traced it to the
blood of various organs after feeding animals upon iron-con-
taining substances. An interesting view in this connection is
that of Hall, whose researches tend to show that the iron of the
organism occurs both in fixed combination — i.e., in haemo-
globin— and in very loose organic combination, the latter vary-
ing constantly with the amount of iron ingested. This would
coincide with the conceptions herein submitted, since they sug-
gest the existence of a fixed ratio of haemoglobin and therefore
of iron, and the onset of disease as soon as the fixed combina-
tion, haemoglobin, is structurally compromised.

A striking association with the suprarenal functions also
appears when the disposal of iron is analyzed. The occurrence
of bronze spots in connection with various infections and in-
toxications, tuberculosis, syphilis, arsenic poisoning, etc., has
already been referred to, the development of this melanoderma
occurring in response to a multitude of abnormal factors. The
bronzing of Addison's disease is due, as is well known, to a
melanin, a pigment which contains no iron, found around the
vessels, and a product of cellular catabolism. Again, the hair
is a recognized depository for eliminated iron; and deeply-
pigmented hair is a characteristic of Addison's disease. We
thus have tangible proof that Addison's disease, the typical
manifestation of suprarenal insufficiency, is attended with
haemoglobin disintegration, and we have seen the close relation-
ship between this disease and chlorosis.

But why is chlorosis not also attended with bronzing be-
sides the other symptoms of Addison's disease discernible? As
previously stated, chlorosis is herein considered as a stage of
suprarenal insufficiency, not necessarily organic nor patholog-
ically connected with Addison's disease. It is attributed in
most cases to physiological incompetence of the adrenals,
whether this be due to inadequate development or to impaired
nutrition. Yet, the accumulation of free pigment must be

40 Macallum: LOG. cit.

41 Kunkel: Archiv fur d. Gesam. Physiol., Ixi.

42 Quincke: Archiv fur exp. Pathol., Bd. xxxvii, 1896.

43 Hall: Archiv f. Anatomie u. Physiol., 1896.

44 Hare: Archiv fiir Verdauungs Krank., vol., 1898.

94 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

accounted for, and, if the cutaneous tissues do not show pig-
mentation,— which they sometimes do; witness the cases re-
ported hy Bouchard and Ponzet45 and perhaps the yellowish-
amber pigment of alkaline haematoporphyrinuria, — that pig-
ment should be present elsewhere, at least in some cases, since
the urine of chlorotics is usually pale, though copious. We
have ample evidence that some unaccounted-for substance ac-
cumulates in the blood of chlorotics, in the frequency of throm-
bosis as observed in these cases. The researches of Leichten-
stein46 have shown that thrombi can occur in practically any
part of the organism, but particularly in the lower extremities
(phlegmasia alba dolens) and the cerebral sinuses. Eeview of
the literature on this subject soon shows that the nature of
these thrombi has remained unascertained and the "peculiar
yellowish-green" pigmentation of the skin likewise. Stengel,47
alluding to the latter, says: "The pigment is doubtless altered
haemoglobin, but its exact nature is unknown." That acid
liosmatoporpliyrin is the basis of all these forms of pigmentation
seems to us probable. In the blood of chlorotics this may (but
secondarily, owing to alkaline surroundings) be transformed into
alkaline hcematoporphyrin, and this yellowish or amber pigment
account for the peculiar hue of the skin. In Addison's disease
a melanin — probably a derivative of haemoglobin, but a more
stable pigment, owing to its probable absorption into tissues
and deposition as a catabolic product into the melanoblasts —
accounts for the bronzing.

But how and why is chlorosis so frequently cured with
iron? Chlorotics do not always recover under the administra-
tion of iron, and other agencies hygienic and medicinal will
sometimes bring on cure where iron has failed. We are there-
fore not dealing with a disease invariably associated with a
quantitative deficiency of this metal, but one in which it is
not properly assimilated. Its effects must, therefore, be in-
direct and be addressed mainly, at first, to hasmatogenic func-
tions, provided the gastro-intestinal tract does not by inade-
quacy too greatly limit absorption. An increase of red blood-

46 Bouchard and Ponzet: Trans. Ninth Inter. Congress, 1888.
M Leichtenstein: Miinchener med. Wochenschrift, 1899.
*7 Stengel: "Text-book of Pathology," edition, 1900.

BLOOD-DISINTEGRATION AND POISONS. 95

corpuscles first occurs, and, according to Osier48: "In some
instances the globular richness rises above normal." The ad-
renals— which, as we have seen, are merely physiologically
deficient (in most cases), through impaired nutrition, their pro-
toplasm failing to receive from the imperfect blood coursing
through them sufficient elements for the creation of a perfect
secretion or enough of it — soon increase their activity. Better
nourished, their secretion improves in quantity and power and
more iron is assimilated and fixed in the formation of haemo-
globin: a phase of improvement which, of course, requires some
time. "The increase of haemoglobin/' says Osier, "is slower,
and the maximum percentage may not be reached for a long
time." Arsenic also cures some cases; this agent is particularly
active as a suprarenal stimulant and the symptoms following
a poisonous dose are those of cholera: i.e., those following
removal of both adrenals. As regards iron, V. H. Meyers and
F. Williams49 state that "both frogs and mammals are killed
by it, the symptoms in warm-blooded animals being vomiting,
purging, great fall of blood-pressure, muscular weakness, and
finally coma and death." A more clearly defined list of the
effects of double adrenalectomy could not be presented. Hence,
iron must directly stimulate the adrenals in chlorosis in addi-
tion to its role as a structural constituent of the haemoglobin-
molecule.

THE ADRENALS IN THEIR RELATION TO BLOOD-DISINTEGRA-
TION UNDER THE INFLUENCE OF POISONS.

Haematuria — i.e., the presence of blood in the urine —
follows injections of suprarenal extract, and therefore typifies
overactivity of the adrenals. The experiments of Swale Vin-
cent, among others, have demonstrated the effects of supra-
renal-extract injections in this connection, "blood-colored
urine" and "bleeding from the mouth and nostrils" in guinea-
pigs and rats having been produced by this agent. These fully
illustrate the influence of pressure in the capillaries brought on
by contraction of the central vascular trunks.

48 Osier: "Practice of Medicine," p. 801.

49 V. H. Meyers and F. Williams: Archiv fur Exper. Path. u. Pharm., Bd.
xiii, 1876; quoted by Wood, p. 418.

1)6 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

Haemoglobinuria, with which haematuria is frequently con-
founded, is an entirely different condition. Keferring to the
former disorder, Osier50 says: "The essential pathology of the
disease is unknown, and it is difficult to form a theory which
will meet all the facts. . . . Increased hajmolysis and solu-
tion of the haemoglobin in the blood-serum (haemoglobinaemia)
precedes, in each instance, the appearance of the coloring mat-
ter in the urine." Again: "The coloring matter is not haema-
tin . . . nor in reality always haemoglobin, but it is most
frequently methaemoglobin. The urine has a red or brownish-
red, sometimes quite black, color, and usually deposits a very
heavy brownish sediment." That the identity of hagmoglobinuria
is also a source of confusion is fully emphasized by the author.
Indeed, from what has been said of bronzing — and if our views
are sound — the true source of what is often termed "haema-
turia" or "haemoglobinuria" is, in truth, methaamoglobin or its
isomer haematin, a decomposition product of haemoglobin, which
we primarily attribute to suprarenal insufficiency. Briefly,
while haematuria indicates overactivity of the adrenals, haemo-
globinuria, methaemoglobinuria, and, we will add, hamiatopor-
phyrinuria, typify, in our opinion, the three downward steps
of suprarenal insufficiency as manifested in the blood. That
all these phenomena appear in the same order in the symptom-
atology of poisons — the degree of blood-disintegration in-
creasing with the virulence of the toxic substance which enters
the blood — will now be shown.

Weir Mitchell long ago observed that, when death came
on rapidly after a rattlesnake-bite, the blood-corpuscles re-
mained intact. This is fully sustained by the need of a certain
time for the disintegration of blood through suprarenal insuffi-
ciency. Weir Mitchell also noted that, in cases in which the
venom did not act promptly, the corpuscles appeared altered,
some being dentated: one of the signs of impending disin-
tegration. This constitutes, in all probability, the primary
result of suprarenal insufficiency. With Eeichert, he subse-
quently ascertained that the corpuscles became spherical.
Brainard51 had also noticed that they became spherical and

60 Osier: "Practice of Medicine," p. 854, edition of 1898.
u Brainard: Academic des Sciences, Nov. 28, 1853.

BLOOD-DISINTEGRATION AND POISONS.

97

that the leucocytes tended to form masses. Albertoni52 found
that alteration of color was the main change observable in the
red corpuscles, their coloring having passed into the plasma,
which had become reddish. The leucocytes appeared to form
broad plaques. A study of this blood showed that its corpuscles
became easily disintegrated; far more so than under usual con-
ditions. Vulpian53 ascertained that the blood-corpuscles were
almost all deprived of their haemoglobin when death did not
occur early.54 Camus and Gley55 found the serum intensely
red: a feature which they attribute to a great quantity of dis-
solved haemoglobin.

Among the blood-disintegrating poisons, acetanilid (anti-
febrin) comes first in alphabetical order. This drug was found
by Herczel, when given to dogs for a length of time, to reduce
the alkalinity of the blood, the serum being also found to con-
tain "dissolved coloring matter": a fact which probably ac-
counts for the inability of blood from poisoned subjects to
adhere in rouleaux. Lepine and Aubert56 furthermore observed
that the oxygen of the blood was distinctly decreased. The
effects of aconite or aconitine upon the blood are not studied
in Wood's work; yet a foot-note refers to subpleural ecchy-
moses, an indication of advanced haemolysis, observed in ani-
mals by Laborde and Duquesnel, and caused by toxic doses of
aconitine. In antimony poisoning the viscera are intensely
congested. Magendre found the lungs studded with hepatized
areas. Ackermann observed marginal emphysema with spots
of atelectasis. The blood is stated by Wood to "usually coagu-
late imperfectly." Alcohol was found by Jaillet and Hayem to
produce in animals "extensive alteration in the blood-corpus-
cles, many of these bodies being shriveled and altered in form,
with yellow precipitates of hemoglobin in their interior."
Arsenic was found by Bettmann57 to cause a marked lessening
in the number of red blood-corpuscles and the percentage of
haemoglobin. Wood, in this connection, notes the interesting

52 Albertoni: Lo Sperimentale, Aug., 1879.

68 Vulpian: Academic des Sciences, March 6, 1882.

54 Quoted by Noe, loc. cit.

55 Camus and Gley: Academic des Sciences, Jan. 31, 1898.

56 Lepine and Aubert: Gazette Me"dicale de Strasbourg, i, 1887.

57 Bettmann: Beitrage zur Path. Anat., etc., xxiii.

98 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

fact that arsenic, antimony, phosphorus, and ammonia act very
similarly, if not identically, upon the blood. He also refers
to the bronze pigmentation "which is almost pathognomonic
of chronic arsenicalism."

The bromides were found by H. Bill to produce "a very
decided decrease in the amount of carbonic acid thrown off
from the lungs. ... On the other hand, the quantity of
urine was usually increased, and the coloring matters invariably
augmented." The blood-conditions of camphor are not referred
to, but Professor Wood alludes to a case in which a drachm
of chloral-camphor swallowed by mistake produced very severe
prostration, feebleness of the pulse, vomiting, fifteen coffee-
ground stools, etc. In carbolic-acid poisoning, according to
the same observer, "the liver, spleen, kidneys, and, indeed, all
the organs are found filled with dark, imperfectly-coagulated
blood, such as is habitually found after death from asphyxia."
The inference that the oxygen of the blood must have been
markedly decreased during life is worthy of note. The urine
is likewise bloody. Chloral was thought by Richardson58 to
cause the blood to coagulate less firmly than when the latter
is normal. Vulpian noted that it gave rise to hsematuria when
injected hypodermically, this phenomenon being markedly in-
creased when the drug was injected into the veins.

Chloroform was found by Harley59 to render the blood
very liquid and to give a bright, arterial hue. After a time
crystals of oxyhaemoglobin form in it. Boettcher,60 Schmidt,
and Schweiger-Seidel61 observed that the blood-disks dimin-
ished in size; but these effects were noted in vitro, and are
therefore of no value to us. Wood refers to the very sensitive
test of the destruction of the red corpuscles in the body which
the presence of icterus affords, and states that the observation
of Frerichs that it does occur, though rarely after chloroform-
ization, is correct. In digitalis chronic poisoning ecchymosis
of the gastro-intestinal mucous membrane, the meaning of

68 Richardson: Medical Times and Gazette, Sept. 4, 1870.
68 riarley: Proceed. Physiol. Society of London, 1865.
60 Boettcher: Virchow's Archiv, xxxii, 126.

81 Schweiger-Seidel: Bericht. d. Konigl. sachs. Gesell. de Wissensch. math,
phys. Kl., 190, 1867.

BLOOD-DISINTEGRATION AND POISONS. \)\)

which has already been referred to, has been noted by Kohn-
horn.62

Hydrocyanic acid causes the blood to assume a dark,
venous hue. Wood refers to Gaethgens, who found that the
blood of the first stage of poisoning clearly showed the absorp-
tion bands of oxyhaemoglobin under the spectroscope, while
Preyer demonstrated that "the dark blood of the advanced stage
gives only the lines of reduced haemoglobin/' In truth, this
poison is the most violent of the pharmacopoeia and the more
advanced stages of blood-disintegration would doubtless occur
were the victim to live long enough. Mercury is stated to cause
the blood to suffer very decidedly, becoming fluid and having
its power of coagulation impaired. Wright found its solid con-
stituents notably diminished, including albumin, fibrin, and the
red corpuscles, and noted that it contained a quantity of foetid
fatty material. In bichloride poisoning the urine is sometimes
bloody. Physostigmine poisoning, according to Fraser, causes
the blood after death to coagulate slowly and loosely, the red
corpuscles presenting various irregularities in outline. The
blood of animals killed with quinine was found by Bonome
and Arverdi, Magendie, Monneret, Melier, and Baldwin to be
dark, defibrinated, fluid, and incapable of forming a clot.
Briquet and Hare, who observed that this alteration was not
constant, probably used smaller doses.

The next step in the process of haemolysis is the forma-
tion of methcemogloHn, which gives the blood a chocolate or
dirty-brown color, as shown by Gamgee. Free haemoglobin was
found by Hayem to be more sensitive than corpuscular haemo-
globin to methaemoglobinizing substances; and as Pugliese
observed that the normal temperature of the body, 37° C.,
favored haemoglobinization, the conclusion of Carreau that an
acute methasmoglobinaemia represents the stage of blood-dis-
integration brought on by snake-venoms seems warranted.
This author63 states that the Martinique viper (fer de lance)
causes the blood to become very dark — almost black — "prune-
juice like," to use his words. That rnetha3inoglobm was present
in abundance was proven spectroscopically. Pugliese has also

B- Kohiihorn: Lancet, i, 583, 1876.
63 Carreau: Semaine Medicale, vol., 1893.

7

100 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

determined64 that venoms first cause alteration of the cor-
puscles, and that the freed hemoglobin is then disintegrated.

Ammonium picrate was found by Erb to cause the blood
of animals to assume a dirty-brown color. Nitroglycerin and
amyl nitrite are referred to as acting alike. Nitrite of amyl
causes the blood to become chocolate colored. Gamgee found
that under these conditions the spectrum bands of oxyhsemo-
globin disappeared, and were replaced by bands almost similar
to those of acid ha3matin. Methsemoglobin is thought by
MacMunn to be a mixture of hsematin and soluble albumin.65
The blood had also lost its power to absorb oxygen. Wood
remarks in this connection: "The accord of the results of this
chemical investigation with those arrived at by a purely phys-
iological study of the drug is very striking and very beautiful,
both teaching the same thing — lessened, but not absolutely
arrested, oxidation"

Copper, in toxic doses, has been found to be attended,
according to Wood, with black urine, due to the presence of
haemoglobin without unaltered blood-corpuscles. He also states
that "after death alterations of the blood and wide-spread fatty
degeneration have been noted by numerous observers." Zinc
poisoning is referred to as giving rise to the same symptoms
as the corresponding salts of copper. Phenacetin is also stated
to be followed, when given in large doses, "by general cyanosis
and discoloration of the blood, due to the formation of methgem-
oglobin." In phosphorus poisoning the blood is stated to be
"often profoundly affected, becoming very dark, losing its
power of coagulation, and apparently suffering also in its cor-
puscular elements, for ecchymoses are almost universal and
haematin crystals are occasionally found in the viscera. . . .
Silbermann66 states that thrombi are found in the blood-
vessels."

In potassium-chlorate poisoning the urine, according to
Wood, is "often of an opaque reddish-brown or blackish color
. . . frequently containing the detritus of blood-corpuscles.
Efemoglobinuria has been noticed, and methaemoglobin is a

64 Pugliese: Archives Italiennes de Biologie, 1895.

e5 MacMunn: "The Spectroscope in Medicine," 100, 1881.

ee Silbermann: Virchow's Archiv, cxvii, 1889.

BLOOD-DISINTEGRATION AND POISONS.

101

common constituent. . . . The blood is usually chocolate
colored . . . the liver and spleen are enlarged and filled
with the brownish debris of red blood-corpuscles; the bone-
marrow and the brain are often similarly colored. . . . The
changes in the blood are the result of the formation of a sub-
stance apparently identical with the methaBmoglobin of Hoppe-
Seyler and characterized by the appearance in its spectrum of
a dark line in the red. . . . That it is produced in the
body during life," continues Wood, "has been proved in cats,
dogs, and rabbits by A. Falck,67 by H. Lenhartz,68 and by
Calm,69 and is also shown in man by the wide-spread staining
not only of the interior of the blood-vessels, but also of the
walls of the whole lymphatic system, found after death from
the chlorate." In antipyrin poisoning H. M. Briggs70 observed
"blackish urine, with albumin and blood-corpuscles." The
peculiar lividity often seen in persons under the influence of
antipyrin "is probably due to changes in the blood itself," writes
Wood. "According to Lepine, methaemoglobm is largely
formed during [antipyrin] poisoning." That other authors
failed to detect it is accounted for by the fact that the doses
of antipyrin used in their experiments were inferior to those
employed by Lepine.

The last stage of blood-disintegration, indicated by the
presence of hcematoporphyrin, and which corresponds with the
bronzing stage of Addison's disease as regards the degree of
suprarenal insufficiency, has only been observed so far in con-
nection with few toxics. In chronic sulphonal poisoning,
which is stated to have been fatal in seventeen cases out of
twenty, the first symptom is hsematoporphyrinuria. "The ex-
planation of the occurrence of hgematoporphyrinuria is at pres-
ent very difficult," says Professor Wood; "frequently it does
not come until several days after the ingestion of the last
dose." He refers to the case of Franz Mullen, in which the
hemoglobin fell during the period of red urine to 45 per cent.,
returning with convalescence to 85 per cent.; and also to

67 A. Falck: Archiv fiir d. gesam. Physiol. des Menschen u. der Thiere,
88 H. Lenhartz: Beitrage zur Path. Anat., etc., Festschrift, 1887.
69Cahn: Archiv fiir exper. Path. u. Pharm., xxiv, 1887.
"•H. M. Briggs: Loudon Med. Recorder, March, 1891.

102 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

Hoppe-Seyler's belief that "the anatomical changes in sul-
phonal poisoning are really secondary to the destruction of the
red blood-disks." Trional poisoning is also stated to be at-
tended with hajmatoporphyrinuria, though to a less pronounced
degree. Santonin is stated to sometimes give the urine a pur-
plish-red color. Oxalic acid was also found by Rabuteau to
cause the blood to become "everywhere scarlet." Taylor71 did
not, according to Wood, observe this phenomenon in all cases:
a discrepancy easily accounted for by differences in the quan-
tity of poison taken.

The toxic agents analyzed in Wood's "Therapeutics" rep-
resent all those in which references to blood-changes have been
made, and we thus have ample evidence that all agents capable
of acting as toxics may give rise to disintegration of the blood
similar to those which were herein described as being of supra-
renal origin. The following postulates, therefore, appear to
us to rest upon a firm foundation: —

1. The adrenals are stimulated or functionally depressed by
venoms or poisons according to the dose introduced into the cir-
culation.

2. Variations in the functional activity of the adrenals induce
corresponding variations in the mutual affinity of the bodies enter-
ing into the haemoglobin-molecule.

INSUFFICIENCY OF THE ADRENALS AS A SOURCE OF BLOOD-
DISINTEGRATION.

METH^MOGLOBIN. — Gamgee has shown that lessened
oxidation coincides, when sufficiently advanced, with the dis-
appearance of the spectrum bands of oxyhaemoglobin, and that
these are replaced by others — practically those of acid haematin
— which give the blood the chocolate color assumed by it in
the earlier stages of haemoglobin-disintegration. Wood says,
referring to this acid haematin: "Recent researches have dem-
onstrated that the spectrum of this new compound is identical
with that of the methaemoglobin of Hoppe-Seyler."72 That this
methsemoglobin represents an early stage of haemoglobin-
disintegration is evident from the fact that Gamgee "showed

71 Taylor: "Medical Jurisprudence," i, 224.

72 Hoppe-Seyler: Zeitschrift f. Prak. Chemie, vols. ii and ill.

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 103

conclusively that this new compound yields its oxygen to re-
ducing agents": a point which we must here emphasize. Fur-
ther, Gamgee found that, when, after nitrite poisoning, this
chocolate blood appeared, it still ozonized prepared guaiacum-
paper, though not so actively as under normal conditions.
"Evidently then," says Professor Wood, "absorption of oxygen
must take place; evidently the blood-corpuscles must perform
their respiratory function; but evidently also they are greatly
crippled and impaired in the rapidity and ease of its performance.
Ha3iiiic respiration is, in other words, greatly interfered with,
but not abolished."

We have already seen that chemistry and physiology have
both established these facts. The deduction that methaemo-
globin is a product of early blood-disintegration therefore is
solidly supported. An important question, however, demands
elucidation: What is the nature of the process? In other
words, how and through what process is methsemoglobin formed
in the organism after poisoning?

The respiratory symptoms are stated by Lauder Brunton
and Fayrer73 to be the most marked witnessed after snake-
bites in India. Wall74 states that a strong dose of cobra-venom
causes almost instantaneous arrest of respiration; a weaker
dose slows it, and asphyxic symptoms follow. Viper-venom was
found by Phisalix to markedly affect the respiratory functions.
It first produced excitement, with "accelerated respiration,"
then "somnolence, with slowing of respiration." We have here
distinct evidence of reduced oxidation and accumulation of
carbonic acid. The next step is illustrated by Carreau's already-
quoted observation that the Martinique fer-de-lance viper caused
the blood to become very dark, "prune-juice like"; the pres-
ence of a large proportion of methaemoglobin had been estab-
lished spectroscopically. Even bee-venom, in sufficient quan-
tity, gives rise to marked dyspnoea and "black blood," as
observed by Paul Bert.

As previously shown, several drugs have been sufficiently
studied in this connection by investigators to indicate that
methaBmoglobinuria occurs after the ingestion of poisonous

73 Lauder Brunton and Fayrer: Proceed. Royal Society, 1874.
7*Wall: Quoted by Noe, iii, p. 368.

104 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

doses of these drugs. Nitroglycerin and amyl nitrite have both
been found to act similarly, in many ways, by Lauder Brunton,
Tait, Murrell, Hay, and Henocque. As the latter drug is the
more completely reviewed by Wood, it will be used as the basis
of this inquiry. "When," says this author, "an animal inhales
amyl nitrite, the arterial and venous blood soon become of a
nearly uniform hue, which resembles somewhat that of normal
venous blood, but is quite distinct from it, having a chocolate
tint." Are we dealing with mere deficiency of oxidation or
accumulation of carbonic acid? Evidently not, since Wood
states that "this chocolate-colored blood does not assume the
arterial hue when shaken up with the air." According to Gamgee,
the nerve-centers are directly affected; but we have already
ascertained that the respiratory centers are not the source of
phenomena that occur in this connection, and, as shown below,
the effects of the toxic occur notwithstanding division of the
spinal cord. As the splanchnic nerve is that connected with
the adrenals, the sympathetic system must be the one morbidly
influenced by the poison. An important fact suggested by this
nervous origin, however, is that the direct haBmolytic influence
of the poison, thought generally to exist, is set aside, and that
we are normally brought to the only agency available to ac-
count for the process: i.e., the adrenals. But why does the
chocolate methaBmoglobinic blood not assume the arterial hue
by exposure to air? Can we concede that whenever, in the
organism, the haemoglobin-molecule becomes dissociated, its
constituents are all eliminated with the excretions? Evidently
not. Even in chlorosis, in which haamic respiration is greatly
impaired, it is not, of course, abolished, and the components
of the hemoglobin-molecule must, in a measure, hold together,
though loosely combined. But evidently some constituent
capable of taking up oxygen must be missing in the metha3mo-
globinic blood referred to, to account for its inability, when
exposed to the air, to become arterialized. Now, the adrenals
being rendered insufficient by the drugs mentioned plus the
known affinity of their secretion for oxygen, clearly suggest,
it seems to us, that, if the methannoglobmic blood could not
be oxidized outside the body, it is because it lacked the supra-
renal secretion. This tends to show that the suprarenal secre-

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 105

tion, which, as we now know, is constantly being supplied to the
body, is oxidized in the course of the respiratory process.

In the light of all that has already been said concerning
the effects of stimulation on the adrenals and the signs of
insufficiency, the symptoms that follow amyl-nitrite inhalations,
as described by Professor Wood, clearly depict the course of
events. "The most prominent symptoms induced when amyl
nitrite is inhaled by a man in moderate quantities," says this
author, "are a sense of great fullness and distension of the
head, amounting at last to severe pain and accompanied by
intense flushing of the face." We can easily recognize here
the result of a sudden spurt of suprarenal activity. The cen-
tral vascular trunks and all the muscular vessels, veins, etc.,
are suddenly contracted, while the peripheral capillaries are
dilated, giving rise to the cerebral pressure, the flushing, etc.
That this dilation occurs independently of the spinal cord is
sustained by the experiments of Wood and Lauder Brunton,
which showed that its division did not prevent the peripheral
congestion. "A deep, labored respiration, an exceedingly rapid
and violent action of the heart," are next referred to, but the
line where suprarenal insufficiency begins is not clearly de-
fined— evidently, since, to use Wood's words, "the succession
of these phenomena is usually so rapid that often they seem
to be simultaneous."

Yet we have precisely at this point additional testimony
that we must be dealing with suprarenal secretion, since Wood
remarks: "But it is said that the cardiac disturbance is some-
times very distinctly manifest before the other symptoms." We
have seen that the heart is the first organ reached by the secre-
tion, and it must therefore be first to receive the brunt of the
suprarenal principle. These facts are also sustained by the
experiment of Bock on an isolated mammalian heart, which
showed that nitrite of amyl has no effect upon the heart itself.
The stage of suprarenal insufficiency is strikingly described:
"After poisonous doses," continues Professor Wood, "the symp-
toms have been great pallor; usually dilation, but sometimes
contraction, of the pupils; excessive muscular relaxation; slow,
scarcely perceptible pulse; haemoglobinuria, and irregular res-
piration." The morbid effects of suprarenal insufficiency — i.e.,

106 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

of dilation of the central vascular trunks, contraction of the
peripheral capillaries, etc. — are self-evident.

That the adrenals are involved is further sustained by the
observation of Lauder Brunton that if the descending aorta
be tied high up no perceptible fall of pressure is produced by
the amyl salt for some time. It is to be presumed that the
ligation was practiced above the suprarenal vessels. "In lower
animals," says Wood, "the first stage of the action is like that
just described in man. After this the breathing becomes
violently hurried and panting, progressive muscular weakness
and diminution of reflex activity ensue, and finally death from
failure of respiration. ... A very peculiar symptom is
that a long time before death both the arterial and the venous
blood become of a nearly uniform chocolate color." The simul-
taneous occurrence of these phenomena clearly defines the mor-
bid process. The chocolate-red blood, though still able to
absorb oxygen, does so "very imperfectly"; hence the "violently
hurried and panting" breathing to compensate by the number
of respirations for the lessened oxidation. The general metabo-
lism, impaired through imperfect hgemic respiration and there-
fore lessened oxidation, accounts for the rest: a symptom-
complex with the suprarenal glands as starting-point.

In view of all these facts, the manner in which metha3mo-
globin is formed in the organism after poisoning seems to us
to be as follows: The adrenals supply an oxidizaUe principle to
the Hood. When a poison causes insufficiency of these glands, a
compound inferior in its oxygen-absorbing power to haemoglobin is
formed, namely: methcemoglobin. The presence of this pigment
in the blood is attended with more or less marked impairment of
the respiratory function.

H^MATOPORPHYRIN. — How is this pigment formed in the
organism as a result of poisoning? Sulphonal and trional have
furnished, of all toxics, the greatest number of recorded cases
of hgematoporphyrinuria, and will therefore be used as the basis
of this analysis.

Hsematoporphyrin is stated by Garrod75 to be present in
normal urine in minimum quantity, in solid excreta, and

76 Garrod: Lancet, Nov. 10, 1900.

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 107

meconium, while Stokvis76 found it in bile and Taylor and
Sailer77 in blood collected post-mortem. As to its origin,
Garrod refers to the observations of Keyser,78 who found "that
a change of diet from red meat 'to white meat without vege-
tables caused the disappearance of the normal trace from the
urine, but that it returned when green vegetables were added
to food/' This is in accord with Stokvis's view, that a part
of the urinary pigment is derived from the food and that even
chlorophyl, from which a very similar pigment may be ob-
tained, may contribute to its formation. Garrod does not be-
lieve, however, that the bulk of the urinary or faecal haemato-
porphyrin has such an origin, though he found it associated
with milk diet in one case, and states that it may be found in
the faeces of sucklings. He is inclined to favor the view, there-
fore, that haematoporphyrin in excess is an indication of haemol-
ysis, and considers that "we are justified in concluding that
the hcematoporphyrin of the body has hcemoglobin for its parent-
substance" Still, when the question is put to the test "by
examining the blood in cases in which unusual amounts of the
pigment are being excreted and by examining the urine in
cases in which active haemolysis is known to be in progress,"
he finds them to "return the same answer: viz., that there is
no necessary connection between excess of haematoporphyrin
in the urine and excessive haemolysis." In pernicious anaemia,
"a disease in which haemolysis is an essential feature, urinary
haamatoporphyrin is not increased unless complicating conditions
are present""*9

This conclusion, when analyzed in connection with the
data we have so far submitted concerning the relations be-
tween the suprarenal glands and haemolysis, is fully sustained.
Sulphonal, trional, and other toxics capable of giving rise to
haematoporphyrinuria seem only to do so when the suprarenal
glands or their centers are more or less diseased, the amount of
pigment in the urine corresponding in a measure to the degree
of insufficiency present. Disease of both adrenals may exist, as

78 Stokvis: Zeitschrift fur klin. Med., Bd. xxviii, p. 1, 1895.

77 Taylor and Sailer: Contributions from the William Pepper Laboratory;
quoted by Garrod, loc. cit.

78 Keyser: Dissertation, Freiburg, 1897.

79 The italics are our own.

108 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

we have seen, without interfering with the general physiolog-
ical operations with which they are concerned until a very
small proportion of normal tissue is left. A demand for supra-
renal protective activity caused by the presence of a toxic in the
blood taxes this physiologically adequate remnant more or less
severely according to the dose and power of the toxic exhib-
ited. If the stage of total suprarenal sufficiency, as the result
of tuberculosis, syphilis, etc., is still remote, an agent, such as
sulphonal, may be given for a long time before it causes 'a high
degree of adrenal insufficiency to bring on marked haematopor-
phyrinuria; if, on the other hand, but a vestige of normal
suprarenal tissue just sufficient to sustain life only remains,
but a few doses are sufficient to cause it. Keith Campbell's
case of haematoporphyrinuria, in which the most marked mor-
bid change observed post-mortem was hyaline degeneration
of both adrenals, may again be referred to in this connection.
Only two 15-grain doses of sulphonal had been taken by the
patient. The symptoms outlined by the following broken sen-
tences: "Very poor circulation, blue oedema, coldness of the
extremities . . . markedly-paretic flexors. . . . Breath-
ing a constant struggle; Cheyne-Stokes breathing . . .
pulse rapid and thready . . . patch of rusty staining over
parietal region," etc., sufficiently indicate advanced suprarenal
insufficiency to show a direct correspondence with the post-
mortem findings.

To illustrate the effects of less advanced disease of the
adrenals when sulphonal is used, the case recently reported by
E. Waldo80 may be cited. Here the drug had been taken dur-
ing a prolonged period before the urine assumed the typical
cherry-red or port-wine-like color. The rapid pulse (180),
prostration culminating in general paresis, a "scarcely-moving
diaphragm," and other symptoms also point here to disease of
the adrenals. An interesting case of this kind, reported by
Stuart Hart,81 was attended with marked cardiac disturbance.
That temporary reduction of a stimulus corresponding to that
attributed to the suprarenal secretion was a factor in its pro-
duction is suggested by the fact that "with the improvement

80 R. Waldo: British Medical Journal, June 15, 1901.

81 Stuart Hart: Amer. Jour, of the Med. Sciences, April, 1901.

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 109

in the muscular tone, the dilation and valvular incompetence
entirely disappeared, leaving a normal heart."

It is only occasionally, and, in fact, very rarely, that hsem-
atoporphyrinuria is sufficiently marked to give the urine the
cherry-red or even pinkish color observed in these cases. The
coincidence of sufficiently advanced suprarenal insufficiency
and the administration of the remedy is likewise rare, especially
in presence of the fact — to be shown later on — that suprarenal
disease is only traceable to conditions in which toxics of various
kinds, including toxins, have given rise to serious general dis-
ease. When the adrenals or their center are normal, it is prob-
able that only excessive or large doses of sulphonal or trional
can produce a marked degree of hgematoporphyrinuria. Kast
and Weiss82 produced it twenty-five times out of one hundred
experiments in rabbits, but only by means of large doses. In
dogs they could not bring it on, notwithstanding repeated and
prolonged experiments.

If, as thought by Garrod, "the haBmatoporphyrin of the
.body has hemoglobin for its parent-substance," how does it
become dissociated from the latter? Chemically, they are, so
to say, only two reactions apart: When hemoglobin is treated
with an acid or a strong alkali, hsematin: i.e., methaemoglobin,
is formed; when the latter in turn is treated with sulphuric acid,
it is deprived of its iron and becomes iron-free haematin: i.e.,
hematoporphyrin. The general belief that the drug acts
directly upon the blood is obviously untenable; indeed, it seems
hardly reasonable to expect that a few 15-grain doses, admin-
istered twenty-four hours apart, will produce upon the seven-
teen pounds of blood in the organism effects which in the
laboratory are only obtained with sulphuric acid or an equally
active reagent. In fact, Kast and Weiss83 were totally unable
to obtain hematoporphyrin from extravasated blood by means
of sulphonal, notwithstanding the use of several processes.
With vulnerable organs, such as the diseased adrenals, to bear
the brunt of the toxic process, on the contrary, a logical con-
nection is established between the violent phenomena witnessed
and the comparatively benign exciting cause. The many con-

82 Kast and Weiss: Berliner klin. Wochenschrift, July 13, 1896.

83 Ibid.

110 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

tradictory physiological effects observed with sulphonal as well
as with other drugs in this connection, and the multiplicity
of causative agents which may give rise to haematoporphy-
rinuria, are likewise accounted for. On the whole, it seems
reasonable to conclude that, while hcematoporphyrinuria may
~be caused in normal subjects when excessive doses of the toxic
agency enter the Uood, it may lie caused by small doses when the
adrenals or their center are diseased, the intensity of the effects
varying with the dose and the degree of insufficiency the adrenals
have reached.

In support of this view we have, in a proportion of cases,
besides the symptoms of suprarenal insufficiency, a more or less
marked reduction of haemoglobin. F. Miiller84 reported a case
in which the haemoglobin ratio fell to 45 per cent, during the
most active stage of haematoporphyrinuria and gradually re-
turned to 85 per cent, as the urine became gradually cleared
of its pigment. The parallelism between the percentage of
haemoglobin and the variations in the urine is well illustrated
in a case reported by J. Calvert,86 probably suffering from
tuberculous adrenals, with an acute exacerbation of supra-
renal insufficiency of unknown origin, no sulphonal or trional
having been taken by the patient. The haemoglobin percentage
was at first 48 per cent, and the red corpuscles 2,292,000.
Gradually the haemoglobin reached 62 per cent, and the red
corpuscles 3,968,000, these changes covering a period of six
days. "After this," says the author, "the percentage of haemo-
globin and the number of the red corpuscles steadily increased
and the urine gradually returned to its normal color."

This should not be taken to mean, however, that in all
cases of haematoporphyrinuria the ratios of haemoglobin and of
red corpuscles keep pace with the alterations witnessed in the
color of the urine. In Keith Campbell's admirably reported
case the blood-count showed throughout 7,000,000 red corpus-
cles, and, when breathing had become "a constant struggle"
and convulsions had occurred, the ratio became even greater:
i.e., "rather over 7,000,000." Yet in this case it was not the

s* F. Miiller: Wiener klin. Wochenschrift, p. 252, 1894.
86 J. Calvert: Lancet, Dec. 22, 1900.

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. Ill

parallelism between the haematoporphyrinuria and the haemo-
globin that had ceased, it was that with the red corpuscles,
since "the percentage of haemoglobin" as taken by Dr. Oswald
in this case "was 49 per cent." Thus, while this ratio was very
low, the blood-corpuscle ratio was exceedingly high: a fact
easily accounted for by the persistent vomiting which repre-
sents one of the striking features of the case, and doubtless
due to effusion of blood-serum into the stomach through the evident
engorgement of central vascular trunks. The loss of fluids sim-
ply condensed the blood; hence the high corpuscular ratio.
But for the vomiting the blood-examinations would probably
have given results very similar to those of the other cases men-
tioned. In truth, the blood-count furnishes but little, if any,
reliable information in any case of haematoporphyrinuria, un-
less the ingestion and loss of fluids by the gastro-intestinal and
urinary tracts and the skin be accurately established, supported
by a specific-gravity ratio of blood taken from a large vessel.
The same cannot be said of the haemoglobin ratio, which sel-
dom exceeds 70 per cent, while the cherry-red urine is present,
and often reaches below 50 per cent.

Are we dealing with a stage in the dissociation of haemo-
globin, or with a reaction in which only a portion of the blood
is involved? To consider, as previously implied, the formation
of haematoporphyrin as a stage in the haemolytic process would
implicate an antecedent reaction: i.e., that affording methaemo-
globin as end-product. But in none of the reported cases which
have come to our notice so far is the chocolate-colored urine
said to have preceded the port-wine-red urine. When the latter
fades off, it does not assume the typical color of methaemo-
globinuria, but becomes dark claret, then light claret, pinkish
in hue, etc. In other words, it presents a totally different
aspect, and it is evident that it does not characterize a stage
of blood-disintegration of which the following are the steps:
Haematoporphyrin -f- iron = methaemoglobin; methaemoglobin
-f proteids = haemoglobin. Again, haematoporphyrin being
iron-free haematin, we cannot, as was the case with methaemo-
globin, grant it the power to take up the oxygen with which
life is maintained. Side by side with the impaired blood-ele-
ments there must exist approximately-perfect blood. The only

112 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

logical conclusion available, therefore, is that only a portion
of the blood is directly involved. We can thus account for the
cases of hrcmatoporphyrinuria in which apparently normal
health is present — though the reserve of suprarenal tissue is
steadily being destroyed by some morbid process — and brought
on by an intercurrent disorder in which a toxic action prevails:
sulphonal, trional, lead, rheumatism, gout, etc., and particularly
hepatic disorders, in which cloudy swelling and fatty degen-
eration are so prominent.

What is the nature of the process? Kast and Weiss,88
in their study of the ha3molytic effects of sulphonal upon the
blood, state that under certain pathological conditions, and
especially in anaemic women, "there exists a loose combination
of the blood-pigment." The same remark is applicable with
insufficiency of the suprarenal glands as the underlying factor
of the hasmolytic process, on the condition, however, that the
suprarenal glands be recognized as producing a secretion en-
dowed with the marked affinity for oxygen which it is now
known to possess, and that this affinity be considered a part
of the process. It is clear that deficiency of suprarenal secre-
tion must carry with it "a loose combination of the blood-
pigment," since oxidation, as shown by the character of the
reducing agents required to disintegrate blood in vitro, repre-
sents the principal bond of union between all the main bodies
involved. With both organs diseased, such a condition of the
blood is always more or less marked, and, when an acute toxic
intercurrent process suddenly appears, this "loose combina-
tion" becomes accentuated in proportion to the intensity of
the morbid effects upon the glands. If these effects are over-
whelming, the "blood is everywhere scarlet," to use Rabuteau's
expression in reference to his oxalic-acid cases; if they are
not, the clinical picture presented is that of the cases reported,
in which the original disease shows more or less marked tend-
ency to pervert the characteristic suprarenal symptoms that
appear when only one pathogenic factor is present. Here,
however, an additional source of blood-disintegration appears
on the field.

86 Kast and Weiss: Berliner klin. Wochenschrift, July 13, 1896.

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 113

As already stated, acids disintegrate haemoglobin, haematin
being formed. This only occurs, however, in the presence of
oxygen. In the lungs, therefore, the "loose combination" in-
volving imperfect absorption of oxygen, while defective res-
piration is further encouraged by the imperfect or arrested
action of the respiratory muscles, the process of haemoglobin
disintegration, if at all influenced, is rather interfered with
than encouraged. It is consequently not in the respiratory area
that the process occurs, and, if elsewhere in the organism, the
reaction must be one in which oxygen is absent. We have
already seen, when chlorosis was studied, that, when haemo-
globin is treated with an acid in the absence of oxygen, a
ha?mochromogen first appears which slowly loses its iron, the
end-product being hsematoporphyrin. What was then said,
therefore, is also appropriate in connection with the process
through which haamatoporphyrin is formed: i.e., the tissues
play the part of the acid employed in the laboratory to disintegrate
hcemoglobin: they abstract its oxygen. The imperfect condition
of the blood involving reduced oxidation, oxyhcemoglobin is not
always formed, and arterial blood fresh from the lungs, while still
containing enough of this compound to more or less perfectly carry
on the vital processes, also contains a more or less great proportion
of free hcemoglobin. Under these conditions, the avidity of the
tissues for oxygen causes them not only to absorb the one molecule
of this gas from the oxyhazmoglobin, but also to make up for the
deficiency by taking up oxygen from hcemoglobin: i.e., the only
remaining source of supply. We thus have in the blood the precise
conditions required for the reaction outlined, namely: absence of
oxygen and a powerful reducing agent, — the tissues, — and, there-
fore, obtain as end-results free iron and hwmatoporphyrin.

This suggests another query. The microscopical examina-
tions of adrenals taken at random at autopsies have shown
Arnaud that 36 per cent, of all adrenals contain evidences, more
or less marked, of fatty degeneration. Why, under these cir-
cumstances does haBmatoporphyrinuria, which may be induced
by a large number of toxic disorders, not appear more fre-
quently? The answer is readily available: hcematoporphyrin.
bilirubin, iron-free hcematin, and haemato'idin are isomers: i.e.,
the same body is now recognized under different names.

114 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

Important in this connection is the close relationship be-
tween haamatoporphyrin and urobilin, formed when the former
is subjected to putrefactive conditions or nascent hydrogen,
which is present in very small amount in normal urine. This
pigment also occurs in fagcal matter, and is here recognized as
"stercobilin." In both urine and fasces, however, it appears
in excess, though apparently with no degree of parallelism, in
many morbid conditions. In acute fevers, for instance, it may
be increased to five or six times its normal ratio; especially
is this the case in pneumonia, typhoid fever, and the septic
fevers, in which rapid disintegration of the blood-elements
occurs. "In febrile disorders of almost every kind," says
Garrod, "temporary urobilinuria may be met with, the dura-
tion of which usually corresponds with that of the pyrexia.
In diseases of the liver, the urobilinuria is usually persistent,
as is well seen in cases of cirrhosis, malignant disease, or passive
congestion secondary to cardiac or pulmonary troubles. . . .
In diseases attended by excessive haemolysis, and during the
absorption of extravasated blood, there is apt to be conspicuous
urobilinuria, and, unless complications are present, there is no
corresponding increase of uroerythrin or haamatoporphyrin.
Such urines have a warm orange color, which is readily recog-
nized by a trained eye, and at the apex of a conical glass a
pinkish tinge is usually seen." He refers to the valuable diag-
nostic signs persistent urobilinuria affords in pernicious anae-
mia, as shown by Mott and Hunter, and to his personal ob-
servation that there is likewise a marked excess of urobilin in
the faaces. It follows hcemorrhages and especially intracranial
hcemorrhage, hsemorrhagic infarctions, pelvic haamatoceles, etc.

The "chief seat of formation of urobilin is undoubtedly
the intestinal canal. This can only be gainsaid," says Garrod,
"by denying the identity of the urinary and faacal pigments."
(The identity of these is evident, and he refers to combustion
experiments conducted personally and with F. G. Hopkins, in
which this is confirmed.) Several investigators consider the
bile as the only source of urobilin. "There is strong evidence,"
says Garrod, "that the urobilin in the bile itself is of intestinal
origin," while "it is equally clear that the substance from
which the intestinal urobilin is formed is the bile-pigment."

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 115

A logical conclusion suggests itself in the presence of these
facts: i.e., that the changes undergone in the liver are a part of
a cycle with the intestine as a starting-point. And so it must
be, since, again using Garrod's words, "it seems to be clearly
established that absorption from the intestine does take place,
and that, of the urobilin so absorbed, some is excreted with the
bile and some with the urine."

Bilirubin, from which at least a portion of the urobilin
found in the urine and faeces is derived, is not found in either
of these excreta. It disappears on its way down the intestine
and is replaced by large quantities of urobilin. When, how-
ever, bilirubin does, under certain morbid conditions, escape
with the faeces, urobilin does not appear in the latter. How
does this transformation in the intestine occur? Garrod states
that the radical change involved is attended with the elimina-
tion of nitrogen, and that there is much evidence to show that
it is brought about by bacteria. Bile inoculated with faecal
matter and placed in an incubator, for example, yields urobilin
rapidly, while the bilirubin simultaneously disappears. F.
Miiller, A. Schmidt, and Esser also "obtained urobilin by
cultivating intestinal bacteria in broth to which an alkaline
solution had been added." The same results were obtained by
Garrod and Drysdale, but only when oxygen was present.
While the absolute identity between this and the natural pig-
ment has not as yet been established, the artificially produced
urobilin was found to possess the chief properties of the latter.

In the body the change chiefly occurs in the upper part
of the large intestine, the contents of which are alkaline, while
those of the small intestine are acid. This is a feature of con-
siderable importance evidently, since Esser found that "acidity
of the culture-medium inhibited the change which took place
under the influence of bacteria in alkaline broth." Garrod fur-
ther states that the green stools occasionally seen in typhoid
fever are always distinctly acid in reaction, and are urobilin-
free, the urobilin also disappearing from the urine. When
alkalinity recurs, urobilin likewise reappears. Yet, the intes-
tinal area in which the urobilin is formed from bilirubin varies
greatly in different individuals, sometimes extending to the
jejunum; but experiments by Vaughan Harley suggest that the

116 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

process of transformation is most active when bacterial proc-
esses are likewise so.

An anomalous phase of the process, however, is the fact
that "the quantity normally present in the faeces is far larger
than that which enters the intestine with the bile," while, as
shown by F. Miiller, "complete occlusion of the common bile-
duct causes urobilin to disappear from the faces, and a few
days later from the urine also." Garrod states that the latter
observation has been repeatedly confirmed. Yet, in animals
with biliary fistula, while no bile enters the intestine, the urine
still contains urobilin. In Copeman and Winston's87 case of
biliary fistula, in which no bile had entered the intestine, the
faeces were uncolored by stercobilin; nevertheless the urine
still contained urobilin. But, even leaving urobilinuria out of
the question, it is difficult to understand how occlusion of the
bile-duct can govern a quantity of pigment greater than that
which the liver takes up: i.e., how it can affect pigment which
the liver has not received. This is but one instance of several
available. Garrod, alluding to the general conclusions sug-
gested by the data presented in his excellent paper, says:
"When, however, we apply this theory to clinical facts, diffi-
culties are encountered which cannot as yet be wholly met, and
it soon becomes evident that the theory, as above stated, is
inadequate, and that some amplification or modification of it
is necessary." This amplification seems less remote when the
physiological functions of the suprarenal glands are introduced
as factors in the process involved.

The fact that urobilinuria is marked in diseases such as
rheumatism, cirrhosis of the liver, etc., in which haematopor-
phyrinuria is also observed, suggests a common origin. Garrod
refers to urobilin and its chromogen "as widely distributed in
the human body. . . . They have been found in the bile
removed from the gall-bladder during life, as well as in that
obtained post-mortem, and are met with in the blood and in
serous effusions. . . . As obtained from all the above
sources, specimens of urobilin agree in all their properties and
are clearly identical in their nature." As to the origin of uro-

87 C. W. Purdy: "Uranalysis and Urinary Diagnosis," p. 46, fifth edition, 1900.

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 117

bilin, the author, after reviewing the main hypotheses bearing
upon this point, says: "It will be seen that the above theories,
one and all, start with the assumption that urobilin is derived
from hcemoglobin, either directly or through the intermediate stage
of Ule-pigment" and refers to Thudicum as alone maintaining
that urobilin is a product of decomposition of urochrome: a
view which need not represent an exception, since this pigment
can likewise be traced back to haemoglobin.

"The very small amount present in normal urine and its
complete absence from that of certain animals, such as dogs,
in whose intestines it is present in considerable quantity," says
Garrod, "suggest that the pigment is, in part, subjected to
change in its passage through the body, and is excreted in some
altered form." This is quoted merely to emphasize the fact
that the formation of any of the pigments referred to, even
stercobilin, is not followed by its immediate evacuation from
the organism, but that the transformation from bilirubin to
urobilin-stercobilin on the colon side of the ileo-caecal valve
probably represents but the first step of various transforma-
tions of a biochemical nature in which the tissues at large take
part, but of which certain organs are the primary seat. Uro-
bilin, as shown by Riva, when introduced into an isolated loop
of intestine undergoes absorption. This and other evidence
available distinctly indicates that this pigment enters the cir-
culation.

We will assume, as a working hypothesis, that urobilin, far
from always representing a product of waste, — some of it at
least, — is constantly traversing the organism, fulfilling its
various missions and returning to the ileo-caacal neighborhood
via the liver. It will then become apparent that the state-
ment— "Its disappearance from the urine when the bile is oc-
cluded . . . disposes of the theory that urobilin is formed
from bilirubin in the tissues at large, for, under such circum-
stances, although the tissues remain loaded with bilirubin,88 the
excretion of urobilin is arrested" — from Garrod's pen seems
to lose weight. If the above hypothesis obtains, complete oc-
clusion of the common bile-duct, as carried out by Friedrich

The italics are our own.

118 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

Miiller, can do but one thing: i.e., block the normal functional
cycle. Urobilin will of necessity disappear from the faces and
from the urine, since the functions of the organism will con-
tinue; and, retransformed into bilirubin, the pigment, in its
turn, must accumulate in the organism behind the obstruction.
It is for this reason, therefore, that "the tissues remain loaded
with bilirubin." The close relation between haematoporphyrin
and bilirubin further affirms itself when we compare their
formulae : —

C32H32N405 C32H36N406

Haematoporphyrin. Bilirubin.

When we consider that the latter differs only from the former
by a surplus of oxygen and hydrogen (C32H32N405 -f 2H20 —
0 = C32H36N406), we are reminded of the avidity of the tissues
for oxygen, referred to when the blood-changes leading to
haematoporphyrinuria were analyzed. We then noted that the
tissues, in the absence of oxygen, took the place of the labora-
tory acid which removed oxygen from haemoglobin, leaving a
chromogen which slowly lost its iron, and which, minus its
iron, became iron-free haematin, or haematoporphyrin. But we
must remember, in this connection, that the reaction given as
illustration refers to a laboratory operation and to sulphuric
acid or an equally powerful reagent, and that in the tissues
the avidity for oxygen continues when blood-disintegration has
reduced respiratory oxidation to a minimum just compatible with
the continuation of life, and they continue, nevertheless, their
deoxidizing effect, more and more depleting the blood of its 0.
In the majority of diseases attended with blood-disintegration
we do not meet with hcematoporphyrinuria, therefore, but with
urobilin in the urine and stercobilin in the faces, both being
formed when the first named or its isomer, bilirubin, are ex-
posed to putrefactive processes, etc.; so that we do witness
haematoporphyrinuria, though slightly modified, with great
frequency. The suprarenal insufficiency involved also reduces
the normal formation of oxyhaemoglobin, but to a less marked
degree, probably because the disease is not complicated with
adrenals previously weakened by advanced disease, and the
avidity of the tissues is correspondingly less. Instead, there-

ADRENAL INSUFFICIENCY AND BLOOD-DISINTEGRATION. 119

fore, of obtaining hsematoporphyrin as end-result, we obtain
hydrobilirubin, the reaction being approximately as follows: —

2(C32H36N406) - 02 + 4H20 = 2(C32H36N405.2H20)

Bilirubin. Hydrobilirubin.

Hydrobilirubin, as is well known, is usually termed "febrile
urobilin" though it often appears in diseases in which fever
does not occur.

All these facts suggest another conclusion: i.e., that
hcematoporphyrin, bilirubin, hcemato'idin, and its other isomers,
as haemoglobin derivatives, are restored to the pulmonary cir-
culation ~by reabsorption from the intestine, and again used in
the building up of haemoglobin. This is sustained by what
evidence is available. It also satisfies the requirements of all
the experiments referred to in Garrod's paper, which the other
hypotheses outlined therein failed to meet.

The reduction to a single pigment of all the isomers of
hoematoporphyrin is not only important from the clinical stand-
point, but it will assist us in elucidating various features of the
question in point: i.e., the relationship between the adrenals
and the respiratory function. Especially does this apply to
haematoidin, one of the pigments referred to. "In old blood-
clots in the body/' says Professor Foster, "the haemoglobin
of the clot becomes in time transformed into an iron-free
body which has been called heamatoidin, but which, both in
composition and reactions, appears to be identical with bili-
rubin." Again, he refers to the identity of both compounds
in the following words: "Virchow89 has described the gradual
changes in old blood-clots, such as those of cerebral haemor-
rhage, which lead to the presence of the so-called haematoidin-
crystals. Though these have not been obtained in sufficient
quantities to enable their composition to be finally fixed by a
chemical analysis, still, the identity of their crystalline form
with that of bilirubin, and the fact that they both give the
same play of colors when oxidized, as in Gmelin's test, justify
the assumption that hcemato'idin and bilirubin are identical."90

The presence of hsematoi'din in conditions of advanced

89 Virchow: Archiv fur path. Anat, Bd. i, S. 383.

90 The italics are our own.

120 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

blood-disintegration and its connection with suprarenal in-
sufficiency have been fully emphasized, but an observation of
Boinet's — already referred to — will prove interesting in this
connection. Eeferring to the blood of one of the rats which
survived removal of both adrenals several months, and in which
bronzing had occurred, this author91 says: "The venous and
arterial blood contained a large proportion of black pigment, with
crystals of hamatoidin." The same black pigment, we have
seen, was also found by him in more or less great quantities in
75 per cent, of 109 decapsulated rats; was traced everywhere
in the body, and was found similar to that obtained from the
bronzed spots of two fatal cases of Addison's disease. But this
did not only occur in decapsulated animals, but likewise in a
series in which lesions had been caused in the adrenals by
means of chemical and bacterial agencies.

Why should removal of the suprarenal glands be followed
by the accumulation of haematoidin in the tissues? Haema-
to'idin-bilirubin being a derivative of haemoglobin, we are again,
and from another direction, led to the conclusion that the supra-
renal glands supply a secretion which serves to hold in com-
bination the various constituents of haemoglobin.

THE SECRETION OF THE ADRENALS AND THE
RESPIRATORY PROCESS.

That the secretion of the adrenals can endow the hasmo-
globin-molecule with its power to take up oxygen seems to us
beyond question. Indeed, removal of the adrenals of a normal
animal does not remove the various constituents of haemoglobin
from its organism. The iron to which the affinity of the blood-
pigment for oxygen is now ascribed, and all of the other ele-
ments whose chemical affinity is supposed to suffice for the
holding together of the haemoglobin-molecule, are present.
The surroundings of all these constituents are not changed;
corpuscles, plasma, temperature are present. Why, therefore,
do they not, in virtue of their affinity, hold together? When
the suprarenal glands are removed we not only have an accu-
mulation of haemato'idin and other pigments in the blood, but

^Boinet: Marseille Medical, April 15, 1896.

THE ADRENAL SECRETION AND PULMONARY RESPIRATION. 121

there occur phenomena which simultaneously point to the cessa-
tion of suprarenal functions and to defective oxidation of the
tissues. With dyspnoea appears muscular weakness: the mus-
cles of the thorax, the diaphragm, have lost their tone — their
pabulum vitce, as it were. But this does not only indicate the
loss of tone which the suprarenal secretion imparts; there is
gradual loss of power, ending in paralysis. Why should this
occur if metabolism can still continue? Nothing has been
changed in the organism but organs which are only supposed
to give tone to the muscular elements. And still metabolism
is obviously arrested. That it is due to the absence of oxygen
and arrest of oxidation — i.e., combustion within the tissues — is
proven by the fact that the temperature is lowered everywhere.
In all of the rats in which Boinet took the rectal temperature
marked hypothermia was noted. The opposite conditions of
temperature between the central organs and the peripheral
tissues no longer obtain here; it constitutes a function of
which the suprarenal glands are the center and which gradually
ceases when these are removed.

Gourfein92 has experimentally shown that the destruction
of these organs greatly influenced nutrition. One-twentieth
of both capsules sufficed to keep animals alive from 18 days
to 9 weeks; but, notwithstanding the fact that they took their
normal food, there was steady loss of weight, death occurring
when the half of their normal weight had been lost. That this
cannot be ascribed to trophic lesions of purely nervous origin
is shown by the fact that motor nerves and even their intra-
muscular ramifications were found to have lost none of their
electrical excitability.

Evidently metabolism ceases when the suprarenal glands
are removed, while the other features referred to point to
arrest of oxidation in the tissues as the cause of this cessation.
This, in addition to the fact stated, that the constituents of
haemoglobin lose their affinity for one another when these
organs are removed, and the invariable presence of suprarenal
symptoms when toxic elements are sufficiently active to cause
methasmoglobinuria, h&matoporphyrinuria, etc., or other evi-

82 Gourfein: Revue inter, de Therap. et de Pharm., May 17, 1896.

122 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

dences of blood-dissociation, warrant the conclusion, it seems
to us, that: —

The adrenals supply a secretion which serves to hold in com-
bination the various constituents of haemoglobin and which simul-
taneously endows the hemoglobin-molecule with its power to tulce
up oxygen.

As in man the pulmonary tract alone is the seat of the
respiratory process, we are again "brought to the lungs as the
organs to which the suprarenal secretion is distributed. If we
now recall (1) the marked respiratory disorders which attend
not only the extirpation of the adrenals, but also advanced dis-
ease of these organs; (2) that the pulmonary tissues do not
respond to the action of suprarenal extract as do other tissues,
even warm extract failing to prove active as elsewhere; (3)
that the adrenals produce a secretion which could be traced no
farther than the lungs, the assumption that so close a physio-
logical relationship between these organs and the suprarenal
glands exists seems to stand on a sound foundation.

We have already referred to the fact that the presence
of haematoidin, a derivative of hemoglobin, in the tissues after
removal of both adrenals suggests, as a working hypothesis,
that the secretion of these organs serves to keep united the
various constituents which enter into the formation of hemo-
globin, and that it is concerned with the affinity of this com-
pound for oxygen. Mathias Duval was shown to have referred
to the vulnerable points of the present conception of the re-
spiratory chemico-physiological process, and the need of "an
action having for its object to rapidly dislodge the carbonic
acid," mere gaseous diffusion failing to satisfy the demands of
various phases of this process. While adducing reasons for the
assumption "that the combination of oxygen with the blood-
corpuscles (oxyhemoglobulin) plays a role analogous to that
of an acid," Professor Duval is also stated to have recalled
Robin and VerdeiPs view in respect to the existence of a
hypothetic "pneumonic acid," and also Garnier's ultramarine-
blue test, which suggested that "a strong acid must exist in
the lungs," though "chemical analysis has not disclosed a spe-
cific acid" in these organs.

But these are not the only investigators who have felt the

THE ADRENAL SECRETION AND PULMONARY RESPIRATION. 123

weakness of prevailing views as regards the intimate processes
of pulmonary respiration. Keichert,93 referring to the inter-
change of 0 and C02 between the alveoli and the blood, re-
marks, after reviewing the generally accepted doctrines: "It
is, however, impossible, under certain conditions, and possibly
under ordinary conditions, to account for the transmission of
all of either the 0 or the C02 by the laws of diffusion. Bohr94
found, in experiments upon dogs, that the tension of oxygen
in arterial blood is almost invariably higher than the partial
pressure of oxygen in the lungs, and in some instances consid-
erably higher. His records of C02, while lacking uniformity,
are of like import, and indicate that the tension of C02 in the
blood is lower than the partial pressure of this gas in the
lungs. Although Bohr's results have met with much adverse
criticism, they have received substantial support in the recent
researches of Haldane and Smith96 on mice, birds, dogs, and
other animals. They found that the normal oxygen-tension in
arterial blood is always higher than in alveolar air, and they
were consequently led to conclude that the transmission of 0
between the alveoli and the blood cannot be satisfactorily ex-
plained by mere diffusion. Moreover, about twice as much
argon exists in solution in the blood-plasma as can be accounted
for by physical laws. Facts of this kind are explicable on the
hypothesis that the living tissues are, as contended by Ludwig,
Bohr, and others, actively engaged in the process, but our
knowledge is as yet too incomplete and contradictory to justify
its acceptance." "In Bohr's experiments," says G. N. Stew-
art,96 "in some of which the animals were made to breathe air
containing carbon dioxide in various proportions, the tension
of that gas in the air of the lungs varied from 5.8 to 34.6
millimeters of mercury, while in arterial blood, taken at the
same time, it usually ranged from 10 to 38 millimeters, and
was often less than in the alveolar air. If we accept these
results we seem shut up to the conclusion that carbon dioxide
does not pass through the walls of the alveoli by diffusion.

98 Reichert: "American Text-book of Physiology," vol. i, 1900.
"Bohr: Skandinavisches Archiv fur Physiologic, Bd. ii, S. 236, 1891.
96 Haldane and Smith: Journal of Physiology, vol. xxii, p. 231, 1897.
96 G. N. Stewart: "Manual of Physiology," p. 242, fourth edition, 1900.

124 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

And, although Bohr's experiments have been severely criti-
cised, it does not seem improbable in itself that the physical
process of diffusion is aided by some other process which may
provisionally be termed secretion." "As to the oxygen, we are
in the same position. Its partial pressure does not appear to
be always higher, even under normal conditions, in the alveoli
than in the arterial blood as it leaves the lungs. Indeed, Bohr
found that, in the majority of his observations on dogs, the
oxygen-tension was distinctly greater in the blood than in the
pulmonary air. And Haldane and Smith, using a new method,
have obtained a value for the oxygen-tension in human blood
(26.2 per cent, equal to 200 millimeters of mercury) that even
exceeds the partial pressure of oxygen in the external air and
is about twice as great as that of the air of the alveoli. . . .
Additional evidence in favor of the view that there is, besides
diffusion, an element of selective secretion in the interchange
of gases through the pulmonary membrane is afforded by a
study of the gases of the swim-bladder of fishes."

Besides all the data recorded in this chapter, generally rec-
ognized facts — i.e., facts generally known before this work was
written — when submitted to a process of logical reasoning, also
lead to the conclusion that an intimate relationship exists
between the respiratory function and the suprarenal glands.
That a physiological relation between these organs and the
blood exists, is shown by the fact that, while characteristic
"bronzing" pigment is a derivative of haemoglobin, Addison's
disease is known to be due to disease of the suprarenal glands.
A "derivative" implicates the element of subdivision. Since,
therefore, the "bronze" pigment is a derivative, the supra-
renal glands must be concerned with the dissociation of the
blood-pigment from which the "bronze pigment" is derived.
This we know to be haemoglobin; the suprarenal glands must,
therefore, be connected with the dissociation of hemoglobin.
Again, since it is a lesion of the suprarenal glands that under-
lies this process, the glands must serve to keep the constituents
of hemoglobin together. To chemically disintegrate hemo-
globin we use reducing agents which act mainly by deoxidizing
this body. Hence, the suprarenal glands must furnish a sub-
stance which supplies oxygen to the hemoglobin constituents.

THE ADRENAL SECRETION AND PULMONARY RESPIRATION. 125

But, as we know that the suprarenal secretion, on the contrary,
possesses a strong affinity for oxygen, it must hold the hemo-
globin constituents together through the effects of this prop-
erty. The lungs are the only organs in man in which the
blood becomes oxidized. Hence, the suprarenal secretion must
also meet the hemoglobin constituents in the lung, and, as
its affinity for oxygen can only serve its purpose in the pres-
ence of this gas, the alveoli must be the seat of the process
through which the haemoglobin constituents are united with
the suprarenal secretion. As the reagents used to chemic-
ally disintegrate haemoglobin include acids which act mainly
through their affinity for oxygen, any combination presenting
a similar affinity for oxygen can chemically simulate an acid.
Hence, haemoglobin, through its union with suprarenal secretion,
acquires a degree of affinity for oxygen commensurate with -that
of the suprarenal secretion, and thus becomes sufficiently active
as a reagent to simulate an acid.

This deduction coincidently meets the needs of the re-
spiratory process denned by Mathias Duval: A degree of
affinity far higher than that thought to depend solely upon
the mutual attraction shown by the various constituents of
haemoglobin is provided. As the hydrogen in hemoglobin or
the various constituents referred to seem at no time to be dis-
placed by a metal during its peregrinations through the normal
or diseased organism, the blood-pigment cannot be considered
as an acid, and Eobin and Verdeil's search for a "pneumonic
acid" in the lungs was obviously fruitless. Yet, when it comes
to Garnier's ultramarine-blue test, the powerful affinity con-
ferred on the hemoglobin by the suprarenal secretion fully
accounts for the loss of color noted in the fluid injected in the
lungs of guinea-pigs. Its contact with alveolar surfaces really
meant contact with a powerful reagent capable of simulating
"a strong acid" in its effects, though no acid, as chemistry
interprets this term, could be said to be present.

Suprarenal insufficiency caused by the entrance of poison-
ous elements into the circulation gives rise, we have seen, to
a condition of the hemoglobin in which it is said to be "in
loose combination." Evidently, then, the suprarenal secretion
serves to hold the constituents of the blood-pigment together,

126 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

and since these constituents tend to fall apart when the secre-
tion fails them, its flow into the circulation must ~be continuous.
Again, we know that venous blood contains not only reduced
haemoglobin, but a considerable proportion of oxyhaemoglobin.
The red corpuscles must therefore always be supplied with
more oxygen than the tissues utilize: a fact which warrants
the conclusion that even reduced haemoglobin, under normal
conditions, is always sufficiently supplied with this gas to
preserve its integrity as a unit. But this conclusion in itself
testifies to the presence in the hcemoglobin-molecule of suprarenal
secretion, and therefore to the fact that, as long as its integrity
is preserved, it is capable of taking up an equivalent of oxygen
in the lungs.

This does not modify, however, the present teachings of
physiology as regards the role of the blood-pigment in the
circulation. "Undergoing no intrinsic change in itself/7 writes
Foster, "the haemoglobin combines in the lungs with the
oxygen which it carries to the tissues; these, more greedy of
oxygen than itself, rob it of its charge, and the reduced haemo-
globin hurries back to the lungs in the venous blood for an-
other portion."

That gaseous diffusion and endosmosis are unimportant
factors of the respiratory process seems probable in view of
the foregoing facts. "Whenever oxygen is mixed with venous
blood, even in vitro during experiments, the carbonic acid
is immediately given off" writes Mathias Duval. "One' is
led to admit, therefore, that the combination of oxygen with
the blood-corpuscle (oxyhaemoglobin) plays a role analogous
to that of an acid and involving the elimination of carbonic
acid from venous blood." The potent agency underlying the
affinity of the blood-pigment for oxygen, we have seen, simu-
lates an acid in its effects. The elimination of carbonic acid,
therefore, includes the physical expulsion of a gas for which
the haemoglobin itself, when normally supplied with the supra-
renal secretion, has less affinity than it has for oxygen. In
carbonic-acid poisoning suprarenal insufficiency prevails, as it
does in the case of poisons and venoms reviewed in this con-
nection. Blood studied outside the body is, therefore, but an
approximate and variable criterion of the physiological func-

THE ADRENAL SECRETION AND PULMONARY RESPIRATION. 127

tions themselves. Both in extravasated blood and in blood
taken from a case of carbonic-acid poisoning the haemoglobin
must be in more or less loose combination: i.e., more or less
deprived of its complement of suprarenal secretion. The fact
that so marked an affinity as that witnessed in venous blood
in the experiment referred to still exists shows how active
must be that exhibited by the blood of the organism when
possessed of its full physiological attributes.

When we come to Bohr's experimental findings, which
tend to show that "carbon dioxide does not pass through the
walls of the alveoli by diffusion," they simply sustain what the
presence of an agency capable of endowing the blood with a
powerful affinity for oxygen at the seat of respiratory inter-
changes,— the walls of the alveoli, — would suggest, namely:
the conclusion that gaseous diffusion and endosmosis are un-
important factors in the pulmonary respiratory process, if they
take any part whatever in the phenomena of which it consists.

Bohr's statement that the pressure of the oxygen in the
alveoli did not always appear higher, even under normal con-
ditions, than in the arterial blood, and that in dogs he had
found the oxygen-tension in the blood distinctly higher in the
majority of his experiments than in the pulmonary air, and
Haldane and Smith's observation, that in the human blood the
oxygen-tension was about twice as great as that of the alveolar
air, are likewise sustained. The hemoglobin, owing to its
powerful affinity for oxygen, takes it up from its surroundings
regardless of the variations of pressure, and, unless the oxygen
is proportionately replaced, it will entirely (Muller) exhaust
the element containing it. The relative tension of oxygen in
the blood and in the alveolar air is not, therefore, a ruling factor
in the process of physiological respiration; and the higher oxygen-
tension in the blood referred to, though subject to constant
perturbations, physiological and pathological, seems but a nor-
mal consequence of the presence in that blood of so potent an
agency for the absorption of oxygen as that represented by the
suprarenal secretion.

If the views outlined in this chapter are based on solid
premises, the process of pulmonary respiration is approximately
as follows: —

128 THE ADRENALS AND THE RESPIRATORY BLOOD-CHANGES.

1. The adrenals secrete a chromogen — a colloid, hyaline fluid
— which leaves the organs through the suprarenal veins, and is
mixed with the plasma of the venous blood in the inferior vena
cava.

2. When the venous Nood reaches the pulmonary alveoli, the
marked affinity of the adrenalized plasma for oxygen causes it to
absorb this gas from the alveolar air.

3. The carbonic dioxide in the blood is thus forcibly replaced
by oxygen, and expelled with corresponding vigor.

4- The red corpuscles, after this operation, bathe in an oxygen-
laden medium, and their haemoglobin becomes reconverted into oxy-
hcemoglobin.

The mechanism of respiration, and the manner in which
the adrenal secretion and the air are brought into contact in
the alveolar elements will be studied in a subsequent chapter.

As regards the relations between this process and the
preservation or dissociation of haemoglobin, the following deduc-
tions seem warranted: —

1. The periodical exposure of the hcemoglobin-molecule to the
oxygen-laden adrenal secretion in the lungs serves to keep its con-
stituents associated."

2. Deficiency, quantitative or qualitative, of adrenal secre-
tion by reducing the oxygen-absorbing power of the plasma corre-
spondingly reduces the mutual affinity of the hcemoglobin constit-
uents.

3. When the molecular combination of the hcemoglobin constit-
uents becomes sufficiently loose from this cause, portions of the
hcemoglobin are detached and follow the arterial blood-stream in
their reduced state, and the efficiency of the blood is reduced in
proportion.

4. The physiological absorption of oxygen by the tissues not
only reduces the oxyhcemoglobin, but further dissociates this ad-
ventitious haemoglobin into its component bodies.

5. The component bodies of haemoglobin thus dissociated are:

(a) Methcemofjlobin or its isomer, hcematin (C32H34FeN406).

(b) Hcematoporphyrin or its isomers, iron-free hcsmatin,
hcemato'idin, and bilirubin (C32H36N406).

(c) HcBmatoporphyrin (usually termed hcemato'idin) appears
in the blood when the adrenals are removed or when their functions

THE ADRENAL SECRETION AND PULMONARY RESPIRATION. 129

are totally inhibited by toxics; it is therefore the lowest of the
cleavage products of the hcemoglobin-molecule.

(d) Hcemoglol)inuria, methcemoglo'binuria, and hcematopor-
phyrinuria indicate, therefore, successive stages of adrenal in-
sufficiency.

CHAPTER III.

THE INTERNAL SECRETION OF THE ADRENALS

IN ITS RELATIONS TO THE GENERAL

OXIDATION PROCESSES.

THE ADRENAL SECRETION AND THE OXIDIZING SUBSTANCE
OF THE BLOOD.

STIMULATION of the adrenals by means of a drug or toxic
gives rise, we have seen, to a marked increase of functional
activity in all organs. Quinine, for instance, causes wakeful-
ness, congestive headache, and sometimes maniacal delirium,
flushed face, spontaneous epistaxis, muscular twitchings re-
sembling those caused by strychnine, active uterine contrac-
tions, etc. How explain this increased activity produced
through these organs? It is evident that it must be due to
the increased production of suprarenal secretion induced by
the drug and a correspondingly enhanced activity of the oxida-
tion processes. But how does the blood become surcharged
with oxygen in order to produce these effects? Whether these
be brought on by stimulation of the cerebro-spinal centers,
increased blood-pressure, contraction of the central vascular
trunks, or any other process, we are always brought back to
the primary active factor: oxygen. Does the corpuscular
haemoglobin take it up in excess? This is hardly probable;
since the haemoglobin-molecule, in assuming the state of
oxyhaemoglobin, appropriates, under normal conditions, all the
oxygen it can carry. Is the proportion of haemoglobin in the
red corpuscles increased in order to correspondingly augment
their carrying capacity? The suddenness with which some
drugs — amyl nitrite, for example — produce active stimulation
precludes such a deduction.

Does the serum itself take up oxygen in the lungs? The

presence of suprarenal secretion in the serum would alone

render this possible; but so little oxygen can be obtained from

blood-plasma with the air-pump that the idea seems hardly

(130)

THE OXIDIZING SUBSTANCE OF THE BLOOD-PLASMA. 131

worth considering. Still, we have seen how marked is the
affinity of the suprarenal secretion for this gas and mechanical
means might prove quite inadequate to dissociate them when
united. Again, the secretion is first poured into the vena
cava and there dissolved in the serum of its venous blood.
Thoroughly mixed with the latter when passed through the
heart, owing to the conformation of the cardiac valves, the
musculaB tendinese, etc., it must find in the serum a normal
vehicle at least during its presence in the prepulmonary vas-
cular channels. Does the serum beyond the lung still contain
suprarenal secretion? We have seen that such is not the case.
Indeed, its remarkable affinity for oxygen would hardly permit
it to pass through these organs and be exposed to the air
therein without its becoming oxidized, or at least converted
into some combination in which both the secretion and the
gas would lose their individual identities.

We must not overlook the fact, however, that this com-
bination, to satisfy the needs of our inquiry, would have to
assume active functions. Again, the secretion and its extra-
pulmonary oxygen-laden successor would have to be antag-
onistic to fulfill physiological needs. In other words, before
reaching the lungs the secretion would possess a marked affinity
for oxygen, while the extrapulmonary compound would show
a correspondingly marked tendency to part with its oxygen
when bodies endowed with greater affinity for this element
would be brought into contact with it.

Have we any ground for the belief that such an oxidizing
compound exists in the blood? An analytical study of this
question is necessarily a somewhat arduous one, but, fortu-
nately, direct evidence is not lacking: evidence that combines
the advantages of absolute reliability and at the same time
covers the field with sufficient fullness to warrant judicious
deductions. The paper to which we refer is that of Salkowski,
already quoted, and which includes, besides his own researches,
the results of those of Schmiedeberg, Jaquet, and Abelous and
Biarnes.

In order to trace the connection between the observations
of these investigators and our views in respect to the part
played by the secretion of the adrenals in the process, it is

9

132 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

necessary to outline them rather fully. An editorial review
of Salkowski's contribution,1 given below,2 so ably presents all
the data necessary to our analysis that it will be utilized for
this purpose. The fact that Salkowski's contribution itself in
no way refers to the adrenals or their functions makes it all
the more valuable, since the evidence submitted cannot even
be said to have been garnered for use, or with a preconceived
idea of the purposes to which it would ultimately contribute
so much weight.

The review of Salkowski's paper is as follows: "In 1892
Jaquet took up the experiments, begun by Schmiedeberg in
his laboratory, upon oxidation by living tissues, using as oxi-
dizable agents those recommended by this author, — namely:
benzilic alcohol and salicylic aldehyde, — because these sub-
stances, under ordinary conditions of the body-temperature,
did not burn in air, while easily consumed in the organism;
and because the oxidation products could only arise from them.
Besides, they could under all circumstances be easily found
and determined quantitatively.

1. "Jaquet at first confirmed the conclusion of Schmiede-
berg, that blood alone could oxidize benzilic alcohol and con-
vert it into benzoic acid in extremely small quantities, but he
concluded that it could not oxidize salicylic aldehyde. His
researches with organs also confirmed Schmiedeberg's view that
benzilic alcohol and salicylic aldehyde, dissolved in the blood,
are easily oxidized into benzoic acid by living organs. The
remarkable data thus acquired may be summarized as fol-
lows:—

2. "The presence of blood is not at all necessary to insure
oxidation through the organs, especially the lungs, so often
used for this purpose; oxidation is more perfect when, instead
of blood, blood-serum is used?

3. "Pulmonary tissue poisoned with quinine and carbolic
acid acts just as well as oxidizing agent as intact lung; hence
the oxidizing power cannot be a property of living protoplasm.
Lung acts perfectly as oxidizant even after remaining in a

1 Salkowski: Virchow's Archiv fiir path. Anat., Jan. 4, 1897.

2 Archives Generates de M6decine, March, 1898, signed "Cart."
8 All italics are our own.

THE OXIDIZING SUBSTANCE OF THE BLOOD-PLASMA. 133

freezing mixture twenty-four or forty-eight hours, and when
frozen as hard as a board.

4. "Horse- lungs and kidneys preserved twelve to fourteen
days in alcohol at 75° C. unmistakably give benzoic acid or
salicylic acid after soaking in a NaCl physiological solution, when
treated as customary in experiments; this is also the case when
the organs are not preserved in alcohol in toto, but previously
reduced to a magma, then hardened in alcohol.

5. "Oxidation of benzilic alcohol and salicylic aldehyde
can be caused, in weak NaCl solution, by extracts of horse- lung
and kidneys. This is even possible when the organs, after
having been treated two hours before with alcohol and ether,
are then washed in salt-water, and also when the extracts are
treated with blood containing salicylic aldehyde.

6. "Organs treated with alcohol and ether gave, all else
being equal, less salicylic acid than fresh organs; still, the
extracts possessed the property of transferring the oxygen of
the air to salicylic aldehyde: a property which is totally absent
in the case of simple alkaline solutions.

7. "That in this oxidation the action of a ferment or
enzyme prevails is proven by boiling the organs: i.e., ebullition
causes entire loss of the oxidizing power.

8. "Jaquet's conclusion that blood alone cannot cause
oxidation of salicylic aldehyde into salicylic acid somewhat
contradicts the results of some of Salkowski's older experi-
ments. Indeed, one year before the publication of Schmiede-
berg's first work (1882) he had obtained oxidations from Hood
alone; so that Jaquet's proposition is valuable in that it con-
firms these older experiments.

9. "This oxidizing power of blood alone, pointed out by
Salkowski in 1881, was recently confirmed by Abelous and
Biarnes.4 These authors so disposed their experiments as to
insure the passage of atmospheric air through the blood treated
with salicylic aldehyde.

10. "In his older work Salkowski attributed this oxidizing
power to the blood-corpuscles, which he thought were the carriers
of oxygen; he now believes that this idea can no longer prevail,

* Abelous and Biarn6s: Archives de Physiologic, vol., 1895.

134 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

since Abelous and Biarnes succeeded in causing oxidation of
salicylic aldehyde by means of blood-serum: that is to say,
blood absolutely deprived of its corpuscles.

11. "It is thus possible to say that the blood acts as an
oxidizant precisely in the sense indicated by Jaquet: i.e.,
through the soluble oxidation ferment it contains. In order
to induce oxidation by means of Hood, the experiments must be
performed under the most favorable circumstances for oxida-
tion, either by reducing the blood or by the continuous passage
of a current of air. Herein lies the great difference between
the results obtained on the one hand by Schmiedeberg and
Jaquet, and by Abelous and Biarnes on the other.

"The experiments that form the original part of the arti-
cle were performed with mixtures of organs, or with their
extracts (with or without blood), left during a fixed length of
time in contact with salicylic aldehyde; then the salicylic acid
formed was determined by means of colorimetry with the weak
solution of perchloride of iron. The number of experiments
performed was twenty-three.

12. "The next experiments were instituted to show that
the oxidizing body is destroyed by boiling, showing it to be a
ferment. It is also destroyed by remaining three days in ab-
solute alcohol.

13. "It is important to note that, in a certain number of
experiments, the quantity of salicylic acid formed was much
less than in others. Many factors certainly influence the results:
abbreviation of the digestion period, the individual peculiarities
of the animal, its age, its previous diet, the time elapsed since its
death, etc.

14. "A result of these various experiments is to confirm
the opinion advanced by Jaquet, that the presence of cellular
protoplasm is absolutely superfluous, and that oxidation is much
more likely to be caused by a ferment soluble in water and
originating in protoplasm, able also to stand a short treat-
ment with absolute alcohol, but which, if prolonged, com-
pletely destroys it, as in the case of pepsin, for example.

15. "It is interesting to ascertain now how the oxidation
property behaves toward various tissues. Muscular tissue was
first examined, because it stands first as to quantity in the

THE OXIDIZING SUBSTANCE OF THE BLOOD-PLASMA. 135

organism, while from the standpoint of oxidation it presents
features of special interest. . . . These experiments showed
that oxidizing power of muscular tissue was extremely small."
Various experiments, which need not be considered in detail
here, showed that 100 grammes of each of the following organs
gave salicylic acid as a result of the reaction produced with
salicylic aldehyde, corresponding with the number of milli-
grammes opposite their names: Liver, 0.138 milligrammes;
spleen, 0.110 milligrammes; kidneys, 0.022 milligrammes;
pancreas, 0.0028 milligrammes; muscles, 0.0014 milligrammes.

16. "Does the soluble oxidation ferment play any signifi-
cant role during life? That such must be the case is revealed
by the great number of substances upon which the action of the
oxidation ferment is exercised. If the aromatic series is first
considered, especially the benzol derivatives, a large series of
known bodies is found, which, incorporated into the organism,
are oxidized therein; for example: methylbenzol, ethylbenzol,
propylbenzol, benzilic aldehyde, benzilic alcohol, acetophenol,
which are oxidized into benzoic acid, salicylic aldehyde into
salicylic acid, xylol into toluic acid, benzol into phenol, etc.
. . . The question whether the action of the oxidation fer-
ment manifests itself in physiological combinations is one of
very great interest.

17. "Salkowski showed long ago that phenylpropionic acid
is a regular product of albuminous disintegration by putrefac-
tion bacteria. He even found that this acid, in the body, is
oxidized into benzoic acid up to its last remnants, and that
the latter leaves the organisms by uniting with glycocol in the
form of hippuric acid. ... Is the oxidation ferment ca-
pable of causing this oxidation? Salkowski's experiments have
not as yet furnished an answer to this question, so that, until
further data are obtained, it may be said that the bodies of
the aromatic series which can be oxidized by the oxidizing
ferment are limited to benzilic alcohol, salicylic aldehyde, and
benzol, all bodies which do not occur physiologically in the
organism.

18. "The action of the oxidation ferment on fats is better
known than that on aromatic substances. Pohl has proven that

136 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

animal organs, especially the liver, — owing to its contained
oxidation ferment, — were able to oxidize formaldehyde and
methylic alcohol into formic acid. The action of the oxidation
ferment upon glycose is well known, as also the researches of
Claude Bernard, renewed by Lepine, who attributes the oxida-
tion of the sugar in the blood to the action of a special fer-
ment: the "glycolytic ferment." Spitzer5 has since shown
that this property of destroying sugar did not belong to the
blood alone, but that it was a general attribute of protoplasm,
though concerned in no way with the life of the latter. In
fact, the glycolytic property still exists in old and dry extracts
of organs. It is therefore very probable that the sugar-destroy-
ing ferment which only acts in the presence of oxygen is identical
with the tissue-oxidizing ferment''

To show the true importance of these researches, their
exact bearing upon our analysis must be clearly defined. Espe-
cially important is it to realize that the experiments referred
to were performed outside the body, the tissues being used as
sources of oxygen, whereas our analysis, on the contrary, ap-
plies to reactions within the body, where the tissues take up oxy-
gen and use it in their metabolism. In the case of the blood-
serum, however, these extra corpore experiments give a true
picture of the intra corpore function, since we are dealing with
an oxidizing ferment. The chemical bodies referred to, there-
fore,— salicylic aldehyde, benzilic alcohol, etc., — faithfully rep-
resent poisons that have reached the circulation, while the
main process of more or less complete neutralization to which
they are submitted is correspondingly portrayed by their con-
version into salicylic acid, benzoic acid, etc. In other words,
they do in the body what the experiments showed them to do
outside the body: i.e., they take up a part of, or all, the oxygen
of the oxidizing ferment, for which the serum acts as a vehicle
or menstruum. Reducing the process to its simplest expres-
sion: both, tissues and poisons, act as reducing agents upon the
oxidizing compound.

A critical analysis of Salkowski's paper clearly shows that
all the attributes necessary to such a process as that just

6 Spitzer: Berliner klin. Wochenschrift, No. 42, 1894.

THE OXIDIZING SUBSTANCE OF THE BLOOD-PLASMA. 137

defined obtain: The third and thirteenth paragraphs show
that it is not the tissues that oxidize poisons, while the tenth
as forcibly demonstrates that this function cannot be attrib-
uted to the blood-corpuscles. That the blood-serum contains
the oxidizing principle is confirmed by Paragraphs 2 and 10.
That the process can be exercised notwithstanding the alkaline
salts of the serum is emphasized in Paragraph 4.

The exposure of the suprarenal secretion to the air of the
lungs as the intermediate function upon which the acquisition
of oxidizing powers depends is typified by the need of a con-
tinuous current of air, — to sustain the oxidizing power of iht
ferment, — referred to in Paragraph 11. That a "great numbei
of substances upon which the action of the oxidation ferment
is exercised" exist, is evident, judging from those given in
Paragraph 16 and elsewhere in the paper. Finally, that there
exists an underlying cause for fluctuations in the oxidizing
power of the serum, digestion, age, diet, etc., — all features
which more or less influence the adequacy of the suprarenal
glands, — is demonstrated in Paragraph 11. As several chap-
ters will contribute abundant evidence to demonstrate the ex-
istence of an oxidizing substance, we will limit ourselves, for
the present, to a single class of affections in which its action
is clearly marked: i.e., those ascribed to "uric acid."

The older view as to the origin of uric acid — i.e., that it
was, as held by Liebig, Wohler, and Frerichs, a product of albu-
minoid decomposition and a preliminary process to the pro-
duction of urea — no longer prevails. Benecke, in 1874, showed
that the greater part of the urea eliminated did not originate
from oxidized uric acid, while Horbaczewski, in 1891, found
that, just as the nuclein of pus-cells and that of the blood-
corpuscles of birds could produce hypoxanthin, guanin, and
xanthin, as noted by Kossel, so could it produce uric acid in
vitro under the effects of marked oxidation. Nuclein adminis-
tered to animals is, moreover, known to increase the production
of uric acid: a fact which led Horbaczewski to conclude that
normally-eliminated uric acid originates from nuclein, which in
turn is liberated through the destruction of cellular structures
and especially of leucocytes. This investigator further noted
that leucocytosis was attended with increased elimination of

138 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

uric acid. These results were sustained by Kuhnau, who ob-
served that pure nuclein administered in large doses was elim-
inated in the form of uric acid, and further confirmed by
Weintraub, Umber, and Mayer after a series of counter-experi-
ments.

Dunin and Nowaczek6 studied the question from another
direction: i.e., in five cases of pneumonia, in which disease, as
we have seen, leucocytosis is very marked. They found that
the quantity of uric acid eliminated rises greatly the day before
the crisis: i.e., when absorption of the exudation and destruc-
tion of the leucocytes begin. Immediately after the crisis the
uric-acid ratio rose to three times that of the precritical period,
and continued high several days. It seems plain, therefore,
that uric acid originates from nucleins, which in turn are de-
composition products of the cells of the organism and particu-
larly of leucocytes.

The nuclein derivatives, — hypoxanthin, guanin, xanthin, —
just referred to and another, adenin, of the same class have
since been termed "alloxuric bases" by Kossel and Kruger, but
E. Fischer, after exhaustive investigations, traced them all to
a carbon-hydrogen nucleus, the purin nucleus, from which
many important derivatives — uric acid, caffeine, theobromine,
etc., besides the nuclein bases mentioned above — can be ob-
tained. This feature obviously demonstrated a close chemical
relationship between these bodies and various substances —
cocoa, coffee, tea, meats, sweet-bread, liver, and others rich in
nucleins, and normally led to the conclusion that articles of
food which had long been associated pathogenically with the
production of uric acid, could also act as sources of nuclein
bases. This was confirmed by experiments in healthy subjects,
from whose urine the latter were obtained daily in varying
proportions.

It then became a question as to which of the two sources
of nuclein prevailed: i.e., whether they were derived from body-
cells, leucocytes, etc., as thought by Horbaczewski, or from
articles of food, as thought by Fischer. Experimental data in

• Dunin and Nowaczek: Zeitschrift fur klin. Med., Bd. xxxii, 1897.

THE OXIDIZING SUBSTANCE OP THE BLOOD-PLASMA. 139

favor of Horbaczewski's view have steadily accumulated, while
Fischer's position has as steadily gained ground. The prevail-
ing view, therefore, is that the alloxuric bases are derived from
the nucleins of which the body-cells, and particularly leuco-
cytes, are the source, and also from certain articles of food.
This constitutes but a subdivision of general metabolism: i.e.,
that recognized as "nuclein metabolism."

Again, Horbaczewski, in a series of experiments, observed
that splenic pulp, allowed to digest several hours with blood
at the body-temperature, gave rise to a marked increase of uric
acid and nuclein bases, but that the relative amounts of these
products depended entirely upon the degree of oxidation. When
simple decomposition prevailed, the nuclein bases were found
to predominate, while the more advanced oxidation processes
led to the formation of uric acid. That the production of uric
acid must be an advanced stage of the processes through which
the waste-products are prepared for excretion is thus made
probable. This is sustained by the high relative proportion
of oxygen — higher even than urea: (NH2)C02 — which its
formula indicates, and the gradual progression toward this
high proportion which the alloxuric bases show: i.e., guanin,
C6H5N50; hypoxanthin, C5H4N40; xanthin, C5H4N402; and
uric acid, C5H4N403. Feeding with bodies rich in nucleins,
spleen-pulp, thymus, etc., causes a proportionate increase of
the most advanced of the alloxuric bodies, uric acid, and in
health the greater part of the nitrogen of the nuclein metabo-
lism is excreted, not as nuclein bases, but as uric acid. All
these facts tend to show that uric acid is not only the normal
end-product of nuclein metabolism, but also the most highly oxid-
ized of the alloxuric bodies.

If this conclusion prevails, what is the utility of the oxida-
tion of alloxuric bases? This soon appears when their toxicity,
as compared to that of uric acid or urea, is realized. Uric
acid, notwithstanding the prevailing belief to the contrary, is
chemically harmless. It has been fed to animals or injected into
their blood in very large doses without giving rise to untoward
symptoms. Even its continued administration has failed to
bring about the least pathological change in the structures
which it is generally thought to assail, as shown experimentally

140 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

by A. C. Croftan.7 True, it may have been found in very
marked quantities in the serum of some gouty subjects during
the active stage, as observed by Garrod; but, if the acute
symptoms of this disease are due to uric acid, why do they
not appear in such conditions as leukaemia, in which uric acid
is also present? Uric acid is insoluble in the body-fluids, and,
if it irritates the renal structures at all, it can only do so
through the asperities of its crystals, since as a chemical body
it is innocuous. Even the view that gouty disorders should be
ascribed to its influence alone hardly stands, since Pfeiffer and
Vogel and other investigators have found that the proportion
of uric acid, when ascertained by modern methods during or
between attacks of gout, shows but little variation.

Urea is also a benign substance; Bouchard found in a
series of painstaking experiments that it was even less toxic
than sugar. Whereas it took 2.5 grammes of bicarbonate of
soda to kill 1 kilogramme of animal, from 5.5 to 6.3 grammes
of urea were required to reach the same result. Water and
normal albumin alone, of the animal fluids, are less toxic than
urea. As to its influence on the kidneys, Bouchard was led to
conclude that, although a product of disassimilation, it played
a useful role in the economy as a diuretic.

Quite another story is unfolded, however, when the allox-
uric bases are analyzed from the same standpoint. As products
of worn-out nuclei which have served their purpose in elabo-
rating blood-corpuscles, both red and white, and other cellular
elements, their effects are those of powerful alkaloids. Eeadily
soluble in the relatively large proportion of menstruum which
the body-fluids afford them, they are carried in all directions,
and become the source of the various phenomena usually
ascribed to "gouty diathesis" and now credited to them by the
more recent writers. Gaucher3 and Kolisch,9 in the order
named, long ago referred to the alloxuric bases — xanthin,
hypoxanthin, adenin, and guanin — as violently toxic agents,
while Levison ascribes to them the renal lesions which are

'A. C. Croftan: Journal of the American Medical Association, July 8, 1899.
s Gaucher: These de Paris, 1884.

• Kolisch: Wiener med. Wochenschrift, 1895; quoted by F. Levison, "Sajous's
Analytical Cyclopaedia of Practical Medicine," vol. ill.

THE OXIDIZING SUBSTANCE OP THE BLOOD-PLASMA. 141

invariably found post-mortem in gouty subjects. The patho-
genic effects of these bodies have since then been emphasized
by several investigators, including Croftan,10 who, in a series
of experiments, observed that "both xanthin and hypoxanthin,
when injected hypodermically in the strength of a 0.3- to 0.7-
per-cent. watery solution for a period of several months, pro-
duced granular degeneration of the epithelial cells lining the
tubuli contorti and a proliferation of the endothelium of the
intertubular capillaries." He also found, in confirmation of
the observations of Charcot, Binet, Coen, and d'Ajutolo, that
the renal lesions of chronic lead intoxication — which, as shown
by Garrod, Lancereaux, and others, is one of the etiological
factors of gout — are identically those caused by alloxuric bases.

The non-toxic nature of uric acid and of urea, the violent
toxicity of the alloxuric bases, and the relative position of uric
acid to the latter, as the most highly oxidized body of the
series, seem fully to justify the view that the alloxuric bases
are converted from physiological toxics to uric acid, an inert body,
by oxidation.

If the functions of the suprarenal glands are what they
are said to be in this work, the classical experiments of Min-
kowski, which showed that uric acid was almost entirely formed
in the liver, lose much of their weight. As will be remem-
bered, this investigator kept geese alive from six to twenty
hours after extirpation of the liver; their urine was then found
to contain but 2 or 3 per cent, of uric acid instead of the nor-
mal 60 or 70 per cent. If large doses of poisons produce
sudden suprarenal insufficiency, it is evident that the removal
of so important a toxic destroyer as the liver should promptly
cause in the system an accumulation of catabolic products
amply sufficient to overwhelm the adrenals in a short time.
Not only are Minkowski's experiments invalidated by this fact,
but all others performed since in which, by diverting the blood
from the liver into other channels, kindred results were
reached. This does not, however, eliminate the liver from
the field of activity; indeed, it takes a part in the protective
process commensurate with its position among organs as a

10 Croftan : Loc. tit.

142 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

storehouse for oxygen, with the spleen, also remarkable in this
particular, as a close second. But the kidneys do not in the
least appear to stand, as thought by many, in the light of
uric-acid forming organs, but, on the contrary, as the main
organs to be protected, since it is upon their tissues that the
brunt of the disorganizing effects of the alloxuric bases is ex-
ercised. "We are indebted to Levison11 and others for the
knowledge that granular atrophy of the kidneys is a constant
precursor of gout," says Croftan.12 Such a morbid process
would precisely coincide with the effects upon renal tissues that
free alloxuric bases would be expected to produce.

Yet, the labors of Garrod, Luff, and others have empha-
sized the fact that uric acid is not present in the blood during
health either in mammals or birds. This is difficult to recon-
cile with the view that the kidneys are not uric-acid-forming
organs, since its presence in the urine exceeds in quantity that
of the alloxuric bodies. But, according to von Noorden,13 the
Heintz method of ascertaining the presence of uric acid in the
blood is so faulty that Garrod's painstaking analyses and those
of the many able successors have lost all scientific value in this
particular. Bouchard, Sprague, Pfeiffer, Vogel, and Croftan,
on the other hand, using more modern methods, have invari-
ably found uric acid in normal blood, thus indirectly eliminat-
ing the kidneys as the uric-acid-forming organs.

Haig's faithful work in this direction must not be over-
looked. While his view that uric acid is the source of the
manifestations of toxicity witnessed is not sustained by mod-
ern research, his numerous analyses distinctly prove two points
which modern experimentation has fully upheld: i.e., that the
uric acid found in the urine is a fluctuating quantity, and that
various foods are capable of augmenting this quantity. The
kidneys once eliminated from the depurative process, we are
relegated to the blood as the main source of the uric acid, and
therefore to the blood as the seat of the reaction, which con-
sists in the conversion of varying quantities of toxic alloxuric
bodies into equally variable quantities of benign uric acid.

"Levison: Zeitschrift f. klin. Med., vol. xxvi, p. 31V.

12 Croftan : Loc. cit.

13 Von Noorden: Quoted by Croftan, loc. cit.

THE OXIDIZING SUBSTANCE OF THE BLOOD-PLASMA. 143

That the reaction through which the alloxuric bases are
converted into uric acid by oxygen occurs in the blood may
be further emphasized by Horbaczewski's experiments in an
unexpected manner — unexpected in the same sense that his
experiments may be used to sustain one of his important
deductions and at the same time prove the presence of oxygen
in the body-fluids. When in the course of these experiments
the spleen-pulp and the blood were brought into contact at
the normal body-temperature in the presence of air, uric acid
was formed, while the same experiments performed after the
exclusion of air produced alloxuric bases. Horbaczewski cor-
rectly concluded from this that the relative quantity of allox-
uric bases formed as to that of uric acid depended upon the
extent of oxidation. In other words, the surplus of oxygen
which the presence of air afforded accounted for the formation
of uric acid. That this confirms the absolute need of air,
insisted upon by Abelous and Biarnes, and further sustains the
view advanced in the present work, that the suprarenal secre-
tion becomes oxidized in the lungs, is evident. We thus obtain
proofs from three different directions that the blood contains
an oxidizing principle, and that the alloxuric bases are converted
through this principle into uric acid.

Brief reference must now be made to the nature of the
symptoms that occur as the result of intoxication from the
alloxuric bases. To state that the suprarenal glands respond
to the more or less great quantities of these toxics that appear
in the blood at various times during health, as the result of
undue nuclein ingestion, or during disease, as the result of
hyperleucocytosis, more or less marked tissue metamorphosis,
etc., is to confirm what the reader has doubtless already recog-
nized. Haig has often emphasized the high arterial tension
of what he thought to be "uric-acid" poisoning; it attends
migraine and the various milder disorders ascribed to the
"gouty diathesis/' If the postulate that "muscular vessels
and capillaries are antagonistic in dilation and contraction" is
recalled, we can readily account for this phenomenon, the
alloxuric bases, like any other poison, causing contraction of the
central vessels and dilation of the peripheral capillaries. The
marked pallor, cold and clammy extremities and skin wit-

144 THE ADRENALS AND THE GENERAL OXIDATION PROCESSES.

nessed in severe cases also typify the stage of marked poison-
ing: i.e., of suprarenal insufficiency. That this stage may
prove fatal is shown by some cases of so-called "retrocedent"
gout, in which the main symptoms, according to Osier, are
"pain, vomiting, diarrhoea, and great depression" — or "cardiac
manifestations — dyspnoea, pain, and irregular action of the
heart." In acute gout, immediately before an attack, "the
patient complains," says Levison,14 "of headache, vertigo,
drowsiness, . . . cramps in the calves and elsewhere." He
also refers to "pain in the various articulations; parassthetic
sensations, such as numbness of the fingers, chilliness, etc.," —
all signs which point directly to the suprarenal glands. We
can legitimately conclude, therefore, that the adrenals react
under the effects of the alloxuric ~bases precisely as they do under
those of any other toxic: i.e., toxins, mineral and vegetable poisons,
venoms, etc.

Such is the process through which probably the most
active oxidizable poison produced in the organism is neutral-
ized. In a perfectly healthy subject the equilibrium of pro-
duction and destruction is constant, and the suprarenal glands
hardly, if at all, assert their presence through their character-
istic symptoms. A benign acid is produced and continu-
ously eliminated, the physiological cycle being performed with-
out interruption, and symptomatic fluctuations only occur when
increased tissue metamorphosis, as a result of exercise, diges-
tion, etc., bring on an increase of the physiological work of
which the adrenals are the primary source. Kindred reactions,
of which the oxidizing substance in the serum is probably the
basis, are brought about by the ingestion of certain fruits, —
green gages, cranberries, and prunes, for instance, — hippuric
acid being then found in the urine in greater quantities than
usual.

The application of the physiological function of which the
oxidizing substance is the active agency to poisoning from
external poisons is well illustrated by the fact that, when cer-
tain agents or poisons are ingested, — toluol, benzylamin, ben-
zoic acid, cinnamic acid, oil of bitter almonds, etc., — the ex-

14 Levison: Loc. cit.

THE OXIDIZING SUBSTANCE OF THE BLOOD-PLASMA. 145

cretion of hippuric acid is likewise increased. This is also
witnessed in acute febrile processes, diabetes, chorea, and
various other disorders. On the whole, the following conclu-
sions appear to us to be sustained: —

1. When the secretion of the adrenals reaches the pulmonary
alveoli, it absorbs oxygen from the air and forms with the latter a
compound, or "oxidizing substance."

2. A part of this oxidizing substance is absorbed by the haemo-
globin of the corpuscles and the balance remains in the blood-
plasma.

3. This oxidizing substance is the reagent to which the oxida-
tion processes that occur in the blood-stream are due.

The far-reaching meaning of the third conclusion will be
emphasized in subsequent chapters, which in reality constitute
a continuous chain of evidence to the effect that the oxidizing
substance underlies all the oxidation processes of the organism.

CHAPTER IV.

THE INTERNAL SECRETIONS OF THE THYROID AND

THYMUS GLANDS IN THEIR RELATIONS

TO THE ADRENALS.

THE THYROID GLAND AND THE ADRENALS.

A FEW years ago Robert Hutchinson1 closed a review of
the literature upon the effects of thyroid extractives on
metabolism with the following remark: "Briefly, then, it may
be said that the effect of the administration of the thyroid is
to increase oxidation in the body; it makes the tissues, as it
were, more inflammable, so that they burn away more rapidly.
The products of the disintegration of the nitrogenous tissues
appear in the urine almost entirely in the form of urea, uric
acid, the xanthin bases, being neither regularly nor appreciably
increased, while the products of the fat-destruction are elimi-
nated as C02 by the lungs, and water by the kidneys." Recent
investigations have but confirmed these deductions.

On the other hand, there is considerable uncertainty in
respect to the physiological role of the thyroid. This is well
exemplified in the following lines by Professor Foster2: "When
in certain animals (monkeys, dogs, and other carnivora* ; and
the same has been observed in man) the gland is extirpated,
even with the greatest care, the operation is frequently fol-
lowed by the occurrence of peculiar nervous symptoms, such
as muscular twitching* and tremors, spasms, and even tetanic
convulsions (more especially observed in young animals), ac-
companied or succeeded by irregularity or failure of voluntary
movements; subsequently there may ensue varied symptoms
which may be described under the general term of disordered
nutrition, ending eventually in death. In a certain number of
cases, however, in the above kinds of animals, no serious
symptoms follow, even the total extirpation of the organ pro-

1 Robert Hutchinson: British Medical Journal, July 16, 1898.

2 Foster: Loc. cit., 465.

8 The italics are our own.

(146)

THE THYROID GLAND AND THE ADRENALS. 147

ducing no marked effect; and in rabbits and other herbivorous
animals removal is said never to be followed by any of the
above results. It has been urged that the symptoms, when
seen, are the effects not of the mere absence of the organ, but
of the mischief set up by the operation in adjoining structures,
more especially in the laryngeal nerves and vagus trunks;
but this does not seem a valid explanation. If, as suggested
above, certain metabolic processes are normally going on in
the organ, we may fairly suppose that, in the absence of the
organ, the interruption of the normal sequence of chemical
change would throw upon the circulation certain strange sub-
stances which, acting like a poison, might produce the nervous
symptoms, throw into disorder the nutrition of various tissues,
and finally bring about death. We may further explain the cases
where symptoms are absent by supposing that, for some reason
or other, "things have taken a different turn": the particular
poisonous substances have not made their appearance, but in-
nocuous ones have taken their place; and we know how slight
a change in chemical composition may turn a poison into an
inert body. This, of course, remains a mere supposition until
we can state what the exact metabolic processes are, and name
the substances which work the mischief; but it seems more
reasonable to accept such a provisional supposition than to
conclude that the thyroid may be removed without producing
any effect whatever on the organism. An animal without a
thyroid may appear perfectly well, because the circumstances
to which it is exposed do not happen to test the imperfection
from which it is really suffering, just as a man's inability to
swim may not be apparent until he happens to fall into the
water. The animals which do succumb to the operation of
removal of the organ are, for some reason or other, put to the
test, and are found wanting. The very discordance of the ex-
perimental results points to the physiological moral that the
phenomena which we are as yet able to observe form, as it
were, a mere surface covering intricate processes at present
wholly, or nearly wholly, hidden from us."4

If the data recorded in the last chapter concerning the

* The italics are our own.

148 THE THYROID, THE THYMUS, AND THE ADRENALS.

direct causal relationship between the adrenals and oxidation
processes are sound, the thyroid must either be considered as
capable of playing a similar role in the organism, or it must
be so related to the adrenals as to, in a measure, govern their
functions. Analysis of the former proposition promptly shows
that it cannot prevail. As to any relationship between the
thyroid and the adrenals, all that can be said is that there
seems to exist a certain degree of functional connection be-
tween them, judging from the effects of their removal and the
character of their blood-supply. Indeed, the arteries of the
thyroid are remarkable in various ways, and particularly for
their number and size. Luschka5 has estimated that the sum
of their transverse section equals the sectional area of the
internal carotid artery of the same side, so that nearly as
much blood passes through the four arteries supplying the
gland as goes to supply the brain through the vertebral and
internal carotid artery. The veins are correspondingly large,
and remarkable also for their number and free inosculation.
This is well shown in the annexed colored plate. Collecting,
as they do, the great mass of blood passed through the organ,
they are found to empty into channels that are suggestive by
their immediate anatomical relations: the internal jugular
and the innominate veins, which ultimately empty their blood
into the superior vena cava. Here again, therefore, we find
a loop with a large arterial trunk as the starting-point, a vena
cava as the main intermediate channel, and the heart as a
common distributing mechanism. As in the case of the supra-
renal secretion, the thyroid secretion must therefore penetrate
the pulmonary circuit, return to the heart, and then be dis-
tributed throughout the organism with blood.

The features available as elements for an analysis of the
functions of the thyroid suggest that we are not dealing with
an intraglandular process having for its purpose to locally
destroy toxic substances. In the first place, the demonstrated
increase of vital activities, growth, metabolism, mental power,
etc., which thyroid extract procures would become unintel-
ligible, since its effect is peculiar to thyroid extractives: a fact

B Luschka: Allen's "Anatomy," p. 366.

VASCULAR SUPPLY DP THE THYRDIU GLAND,

THE THYROID GLAND AND THE ADRENALS. 149

which eliminates them from the list of poisons and indicates
a direct relationship with a physiological function. In the
second place, it is well known that the symptoms that occur
after removal of the thyroid in animals may be arrested for a
time by injections of thyroid extract, while grafting or trans-
planting of a gland into the peritoneum, the abdominal wall,
or elsewhere may arrest them completely. Christiani,6 in a
series of experiments on reptiles and mammalia, found that
properly transplanted thyroids continued their functions, and
that they preserved their morphological characters without
showing any tendency to atrophy. Von Erlenden7 ascertained
that such glands continued to produce their colloid material
and formed new vascular connections, — all facts which SchifE,
Horsley, von Eiselsberg, Canizzaro, and many others had al-
ready noted. Christiani also8 ascertained, by means of micro-
scopical examinations of fragments of transplanted organs,
repeated at short intervals, that vascular regeneration of the
gland occupied three months.

Again several experimenters have successfully performed
transplantations in carnivorous animals, — cats, dogs, etc., —
which, we have seen, often die after thyroidectomy. How could
we account for the absence of even marked symptoms in these
animals during the prevascular period — i.e., that ensuing be-
tween the date of transplantation and the third month — if the
thyroid had for its mission to destroy toxics in situ? If the
function of the organ is to destroy these bodies within its own
structures, can we reasonably expect the insignificant quantity
of blood which then courses through the transplanted organ
to satisfy the needs of the function? In order to carry it on
satisfactorily the entire blood would have to course through
the grafted thyroid, whereas even when the organ is in its
normal position in the neck, only a comparatively small pro-
portion of the blood of the organism passes through it not-
withstanding its large vascular supply. On the other hand,
we can easily understand how immediate benefit could be ob-

8 Christiani: Revue M6dicale de la Suisse Romande, Dec. 20, 1900.

7 Von Erlenden: Centralblatt fur d. Grenzgebiete der Medicin und Chirurgie,
Nov., 1899.

8 Christian! : Archives de Physiologie, Jan., 1895.

1-50 THE THYROID, THE THYMUS, AND THE ADRENALS.

tained from a transplanted thyroid brought into contact with
a raw surface prepared for its reception, through absorption
into the blood, not necessarily of a secretion at first, since the
glandular functions would then be in abeyance, but of the
glandular juices themselves, which have been found so remark-
ably active in cretinism, myxcedema, etc.

We are brought nearer to the suprarenal glandular func-
tions when the symptoms usually referred to as "nervous" are
reviewed. The "muscular twitchings and tremors, spasms, and
even tetanic convulsions" remind us vividly of the stage of
stimulation of the adrenals, though they occur as results of
removal of the thyroid. That the functions of the thyroid
must be connected with the destruction of toxic elements of
internal origin is evident. Yet if its secretion enters the cir-
culation and enhances metabolic processes and oxidation, and
since it is not itself endowed with properties that enable it to
directly carry on such a process as stated, it can only do so
indirectly. In view of the data incorporated in previous chap-
ters, may the thyroid gland not supply the blood with some
agency through which, directly or indirectly, the suprarenal
glands are stimulated?

Removal of the thyroid in rabbits and other herbivorous
mammals and birds is net followed by the above-mentioned
symptoms, whereas these are prominent in the carnivora: the
dog, cat, monkey, man, etc. Still, the so-called nervous dis-
turbances do not always occur in the latter: a fact which has
caused some authoritative physiologists — Munk, of Berlin, for
instance — to conclude that the thyroid was not an organ of
extreme importance to life. In his experiments 50 per cent,
of monkeys and rabbits and 25 per cent, of dogs and cats re-
mained unaffected notwithstanding the ascertained absence of
accessory organs. Cunningham,9 in a series of very carefully
conducted experiments, also found that the ingestion of some
tissues — thymus, muscle, etc. — produced symptoms strikingly
similar to those observed in the thyroid intoxication, and con-
cluded that the latter cannot, therefore, be looked upon as
due to a specific derivative of the thyroid gland. Unlike Munk,

9 Cunninghrm: Journal of Experimental Med., March, 1898.

THE THYROID GLAND AND THE ADRENALS. 151

however, he found that fresh thyroid and thymus extractives
were capable of relieving for a time the symptoms of acute
cachexia in young dogs from which the thyroid had been
removed.

While these observations have been considered as opposed
to prevailing views, they lose this characteristic when the
suprarenal glands are looked upon as connected, though pas-
sively, with the toxic manifestations observed. The thyroid
may not necessarily be an organ of extreme importance to life,
for instance, as thought by Munk, since it thus becomes the
source of a substance which is merely intended to stimulate
the adrenals: i.e., to produce effects similar to those of a
poison upon them or their center precisely as did the many
drugs we have reviewed. In the animals in which acute ca-
chexia did not occur in Munk's experiments the adrenals were
simply adequate to meet the .extra call upon their functions,
while in those that succumbed — the majority — the adrenals
yielded to accumulated waste-products, owing to the supra-
renal insufficiency engendered. So was Cunningham right in
saying that the symptoms of intoxication could not be ascribed
to the specific thyroid derivative, since all the toxic symptoms
observed, whether obtained from tissue toxalbumins, thyroid
extract, or any other active body, can now all be traced to the
adrenals.

Under these circumstances it is obvious that continued
administration of thyroid extractives should so stimulate the
adrenals as to enable them, through overactivity, to increase
the oxidizing substance in the serum and destroy the toxic
waste-products. Baumann and Goldmann10 found that thy-
roidectomized dogs did not show tetanic convulsions as long
as iodothyrin was administered regularly each day in doses
ranging from 2 to 6 grammes, but the convulsions returned
as soon as the iodothyrin was no longer administered. A
striking reminder of the effects of antitoxic serum is the fact
that the more marked were the symptoms and the longer was
the administration of thyroid delayed, the larger had the dose
to be to counteract the phenomena witnessed. This simul-

Baumann and Goldmann: Miinchener med. Wochenschrift, p. 1153,

152 THE THYROID, THE THYMUS, AND THE ADRENALS.

taneously confirms the enormous mass of clinical evidence
accumulated in recent years as to the value of thyroid extract
and accounts for the contradictory evidence recorded. The
features that have remained unrecognized, however, provided
the views advanced herein are sound, are: —

1. That the symptom-complex termed "cachexia strumipriva,"
though of thyroidal origin, is a direct consequence of adrenal in-
sufficiency.

2. That the thyroid gland is but an auxiliary organ to the
adrenals, in that it supplies the blood with a secretion which di-
rectly or indirectly increases the adrenal secretory functions and
thereby augments the activity of oxidation processes.

EXOPHTHALMIC GOITER AND IMPAIRED FUNCTIONAL
ACTIVITY OF THE ADRENALS.

The relationship between the adrenals and the thyroid
soon asserts itself when we transfer the analysis to the dis-
eases that are ascribed to excessive or insufficient thyroid
secretion: interpretations that are fairly exact, but which
nevertheless would now convey any meaning other than that
generally accorded them. Exophthalmic goiter at once sug-
gests itself in this connection. Instead, however, of attributing
the phenomena witnessed to the immediate action of an ex-
csssive amount of thyroid secretion upon the organism at
large, it now seems more exact to ascribe them to excessive
and continuous, direct or indirect, stimulation of the adrenals
produced by the corresponding excess of thyroid secretion.

To demonstrate the existence of such a causal relation-
ship, however, the symptoms of this disease should be shown
to vary in a measure as they do when external poisons are
introduced into the blood. A relatively small excess of thyroid
secretion should also produce symptoms of suprarenal over-
activity, while a large excess should give rise to signs of in-
sufficiency. All these features are clearly sustained by the
semeiology of this affection: — .

Adrenal overactivity is exemplified by: 1. The cerebral
hyperoxidation, as manifested by headache, irritability, ex-
citability, capriciousness or unnatural gayety, hallucinations,
mania, and epileptic convulsions. 2. The unusual muscular

EXOPHTHALMIC GOITER AND THE ADRENALS. 153

metabolism and consequent muscular fatigue, — also due to
excessive oxidation, — as manifested by the fibrillary tremor
similar to that of excitement and to be distinguished from the
paretic tremor, the painful cramps in the extremities, the
reduced chest-expansion, the tetanic spasms of the hands, and
general emaciation. 3. The contraction of central and other
muscular vessels and centrifugal dilation of the capillaries,
as manifested in the brain by the signs just referred to; in
the peripheral tissues by cutaneous flushing and superficial
heat, urticaria, erythema, purpura, localized and general,
oedema; and in the deeper organs by dyspnoea, dry cough,
epistaxis, and haemoptysis as to the respiratory organs; saliva-
tion, vomiting, intense thirst, capricious and often ravenous
appetite to compensate for the excessive oxidation, as to the
stomach; and the earlier retro-ocular vascular, sometimes
varicose, turgescence with slight exophthalmos, flashes, sensa-
tion of pressure, and brow-ache as to the visual apparatus. 4.
The increased cardiac stimulation, as shown by the rapid and
violent action, — due to cramped heart, a condition that prevails
when, as will be shown, the continued presence of poisons in
the blood causes the suprarenal secretion to continuously flow
in excess, — the violent action being transmitted to the carotid
and other large vessels, and to the liver and spleen, which may
also be felt to pulsate (cardiac hypertrophy is often found post-
mortem in such cases). 5. And, finally, by the exaggerated
tendon-reflex, due to excessive muscular and spinal oxidation.
Adrenal insufficiency, though not encountered in all cases,
is fully as well exemplified: 1. By the cerebral suboxidation
and nutrition, as manifested by the mental impotence and low
spiritedness; melancholia. 2. By the reduced muscular me-
tabolism, as suggested by the loss of strength, stumbling,
paretic tremors, paralysis agitans, and finally hemiplegia and
other forms of motor paralysis. 3. By the dilation of the cen-
tral and other muscular vessels and passive contraction of the
capillaries, as illustrated by the cerebral and muscular symp-
toms just referred to, the pallor and general marasmus; sweat-
ing due to relaxation of the sweat-gland muscles; alopecia;
dental caries; vitiligo, leucoderma, scleroderma, and in ad-
vanced cases bronzing; and also by the colliquative diarrhoea

154 THE THYROID, THE THYMUS, AND THE ADRENALS.

and persistent terminal vomiting, as to the gastro-intestinal
tract; and glycosuria, albuminuria, acetonuria, excess of urea,
as to the general metabolic processes. 4. By the eye-symp-
toms: the slow descent of the upper eyelids (von Graefe's
sign), due to paresis of the orbicularis; increase of the palpe-
bral fissures and infrequent winking (Stellwag's sign), due to
muscular paresis plus exophthalmos, ascribable to paresis of the
ocular muscles, and reaching sometimes to complete ophthal-
moplegia. 5. By the insufficient cardiac stimulation, as shown
by the weak, rapid (sometimes 200), and irregular heart-
beat, air-hunger, and cyanosis (cardiac dilation with muscular
degeneration is usually found post-mortem in such cases). 6.
And, finallyj by numerous evidences of impaired nutrition,
softness of the bones, atrophy of the uterus, degeneration of
the arterial walls, etc., etc.

It is important to bear in mind, in this connection, how-
ever, that the symptoms of suprarenal insufficiency are the
result of an excessive supply of thyroid secretion, the supra-
renal glands finally lapsing into this condition as they would
under the effects of any toxic, through overstimulation and
exhaustion of their cerebral centers. As is well known and
as herein sustained, a deficiency of thyroid secretion gives rise
to another disease: i.e., myxoedema.

The above list only includes the main symptoms of the
disease: i.e., those that emphasize most strikingly the physio-
logical and pathological connection between the thyroid and
the adrenals. The manner in which all the symptoms of over-
stimulation and insufficiency of the adrenals are reproduced
seems to clearly show that exophthalmic goiter is the result
of an excess of suprarenal secretion, due primarily to increase
of thyroid secretion.

Doubt has been expressed, however, that excessive thy-
roid secretion could occur as the only pathogenic factor. Thus,
Ord and Mackenzie11 contend that, "if overactivity or over-
secretion of an hypertrophied thyroid gland were the whole
disease, it ought to be possible to produce it by administration
of large quantities of thyroid gland. No one has yet succeeded

11 Ord and Mackenzie: Quoted by Godfrey Carter, Edinburgh Medical Journal,
Oct., 1899.

EXOPHTHALMIC GOITER AND THE ADRENALS. 155

in producing exophthalmos in this way." That such cases do
occur may be shown by the following instance reported by
Notthaft12: His patient, a man 43 years of age, had, on his own
responsibility, taken thyroid extract for obesity. Not content
with the slow progress witnessed at first, he increased the dose,
and within five weeks took nearly 5000 grains of the extract.
"For the first three weeks nothing was noticed, except loss of
flesh, but after this time dyspnoea came on, with swelling of
the neck and very rapid loss of weight. Altogether, thirty
pounds were lost, and five-sixths of this loss took place in the
last three weeks. When examined, the patient had marked
exophthalmos, with both Stellwag's and von Graefe's signs; the
thyroid gland was enlarged and pulsated, and there was a thrill
over it. A fine tremor of the fingers and tongue was quite
evident; the cardiac apex-beat was displaced outward, and the
pulse was 120 to the minute; there was cough and severe
mental depression; polyuria and glycosuria were also present.
Under the use of Fowler's solution and after the withdrawal
of the thyroid extract, most of the symptoms rapidly disap-
peared, only the ocular manifestations and the goiter persist-
ing for nearly six months." We have here, not only the stage
of suprarenal overactivity, including the cramped heart, as
witnessed by the displacement of the apex, but also the earlier
manifestations of insufficiency: mental depression, glycosuria,
Stellwag's and von Graefe's signs — all features to which the
gradual recovery, after withdrawal of the thyroid extract, con-
tributes the necessary complementary evidence.

A mass of testimony could furthermore be deduced from
the results of thyroidectomy. How could we account, for in-
stance, for the cases reported by Doyen,13 in which, after
removal of the gland, followed by recovery, all the symptoms
returned when they were given thyroid extract, then disap-
peared as soon as its administration ceased, without implicating
oversecretion of the thyroid as the primary pathogenic factor
of the disease? This also invalidates all the theories in which
the thyroid is credited with the power of reducing toxic sub-
stances in loco, since the glands are absent in these cases and

12 Notthaft: Centralblatt fur innere Med., April 9, 1898.

13 Doyen: Semaine Medicale, July 29, 1897.

156 THE THYROID, THE THYMUS, AND THE ADRENALS.

the supposed physiological function cannot occur; it also sug-
gests, when considered with the other data adduced, that
excessive thyroid secretion, by overstimulating the cerebral
centers of the suprarenal glands, as would any equally active
agency, gives rise to the symptoms of suprarenal overactivity
followed by symptoms of suprarenal insufficiency that have
been termed collectively "exophthalmic goiter." To establish
this view on a solid footing, however, other features of the
problem must be considered.

What is the nature of the agency through which these
phenomena are produced? Whether it be Baumann's iodo-
thyrin, E. Hutchinson's colloid substance, — which, by the way,
is very soluble in dilute alkaline fluids, such as the blood-
plasma, — FrankePs so-called thyreo-antitoxin, Oswald's more
recently introduced thyreoglobulin, or any of the thyroid de-
rivatives, the one agent upon which all their advocates depend
for physiological effects is the iodine which all effective ex-
tractives contain. Yet the well-known untoward effects of this
halogen when administered therapeutically in large doses —
such as would be deemed necessary to produce exophthalmic
goiter — would seem to suggest that there should be present
in organic combination with it an agent capable of antagonizing
iodism.

To counteract iodism we use arsenic. In a valuable paper
Professor Armand Gautier14 has recently shown that, while
arsenic could be found in the various structures of the organ-
ism, the thyroid gland contained more than any organ, the
thymus, the mammary gland, the skin, hair, and nails being
next in quantitative sequence. He found it incorporated in
the glandular nucleins along with the iodine. To these iodized
and arsenized nucleoproteids Gautier ascribes the physiological
functions of the glands, and he found that the structures which
are especially benefited by arsenical treatment, the hair and
the nails, are precisely among those which normally contain
the most iodine and arsenic. With his pupil, Bourcel,15 he
ascertained, furthermore, that menstrual blood contained a
notable proportion of arsenic and iodine. Gautier's experi-

14 Armand Gautier: Trans. Thirteenth International Congress, 1900.
« Bourcel: These de Paris, 1900.

EXOPHTHALMIC GOITER AND THE ADRENALS. 157

ments led him to the conclusion that the bodies referred to
"were continuously poured in small quantities in the lym-
phatics and in the blood to play therein the role of vitality
stimulants and to enhance cell-reproduction." This thought
is quite in accord with the views herein recorded, particularly
those pertaining to the increased oxidation which suprarenal
overactivity procures, since, after all, to increase oxidation
is to enhance all manifestations of vital energy.

Yet the presence of arsenic in the thyroid introduces a
source of confusion, since, as we have seen, all the toxic phe-
nomena ascribed to poisons are of suprarenal origin, and
arsenic might therefore as well be the source of the supra-
renal phenomena of exophthalmic goiter as iodine, to which
we have traced them. The question reduces itself to this,
however: does the arsenic offset iodism as we have suggested,
or does it also act as a suprarenal stimulant?

As to the connection between arsenic and exophthalmic
goiter, Notthaft's case, produced by thyroid extract, suggests
that a combination of these agents does not produce the dis-
ease. Since thyroid extract was used, we can assume that all
active constituents took part in the production of the effects
witnessed. With the extractives, — iodothyrin, thyreoglobulin,
etc., — however, it would seem, in view of their mode of prepa-
ration and the smaller dose administered, that in the undoubt-
edly active effects obtained the arsenic should count for prac-
tically nothing: a fact which would relegate all the phenomena
to the action of the iodine. That such is actually the case is
sustained by chemical and experimental evidence.

Mabille has observed that the untoward symptoms caused
by iodothyrin, when used in the human subject as a remedy,
or in experimental animals, could be reduced to a great extent
and even prevented by the simultaneous use of arsenic. Ex-
periments in dogs showed that the toxic effects of large doses
did not appear when arsenic was used simultaneously, while
they could be arrested by it when iodothyrin had been given
alone. In the case of a goitrous woman 42 years of age, he
administered this preparation in doses varying from 3 to 10
grains daily. Marked palpitations, lumbar pains, and tremor
having appeared, the dose was reduced and the untoward

158 THE THYROID, THE THYMUS, AND THE ADRENALS.

symptoms vanished. lodothyrin was then administered in in-
creased doses, — 12 grains daily, — but simultaneously with 12
drops of Fowler's solution. Not a single sign of thyroidism
showed itself; but, when the use of the arsenic was discon-
tinued for three days, the toxic symptoms recurred, and again
disappeared when the use of arsenic was resumed. This re-
markable property of arsenic was confirmed by Ewald.16 This
investigator was not only led to grant it all the properties
referred to by Mabille, but he found it to exert its antagonistic
action against thyroidism far more promptly than atropine
when administered to attenuate or prevent the noxious effects
of potassium iodide. On the whole, we can fairly conclude that
iodine is the most active factor of the thyroidal constituents and
that it is through its effects that the adrenals are directly or in-
directly over stimulated in exophthalmic goiter.

There is another feature of the problem which demands
elucidation. Overaetivity of the thyroid being accepted as the
cause of exophthalmic goiter, how can we account for the
undoubted cases of recovery that have occurred as the result
of treatment with thyroid extract and other thyroid deriva-
tives? When some years ago Owen reported that he had wit-
nessed marked improvement after this treatment, it was tried
on all sides, generally with unfavorable results. Since then,
however, quite a number of successful cases have been reported.

These contradictory results are easily accounted for when
we consider the part played by the suprarenal glands in the
process, and particularly the fact that overactivity and insuffi-
ciency of these organs give rise to different, though co-related,
symptoms. Interesting in this connection is a clinical ob-
servation of Solomon Solis-Cohen's, quoted as given by a
reviewer17: —

"Dr. Cohen remarked that his experience went to show
that in exceptional cases thyroid preparations might benefit
goitrous patients, both those with simple goiter and those with
Graves's disease; but that, as a rule, the effect was nil or not
good. He could give no definite rule for discrimination, al-

16 Ewald: Die Therapie der Gegenwart, No. 9,

17 Alienist and Neurologist, Oct., 1896.

EXOPHTHALMIC GOITER AND THE ADRENALS. 159

though the effect of temperature18 upon the patient might be
found to be of use, it being his present impression that those
who were unduly susceptible to cold would do well, and those
who were unduly susceptible to heat would do badly, under treat-
ment with thyroid preparations."

If during the stage of overactivity the central vascular
trunks are contracted and the peripheral capillaries are over-
filled and dilated, we can readily understand why the patient
is "unduly susceptible to heat" and why thyroid preparations,
by adding to the stimulation, accentuate the symptoms. A case
reported by H. L. Winter19 will serve to illustrate this fact.
The patient, a woman aged 32 years, had a pulse of 160, with
marked tremor and flushings, and was extremely irritable; the
goiter was firm and pulsating and the exophthalmos marked.
She was given thyroid extract, 5 grains daily; all the symp-
toms were exaggerated and she complained of severe frontal
headache. The thyroid extract was discontinued, and tincture
of digitalis, with a saline purgative, given; the next day there
was marked relief. Ten days later thyroid extract was again
exhibited, 2 Y2 grains daily. All the symptoms steadily grew
worse; and at the end of two weeks the attacks of tachycardia
were so violent on attempting to sit or stand that she had to
keep to her bed, her pulse being 160. The extract was then
discontinued and a temporary improvement followed under
other methods of treatment.

The opposite result may be expected when the patient is
"unduly susceptible to cold," because his central vascular
trunks are dilated and his superficial capillaries contracted as
the result of suprarenal insufficiency — the characteristic of
advanced cases. In exophthalmic goiter, the "advanced stage"
means more, however, than it does in the average disease. The
first stage being due to overactivity of the thyroid, as soon
as the insufficiency of the adrenals appears, oxidation becomes
less active, and the thyroid, with all other organs, correspond-
ingly so. The main source of trouble thus gradually disappears
and is replaced by another form of toxamia, one resulting from

18 All italics are our own.

19 H. L. Winter: American Medico-Surgical Bulletin, July 11, 1896.

160 THE THYROID, THE THYMUS, AND THE ADRENALS.

deficient oxidation, the immediate consequence of suprarenal
insufficiency. A vicious circle is thus created; the toxic prod-
ucts of metabolism engender further insufficiency of the ad-
renals, while this condition, in turn, allows the toxics to ac-
cumulate in the organism. Finally, marasmus appears, if
some intercurrent pulmonary or cardiac acute disorder does
not cause death before this stage is reached. This stage of
the disease includes the cases in which exophthalmic goiter
and myxoedema appear jointly, since in a small proportion of
instances the thyroidal secretion becomes reduced below the
needs of the suprarenal glands.

It seems evident that these advanced, not necessarily
grave, cases of exophthalmic goiter, should be assisted by a
supply of the very agent which they now lack: i.e., their nor-
mal suprarenal stimulus. A case reported by Silex20 and char-
acterized by Kroenig, who had seen it, as "very grave," was
thus cured after taking 1200 grains of thyroid extract. All
the typical signs had been present, and so advanced was the
muscular weakness that the patient, a woman aged 42 years,
could hardly walk. A case cured by K. Cox21 also showed
"general prostration," but the thyroid extract used was doubt-
less greatly assisted by the intestinal irrigations simultaneously
employed. Another case successfully treated by 0. Martin22
"could not rise without experiencing great fatigue" when first
seen. Another case greatly benefited by C. L. Lang23 presented
"an emaciated, tremulous, dusky countenance" and "was con-
fined to bed," etc.

Another class of cases that clinical evidence shows to be
benefited includes those which, through acquired or inherited
suprarenal weakness, promptly yield to the primary hyper-
oxidation. Such cases often show signs of a quasi-myxcedema
during their earlier years of life. An example of this class is
afforded by Kerley.24 The father of the patient had suffered
from epilepsy and a sister had died of tubercular meningitis:

20 Silex: Berliner klin. Wochenschrift, No. 6, 1896.

21 R. Cox: Montreal Medical Journal, August, 1899.

22 O. Martin: La Presse M6dicale, August 27, 1898.

23 c. L. Lang: Medical Council, April, 1900.

24 Kerley: Pediatrics, June 1, 1897.

EXOPHTHALMIC GOITER AND THE ADRENALS. 161

both disorders traceable to suprarenal inadequacy. "The pa-
tient developed slowly, both mentally and physically. She did
not walk until nearly three years old. She was frail and
excitable as a growing child. When six years old she had a
severe attack of measles. During the six years that intervened
she enjoyed fair health. She made slow progress at school."
Not only was there evidence of infantile myxcedema, there-
fore, but the general vulnerability of the adrenals had been
increased by severe measles. That the cellular protoplasm of
this child should be correspondingly vulnerable to disturb-
ances, chemical or physical, as a result of the suboxidation to
which her organism had been submitted since her birth, seems
reasonable. When twelve years old, "a blow on the right side
of the neck, from behind, which caused intense fright and hys-
teria," served as starting-point of the exophthalmic goiter. A
feature to be emphasized here is that "the pulse was small and
soft": evidence that the adrenals were unable to respond above
a certain limit to the excess of thyroidal secretion poured into
the circulation, or that the case had promptly lapsed into that
of suprarenal insufficiency. Five months' treatment with thy-
roid yielded a satisfactory result.

Two cases reported by H. L. Winter25 may also be included
in this class. The patients were sisters, 22 and 17 years of
age, respectively, of Swiss birth. The former was "stout and
anemic," in the latter there was "no marked anaemia" — evi-
dence that some degree of anaemia — pallor — was present. The
flushing was not of the continuous kind, but of the kind
brought on suddenly, and characterized by the author as
"flushes," just as the muscular signs are termed "startings" —
sudden expressions of equally sudden contractions or spasm of
the central vascular trunks, arising from weak adrenals, as
flashes of flame arise from stirred embers. "In Cases I and II"
(the cases referred to), says the author, "exception might be
taken to the diagnosis. The rapid heart-beat, usually the first
symptom of a typical case of exophthalmic goiter, was not
present; the pulse was high only during an attack of palpita-
tion." In the light of our views no exception could with

26 H. L. Winter: Loc. cit.

162 THE THYROID, THE THYMUS, AND THE ADRENALS.

justice be taken to the author's diagnosis. Both cases had
weak adrenals, and to this weakness were mainly due the signs
witnessed, and it is owing to this, as well as in all cases of a
similar kind, that thyroid extract proved efficacious.

To illustrate the solidity, of these deductions, the follow-
ing selection from A. J. Hutchinson's20 review of an article
by Maurice Faure may be adduced: "A woman, aged 32, began
to develop symptoms of Graves's disease, and by the end of
six years presented a complete picture of exophthalmic goiter.
During the seventh year cardiac insufficiency supervened; during
the eighth year the signs of exophthalmic goiter retrogressed,
and the cardiac condition improved; then during a period of
about three years, during which the signs of Graves's disease,
especially the tachycardia, still persisted, myxcedema appeared.
During these three years the treatment was at times directed
against the myxcedema, — viz.: thyroidin or thyroid gland; at
others against the cardiac condition, — viz.: digitalis, with suit-
able diet, etc. During the eleventh year cardiac insufficiency
became very serious, the myxcedema increased, and finally the
patient died in asystole." . . . "Exophthalmic goiter and
myxcedema co-existed in this case during at least two years.
It is therefore impossible that the former should be due to
increased secretion, while the latter should be due to dimin-
ished secretion by the thyroid gland. ..." A number of
cases have been reported by Baldwin, Gowan, L. Gautier,
Jeffrey and Achard, and others in which myxcedema followed
exophthalmic goiter.

That this conception of the pathology of exophthalmic
goiter and its close connection with suprarenal functions is
able to bear close scrutiny may also be illustrated by the re-
searches of Scholtz.27 If the first stage of the disease, that
of overactivity of the adrenals induced by excessive thyroid
secretion, is really characterized by hyperoxidation, rapid
tissue-waste must occur, and the products, being oxidized as
fast as formed, must also be eliminated as highly oxidized end-
products. Scholtz, seven years ago, found that there was in

26 A. J. Hutchinson: British Medico-Chirurgical Journal, from La Presse
M^dicale, Sept. 23, 1899.

87 Scholtz: Centralblatt fur innere Med., Nos. 43 and 44, 1895.

EXOPHTHALMIC GOITER AND THE ADRENALS.

163

exophthalmic goiter an increased excretion of phosphoric acid
in the stools amounting to tenfold the normal, as compared to
one of only 25 per cent, in a healthy person. He concluded,
therefore, that the thyroid gland has an important influence
on the metabolism of phosphoric acid. Experimental evidence
also bears this out, since Eoos28 found that, in healthy dogs,
feeding with thyroid caused an increased excretion of nitrogen,
sodium chloride, and phosphoric acid. This is further confirmed
by the beneficial effects obtained empirically with sodium
phosphate, which will be referred to when exophthalmic goiter
is further analyzed. Again, G-. R. Murray29 refers to a case
examined post-mortem by Dr. Auld as follows: "The state of
the pituitary and thymus glands had received considerable
notice in connection with morbid alterations of the thyroid,
but Dr. Auld suggested a more systematic examination of the
suprarenal gland. In a case of fully developed exophthalmic
goiter in a young woman, aged 25, in whom death occurred
from an intercurrent malady, he had had an opportunity of
examining this organ. He was much interested to find that
the medullary portion of the gland was much hypertrophied
and the nuclei of many of the glandular cells were undergoing
division." That "hypertrophy" is the result of overaction of
the glands has, as we have seen, been experimentally demon-
strated. Finally, the clinical observations of Breuer30 may be
adduced to show that the active factor in the whole process is
iodine. Swiss investigators had already noted that even small
doses of iodide of potassium were capable of bringing on mild
symptoms of exophthalmic goiter. Breuer witnessed nine cases
in which the disease could directly be traced to the adminis-
tration of iodine.

If we now endeavor to garner the progress so far made
in the present inquiry, a prominent feature soon appears: i.e.,
that we have transferred to the adrenals a long list of symp-
toms that were thought to be associated with abnormal activity
of the thyroid gland. We have done more: the signs referred
to are no longer incidental elements of the symptom-complex'

28 Roos: Zeitschrift fur physiol. Chemie, Bd. 21.

29 G. R. Murray: British Medical Journal, Jan. 20, 1896.

30 Breuer: Wiener klin. Wochenschrift, July 19, 1900.

11

164 THE THYROID, THE THYMUS, AND THE ADRENALS.

we term "exophthalmic goiter" or "Graves's disease"; they have
been traced as pathological entities to their source: the supra-
renal glands. In other words, the thyroid gland merely sup-
plies a physiological stimulus to the adrenals that they need
to keep up their functions to the proper level. Having ascer-
tained that when this stimulation is excessive certain symp-
toms appear, we can conclude that, whenever they appear, they
invariably have the one and same origin: i.e., excessive supra-
renal activity.

Again, we have ascertained, by analyzing the modus
operandi of thyroid extract in the treatment of exophthalmic
goiter, that the cases benefited could no longer be considered
as examples of suprarenal overstimulation, but, on the con-
trary, as cases of suprarenal insufficiency totally independent
of the thyroid glands. Indeed, it has become evident that some
cases of exophthalmic goiter are primarily due to inadequate
functional power of the adrenals, the unusual stimulus of even
an incipient case of Graves's disease inducing suprarenal insuffi-
ciency at a very early stage of the disease. This is doubtless
a compensative process which must greatly reduce the number
of instances among children, adolescents, and weaklings of all
kinds. We are thus normally led to the conclusion that: —

1. What we term exophthalmic goiter is a syndrome ascrib-
dble : —

(a) To overactivity of the adrenals, due primarily to ex-
cessive thyroidal secretion in the blood; then, in the second stage: —

(b) To insufficiency of the adrenals: i.e., when the excessive
thyroid secretion has induced their exhaustion or that of their
centers.

2. All symptoms which have heretofore been directly or indi-
rectly ascribed, in this disease, to the thyroid gland should be
attributed to excessive or insufficient activity of the adrenals.

Exophthalmic goiter has given us a general idea of the
phenomena brought on by suprarenal overactivity, but it af-
fords but a very limited expose of those of insufficiency. We
will, therefore, continue our analysis of the relationship be-
tween the thyroid and the adrenals through myxcedema and
cretinism (infantile myxcedema), the remaining general proc-
esses at present ascribed to the thyroid gland.

MYXCBDEMA, CRETINISM, AND THE ADRENALS. 165

MYXCEDEMA AND CKETINISM AND INSUFFICIENCY OF THE
ADRENALS.

Removal of the thyroid gland, when it is followed by
death, gives rise to a characteristic train of symptoms in ani-
mals. The latter appear dull and apathetic; muscular inco-
ordination, shivers, precede spastic paralysis; the temperature
falls rapidly. The cause of the violent dyspnoea witnessed is
now apparent; and a casual remark of Wesley Mills's,31 that the
thyroid gland "plays a special part in connection with oxida-
tion," indicates that we must be treading on the right path
when we include the adrenals in the process. While Albertoni
and Tizzoni32 observed that the blood showed less power to
fix oxygen, Masoin33 found that the relative quantity of oxy-
ha3moglobin in the blood was diminished in proportion as the
morbid results of thyroidectomy progressed. We can at least
assume, therefore, that the marked emaciation witnessed is
due to the imperfect nutrition which impaired oxidation of
the organism involves, that the tetanic convulsions point to
imperfect oxidation of waste-products, and that insufficiency
of the adrenals due to reduced thyroidal activity underlies all
the morbid phenomena that follow thyroidectomy.

That imperfect, inadequate, or arrested thyroid secretion
can cause myxoedema has been established. In all cases in
which the diagnosis was unmistakable, the glandular elements
of the thyroid have been found markedly compromised.
Adami34 found the specific cells replaced by fibrous tissues in
the majority of cases collected, and in less advanced cases the
degenerated remains of vesicular epithelium, along with areas
of the latter showing a tendency to compensatory hypertrophy.
In no case diagnosed as myxcedema did he find the gland nor-
mal or but little affected. In infantile myxoedema — i.e., cretin-
ism— either the thyroid is totally absent or there is more or
less deficiency of glandular elements and excess of connective
tissue with cellular debris. De Coulon35 found that the colloid

31 Wesley Mills: Canadian Practitioner, Oct., 1895.

82 Albertoni and Tizzoni: Maragliano: Gaz. degli Ospedali, Oct. 20, 1894.
«» Masoin: Bulletin de I'Academie de M6d. de Belgique, No. 1. p. 88, 1895.
84 Adami: Trans. Congress of American Physicians and Surgeons, 1897.
86 De Coulon: Virchow's Archiv, vol. cxlii, p. 53.

166 THE THYROID, THE THYMUS, AND THE ADRENALS.

substance was absent in the majority of the alveoli. If thy-
roidectomy can so inhibit the suprarenal functions as to so
materially interfere with the oxidation processes as to cause
death, such marked structural lesions as these must produce
correspondingly great functional disorders also ascribable to
impaired oxidation.

The symptomatology of infantile myxcedema upholds this
view in every way. The temperature of cretins is invariably
subnormal; they always suffer from cold. The nutrition of
all tissues is impaired: the brain remains undeveloped, the
fontanelles often remaining patent; the first and second denti-
tions are delayed; the skin is dry and thickened; the hair is
thin and coarse, sometimes absent; the nails are short, brittle,
and striated. Growth is very slow and arrested at an early
age, ossification being tardy and the epiphyses appearing late.
The muscular system is weak and the head tends to droop
forward, but no spasmodic or epileptoid movements occur.
The genital organs show no sign of development, testes and
ovaries being infantile. There is a marked tendency to severe
haemorrhage from the uterus, gums, and nose, and cyanosis
is often observed. Osier and Norton36 refer to the investiga-
tions of Magnus Levy37 as follows: "In four cases which he
studied he found a diminution in the consumption of oxygen
and formation of C02, whereas in Graves's disease it has been
more than once proved that there is a marked increase in the
consumption of oxygen and in the formation of carbon dioxide."
Finally, the well-known effects of thyroid extract in these cases
in enhancing oxidation may be exemplified by the prevailing
views, which the following excerpt, taken from an article by
G. 1ST. Crary,38 correctly shows: "Increased metabolism is shown
by (1) elevation of temperature; (2) increased appetite, with
more complete absorption of nitrogenous foods; (3) loss of
weight, with nitrogen excreted in excess of that taken in the
food; (4) growth of skeleton in the very young; (5) marked
improvement in the body-nutrition generally." Indeed, every

38 Osier and Norton: "Sajous's Analytical Cyclopaedia of Practical Medicine,"
vol. iii, p. 590.

37 Magnus Levy: Verhandl. des Congr. t. innere Med., Wiesbaden, 1897.
88 G. N. Crary: St. Louis Med. and Surg. Journal, July, 1895.

MYXCEDEMA, CRETINISM, AND THE ADRENALS. 167

abnormal condition present, including the mental torpor, seems
to gradually recede, until in many cases the change produced
is truly phenomenal, a fact readily understood when we con-
sider that the process enhanced by the thyroid is the one upon
which all vital functions depend: i.e., general oxidation.

Myxcedema in the adult affords a picture varying from
that of cretinism in that the morbid phenomena are the result
of retrograde changes in normal tissues, whereas in infantile
myxcedema the cellular structures have never been brought to
their normal nutritional standard. The most striking differ-
ence shows itself in the superficial swelling, the result of per-
verted cutaneous and subcutaneous functions, which functions
have not been fairly developed in the cretin. If, for example,
the thyroid arsenic found by Gautier does play a role in this
connection, the skin, nails, and hair of the cretin may have
never received their normal supply, while those of the myx-
cedematous subject may have lost theirs through the thyroid
disorder. The other signs, however, are very similar: the
hypothermia is the same, the tip of the nose, the lips, and the
ears being sometimes bluish, and as cold as marble; the pallor
of the skin is also observed over all mucous surfaces; the nutri-
tion of all tissues is impaired — witness the mental torpor, the
brittle teeth, the tumefied tissues, the lusterless hair, the alo-
pecia, the brittle nails, etc.

The muscular impotence recalls that of the secondary
stage of exophthalmic goiter even to the paresis of the orbicu-
laris; the lids droop over the eyeball, and, if exophthalmos
does not occur, it is because the orbital vessels have not been
submitted to the centrifugal pressure of the first stage. The
copious lacrymation and nasal secretion is also observed in
the cretin. The patient is capable of spurts of strength, how-
ever, as shown by Charcot: an index that vital functions are
only in abeyance and that we are not dealing with structural
changes. The muscular exhaustion further shows itself by
the inability of the patient to stand normally, the quivering
of weakness, the ataxic gait observed at times (Hammond), and
the oft-noticed fibrillary tremor, ending in some cases with
paralysis. But again must we note the absence of tetany, that
condition brought about through accumulation of physiological

168 THE THYROID, THE THYMUS, AND THE ADRENALS.

waste-products, which products, in myxoedema, the unstimu-
lated adrenals can just about destroy through what oxidation
they are able to induce. Indeed, this is the key to the differen-
tial results observed in thyroidectomized animals especially as
between the carnivorus and herbivorous. Nature again provides
protection against this source of danger, since myxcedematous
subjects dislike meat (Pel). That tissue-metabolism is mark-
edly reduced in myxcedema is shown by the decrease of urea
and uric acid in the urine; but, given an animal suddenly
deprived of its thyroid, the equally sudden interruption of
adequate adrenal function involves arrested destruction of what
toxic products are already in the system, xanthin bases espe-
cially. A second cause for suprarenal insufficiency is thus
created which correspondingly reduces oxidation, with all its
nefarious results. Here, however, an important factor comes
into play: the avidity of the tissues for oxygen.

The oxygen-carrying corpuscular elements are not only
depleted of their oxygen by them, but that available for anti-
toxic purposes in the serum is also taken up. Obviously accu-
mulation in the latter of unoxidized toxic products of cellular
and food metabolism must occur. As a result, practically all
the energy which the remaining suprarenal activity affords
through the oxygen it supplies the organism, is concentrated
in the organic cellular elements, while the blood-stream teems
with toxic products.

We can now understand why various investigators, as
previously stated, found that the blood of an animal deprived
of its adrenals and which is beginning to show toxic symptoms
has such poisonous effects when injected into another animal
from which the adrenals have been removed shortly before.
It is to this difference between the comparatively immune tis-
sues and the highly toxic blood that the tetanus and epileptic
convulsions witnessed seem to be due, since the latter are, after
all, but intense manifestations of activity, caused, judging from
the action of toxic drugs, by large doses of physiologically-
produced toxics. Yet, why the paroxysmal feature of these
manifestations? We have seen that in the type of exoph-
thalmic goiter attended with congenital or acquired suprarenal
inadequacy there occur what Dr. Winter called "flushings'' and

MYXCEDEMA, CRETINISM, AND THE ADRENALS. 169

"startings." These represent the subacute phenomena of which
suprarenal spurts of activity are the source and of which
tetanus, epilepsy, rabies, and kindred disorders are the acute
expressions.

Disorders of sensation become normal results when we
consider that the total loss of tone of the central vascular
trunks practically depletes the peripheral tissues of their blood
and that what blood does reach them is poor in oxygen. Sen-
sation is blunted especially where, as is the case with touch,
it is usually most delicate. When under the influence of thy-
roid extract the tumefaction disappears, the sensibility returns,
proving that the nervous and cutaneous structures were not
structurally impaired, but merely inactive through the absence
of their pabulum vilce. Perversions of the senses of smell and
taste; mental apathy, hallucinations, melancholia, vertigo,
marked reduction of the flow of urine, albuminuria, and glyco-
suria are also witnessed. Death occurs from exhaustion when,
as in exophthalmic goiter, an intercurrent acute disorder does
not, as is usually the case, carry the patient away before this
stage is reached.

To emphasize the remarkable effects of thyroid extract
in myxcedema and cretinism is unnecessary. All the symptoms
enumerated sometimes disappear, and it is evident that this
wonderful result is obtained through enhanced oxidation in
all parts of the organism, and procured through the suprarenal
overactivity induced.

Proof of all this is afforded by the fact that it is not only
in diseases in which the entire vital mechanism is held in
check by the absence of thyroid secretion that the effects of
the extract prevail. They are the same whenever, as in most
cases of myxcedema benefited by it, organic lesions of the
adrenals themselves or of any other vital structure are not
present to totally prevent the continuation of life. Probably
the nearest condition to uncomplicated myxcedema — i.e., a
condition in which the human machine is simply in a state of
vital abeyance — is catalepsy. In this disorder thyroid extract
should also prove efficacious if oxidation through induced
activity of the adrenals is the key to the process involved. The
experience of K. Hessler, of the Northern Indiana Hospital

170 THE THYROID, THE THYMUS, AND THE ADRENALS.

for the Insane,39 may be adduced to show that it is as active
here as in myxcedema: —

"The case was that of a cataleptic who had lain immovable
in bed for over three years; there was an absence of motor
and sensory activities; the feeding was by means of the nose-
tube. Under increasing doses of gland constantly increasing
activities resulted, until finally the patient 'returned to life'
and was able to speak and walk. At a time when 75 grains WITI?
given daily, symptoms of exophthalmic goiter appeared, and
the remedy had to be discontinued temporarily, the pulse going
up to 160. In the course of a few days the patient relapsed
to his usual condition, but 'revived' on again receiving the
remedy, with a return of the symptoms mentioned. A similar
case recovered promptly in a few weeks on small doses."

It thus seems conclusively shown that, to the long list of
symptoms ascribed to the suprarenal glands, as represented by
the first stage of exophthalmic goiter, we can now add another
equally long list of phenomena: i.e., those represented by
myxcedema and infantile myxcedema, but due to suprarenal
insufficiency instead of overactivity. It also appears that, as
is the case with the signs of the latter, those observed in both
forms of myxcedema, whenever they occur, are also invariably
traceable to insufficiency of the adrenals. We have also estab-
lished the connection between myxcedema and the second stage
of exophthalmic goiter, and realized that thyroid extract is
efficient in this stage of the disease because of the latter's
identity as myxcedema in some cases and as simple suprarenal
insufficiency in others, the thyroid gland in the latter case
remaining active and therefore obviating the cutaneous symp-
toms, through, perhaps, the arsenic it furnishes these struct-
ures. On the whole, it thus becomes apparent that: —

1. Myxcedema and infantile myxocdema (cretinism) are due
to insufficiency of the adrenals, the result, in turn, of absence
or diminution of the secretion supplied to the blood ly the thyroid
gland.

2. All individual symptoms witnessed in the course of these
diseases should be ascribed to reduced activity of the adrenals.

39 R. Hessler: Jour. Amer. Med. Assoc., and Dublin Jour, of Med. Science,
March, 1897.

THE THYMUS GLAND AND THE ADRENALS. 171

THE THYMUS GLAND AND THE ADRENALS.

If the conclusions just recorded as to the relationship
between the thyroid gland and the adrenals are sound, there
is considerable analogy between the effects of thymus on the
organism and those of the thyroid. Svehla's40 well-known
experiments add further evidence to that submitted to the
effect that the thyroid gland only assumes its functions at
birth, extract of foetal thyroid having proven inert, while ex-
tract obtained from the thyroids of infants during the ^ first
month of life was effective. Precisely in the same manner did
thymus extract behave: foetal-thymus extract produced no ef-
fect, while that obtained from the thymus glands of infants in
the first month caused increase in the frequency of the pulse
and lessened blood-pressure. Further proof of the solidity of
the views herein advanced is also shown by his conclusions
— based on experimental evidence — that "among children of
the same age the thymus extract is the strongest; less so the
thyroid; and still less the adrenal. In adults, however, the
adrenal outstrips both other glands." The influence of this
suprarenal inadequacy is an important factor, we have seen,
in the predilection of children for infectious diseases.

Svehla refers to "increased frequency of the pulse and
lessened blood-pressure'5 as the prominent effects of thymus
extract: evidence, if its action corresponds to that of thyroid,
that a toxic dose had been administered to the experimental
animal This is confirmed by the fact that other typical symp-
toms were present: i.e.. muscular weakness, dyspnoea, and gen-
eral collapse, — a condition from which the animals could be
saved by the timely administration of thymus extract, which
promptly restored the normal vascular pressure. The simi-
larity between the physiological actions of thyroid and thymus
as suprarenal stimulants is further shown by the experiments
of Isaac Ott41 in rabbits. In these animals powdered thymus
caused the pulse to increase its rate and the blood-pressure
momentarily to rise, but soon to fall considerably: a suggestive
sequence of events. In another animal he found that the thy-
mus caused the respiration to increase and that section of the

*o Svehla: Archiv fur exper. Pathologic, Bd. xliii.
« Isaac Ott: Medical Bulletin, May, 1898.

172 THE THYROID, THE THYMUS, AND THE ADRENALS.

vagi did not alter the result. In a third case he noted that the
"thymus caused a slight increase of temperature, but that the
increment was not beyond the normal variant/' That the action
is not antagonistic to the action of the thyroid secretion, as
thought by some observers, can easily be shown. If such were
the case Svehla could not have caused temporary recovery of
his collapsed animals; nor would Cunningham42 have found it
as efficacious after removal of the thyroid gland as thyroid
extract itself, nor would Ott have found the "rise" to precede
the "fall."

Thymus extract seems to prove efficacious in precisely the
same class of cases of exophthalmic goiter as thyroid extract.
Owen,43 for example, recalled his successful result in a marked
case of twenty years' standing, but he indirectly points to his
patient's advanced condition by the statement "the next three
months he spent mostly in bed." His second case complained
of feeling "low and weak," sweated profusely, became bald, and
had tremors and pigmentation. A third case benefited was
one in which breathlessness, general weakness, and emotional
outbreaks prevailed. He also refers to an extremely aggra-
vated case treated successfully by Maude,44 in which drugs,
including belladonna, had proven ineffectual. Under thymus
tabloids, 45 grains daily, the patient rapidly improved, and
invariably relapsed when they were discontinued. Maude hav-
ing observed that the tremors were particularly relieved by
this form of treatment, Owen tried fresh thymus in paralysis
agitans, — which, as shown, is a sign of the advanced stage,
that of suprarenal insufficiency, — "with the result that the
tremors were unmistakably benefited and the mental state and
the muscular condition greatly improved."

An analytical study of Maude's cases shows that they are
all of the advanced type. In the first "the heart and paralytic
conditions were such as to confine her to bed for over a year."
The second "belonged to a highly neurotic family; goiter had
existed since childhood," and the "tremor, excessive muscular
weakness, and cardiac disturbance were all well marked." The

42 Cunningham: Jour, of Experimental Medicine, p. 225, vol., 1898.
*3Owen: British Medical Journal, Oct. 10, 1896.
" Maude: Lancet, July 18, 1896.

THE THYMUS GLAND AND THE ADRENALS. 173

third had recovered from a previous attack without thymus;
hence its use after recurrence as the result of grief cannot
serve as fair example. The fourth was of thirty-two years'
standing, and the patient had suffered from "various severe
nervous symptoms," viz.: paralysis of various basal nerves,
ophthalmoplegia, paralysis of facial, ambulatory epilepsy, etc."
. . . "She had had, in 1894, twenty-four motions in one
day of almost pure arterial blood. In November, 1895, she
had a sudden profuse haematemesis, followed by collapse so
extreme that she seemed moribund. After she rallied she was
given 45 grains of thymus tabloids per day, for a month, and
her improvement was very remarkable; she remained in a fair
state of health for many months." Degeneration of the arterial
walls probably existed in this case, and it seems likely that
the loss of blood can be credited with the relief afforded.
Todd's case45 had an epileptic mother, her sister had suffered
from myxoedema and had been cured with thyroid extract, and
she was herself a "very delicate" girl. N. J. McKie's case48
and those of R. T. Edes47 and Philip James48 also represent
instances in which there were debilitated adrenals. In a case
successfully treated by Boisvert49 the presence of melancholia
also shows that weakened adrenals were present and that the
increased insufficiency of these organs brought on by the thy-
mus, as was the case with two of the patients referred to by
Dr. Winter in which thyroid extract was used, led to recovery.
These examples, which could be multiplied, not only indicate
that thymus extractives are active when there is impaired func-
tional activity of the adrenals, but they also tend to prove that
the thymus gland is very similar to the thyroid in its action
upon these organs.

The harmful effects of thymus in the first stage are illus-
trated by a case described by Watson Williams,50 who found
that it aggravated the tachycardia and pyrexia: evidence that
it had been given while suprarenal overactivity was present.

45 Todd: British Medical Journal, July 25, 1896.

*« N. J. McKie: British Medical Journal, March 14, 1896.

47 R. T. Edes: Boston Med. and Surg. Journal, Jan. 23, 1896.

48 Philip James: Australasian Med. Gazette, July* 20, 1897.

49 Boisvert: Revue Medicale de Montreal, June 21, 1899.
60 Watson Williams: Clinical Journal, Dec. 11, 1895.

174 THE THYROID, THE THYMUS, AND THE ADRENALS.

In the large proportion of cases reported, however, there is no
marked untoward effect produced. It seems to be much less
active in this connection than the thyroid extractives. In fact,
in some cases — probably those on the border-line of suprarenal
insufficiency — it appears to act as a nutrient tonic, as noted by
Hector Mackenzie51 after a study of twenty cases in which he
had tried thymus gland, and to which further reference is made
below.

The connection between the thymus and the adrenals is
also illustrated by the experiments of Abelous and Billard,52
in which removal of the former gave rise to symptoms similar
to those that follow adrenalectomy: even to discoloration of
the skin, great muscular weakness — lapsing into paralysis,
blood-changes, cedema, etc. They also found that the secre-
tions of the experimental animals were markedly toxic: evi-
dence of inadequate oxidation. On the whole, this evidence,
considered collectively, seems to indicate that the tliymus gland
supplies some substance which directly or indirectly stimulates the
secretory functions of the adrenals, and thereby enhances the
activity of the oxidation processes.

What is the nature of the agency through which the thy-
mus stimulates the adrenals, and what is the specific relation-
ship between these organs? These questions are suggested by
the fact that, while undue activity of the thymus increases that
of the adrenals, there seems to be no evidence that the thymus
can alone — i.e., independently of the thyroid — give rise to
either exophthalmic goiter or myxcedema. In all cases of the
former disease ascribed to the thymus found in available litera-
ture there is invariably thyroidal involvement. Yet the thy-
mus seems sufficiently active to bring the adrenals to their
normal activity when the general vital processes are depressed.
We have seen, on the other hand, that its removal gives rise to
symptoms recalling those of adrenalectomy.

Baumann53 found minute quantities of iodine in the thy-
mus also; but other experimenters have failed to find even
this trace, and have ascribed Baumann's findings to contamina-

61 Hector Mackenzie: American Journal of the Medical Sciences, April, 1897.
n2 Abelous and Billard:. Archives de Physiologie, Oct., 1896.
63 Baumann: Miinchener med. Wochenschrift, p. 311, 1896.

THE THYMUS GLAND AND THE ADRENALS. 175

tion from neighboring thyroidal tissues. Even granting that
such a trace of iodine exists, we are well aware that the thyroid
does not owe its power to stimulate the adrenals to "a trace'7;
the labors of many investigators have conclusively shown that
it must supply the organism with a considerable amount of
this substance. Evidently we must look elsewhere for the solu-
tion of this problem, and, data bearing directly upon the sub-
ject being wanting, we shall have to seek for the required sub-
stance through its comparative behavior in the organism, and
the manner in which its effects vary in the latter from those
of thyroid extractives.

Valuable in this connection are the autopsies of 61 chil-
dren at the Hopital des Enfants-Malades, of Paris, performed
by Albert Katz at the request of Bourneville.54 All these
children had died of various diseases, their ages varying from
one month to thirteen years, though 41 were under two years
of age. In all of the 61 bodies the thymus gland was present,
while in 28 mentally weak and epileptic children examined by
Bourneville the thymus was absent in 25. In another series
of 292 cases it was absent in 74 per cent. But these comprise
not only all varieties of mentally abnormal children, but also
various degrees of imbecility; so that the remaining 26 per
cent, may have included a number of instances in which mental
development was high as compared to that of the cases in which
the organ was absent. Yet, to avoid favoring our own line of
argument, we will consider that in three-fourths of imbecile
children, some of which were epileptics, the thymus gland was
absent.

These observations become elucidative when analyzed
through the effects of thyroid extract. Especially suggestive
is the following casual remark of Cabot's, in the course of a
valuable paper published some years ago55: "The fact that in
myxcedematous children and cretins the thyroid treatment is
associated with notable growth in height has led some observers
to try its effects in dwarfed children not myxredematous, to see
if their development could not be helped. I have collected 10
such cases, 3 in idiotic children and 6 in whom the lack of

M Katz: Le Progres Medical, June 23, 1900.
55 Cabot: Medical News, Sept. 12, 1896.

176 THE THYROID, THE THYMUS, AND THE ADRENALS.

development was mainly physical. A considerable increase in
height was observed in all the cases, but the mental symptoms
ufere not improved."™ It seems evident that if, on the one
hand, the vast majority of cases of mentally weak children do
not possess thymus glands, and that, on the other, thyroid
extract will enhance growth of idiotic children (not mvx-
cedematous ones, i.e., cretins), the oxidation processes, stimu-
lated by the thyroid through its action on the adrenals, are
inadequate to alone bring on improvement of the mental
symptoms. Again, it becomes evident that it is upon the
thymus that the mental development depends, and, finally,
that it is to some agent which the thyroid gland does not
contain that this development is due.

This enables us to eliminate iodine as the main active prin-
ciple of the thymus gland, and, our inquiry being disconnected
from the oxidation process through the evident inefficiency of
the thyroid to restore mental functions, we are led to seek for
a chemical body that will enhance cerebral nutrition. Can we
expect such an hypothetical agency, however, to concentrate
its effects upon the brain alone? This is hardly probable,
judging from analogy, and the nervous system at large must
also utilize it physiologically. Our field is therefore broadened,
since an agency connected with the nutrition of the brain
alone, or one playing the same role in respect to the entire
nervous system, may serve our needs. This is, to say the least,
fortunate, for the chemistry of brain- and nerve- matter is far
from well known, and even a good analysis — i.e., one based
upon the more salient data available — would be impossible
were the limits of the inquiry at all narrowed.

Of the solid constituents of nerve- and brain- matter,
three stand out prominently: cholesterin, cerebrin, and lecithin.
Cholesterin, considered by Austin Flint, Jr., as a waste-product
of cerebral and nervous origin, though it represents one-half
of all the solids, shows no molecular constituent capable of
assisting us (C26H440), the fact that the thyroid secretes a
specific agency being taken as standard; nor does cerebrin
(C17H33N03), though both this and the preceding body are
found in abundance in the cerebro-spinal axis and nerves.

The italics are our own.

THE THYMUS GLAND AND THE ADRENALS. 177

With lecithin, sometimes termed "phosphorized fat/7 which
represents about one-tenth of the solids, the case is different,
since its formula (C44H90NP09) suggests that phosphorus may
represent the constituent we are seeking. It is not only a
prominent component of the whole cerebro-spinal and nervous
systems, however, but it is also a constituent of the red and
white corpuscles, milk, bile, serum, semen, and pus. Another
body, protagon (C160H308N5P035), has also been isolated from
brain-substance by Liebreich, who considered it as the main
cerebral constituent: an opinion sustained by Gamgee and
Blankenhorn.67 Hoppe-Seyler and other investigators are,
however, inclined to consider it as a mixture of lecithin and
cerebrin. Whether this be the case or not, phosphorus again
appears as the only element capable of being at all associated
with the question in point.

To merely adopt phosphorus as the characteristic con-
stituent of the thymus gland, however, and declare that it is
through its minus or plus production that the mental attributes
of children are developed, would merely constitute a theory.
As a stronger position is desired for all the deductions vouch-
safed in this work, collateral evidence must be sought.

The observations of Cabot, that, while thyroid extract
stimulates growth, it fails to enhance mental development in
idiots other than myxcadematous ones, raises the question as
to whether such results can be due to the absence of phos-
phorus in the thyroid. If such is the case, the absence of this
element should also show itself in the results obtained from
the extract in some other disease, if any structure other than
the brain and nervous system, in which a morbid deficiency
of phosphorus also exists, is a feature of that disease. We
know, for example, that phosphorus is introduced into the
organism with food, and that calcium phosphate, by becoming
deposited in the bones, gives them their hardness. Is there
any evidence that the bones of subjects in which thyroid ex-
tract is successfully administered lack of this hardening con-
stituent? Referring to the use of thyroid extract in cretinism,
T. Telford-Smith58 makes the following statement: "I have

67 Gamgee and Blankenhorn: Journal of Physiology, vol. ii, 1879.

68 T. Telford-Smith: Lancet, Oct. 2, 1897.

178 THE THYROID, THE THYMUS, AND THE ADRENALS.

found that during thyroid treatment the rapid growth of the
skeleton leads to a softened condition of the bones, resulting
in a yielding and bending of those which have to bear weight;
and, as cretins under treatment become more active and in-
clined to run about, this tendency to bending has to be guarded
against/7 After referring to the experiments of Hoffmeister in
'rabbits and those of Eisenburg in sheep and goats in which
bending of the legs was caused by removal of the thyroid, he
adds: "While in rickets, however produced, there is perverted
and delayed ossification resulting in softening and bending of
the bones, under thyroid treatment in cretinism there is rapid
resumption of growth in the skeleton, leading to softening,
which is most marked in the long bones and at the epiphyses."
That we are dealing here with an absence of phosphorus and
that the calcium phosphate serves to harden the bones con-
currently with their growth seem obvious.

But why does this not occur in all cases? Simply through
the fact, ascertained by Marie,59 that the thymus is almost
always persistent in cases of cretinism. When thyroid extract
is administered, therefore, the increased oxidation procured by
stimulating the adrenals also enhances thymic activity, and the
assimilation of phosphorus is increased in proportion. This is
proven by the experiments in animals by Hoffmeister and
Eisenburg, referred to by Telford-Smith. If removal of the
thyroid caused bone-softening in these, it is because — in the
light of our conception of the process — the adrenals were ren-
dered inadequate, and, oxidation being impaired in proportion,
the thymus also failed functionally.

This process, however, involves the need, in the structures
of the thymus gland, of a metabolic process culminating in the
production of an internal secretion laden with phosphorus-
containing bodies. Quotations from a study of the nucleins
and nucleoproteids in their relation to internal secretion by
Chittenden60 will serve to enlighten us: "The manufacture of
the specific substances which give character to the various
internal secretions is obviously a function either of special

59 Marie: Bulletin et Memoires de la Societe Medicale des H6pitaux de Paris,
p. 136, 1893.

00 Chittenden: Boston Med. and Surg. Journal, August 20, 1896.

THE THYMUS GLAND AND THE ADRENALS. 179

cells contained in the gland or it may be in some cases an
inherent quality of all the cellular elements of a given gland.
In the pancreas the formation of the active agent is apparently
limited to an interstitial, epithelium-like tissue occurring in
isolated patches throughout the gland and especially charac-
terized by its vascularity. This epithelioid tissue is certainly
distinct from the secreting alveoli, and is suspected, at least,
of being the source of the internal secretion. Again, in the
suprarenals, as Schafer and Oliver have shown, the active
principle, which has such a marked influence upon the heart
and arteries, is contained only in the medulla of the gland,
and not in the cortex, the medulla forming about one-fourth
of the gland by weight." . • . . "If we take the content of
phosphorus as a measure of the proportion of nucleic acid
contained in the various forms of nucleoproteids thus far
studied, we find exceedingly great variations in the amount
of this acid present in the molecule: a fact which may be taken
as evidence of the large number of molecular combinations
present in the protoplasm of different cells. Thus, from the
kidneys we obtain a nucleoproteid with only 0.37 per cent, of
phosphorus, while, as representing the other extreme,61 we have
in the pancreas a nucleoproteid containing 4.71 per cent, of
phosphorus and in the lymphoid cells of the thymus a correspond-
ing body with 3.5 per cent, of phosphorus. . . . The very
nature of the many bases which come from the cleavage of
the nucleic acids outside the body; the ready convertibility
of these bases into other allied bodies ly oxidation and reduc-
tion; their own physiological action, which, though mild, is
marked; the possibility — nay, the probability — that many
other catabolic products may be obtained from these nucleic
acids; and, further, that still other nucleic acids at present
undiscovered may exist in the cell-protoplasm, all offer good
reasons for believing that the nucleins and nucleoproteids,
which are the most prominent constituents of the protoplasm
of all cells, are the most probable antecedents of the internal
secretions."

81 All the italics are our own.

12

180 THE THYROID, THE THYMUS, AND THE ADRENALS.

There is evidently a sound foundation for the belief that
phosphorus is the active constituent of the thymus gland. If
thyroid extract failed to improve the mental condition of the
ten cases collected by Cabot notwithstanding the increased
growth witnessed, it is either because the thymic gland in all
was structurally unable to respond to the increased oxidation
which the stimulated adrenals induced or because no thymus
gland was present. That this gland is absent in the vast ma-
jority of weak-minded, but not myxoadematous, children is
shown by the researches of Bourneville and Katz. That phos-
phorus is the main specific constituent of brain- and nerve-
substance is a recognized fact, fully sustained by physiochem-
ical data. That thyroid extract does not improve non-myx-
oadematous idiocy or weak-mindedness in children owing to the
absence of phosphorus in the organism is shown by the corre-
sponding effects it has on the skeleton of some cretins, as
observed by Telford-Smith, the bones, by their softness, show-
ing the absence of the hardening that calcium phosphate
procures. Finally, that the adrenals, through the normal oxi-
dation processes insured by them when adequately stimulated
by the thyroid secretion, sustain the activity of the thymus up
to its proper standard is shown by the experiments of Hoff-
meister and Eisenburg, in which removal of the thyroid of
various — herbivorous — animals caused bending of the legs.
The thyroid is thus able to stimulate the adrenals, and the
adrenals in turn can stimulate the thymus. But does the
thymus physiologically stimulate the adrenals?

The fact that the thymus gland is but a temporary struct-
ure, one calculated to atrophy when its functions as a building
organ are accomplished, would seem to suggest that stimulation
of the adrenals is not one of these functions. If the deduc-
tions herein submitted are sound, it would appear to stand
prominently as a bone-forming organ and general phosphorus-
purveying organ from the time of the completion of its lym-
phadenoid elements during intra-uterine life until the final
elaboration of the skeletal frame-work, — i.e., around the period
of puberty, — its powers gradually receding as permanent or-
gans are developed. This conception of its purpose does not
appear to have suggested itself to anyone so far, but it is quite

THE THYMUS GLAND AND THE ADRENALS. 181

in keeping with the collateral observations of a number of the
best of modern embryologists.

The most prolific source of leucocytosis, as is well known,
is the bone-marrow. In the process of bone-formation during
foetal life, the first points of ossification appear during the
second month, but it is only during the fourth that the devel-
opment becomes markedly active on all sides. That the most
active work of the thymus is performed during intra-uterine
life is well known; this, therefore, coincides with its most
active bone-forming period. It seems reasonable to conclude
that so important a function as leucocytogenesis should not
devolve upon structures undergoing formation, and also that
the bone-forming organ should be intrusted with the function
which ultimately would constitute the main active attribute
of their product. Bone-marrow being the main leucocyte-
forming structure, we should therefore expect the thymus to
assume this role until the bone-marrow had reached its normal
physiological development.

Kolliker has always maintained that the formation of
leucocytes was a function of the thymus: a position in which
he has been sustained by Prenaut and Oscar Schultze. J.
Beard62 more recently took up the question and studied it with
considerable care in the Raid batis, the smooth skate. He
ascertained that the absence of leucocytes in the earliest period
of embryonic blood in vertebrates persists until the first ones
are formed within the thymus epithelium and from its epithe-
lial cells. In embryos from twenty-eight to forty-two milli-
meters long the formation and emigration of leucocytes from
the thymus becomes very active, and at this time there is no
part of the embryo, including the blood, that is not infiltrated
with leucocytes. This happens before lymphoid structures are
developed elsewhere within the body of the smooth skate.
Beard believes, with Kolliker, that the formation of leucocytes
is a function of the thymus gland; and "the first leucocytes
arise in the thymus from its epithelial cells; thus it is the
parent-source of all the leucocytes of the body": a conclusion
which is further sustained by what appears to us to be a war-

62 J. Beard: Lancet, Jan. 21, 1899.

182 THE THYROID, THE THYMUS, AND THE ADRENALS.

ranted deduction: i.e., that the tliymus is the main organ upon
which the osseous, cerebro-spinal, and nervous systems depend for
their phosphorus during tJieir development.

We have also seen that leucocytes are included among the
bodies that contain phosphorus. The identity of the thyroid
as a bone-forming organ is apparently contradicted by Svehla's
observation that fcetal thymus proves inert experimentally;
but when we recall the fact that it only assumes its function
the fourth month,, that its inordinate activity may cause it to
fix but little of the element itself, there is ample room for
doubt as to the value of the experiments. If these facts do
not prevail, then all the data submitted, the recognized intra-
uterine supremacy of the thymus over other glands, Chitten-
den's analysis, and several physiologically established facts
would also have to be considered wrong.

If the temporary role of the organism of the thymus pre-
cludes a physiological connection between it and the adrenals,
how are the beneficial effects in exophthalmic goiter, to which
reference has been made, produced? If the cases analyzed by
Hector Mackenzie63 are studied with a view to ascertain which
of the various remedies used by him, including thymus gland
and extract, have proven of greatest value, it soon becomes
evident that the thymus does not differ much from belladonna,
phosphate of sodium, and other agents tried by him. In Case
XVIII, for instance, thymus and tincture of belladonna proved
beneficial; on the remedies being changed to belladonna and
bromide considerable improvement occurred. In Case XXIII
all the symptoms except the rapid cardiac action greatly dimin-
ished under belladonna and phosphate of sodium. A relapse
occurring, the treatment was changed to thymus extract, which
also caused decided improvement. Case XXVIII was given
belladonna, potassium bromide, and thymus extract, also with
excellent results. Case XXX was also given sodium phosphate
and belladonna for the first fortnight, which caused the patient
to feel "better each time." He was then ordered, in addition
to the sodium phosphate, some thymus extract. This caused
him to feel "better generally." Case XXIII was evidently one

83 Hector Mackenzie: Loc. cit.

THE THYMUS GLAND AND THE ADRENALS. 183

which had already reached the border-line of suprarenal insuffi-
ciency; the patient, after having "wasted almost to a skeleton/'
had more than made up for what she had lost; thyroid and
thymus combined proved beneficial. Case XXIV was still
further advanced, since "she had no strength or energy" and
a good deal of pigmentation about the face; took an alkaline
tonic, thymus with thyroid, belladonna, potassium, and grew
"weaker and more nervous"; but extract of thymus alone
caused her "general condition" to become "better." On the
whole, it is plain that thymus acts like any other more or less
useful drug, as "a remedy of some value," using Dr. Mackenzie's
words, "improving the general condition," and which "in this
way may assist toward the recovery of the patient." This con-
firms the absence of physiological relationship with the ad-
renals, and tends to show that the benefit obtained from the
therapeutic use of thymus gland is mainly due to the phosphorus
it contains.

This does not mean, however, that it may not prove an
exceedingly valuable therapeutic agent in properly-selected
cases. In fact, it seems possible that, in the very cases treated
with thyroid extract referred to by Cabot, the addition of
thymus might have caused the improvement in the mental
condition which thyroid alone failed to procure. The absence
of the thymus in Bourneville's cases supplies a firm foundation
for this thought. Though some benefit has been obtained from
sodium phosphate, it seems reasonable to believe that in phys-
iological combination, as it occurs in thymus, phosphorus will
prove far more efficacious. Whether it enhances suprarenal
activity through this element, or, as does thyroid, through a
specific physiological body intended for this special purpose,
matters little. It also stimulates the adrenals, and if we do
not lose sight of the fact that the entire cerebro-spinal axis
and the nervous system utilize phosphorus as an all-important
specific source of energy, and associate with this the enhanced
oxidation which its stimulation of the adrenals procures, we
cannot but realize that its intelligent use may insure results
unattainable through any other agency. The benefit obtained
by Owen in a case of paralysis agitans shows that these are not
vain words. Indeed, we must not overlook the fact that im-

184 THE THYROID, THE THYMUS, AND THE ADRENALS.

paired suprarenal activity reduces the nutritional standard of
all structures and that all cells fail to appropriate through
the reduced metabolism involved their physiological con-
stituents. While, therefore, paralysis agitans should not be
classed as a nervous disease, it is nevertheless true that the
nervous system, if the adrenals underlie the whole trouble, also
suffers from impaired nutrition, and that phosphorus, its source
of intrinsic energy, is as necessary to it as oxygen itself.

The purpose of this chapter being to ascertain, as we did
in the case of the thyroid, whether any special symptom or
disorder could be traced to the adrenals through the mediation
of the thymus, we will now summarize the results attained in
this connection: —

The testimony adduced seems to show that the stimulation
of the adrenals by the thymus is purely incidental, and due to
the phosphorus the latter contains in organic combination.
Yet experimental evidence demonstrates that the withdrawal
of this stimulation and deprivation of phosphorus to which the
adrenals are thus subjected can induce suprarenal insufficiency,
while, on the other hand, its therapeutic and experimental ad-
ministration has shown that thymus is able not only to restore
the activity of insufficient adrenals, but also to induce over-
activity of these organs. A normal deduction suggested by
these phenomena is that they are interdependent as long as the
activity of the thymus lasts, — i.e., until puberty, — and that
insufficiency of either the adrenals or the thymus during the
development of the organism gives rise to morbid phenomena
in which both oxidation and the nutritional processes that de-
pend upon bodies containing phosphorus in organic combina-
tion are the leading pathogenic factors. Insufficiency of the
thymus by correspondingly reducing the supply of phosphorus
to the nerve-centers of the adrenals impairs the activity of
both, while the deficient oxidation of the cellular elements of
the thymus further inhibits their function. This vicious circle
may also prevail in the opposite direction: i.e., in connection
with overactivity of either organ.

We thus have again constituted two general classes of
pathogenic factors, i.e., overactivity and insufficiency of both
organs, which, if examined into in respect to their far-reaching

THE THYMUS GLAND AND THE ADRENALS. 185

influence during the process of physical development, are fully
ns important as those in which the thyroid plays an active
part. Indeed, while the thyroid gland physiologically stimu-
lates the adrenals through its iodine constituent and perhaps
supplies the cutaneous tissues with their main inorganic body,
— i.e., arsenic, — the thymus incidentally stimulates the supra-
renal glands, and supplies the bones, the brain, the cord, the
nerves, and other structures with their main inorganic con-
stituent, phosphorus. The conclusion seems warranted, there-
fore, that:—

Impairment of the functions of the thymus and of the ad-
renals underlies the disorders of nutrition which inhibit the devel-
opment of the cerebro-spinal, nervous, and osseous systems, during
infancy, childhood, and early adolescence.

CHAPTEE V.

THE ANTERIOR PITUITARY BODY, THE THYROID GLAND, AND
THE ADRENALS AS PARTS OF AN AUTONOMOUS SYSTEM.

IN his valuable essay on "Acromegaly" Guy Hinsdale1
refers to Gauthier's2 view, that the symptoms of this disease
could be divided into two stages, as follows: "Two stages in
the course of acromegaly have been differentiated, viz.: the
erethic stage and the cachectic stage. The phenomena of
erethism3 which characterize the first stage embraces, first, a
painful hyperaesthesia, which manifests itself in headaches and
rheumatic pains; second, an hypertrophy of the muscular
fibers, which may give to patients a muscular power greater
than usual; third, palpitation of the heart accompanying the
hypertrophy of that organ; and, finally, the polyphagia and
polyuria, which may be considered to be connected with an
erethic state of the respective organs. The second stage is
characterized by a cachexia or a period of decadence. The
stage of increase has abated and the phenomena of erethism
have disappeared. Muscular atrophy and cardiac dilation and
a consequent enfeeblement of the circulation render the pa-
tient quite helpless. It is in this stage that bleeding from
the nose may ensue, and progressive debility marks the period
of decline, which ends in syncope. Epistaxis may also occur
early."

It is perhaps unnecessary to point out that all these
symptoms recall those of exophthalmic goiter, barring certain
characteristics of the latter disease. We have seen, however,
that exophthalmic goiter was, in reality, the direct result of
suprarenal overactivity, though initiated through thyroid over-
activity. The foregoing acromegalic symptoms, therefore, must

1 Guy Hinsdale: "Acromegaly"; Boyleston Prize Essay of Harvard Uni-
versity, 1898.

a Gauthier: Progres Medical, May 24, 1890, and Jan. 1, 1892.
• All italics are our own.

(186)

THE PITUITARY AND THE ADRENALS. 187

also originate from the adrenals, with some disordered func-
tion of the pituitary gland as primary factor. That the latter
organ is associated with the characteristic symptoms of acro-
megaly — i.e., those not observed in exophthalmic goiter — is
practically established; we have seen that the thyroid gland
also gives rise, probably through its arsenic, to special cuta-
neous symptoms. Our first line of inquiry, therefore, should
enable us to ascertain whether the pituitary is also, as are the
thyroid and thymus glands, connected functionally with the
adrenals.

Vassale and Sacchi4 found, in 1892, that complete destruc-
tion of the pituitary gland in dogs and cats had fatal conse-
quences within two weeks. The symptoms that followed removal
were rigidity of the gait, fibrillary muscular contractions and
spasms, anorexia, depression, and lowering of the temperature.
In more recent experiments they ascertained that all these
phenomena, including the hypothermia, could be relieved by an
injection of extract prepared from bovine pituitary. In one
of the animals experimented upon the symptoms, after lasting
for some weeks, gradually disappeared. It was then killed and
the fact revealed that the gland had only been incompletely
destroyed. Arnoldo Caselli5 has also found that complete
abolition of the functional activity of the pituitary in dogs and
cats caused, in the first instance, slowing of the respiration and
acceleration of the pulse, then mental depression and disturb-
ances of movements. The latter were characterized by arch-
ing of the back and spastic gait, without tonic or clonic con-
tractions of the limbs. Progressive cachexia then appeared,
the animal dying comatose. These results have been indirectly
sustained by those of other observers. Oliver and Schafer, for
example, found that extract of pituitary caused a marked rise
of blood-pressure, with increased force of the heart-beat: an
action which they compared to that of suprarenal extract, but
with the difference that no slowing of the heart-beat occurred.
Szymonowicz reached the opposite result: He found that in-
jections of pituitary extract produced in dogs a slight fall of

* Vassale and Sacchi: Rivista Sperimentale de Freniatria, p. 83, 1894.
5 Arnoldo Caselli: "Studii anatomici e sperimentali sulla Fisiopatologia della
Glandola pituitaria," 1900.

188 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

blood-pressure, while simultaneously quickening the heart-
In -at. Howell8 then ascertained that extracts of the infun-
dibular portion alone of the pituitary body gave rise to a
pronounced slowing of the heart, but with an increase of
blood-pressure. The latter rose more slowly than it did when
suprarenal extract was used, and sank gradually. Repeated
injections caused the effects to become less marked or to fail
altogether, especially when administered in rapid succession:
i.e., before a preceding injection had lost its effect (half an
hour or more). The organs affected appeared to have become
temporarily immune to the effects of the extract. De Cyon7
also noted that slowing of the pulse accompanied the rise of
blood-pressure. Isaac Ott8 even obtained this elevation of the
arterial tension in rabbits after severing the cord between
the atlas and occiput. Hinsdale9 witnessed a rise of 11 milli-
meters Hg above normal (90 millimeters), followed by a decline
of 13 below normal, also in the rabbit. In a dog, it caused no
immediate change of pressure injected intravenously, but at
the end of an hour there had been a gradual fall of 10 milli-
meters.

E. A. Schafer and Swale Vincent10 found at least two
active substances, in extracts used by them, having distinct
physiological actions. From the one they obtained "a simple
rise of blood-pressure caused by contraction of the arterioles":
a fact ascertained by them "in the splanchnic area" and "not
very dissimilar to that caused by extract of medulla of supra-
renal." This pressure-raising substance is not soluble in alco-
hol. The second substance produced "a well-marked fall in
arterial pressure, the effect being almost identical in its char-
acters with that caused by cholin."11 The marked fall of press-
ure could be obtained repeatedly at short intervals, thus dif-

• Howell: Journal of Experimental Medicine, vol. iii, No. 2, 1898.

7 De Cyon: Archives de Physiologie, July, 1898.

8 Isaac Ott: Medical Bulletin, Feb., 1898.

• Hinsdale: Loc. fit.

10 E. A. Schafer and Swale Vincent: Journal of Physiology, May 11, 1899.

11 In a foot-note the authors state that it cannot be cholin, since its action
persists after administration of atroplne, whereas they found that the depressant
action of cholin is prevented by atropine. It is evident, if the views outlined in
this work are correct, that the dose of atropine regulates the effect produced,
and that physiological tests of this kind are misleading, since all toxic symptoms
are due to the functional variations of the single set of organs — the adrenals.

THE PITUITARY AND THE ADRENALS. 189

fering from HowelFs observation in connection with the rise
of pressure. They recall the fact that the infundibular part
of the pituitary is mainly made up of gray, nervous matter.

The same authors12 obtained from decoctions of the in-
fundibular part of the pituitary (thus confirming Howell's
observation that this part alone of the gland caused the rise
of blood-pressure) "results resembling, in a general way, those
of suprarenal extract. They cause quickened respiration, in-
creased heart's action, and ultimately paralysis, commencing
in the hind-limbs/' facts which they demonstrate by tracings.
Yet these experiments were carried on at times with animals
under the influence of morphine and curare, both of which
drugs may induce, as we have seen, the above symptoms. At
other times and besides these two toxics, they injected atro-
pine, an agent which stands among the first of the blood-
pressure-raising drugs, through its ability to excite a high
degree of suprarenal overactivity. Hence they note that
"after the administration of atropine the rise of blood-pressure
which is got on intravenous injection of the infundibular ex-
tract is enormous and is accompanied by very little slowing
of the pulse." As all the experiments include the simulta-
neous use of two or three of the above agents, the conclusions
based on them lose their value for us, except in one connection,
which will be referred to later on. In further experiments
Osborne and Swale Vincent13 obtained from a saline decoction
of the gland an alcoholic precipitate which produced depressor
effects, and with ammonium sulphate, a precipitate which pro-
duced pressor effects. The "depressor" effects, which could also
be obtained with extractives of any portion of the nervous
system and especially of the cerebral gray matter, could not
be prevented by section of the vagi.

What can we conclude from this evidence? Gauthier's
clinical subdivision of acromegalic symptoms distinctly recalls
those produced by any form of active intoxication — provided
the suprarenal glands, as herein suggested, are made the active
factors of these symptoms. His "erethic" stage is evidently
that due to overactivity of the adrenals; the "cachectic" stage,

12 E. A. Schafer and Swale Vincent: Journal of Physiology, Sept. 18, 1899.

13 Osborne and Swale Vincent: British Medical Journal, March 3, 1900.

190 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

that of insufficiency. We are brought back to the similarity
of these symptoms to some of those observed in exophthalmic
goiter, the specific signs of the latter being the missing ones.
Why should the latter — the intense tissue-waste, the rapid
heart-action of the first stage — be peculiar to Graves's disease?
There seems to be good ground for the belief that they repre-
sent the highest expressions of suprarenal activity, especially
the cramped heart: a fact easily accounted for by the phys-
iological nature of the stimulant, the only truly physiological
stimulant so far met with in our inquiry. In thymus we found
a product connected with bone- and nerve- nutrition, but
capable of incidentally stimulating the adrenals. Have we in
the pituitary another physiological stimulant, as in the thy-
roid, or an indirect stimulant, as in the thymus?

The experiments of Vassale and Sacchi will assist us in
clearing this question. Again do we meet with death as the
result of removal of the organ; it also followed, we have seen,
removal of the thyroid and the thymus. This brings the prob-
lem to the common plane of suprarenal insufficiency, if the
symptoms are similar to those observed after removal of the
other glands. Rigidity of gait, fibrillary contractions, and
spasms, — followed by anorexia, depression, and hypothermia, —
point to the two familiar stages, however, and surest that
removal of the pituitary is followed by the accumulation of
poisons in the organism which it is the organ's function to
destroy: a theory which many investigators have advanced.
But if they ascribe to the pituitary the role of a laboratory for
the destruction of toxics, restoration of the laboratory to its
normal functions should alone insure continuation of the
prophylactic process; and the injection of a small quantity of
the glandular extractive should not suffice to temporarily elim-
inate the morbid symptoms unless that extractive stimulate
some other organ in the body capable of carrying on the proph-
ylactic function. Vassale and Sacchi have not only obtained
restoration by this means, but the many experiments just re-
ferred to have demonstrated that pituitary extract was essen-
tially a blood-pressure-raising substance which, in the light
of our work, means a powerful suprarenal stimulant.

This feature completely transforms the question. Indeed,

THE PITUITARY AND THE ADRENALS. 191

we can now see why two stages occur after removal of the
pituitary. Since we have a stage of suprarenal overactivity,
there must have been, as stated, an accumulation of poisons
in the organism as a result of the extirpation of the organ.
The rigidity of gait, spasms, etc., point to the nature of the
poisons: i.e., waste-products of metabolism. The pituitary
must, therefore, also be able to stimulate the adrenals, since
we now know that the oxidation processes of which they are
the underlying factors destroy these toxics. But as there is
also a stage of insufficiency in the operated animal, we are
normally led to the conclusion that the metabolic products
have been more than a match for the adrenals and that the
latter have finally succumbed, just as they would have under
the effects of any active poison.

Precisely, therefore, as we have in the thyroid and thymus
a product capable of stimulating the adrenals, so do we have
in the pituitary gland a product capable of stimulating the
adrenals. The effects witnessed in the experiments of Oliver
and Schafer, Szymonowicz, Howell, de Cyon, Ott, Hinsdale,
Schiifer and Swale Vincent, and Osborne and Swale Vincent,
if this be true, are all ascribable to the latter organs. We can
readily understand now why Howell had to allow the effects
of one dose of extract to pass off before a repetition of these
effects could be obtained from a succeeding one. The first
dose had brought the adrenals up to a high degree of activity,
— perhaps that specific to pituitary extract, — and the next dose
could do no better. Such was not the case when the stage of
insufficiency was reached, however; here specificity no longer
existed, and, the larger the dose, the deeper became the lethal
tendency: i.e., the suprarenal insufficiency. This is shown by
the results of Schafer and Swale Vincent in this connection.

Again, the experiments of the last-mentioned authors
point to the differential effects of various agencies. After the
administration of atropine the rise became "enormous": fur-
ther evidence that they had incited suprarenal overactivity
to a degree far exceeding that of which the pituitary extract
itself was capable. As to the pressor and depressor effects
noted by Osborne and Swale Vincent, it seems probable that
they were merely using solutions of different strengths. Yet

192 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

their saline decoctions, which produced depressor effects, must
have been potent agents. This observation, linked with the
fact that cerebral gray matter produced similar effects, is valu-
able and suggestive, and will serve as the starting-point in our
search for the active principle of the organ referred to. For
the time being, we can safely, however, forimilate the proposi-
tion that the pituitary gland stimulates the secretory functions of
the adrenals and thereby enhances the activity of the oxidation
processes.

THE PATHOGENESIS OF ACROMEGALY.

What is the nature of the specific symptoms, independent
of those ascribable to the adrenals, to which morbid changes
of the pituitary can give rise? We have in exophthalmic goiter
the type of a disease brought on indirectly through functional
overactivity of the thyroid and adrenals. May we not have in
acromegaly a disease also brought on through excessive func-
tional activity of the pituitary and the adrenals?

There seems to be good ground for a separation of the
morbid phenomena generally ascribed to the pituitary into
two distinct, though related, syndromes. Thus, Marinesco,14
after examining four cases of acromegaly by means of the
Eontgen rays, reached the conclusion that, if this disease
comes on in adult life, the osseous hypertrophy is of a massive
type, while, when it affects adolescents, the bones increase in
length as well as in volume. The latter represents the "giant"
type of acromegaly. Again, Brissaud and Meige,15 in a study
of the statistics of gigantism, including two personal cases,
found that this condition often precedes acromegaly, although
both are traceable to the same anatomical process. Gigantism
can, however, remain such and not be followed with acro-
megaly; the latter, on the other hand, can appear alone, since
it is by no means always attended with gigantism. The giant
type appears during the process of normal growth, while acro-
megaly can appear subsequent to this process. M. Sternberg16
goes even so far as to state, that gigantism is not a disease

14 Marinesco: Gazette Hebdomadaire de M6decine, June 18, 1896.

18 Brissaud and Meige: Nouvelle Iconographie de la Salpgtriere, No. 6, 1897.

18 M. Sternberg: Zeitschrift fur klin. Medicine, vol. xxvii, 1895.

THE PATHOGENESIS OP ACROMEGALY. 193

per se, but a condition capable of readily associating itself
with other disturbances of nutrition, especially acromegaly.
This may be true, since gigantism may not be followed with
acromegaly, while the statistics of W. Hutchinson17 show that
40 to 60 per cent, of these prodigies are also acromegalic.
This statistical proportion suggests, therefore, that 40 to 60
per cent, of giants are not cases of acromegaly.

Yet this does not bear very deep examination. Typical
giants are really weaklings; while abnormal strength may pre-
vail, this does not last, and they reach an early grave. Indeed,
Hutchinson found that the ultimate result was similar in both ;
the location of the outgrowths and the sexual disturbances are
similar, and about the only difference between them that he
could detect were the symptoms due to the intracranial press-
ure of the growth and the more rapid course of true acromeg-
aly as compared to gigantism. The position that seems best
to harmonize with the data available is that of Marie,18 who
first described the disease and gave it its name: acromegalic.
His view has always been that gigantism occurs in the adoles-
cent when the acromegalic tendency is present during the
period of growth, whereas if it appears after full development
—i.e., in the adult — the hypertrophic process occurs mainly at
the extremities of the long bones, due to intense peripheral
histogenesis. Further studies have extended these restricted
limitations, however, and it is now known that there is not
only hypertrophy of the extremities, but also of the bone
proper, the voluntary muscles, the cellulo-adipose tissues, the
skin, the lymphatics and often of the viscera, the liver, spleen,
the kidneys, etc., — a true histogenesis of practically all tissues.

A logical inference to be drawn from this abnormal de-
velopment is that the underlying causative factor must be a
morbid overproduction of building elements. In other words,
if the pituitary serves to provide the organism with a building
product manufactured by it from elements obtained through
food, etc., — a view in conflict with many prevailing doctrines,
even that of Marie, who believes that the pituitary through
disease becomes incompetent to neutralize various substances

17 W. Hutchinson: New York Medical Journal, July 21 and 28, 1900.

18 Marie: Bulletin de la Soci6t6 des Hopitaux de Paris, vol. xii, 1896.

1(J4 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

that are capable of causing acromegaly, — it would seem reason-
able to suppose that inordinate assimilation of the primary
elements and correspondingly excessive production would alone
account for the excessive growth witnessed. But this appar-
ently involves another conflicting feature, as against the many
theories in which disease of the pituitary is rendered respon-
sible for loss of function and resulting neuroses, auto-intoxica-
tions, vasomotor disturbances, asphyxia of extremities, etc.:
i.e., the need of overactivity of the pituitary and simultaneously
of the adrenals to satisfactorily account for the increased pro-
duction of cellular elements witnessed.

Tamburini,10 after an analysis of twenty-four cases in
which post-mortem examination had been made, concluded
not only that "in all typical20 cases of acromegaly a growth of
the pituitary prevailed, but that there was at first hypertrophy
of the gland, with exaggeration of its functions and, later on,
abolition of these functions."

Harlow Brooks,21 after a careful study of the entire sub-
ject, refers to the feature in point in the following words:
"It is manifest that the only reliable key to the unraveling
of this rather chaotic mass of morphological alterations in
the hypophysis obscuring the pathogenesis of acromegalia is
on the basis of function." He then shows the solidity of this
view in the following lines: "By the process of elimination,
in the last chapter, the field of pituitary lesions was virtually
narrowed down to the second or hyperplastic class of changes,
and these are the true and essential lesions in acromegalia.
Besides the reasoning from the method of exclusion, there are
also positive data supporting this theory, for, in several cases,
observers have interpreted the results of their examination
of the pituitary changes as hyperplasia or adenoma. These
data furnish the key to disentangle the discordant observations,
and if we adhere to these results the subject seems clear.

"Against the view of the increased function and hyper-
plasia theory, however, stand the observations of the cases of

19 Tamburini: Rivista Sperimentale de Freniatrta, p. 559, 1894, and p. 414, 1895.

20 All italics are our own.

21 Harlow Brooks: Archives of Neurology and Psychopathology, vol. i, No. 4,
1898.

THE PATHOGENESIS OF ACROMEGALY.

195

sarcoma and morphologically similar neoplasms of the hypoph-
ysis in acromegalia. These observations greatly outweigh in
number the instances recorded as hyperplasia and adenoma,
and, in fact, constitute the great bulk of evidence in cases
examined microscopically.

"If we can show, however, that there are good reasons
for believing that these instances of sarcoma have been wrongly
interpreted and are really examples of hyperplasia, the patho-
genesis of acromegalia stands out clearly on a basis of harmo-
nious data. This is not difficult. The mistake of confounding
hyperplasia and even adenoma of the gland for sarcoma might
be very easily committed, indeed. The glandular structure
of the hypophysis is rather atypical, its cells are small and
rather densely huddled together, and the connective tissue is
very scanty. Consequently in an hyperplastic overgrowth the
appearance resembles, very closely, indeed, a sarcoma of the
small round-celled or lymphosarcomatous type/7 The author
then refers to several cases in which he had at first consid-
ered the enlargement of the pituitary as due to small, round-
celled sarcoma, and which, under the guidance of the idea of
hypersecretion, gave every evidence of hyperplasia. He fur-
thermore noted that "these so-called sarcomata of the hy-
pophysis in acromegalia are lacking in two rather predominant
traits of sarcoma," and remarks: "We should expect evidences
of metastasis and comparatively rapid growth, yet both of these
characteristics are absent. With the exception of a few cases,
the course of acromegalia is notoriously slow, gradual, and
chronic, and extends over a number of years. Such a course
in the growth of a sarcoma would be a rather striking excep-
tion to the rule.

"The hypersecretion theory, as far as I am able to learn,
was first brought forward by Tamburini, but I feel like stating
it much more positively." Indeed, Tamburini had also affirmed
that, while one is justified in concluding that the lesion that
is constantly met with in autopsies upon typical cases is tumor
of the pituitary body, this usually assumes the form of ade-
noma, the next of kin to hyperplasia of the glandular tissues.

Whether, as Marie says: "acromegaly is gigantism in the
adult," or "gigantism is acromegaly in the adolescent," we are

13

196 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

always dealing with acromegaly, and this fact, coupled with
the probability emphasized by the above data that there is
always overactivity of the pituitary when either of these two
conditions is present, may help us to ascertain the nature of
the symptoms of pituitary origin.

Whether they appear in the adolescent or in the adult, the
earlier symptoms of acromegaly are always insidious. Enlarge-
ment of hands, feet, or head may constitute the first indications
of disease and be perceived only through the unmistakable
tightness which the shoes, gloves, or headgear may assume.
There may be some headache, rheumatic pains, or impairment
of vision, and the disease may be considerably advanced before
it is recognized as such. In a case reported by Leszynsky,22
for example, the patient had frequently been the object of
jocular remarks concerning the size of his feet and hands
before he suspected disease, and visited the hospital because
of his vision, which had become "blurred" a year before. In
another case reported by Johnston and Monro23 acromegaly
followed parturition. A swelling around the eyes was the first
sign, and never disappeared. Shortly afterward enlargement
of the face, hands, and feet became apparent. About two and
one-half years later her vision began to fail, and it was about
this time that she first complained of headache, which, from
being paroxysmal, soon became constant. We have in these
two instances, among the many that have been reported, clearly
defined symptoms of hyperplasia of the pituitary. If now ex-
cessive activity of the latter enhances suprarenal activity and
correspondingly increases oxidation, we should, even among
these earlier manifestations, find evidence of this excessive
oxidation.

While the suprarenal phenomena of the earlier stage are
not always referred to in all accounts of cases, they are given
in many, and their enumeration will suffice to at once recall
their relative frequency: i.e., excessive and sometimes ravenous
appetite, thirst, polyuria, a full and hard pulse, and, often, cuta-
neous hypercesthesia, a sensation of abnormal superficial heat, and,
after the case has progressed some time, muscular hypernutri-

22 Leszynsky: Medical Record, March 4, 1899.

88 Johnston and Monro: Glasgow Medical Journal, August, 1898.

THE PATHOGENESIS OF ACROMEQALY. 197

tion. All these symptoms except the latter are witnessed in
exophthalmic goiter, though muscles do not show, at first, the
general emaciation which is observed in this disease. Yet there
is every reason to believe that the activity imparted to the
adrenals by the secretion of the pituitary is less marked than
that caused by the thyroid secretion. Hinsdale, in his essay,
based on a study of one hundred and thirty cases of acro-
megaly reported in literature, refers to the muscular symptoms
as follows: "The muscular system varies in development with
the type and stage of the disease. Naturally, the strength is
great in the early period and particularly in the giant form.
. . . The facts that the disease has existed for a consider-
able time when the cases are reported and that they apply
to physicians for relief of symptoms explain why muscular
power is commonly noted as weak, as a rule. ... As
the period of decadence sets in, muscular atrophy renders
the patient quite powerless, and cardiac dilation adds to the
weakness of the circulation. Tremor24 is not unusual in acro-
megaly."

The cachectic stage as typically indicates the part played
by the adrenals in the morbid process. Besides the muscular
weakness just referred to, there is often marked sensitiveness
to cold. The reduced vascular pressure is shown by increased
rapidity and weakness of the pulse; and examination reveals a
dilated heart. Brooks, referring to the lesions of the vascular
system, says: "In short, the vascular lesions are found in their
most exquisite type in those portions of the body where the
circulation is slowest and where capillaries are most numer-
ous." Exoplifhalmos is also witnessed in many cases, including
the slow lid-motions, all probably due to the muscular debility;
sweating in common, and is doubtless ascribable to the weak-
ness of the muscular elements of the sweat-glands. Glycosuria
is commonly observed. Eeferring to the lesions of the skin,
Brooks also states: "Macroscopically, the skin in these areas
is considerably thickened; the surface is rough and often
fissured. A general brownish pigmentation is present in the
average case, which, at times, strongly resembles that found
in Addison's disease."

2* The italics are our own.

198 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

That the suprarenal glands should be credited with the
great majority of the symptoms now ascribed to the pituitary
alone is evident. Indeed, the remaining signs that might be
attributed to the latter may be still further limited in number.
Among those to be excluded are the various phenomena due
to pressure of the enlarged pituitary. The headache is one of
these, although its severity is probably increased during the
first stage by the cerebral hyperaemia caused by overactivity
of the adrenals. The many symptoms of which the visual
apparatus is the source, excepting those due to the loss of
local muscular power already referred to, are also ascribable
to pressure of the hypertrophied pituitary. The senses of
smell, taste, and hearing are occasionally involved.

Mental phenomena are frequently observed, but, as a rule,
they are credited to the mortification suffered by the patient
because of the deformities of features and form which the dis-
ease brings on. They appear to us to merit a far more con-
spicuous position in the pathology of acromegaly than they are
given, owing mainly to the light their close connection with
so manifestly a trophic disorder may shed upon the mental
diseases in general. Do they belong to the domain of the
pituitary or to that of the adrenals? We have seen that mania
is associated with suprarenal overactivity while melancholia is
observed during the stage of insufficiency.

In referring to Blair's case of persecutory mania asso-
ciated with acromegaly,25 and to his remark that but three
cases had come to his knowledge, one in England and two on
the Continent, R. H. Hutchings28 likewise emphasizes the fact
that sufficient attention has not been given the mental symp-
toms of the latter disease. He also reports two instances, one
of which, a typical case, is particularly interesting to us, since
death occurred before the second — or cachectic — stage had
been reached. Unfortunately the pathological histology of the
brain is not given, but the statement that it "was compact,
of good weight and firm," while no reference is made to pe-
ripheral pressure lesions in the neighborhood of the enlarged

28 Blair: Journal of Mental Science, April, 1899.

M R. H. Hutchings: Archives of Neurology and Psychopathology, vol. i, No.
4, 1898.

THE PATHOGENESIS OP ACROMEGALY. 199

pituitary, suggests that the mental disease could not be at-
tributed with justice to pressure of the growth. This is fur-
ther sustained by the fact that visual disturbances, so fre-
quently noted, are not referred to, the eyes being "deeply
set and small." The case was, mentally, one of "mild, gradually-
increasing dementia." The second case is an instance of
feeble-mindedness with marked amnesia, with no tendency to
irritability, as in the former. With this feeble-mindedness,
however, is associated another disorder (one probably due,
as we have seen, to the sudden production and accumulation of
waste-products, and referable, therefore, to the adrenals, or,
rather, to exacerbative suprarenal overactivity) : i.e., epilepsy.
That mental shocks of various kinds often initiate exophthal-
mic goiter is well known. The patient had never been very
bright. At the age of seventeen he had been frightened, and
this marked the first of his fits, which have continued ever
since: i.e., twenty-seven years. As the acromegaly began
about seventeen years after the onset of the epileptic seizures,
it appears possible that this long-continued overnutrition of
the pituitary may have been the cause of his acromegaly — •
typical not only in respect to its specific symptoms, but also
to those distinctly traceable to the adrenals. Three years
before the report the more acute symptoms began to appear,
and when Dr. Hutchings's paper was published he had had
fewer epileptic seizures than formerly, but amnesia was more
marked: both signs that the cachectic stage — i.e., that of
suprarenal insufficiency — was approaching. In a very similar
case, in which weak-mindedness also prevailed, though no
epilepsy is referred to, Roxburgh and Collis27 found at the
necropsy softening of an enlarged pituitary gland.

Valuable in this connection is one of two cases of acro-
megaly with imbecility in adolescents reported by W. G. Shall-
cross28 after a daily observation during a period of nearly six
years. In this case, now aged 18 years, rated as a "high-
grade imbecile" when admitted into the Pennsylvania Train-
ing-school, a marked change, both mental and physical, ap-
peared at the age of fourteen years, and a year later the signs

27 Roxburgh and Collis: British Medical Journal, July 11, 1896.

28 W. G. Shallcross: Philadelphia Medical Journal, April 20, 1901.

200 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

of acromegaly appeared. He then began to grow rapidly, and
in one year had nearly reached his present size, 6 feet, 3
inches. At sixteen years and ten months he weighed 210
pounds. Yet a Rontgen-ray examination showed "a uniform
hypertrophy, merely an exaggeration of the normal state."
Here, again, we find evidence of suprarenal overactivity, though
none of the pressure symptoms — headache, etc. — are as yet
present. The arterial tension is increased, the hyperidrosis of
peripheral vascular pressure is present, the apex-beat is forcible,
and there is increasing polyuria — March 10th, for instance,
2400 cubic centimeters daily, and October 15th, 6810 cubic
centimeters daily. That the vision is becoming impaired is
also suggested by an examination of the eyes by Dr. Thoring-
ton, who found double optic atrophy and other signs pointing
unmistakably, with the general symptoms, to a growth of the
pituitary. The predominating sign in this case, however, is
marked dullness over the upper portion of the sternum, indicative,
as shown by Erb, of an enlarged thymus.

These few illustrations will suffice to emphasize two ruling
factors in the study of this question: (1) that the adrenals and
the pituitary are interdependent, and (2) that acromegaly may
be the result of more than one pathogenic factor. In Hutch-
ings's second case, for instance, there is every reason to believe
that an already inadequate, and therefore vulnerable, pitui-
tary, as shown by the patient's mental torpor, traced back to
his childhood, underwent morbid development under the in-
fluence of the adrenal overactivity to which the accesses of epi-
lepsy point. The normal dense vascular supply of the pituitary
readily shows that such a process is possible if its physiological
resistance is below the normal standard. Unduly stimulated
itself by overoxidized blood, it may thus have been able to over-
nourish the various structures under its functional influence.
The various tissues — bone, muscles, etc. — involved in such
cases are developed to an abnormal degree, the whole process
being further sustained indirectly by the suprarenal over-
activity, which affords a corresponding and necessary increase
of oxygen to insure nutritional metabolism. We thus have a
form of acromegaly directly due to suprarenal overstimulation
of the pituitary, in which, as in Hutchings's case, a structurally

THE PATIIOGENESIS OF ACROMEGALY. 201

weak organ first undergoes the causative hypertrophy, then
finally yields by retrograde metamorphosis to the undue and
continuous labor imposed upon it. But during all its period
of overgrowth and overactivity the pituitary had in turn stim-
ulated the adrenals, thus establishing a vicious circle, with
overwork of both organs as result.

That this conception of the pathogenesis of the disease
is based on solid foundation is shown by the experimental use
of pituitary extract by Mairet and Bosc29 in twenty-one epi-
leptics, administered by the mouth or by subcutaneous injec-
tion. The number of seizures was not only increased, but a
state of mental exaltation appeared which, in some of the cases,
was totally different from any mental aberration that they had
previously shown.

As to the second stage, here, as elsewhere, the pituitary
merely yields to the overwork imposed upon it. undergoes
deterioration, — not a mere return to normal conditions, but
either softens, as in the case recorded by Eoxburgh and Collis,
or undergoes the far more common process of fibrous indura-
tion. The suprarenal glands then not only fail to receive the
additional stimulation resulting from the overactivity of the
pituitary, but they lose the normal support which the latter
had afforded them. Thus seems to be inaugurated not only
the stage of suprarenal insufficiency, but also the cachectic
stage of the acromegalic syndrome itself.

If all this is true, we should have evidence of suprarenal
insufficiency, as manifested through its cardinal expression, —
myxcedema, — along with those of insufficiency of the pituitary,
since reduced functional activity of the adrenals should corre-
spondingly impair the nutrition of both the other organs.
That simultaneous and sufficiently advanced inadequacy of all
three sets of organs gives rise to but one result — i.e., myx-
cedema— is well shown by two cases in which necropsies were
performed by Ponfick30 and quoted here purposely from an
abstract to show the solidity of the position taken: "One
patient died early in the course of the disease from inter-

28 Mairet and Bosc: Archives de Physiologic norm, et path., July, 1896.
30 Ponfick: British Medical Journal, June 16, 1900, from Zeitschrift fiir klin.
Medicin, Bd. xxxviii, H. 1.

202 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

current pneumonia, the myxoedema itself being in a mild and
early stage?1 The changes found in the thyroid gland were
of two kinds, namely: interstitial inflammation32 and pure
atrophy. In the above case there were found an atrophy of
the pituitary (its size being three-fourths that of the normal)
and a marked involvement of its blood-vessels. Some parts
of the thyroid gland showed a marked colloid change. On
examination of the pituitary body an almost complete loss of
the glandular substance was found, together with marked in-
duration of the fibrous stroma, and the resemblance between the
pathological changes in the two glands was striking. The post-
mortem examination in the second case also showed destruction
of the glandular elements of the pituitary and a growth, in
its stead, of fibrous tissue. Ponfick observed that these and
other recorded cases go far to show that in a good many cases
of myxcedema where a considerable portion of the thyroid may
be found intact the hypophysis is so changed and its glandular
substance so much destroyed that it seems probable that the
morbid changes had begun in the hypophysis before there were any
alterations in the thyroid body."

The sequence of events is clearly indicated in these cases.
But why did they not give an early history of acromegaly?
For the same reason that some cases of exophthalmic goiter
lapse into the second, or cachectic, stage soon after the onset
of the first: i.e., because their suprarenal glands were mor-
bidly inadequate, rapidly yielded, and became insufficient
through the combined effects of the thyroid and pituitary se-
cretions which their own overactivity had brought on. Once
overnourished for any length of time, the tendency of tissue
is not to resume its normal histological organization, but to
degenerate, as is well shown in the case of the heart-muscle.
All three organs, therefore, underwent retrograde metamor-
phosis. This is proven by the fact that the progress of either
disease is not impeded when the three organs involved in such
cases are adequate and able to withstand for a sufficiently long
period, and simultaneously, a high grade of overstimulation.
The typical syndrome of thyro-suprarenal overactivity, exoph-

81 All italics are our own.

82 Doubtless due to the toxic process.— S.

THE PATHOGENESIS OF ACROMEGALY. 203

thalmic goiter, then appears along with the pituitero-supra-
renal symptom-complex, acromegaly, in the same case. Wit-
ness the case reported by G. R. Murray.33 The patient pre-
sented the characteristic signs of acromegaly, — enlargement
of the bones and tissues, — and those of exophthalmic goiter, —
the enlarged thyroid, early exophthalmos, rapid heart-action,
etc. Hinsdale34 refers to five such cases found in literature.
Again, the influence of overactivity of the three sets of
organs in bringing on the first stage of acromegaly is well
illustrated in a case described by Pearce Bailey.35 Though the
patient was a woman 65 years old, the first signs of acro-
megaly had only occurred five years before her death (due to
an intercurrent pulmonary disorder) and were still plainly
those of the first stage. At the autopsy the thyroid was found
to be nearly three times its normal size; and "microscopical
examination showed that the gland-substance was generally
normal, although in places the acini were much dilated and
filled with colloid material." The pituitary was more than
eight times its normal weight. The posterior, or neural, lobe
presented no structural alteration; while the anterior, or
glandular, lobe was very vascular, the capillaries being dilated
and filled with blood. The history of the case, only obtained
after death, is very brief, and signs of suprarenal overactivity
suggesting exophthalmic goiter are not mentioned. But the
causes of death, "uraemia and pulmonary congestion," are, as
we will see, direct expressions of the capillary centrifugal
pressure that intense activity of the adrenals can produce, the
existence of which is shown in the pituitary itself by dilation
of its vascular net-work. Bailey also refers to a case of Van
Home Nome's, in which phenomena recalling the earlier
symptoms of acromegaly were found after death, associated
with a pituitary "enlarged to three or four times its natural
size, in which an extensive hcemorrhage had recently taken
place." During life another sign of peripheral capillary en-
gorgement, wide-spread parassthesia, had been present, evidence

33 G. R. Murray: Edinburgh Medical Journal, Feb., 1897.

34 Hinsdale: Loc. cit.

85 Pearce Bailey: Philadelphia Medical Journal, April 30, 1898.

204 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

of another vicious circle in which the organs enhanced each
other's activities.

Resuming the consideration of the mental phenomena
observed in practically all cases of acromegaly — hardly percep-
tible in some and very marked in others — to the query as to
whether they can be ascribed to the adrenals or the pituitary,
the only answer possible so far is the following: The above
evidence tends to show that intense suprarenal overactivity can
so engorge the cerebral capillaries as to cause a disruptive
hemorrhage in an enlarged pituitary body. Whether the men-
tal symptoms are ascribable to the cerebral hyperaemia or to
the impairment of certain functions of the pituitary itself or
to both it is as yet impossible to say. We can only recognize,
for the time being, that, with the stage of acromegaly in which
the adrenals are overactive, the mental aberration is of a kind
usually associated with cerebral hyperaemia and which may in
some cases of acromegaly assume considerable violence. Thus,
in Tamburini's case36 some years after the onset of the acro-
megalic symptoms the patient, a young woman, manifested
delusions of persecution with violent excitement, terminating
in dementia. In another instance, reported by H. W. Coe,37
the patient, a woman aged 50 years, finally assumed such
homicidal proclivities that she was committed to an asylum.
In Tamburini's case a very large pituitary was found, an
adenoma; Coe's case was still living and in the asylum at the
time of the report. We may perhaps acquire more light in this
connection through the next feature to be analyzed: i.e., the
relationship between the thymus and acromegaly.

We have seen that in Shallcross's case of acromegaly in
an adolescent imbecile there was marked dullness over the
upper portion of the sternum. Klebs38 and Erb39 have em-
phasized the importance of the persistence of the thymus in
acromegalic subjects, and "Erb's sign," dullness on percussion
over the upper third of the sternum, was once deemed an im-
portant diagnostic feature of the disease. It gradually lost

89 Tamburini: Loc. cit.

87 H. W. Coe: Journal of the American Medical Association, Dec. 3,

88 Klebs: Allgem. Pathol., vol. ii, 1889.

89 Erb: MUnchener med. Wochenschrift, No. 24, 1894.

THE PATHOGENESIS OF ACROMEGALY. 205

its weight, however, as many other valuable hints have in
medicine, simply because it did not happen to fit every case,
and notwithstanding the fact that the organ had been found
persistent at autopsies and in some cases enlarged, by a num-
ber of pathologists. The form of acromegaly due to supra-
renal overactivity just discussed seems totally disconnected
from the thymus; but this does not mean that a persistent
thymus should not play the main role in the causation of a
second form: i.e.., one prevailing in adolescents or young adults.

Percy Furnivall,40 in an analysis of 17 cases of acromegaly,
found that the thymus was absent in 7, but hyperlrophied in 3,
and persistent in 7: i.e., nearly 60 per cent, of the cases. The
only constant associated changes appeared to be in the pituitary
body. At the same meeting of the Pathological Society, Rol-
leston41 referred to the case of a woman, aged 35 years, who had
shown symptoms of acromegaly for three years. "She suffered
from optic atrophy due to the pressure of the tumor; head-
ache, which was intense at times; and transient glycosuria.
The skeletal changes were quite characteristic.". The patient
died "after an epileptiform fit." . . . "The pituitary tu-
mor was a round-celled sarcoma the size of a walnut." . . .
While the thyroid gland appeared normal, "the thymus gland
was persistent, and was much in the condition of that of a
child before the changes of involution had set in." We have here
not one phenomenon, but two distinct manifestations of. as
many individual functions: Suprarenal overactivity, as repre-
sented by the epileptiform fit; excessive activity of the pituitary,
as represented by the acromegalic symptoms.

Why do we not have in the above case a third manifesta-
tion traceable to the — presumably active — thymus? We have
seen, when considering the physiological action of the thymus,
that this organ and the adrenals are interdependent as long
as the activity of the thymus lasts: i.e., until puberty. But
after puberty, and when the thymus becomes normally atro-
phied, are the adrenals deprived of this stimulus? To answer
this question negatively would be to concede that after puberty
the bodies that furnish phosphorus in organic combination, and

*° Percy Furnivall: Lancet, Nov. 6, 1897.
41 Rolleston: Lancet, Nov. 6, 1897.

206 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

which we have traced to the thymus, are no longer produced
in the organism. Such an assertion is contradicted by consid-
erable clinical evidence and by the pathological phenomena of
the cases of acromegaly in which the thymus is not persistent.
There must be, therefore, a successor to the thymus capable
of continuing actively or passively its physiological functions.
Especially must this be the case since, as we have seen, impair-
ment of the functions of the thymus and of the adrenals un-
derlies the disorders of nutrition which inhibit the develop-
ment of the cerebro-spinal, nervous, and osseous systems —
all structures involved in acromegaly. It would appear, there-
fore, that, if overactivity of the pituitary gland is the source
of acromegaly, this organ should assume at least some of the
functions of the thymus at puberty.

That this conclusion is justified seems sustained by con-
siderable testimony; it would remove the obstacles that are
themselves as strongly supported by existing data. Gigantism,
for instance, can thus assume the apparent autonomy observed
in some cases. A persistent thymus overlapping an efficient
pituitary, plus adrenals that are necessarily overactive through
the extra stimulus which the additional organ procures, make
up a physiological trio fully capable of causing the additional
formation of cellular elements which excessive growth involves.
We know that when overgrowth is a feature of acromegaly it
mainly appears in adolescent subjects or young adults, while
it is the exception when the disease appears in middle-aged
subjects or later. Indeed, the stature of some of the latter is
sometimes shortened by scoliosis. Again, there is a marked
distinction between the forms of acromegaly observed during
youth or adolescence and that occurring after maturity: a
feature emphasized by Woods Hutchinson.42 The overdevel-
opment of the former is comparatively symmetrical; the over-
growth in the latter mainly shows itself at the points of least
resistance: i.e., the extremities, hands, feet, nose, lower jaw,
etc.

It seems probable, however, that, while Maximilian Stcrn-
berg's view that there are two forms of gigantism, the first

"Woods Hutchinson: Loc. cit.

RELATIONS OF ANTERIOR AND POSTERIOR PITUITARY. 207

normal, mere overgrowth; the second pathological, the former
predisposing to the latter, prevails, true gigantism (not the
mere overgrowth of very tall subjects) is probably rare without
acrornegaly. Marie's view that "gigantism is acromegaly of
the adolescent," while "acromegaly is gigantism of the adult"
probably comes nearer the actual condition present in both
forms. This is suggested by the fact that, if the pituitary does
succeed to some of the functions of the thymus and the latter
persists sufficiently long to add materially to the stimulating
effects of the former upon the adrenals, a vicious circle of
overnutrition is formed through which the longevity of the
thymus is prolonged and sustained until softening, fatty de-
generation, or fibrosis — i.e., insufficiency of either of the three
sets of organs — initiates the cachectic stage. This is clearly
indicated by the terminal symptoms that attend cases of true
gigantism. "'Myth and popular impression to the contrary,"
says Woods Hutchinson,43 "giants are a short-lived, feeble-
minded, weak-bodied race." This nevertheless leaves us free
to distinguish at least three main forms of acromegaly from the
standpoint of pathogenesis: —

1. A form due to overnutrition of predisposed pituitary
through continuous overactivity of the adrenals, maintained, in
turn, by a chronic toxaemia.

2. A form due to persistence of the thymus and brought on
by over stimulation of the adrenals by the phosphorus-containing
thymic secretion, resulting in overnutrition and hypertrophy of
the pituitary.

3. A form due to morbid processes — tumors, etc. — in the
pituitary itself.

THE FUNCTIONAL RELATIONS BETWEEN THE ANTERIOR
AND POSTERIOR PITUITARY BODIES.

We have seen the remarkable observations of Bourneville
and Katz in respect to the absence of the thymus in idiots.
If we couple this feature with the clinical evidence attesting
that the pituitary gland is the growth-center of the organism,
we can analyze and perhaps find the connection between these
organs and between the two pituitary lobes.

43 Woods Hutchinson: Quoted by Hinsdale, Joe. cit.

208 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

E. de Cyon,44 after an exhaustive experimental study of
the pituitary gland, reached the conclusion that this organ, like
the thyroid, possessed two functions: the one mechanical and
the other chemical. Unaware, of course, of the role played by
the suprarenal gland as given in the present work, he care-
fully recorded the effects of mechanical pressure upon or elec-
trical stimulation of the pituitary. He found that either of
these sources of irritation immediately gave rise to variations
of blood-pressure and to a notable increase of power and slow-
ing of cardiac action, and ascribed these phenomena to excita-
tion of the vagus, which nerve was supposed by him to cause
vasodilation of the thyroid, followed, in turn, by depletion of
the cerebral circulation.

From our standpoint it seems more probable, as we have
seen, that an entirely different process occurs: i.e., that the
pituitary directly stimulates the suprarenal glands. Even in
this connection, however, de Cyon's experiment is a valuable
one, especially when connected with one performed by Howell
with pituitary extract and which showed that extract obtained
from the posterior lobe alone contained the blood-pressure-
raising substance. While de Cyon's observation enables us to
distinctly prove a direct connection between the pituitary body
and the adrenals, Howell's suggests that the posterior lobe must
be the one functionally connected with the latter organs. In-
deed, so marked was the suprarenal stimulation thus produced
that, although unaware that he was witnessing effects of supra-
renal origin, the resemblance suggested itself to him. Thus, he
says: "These extracts injected into the normal animal with its
vagi intact cause a very pronounced slowing of the heart-beat,
similar to that caused by suprarenal extracts, but lasting a much
longer time. The heart-beat is not only slowed, but is consid-
erably augmented in force, as is shown by tracings taken with
a Hiirthle manometer/'

If the anterior lobe does not contain a substance capable
of producing similar effects, what can its functions be? It
seems disconnected from the posterior in this particular, though
related with the infundibular walls by connective tissue and

** E. de Cyon: Archives de Physiologie, July.

RELATIONS OF ANTERIOR AND POSTERIOR PITUITARY. 209

many vessels, arterial and venous. This lobe — unlike its mate,
in which are found neuroglia, nerve-cells and epithelial-cell
tubules that contain a colloidal material — is subdivided into
numerous cavities, or vesicles, that vary in size and the walls
of which are lined with acini, made up of epithelial cells. Some
of these acini, especially those near the posterior lobe, also
contain a colloidal substance. The glandular elements are sur-
rounded by a close net-work of lymphatics and capillaries,
which, as we have seen, may become the seat, not only of in-
tense engorgement, but also of haemorrhage. The anterior
lobe, on the whole, recalls the thyroid in histological structure,
and several investigators — Rogowitsch, Gley, Stieda, and others
— have observed hypertrophy of its elements when the thyroid
was removed. In a large proportion of the cases of acromegaly
it is also this lobe that exhibits the morbid changes: an analogy
which suggests that its secretion might also be similar to that
of the thyroid. Is this the case?

If the secretion of the anterior lobe were similar to that of
the thyroid, there should also be considerable analogy between
the products of these organs and the secretion of the thymus,
since, as we have suggested, the pituitary appears to be, in this
particular at least, one of the successors of the latter. This
involves the presence, in all three of the organs, of the chem-
ical bodies upon which the hardness of the osseous frame-work
depends, since the preponderating phenomenon of disease of
the anterior lobe of the pituitary is bony overgrowth, while
removal of the thymus, as shown experimentally, is followed by
softness and bending of the bones. The administration of
thyroid extract in cretinism, on the other hand, is followed by
overgrowth, but with coincident softness of the bones: a feat-
ure which in itself seems to negate the presence of phosphorus
in the thyroid secretion.

R. HutchinsonV5 analyses of the thyroidal colloid have
shown that the proportion of phosphorus was 0.4 per cent., all
contained in a non-proteid part separated from the colloidal
substance by the action of boiling acids or the gastric juice.
Baumann's iodothyrin owes its activity to this non-proteid con-

R. Hutchinson: Journal of Physiology, Dec. 3, 1896.

210 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

stituent, according to him; but he also states that iodothyrin
contains practically all the iodine found in thyreoglobulin, — a
proteid of which he had just said40: "It contains the whole
of the iodine in the gland and is the seat of the active con-
stituent." Hence iodothyrin not only contains all the iodine
of the colloid material, but also its phosphorus. In the paper
last mentioned, however, — written over four years after that
in which he refers to phosphorus, — the various bodies found in
small amounts in the thyroid — xanthin, hypoxanthin, inosite,
creatin, sarcolactic acid, etc. — are mentioned, but phosphorus
is not referred to. He further states that, "with the exception
of iodothyrin, no substance has yet been isolated from it to
which therapeutic properties can certainly be ascribed." This
in no way invalidates the evidence adduced as to the presence
of arsenic, discovered by Armand Gautier, since Hutchinson
evidently did not look for it, but it coincides with the clinical
observation that, while thyroid extract increases the growth
of young cretins, it fails to supply them with phosphorus. The
small amount of phosphorus obtained is doubtless that con-
cerned with the metabolism of the glandular tissues themselves;
and it may be concluded that the thyroid secretion does not
supply this metal to the tissues with which it is concerned, and
that the role of phosphorus in the thyroid itself is limited to
its use in the intrinsic cellular metabolism of this organ. Of
course, the output of phosphoric acid is greatly increased after
the ingestion of thyroid extract, but we have in this fact only
further testimony as to its ability to enhance the activity of
the pituitary, this organ, in turn, stimulating the adrenals,
thereby increasing oxidation. Evidently iodine remains the
predominating thyroidal product.

That the thyroid and the pituitary differ in this particular
is clear. The connection between the pituitary and the various
pathological processes reviewed, and especially the influence of
this organ on bone overgrowth obviously points to the pres-
ence of phosphorus in its secretion. This is verified by de
Cyon, who isolated a phosphorus-containing substance from the
pituitary which he termed "hypophysin." He obtained from

40Baumann: Practitioner, April, 1901.

RELATIONS OF ANTERIOR AND POSTERIOR PITUITARY. 211

this substance, when injected into the veins of animals, effects
identical to those previously referred to when the organ was
electrically stimulated or touched: i.e., it caused slowing of
i the heart's action and increased vascular pressure. He further-
more obtained clinical results with it which led him to conclude
that "mental disorders, cephalic pains, and irregularities of
the heart-functions are the irrefutable results of impaired
function of the hypophysis/' so active did his phosphoro-
hypophysin prove in the particular symptoms mentioned. The
effects might be ascribed to the property common to all toxics,
— of stimulating the adrenals; but this could not hold in the
presence of the results of pressure on the gland and the col-
lateral testimony previously adduced herein.

Notwithstanding the fact that their organic active con-
stituents are totally different, we have ascertained that there
is a functional relationship between the pituitary and the thy-
roid. The former organ may become enlarged after removal of
the latter (Eogowitsch, Stieda, Gley), or during myxcedema
(Boyce and Beadles, Comte, Gron), or in cretinism (Bourne-
ville and Bricon, Dolega, Niepec, Osier), after thyroidectomy
(Kocher), or in goiter (Comte, Mitchell and le Count),47 while
de Coulon,48 in a careful study of the thyroids and the pitui-
taries of five cretins, found a similar atrophy of both organs
in each instance. As both lobes contain acini in which col-
loidal substance is to be found, and as the anterior lobe is the
more glandular of the two, while also that most frequently
involved vicariously when the thyroid becomes incompetent, it
stands prominently as the one upon which the compensatory
function should devolve.

When this question of compensation is at all searchingly
scrutinized, however, it is soon found wanting. In the first
place, its claims are based only upon more or less marked
fluctuations in the dimensions of the pituitary as compared
to those of the thyroid. While there is considerable parallelism
between these organs, both in hypertrophic and atrophic
processes, owing to hypernutrition and hyponutrition of both
through general disease, such parallel variations cannot be con-

« Mitchell and le Count: New York Medical Journal, April 29, 1899.
« De Coulon : Virchow's Archiv, vol. cxlvil, p. 53, 1898.

14

212 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

sidered as compensative. Nor can enlargement found post-
mortem in cases of goiter, exophthalmic goiter, etc., be re-
garded as the result of ante-mortem vicarious excessive work,
since the hypertrophic process may have occurred during a
primary stage of overactivity and the pituitary have remained
in its enlarged condition, though perhaps histologically modi-
fied. Thus, in his analysis of 36 cases of acromegaly in which
the relative conditions of thyroid and pituitary were noted,
Hinsdale found that, while the pituitary was diseased in all,
13 thyroids were hypertrophied, 11 were atrophied, and 12
were normal. Even cases of myxcedema in which an enlarged
pituitary is found prove nothing, since the enlargement may
have occurred before the myxcedematous process, along, per-
haps, with unnoticed symptoms, the adrenals having soon lapsed
into insufficiency and reduced nutrition of the thyroid tissues:
the starting-point of the myxcedema.

Of great value in this connection are the results observed
after experimental extirpation of the thyroid gland in animals,
especially if analyzed through embryological data. Thus,
Eogowitsch, among other investigators, noted enlargement of
the anterior lobe after extirpation of the thyroid in animals.
If the fact, pointed out by Andriezen, that both the thyroid
and the pituitary originate from a common region, the ecto-
derm of the primary oral cavity, is coupled with the view herein
advanced, that the thyroid supplies a substance which directly
stimulates the adrenals, these experimental results may easily
be accounted for. Indeed, to stimulate is to energize, — i.e., to
enhance the tone of organic structures; to remove the thyroid,
therefore, is to eliminate the tone-giving function of the ad-
renals; the pituitary, especially the anterior lobe, being an
exceedingly vascular organ, relaxation of its vessels means
passive engorgement, followed by the enlargement observed
by Rogowitsch and others. Under these conditions it becomes
apparent that a morbid change in the thyroid may implicate the
pituitary without bringing compensation into the process.

Indeed, a similarity between the secretions of these two

organs is negated by the strongest kind of evidence besides

that already adduced. Iodine, for instance, being undoubtedly

' the main constituent of the thyroid secretion, and phosphorus

RELATIONS OP ANTERIOR AND POSTERIOR PITUITARY. 213

that of hypophysin, the teachings of chemistry are peremptory,
since iodine and phosphorus, when combined, either form a
di-iodide (P2I4) or a tri-iodide (PI3), both solid bodies. This
clearly shows that these elements cannot be considered as the
basis of physiological reactions in which any considerable quan-
tity of both would be actively engaged. Again, Andriezen, as
the result of his exhaustive investigation, says: "It must be
remembered that the pituitary belongs both anatomically and
physiologically to the central nervous system,49 while the thy-
roid belongs to the respiratory function of the blood-vascular
system, and thereby to the tissues generally."

We could easily, with all these data, arrive at a final con-
clusion by contenting ourselves with the mere statement that
Andriezen's researches indirectly sustain the view that, while
the pituitary supplies the nervous system with phosphorus in
organic combination, the thyroid, by its iodine constituent,
stimulates the adrenals and thus insures an adequate supply
of oxygen. And this would plausibly account for the various
phenomena witnessed in connection with the morbid process
of either of the organs involved. Still, the pituitary is not
composed of one lobe, but of two, and such a conclusion would
involve the acceptance of both lobes as chemically and physio-
logically similar, or of one of them as alone active, the other
being classed as vestigial. Ample clinical evidence shows that
the anterior lobe is physiologically active in some way, — not-
withstanding the inertness of its extractives, — while the poste-
rior lobe has been shown by Howell, Schafer and Vincent and
others, to contain very active constituents. The only course to
pursue, in view of these facts, is to consider that both lobes are
active, either jointly, in carrying out a single function, or
singly, each having a separate role in the organism.

The final conclusions to which Andriezen arrives, read in
the light of the functions which, to us, seem to be those of
the adrenals, strikingly confirm the existence of a physiological
relationship between the pituitary and the latter. To give the
author's remarks their full value, they are quoted in full: "The
main conclusions from the above lines of investigation all point

49 All italics are our own.

214 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

to the important trophic influence of the pituitary gland on the
central nervous system of vertebrates," . . . which, "in
more definite terms, means (a) enabling them to take up and
assimilate oxygen from the blood-stream and (b) to destroy
and render innocuous the waste-products of metabolism, and
that at root these two functions are intimately related and are
really at root part of one process (vital, or biochemical), an
adequate assimilation of oxygen by the nerve-tissues securing
an adequate destruction (by oxidation) of the waste-products."
Of course, Andriezen here does not distinguish between the
two lobes: t.e., he refers to both jointly.

"The predicable results of the ablation or destruction of
the gland would, therefore," continues this investigator, "be
those due to (a) a malassimilation of oxygen by the nerve-
tissues, and simultaneously (b) an insufficient destruction, and,
therefore, accumulation of waste-products, thus bringing about
a rapid nutritional failure and death of the central nervous sys-
tem. In general terms, we would, therefore, expect in the
animal: —

"1. Depression and apathy (the commencing failure of
activity of the nerve-centers), and

"2. Muscular weakness (the first peripheral effect).

"3. Loss of fine co-ordination and equilibration (correlated
to Nos. 1 and 2), and

"4. The development of twitchings and irregular contrac-
tions (spasms) of the muscles (in relation to the further prog-
ress of nutritive failure of the nerve-centers).

"5. A want of sufficient heat-production and subnormal
temperature.

"6. A wasting of the body-tissues (in relation to the more
rapid failure of nutrition of the central nervous system).

"7. A probable compensatory polypnoea, or attacks of
dyspnoea (the peripheral indication of the failure of the nerve-
centers to assimilate oxygen).

"8. A rapid progress toward death. Future research must
negative or confirm these statements."

All the phenomena considered by Andriezen as "predi-
cable results of the ablation or destruction of the gland" are
ascribed to the organ as a whole, irrespective of any influence

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 215

of the thyroid, which he associates with the respiratory func-
tion, and, of course, irrespective also of any connection with
the adrenals.

THE ANTERIOR PITUITARY BODY AS THE ADRENAL
CENTER.

Hirschfeld,50 referring to nervous connections of the pitui-
tary, states that a number of anatomists classify this organ
among the sympathetic ganglia; then adds: "I am all the
more inclined to adopt the latter opinion since I have always
seen, in my dissections, a great number of nerve-fibers extend
from the superior cervical ganglia to this organ." Unfortunately,
no reference is made to the exact distribution of these fibers,
but we are fully compensated by an admirable histological study
of both lobes of the pituitary by H. J. Berkley,61 in which he
says, referring to the anterior lobe: "Nerves, other than those
belonging to the sympathetic system, are not found."

The nervous supply of the anterior pituitary lobe consists
of very fine fibers with numerous ramifications and branchlets,
and of bundles of small nerves that follow the course of the
arteries. From these originate single fibers which are dis-
tributed upon the coils of the epithelial cells, forming the
follicles, their ends breaking up in this location into numerous
terminal fibers with ball-shaped endings. The follicles re-
ferred to, according to G-uepin,52 average less than 1/2 milli-
meter in diameter (300 to 600 microns). Though often termed
acini, — i.e., glands, — they are, in reality, closed cavities, alveoli,
or vesicles, enveloped in a rich capillary net-work supported by
a sparse frame-work of connective tissue. The capillaries of
the lobe are made up of a single endothelial coat. The alveoli
themselves are built of two kinds of epithelial cells, the one
containing a large nucleus surrounded by a relatively clear,
though granular, cytoplasm, the other containing a similar
nucleus, but buried in a coarsely granular cytoplasm. The
arteries reach the organ by way of the infundibulum, and are
distributed to the alveoli without at any time penetrating

60 Hirschfeld: "SystSme Nerveux et Organes des Sens de 1'Homme," Paris,
8.

01 H. J. Berkley: Brain, Winter, 1894.
B2Guepin: Tribune Medicale, Dec. 10, 1891.

216 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

them, while the veins return by the same path as the arteries.
The partition between the two lobes contains, according to
Miiller,53 a net-work of lymphatics lined with ciliated epithe-
lium.

The predominating feature of these anatomical relations
is, of course, the connection with the sympathetic system,
which suggests that the anterior lobe may prove to be the
suprarenal center to which we have so frequently referred.
Indeed, we have had abundant evidence of the limited control
or influence the bulb and cord have over the adrenals, while
the experiments of Vassale and Sacchi have shown that re-
moval of the pituitary gives rise to symptoms of total supra-
renal insufficiency. Were the anterior lobe the seat of this
all-important function, however, it would necessarily lose its
identity as a secreting organ, since its role would be to gen-
erate, under the influence of a stimulus — toxic blood, for in-
stance— an impulse or impulses that the sympathetic nerves
would transmit to the adrenals. The large nuclei of the epi-
thelial cells, the wealth of endothelial and epithelial elements,
and the remarkable vascular supply of this lobe, all seem to
lend weight to this hypothesis.

As we will see in the chapter on "Immunity," all such
protoplasmic elements are endowed with immunizing attributes.
Either as stationary phagocytes or alexocytes they are able to
react aggressively against various pathogenic elements. That
this denotes a latent power in each cell to exert chemotactic
influence is generally recognized. But Buchner has shown
that leucocytes are not only chemotactic to bacteria, their
powerful toxins and bacterial proteids, but also to various
substances, down to so inert a material as wheat-flour. This
affords evidence that the cellular elements of which the vas-
cular and alveolar structures are composed are endowed with
latent energy, which, in the presence of any one of a large
number of substances, may become active. That in so impor-
tant an organ as the pituitary now seems to be this reserve of
energy should be unusual is apparent; we have testimony that
such is the case in the anterior lobe in the large size of the

M Miiller: Jenaische Zeitschrift, Bd. vi, 1891.

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 217

nuclei of its epithelial cells. Indeed, if a cell is so divided
that its nucleus will remain in one part, the other, composed
entirely of protoplasm, will die; but if the latter contain a
fraction of the nucleus, it will continue to live: evidence that it
is in the nucleus that the main source of energy resides, though
it cannot itself live without protoplasm. Whatever interpreta-
tion we may give "physiological functions," we are invariably
dealing with manifestations of chemical energy. Indeed, we
have in organic structures ample evidence to show that during
metabolism this chemical energy may become latent or poten-
tial mechanical energy, which in turn may pass into vital
energy. The seed-pods of certain plants exemplify this ad-
mirably: The chemical energy underlying their growth accu-
mulates as latent mechanical energy, and if the pod is merely
touched this energy suddenly passes into one connected with
the plant's own physiological functions: it explodes and scat-
ters its seeds in every direction.

When these elementary biophysical facts are considered as
features of the intrinsic functions of the anterior lobe, it be-
comes apparent that its dense array of nucleated cells, its endo-
thelial capillary walls, etc., may, with justice, be considered
fit constituents for a powerful energy-storing center. The
protoplasmic and cellular elements massed in this lobe are now
known, through the labors of Metschnikoff, Pfeiffer, Buchner,
and others, to react everywhere else in the organism in the
presence of a multitude of different toxic agencies: a process
doubtless referable to the one property of the protoplasmic
cell, formerly recognized as "irritability." If toxic blood, cours-
ing through endothelial walls elsewhere in the body, can excite
a protective reaction, it must certainly be able to do so in an
organ in which endothelial and epithelial cells and their nuclei
are so densely crowded together. If the anterior lobe of the
pituitary is really the suprarenal center, the intensity of the
reaction that any toxic in the blood might excite in the center
would regulate the violence of the symptomatic phenomena
engendered. We have seen, when studying the adrenals, that
poisons cause reactions in these organs that vary in their in-
tensity proportionally with the violence of the toxic energy of
these poisons and the dose introduced into the blood-stream.

218 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

That the anterior lobe of the pituitary and the adrenals
are directly connected, the former constituting the center of
the latter, is further sustained by the fact that both organs are
united solely by sympathetic structures. Thus, while Berkley,
referring to this lobe, says, "nerves, other than those belong-
ing to the sympathetic system, are not found," — confirming
de visu what other anatomists, among which are Tiedmann,
Pourfour de Pettit, Fontana Bok, Hirschfeld, and Bourgery,
had been led to surmise, — Dogiel,54 alluding to the nerve-ele-
ments of the adrenals, says: "There are, in the medullary sub-
stance, glandular and nerve-cells; . . . the nerve-cells in
no way differ from those of any sympathetic ganglion'7: a con-
clusion as to the system involved which Cybulski, Biedl, Dreyer,
and others have sustained by experimental investigations.

Again, we have seen that Hirschfeld always found a large
number of fibers to connect the cervical sympathetic ganglia with
the pituitary. Berkley states, referring to the anterior lobe:
"All nerves belonging to it appear to be derived from branches
of the carotid sympathetic plexus." As this plexus is made up
of filaments from the superior cervical ganglion on each side,
the latter observation confirms the former. We thus have un-
deniable evidence of a structural connection between the ante-
rior lobe and the sympathetic system. The directness of the
path that an impulse starting from this lobe could follow to
reach the suprarenal glands — i.e., through the chain of sym-
pathetic ganglia on each side of the vertebral column down to
the splanchnic nerves, and through them to the solar plexus,
the source of the suprarenal plexus — also points to the ante-
rior pituitary body as the suprarenal center. This is clearly
indicated in the annexed colored plate, which shows the course
of the nervous tract. The entire adrenal system is colored
yellow.

The prevailing doctrine as to the source of the functions
of the sympathetic is well illustrated by M. Duval55 when he
says: "It is now recognized that most of the nervous phe-
nomena of the visceral functions have the spinal cord for their
center, and that even for its vasomotor functions the sympa-

M Dogiel: Archiv fttr Anatomie u. Physiologic, p. 90, 1894.
66 M. Duval: Loc. cit.

I

NERYDUS PATH FRDM THE ANTERIOR PITUITARY
BDEY TD THE ADRENALS, [Sajous.J

A, Anterior Pituitary Body. 1, Thyroid Eland. 2, Superior
Cervical Ganglion. 3, Thoracic Ganglia. 4, Greater Splanchnic
Nerve. 5, Lesser Splanchnic Nerve. B, Solar Plexus. 2, Supra-
renal Plexus. B, Right Adrenal. H, Posterior Pituitary Body,
the Governing Center of the Anterior Pituitary Body's Nervous
Supply, and General Centar of the Cerebro-spinal System.

Vascular Supply of the Adrenals : 3, Suprarenal Vein.
ID, Suprarenal Arteries.

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 219

thetic nerve utilizes only borrowed power originating in the
upper portion of the spinal axis; the case is the same in respect
to its influence upon the heart, and also with most visceral
reflexes, the centers of which are in the cord; so that even
the expression 'sympathetic system' to-day means nothing."

If the pituitary' s anterior lobe is the nervous center of the
adrenals, the confusion in our ideas of the functions of this
system are easily explained, since many phenomena ascribed
to it have the adrenals as their source. The latter organs ful-
filling their functions through a secretion, a further cause of
confusion must have insinuated itself in all the experimental
work connected with the sympathetic, so that the latter has,
in reality, never appeared in its true light. Eelieved, however,
of all the elements of conflicting testimony which the adrenals
involve, its true role in the organism cannot but soon be ascer-
tained. Indeed, the system of which the pituitary body seems
to be the center would constitute with the adrenals an abso-
lutely autonomous one. This will appear among the data now
to be submitted, which indicate that a direct connection exists
between these two organs.

As is well known, response is not as prompt when the cut
ends of some sympathetic nerves — the splanchnic, for instance
• — are electrically stimulated, as when the cerebro-spinal nerves
are treated in the same manner. When the splanchnic nerve
is thus stimulated, several seconds elapse before a slow con-
traction of the intestines — i.e., of their muscular coat — begins,
and this continues some time after the stimulation ceases:
evidence that we are dealing with something more than a
nervous impulse and with an indirect effect. This recalls ex-
periments to which we have already referred and which now
explain this anomaly. Dreyer36 observed that the effects of the
suprarenal blood-raising constituent were increased after stim-
ulation of the splanchnic. Biedl57 also noted that when the
suprarenal branches of the splanchnic nerve were cut below
the diaphragm, and the lower fragment was stimulated, injec-
tions of blood that flowed from the adrenal veins into animals
brought on the characteristic phenomena. That the indirect

56 Dreyer: American Journal of Physiology, Jan. 18, 1899.
87 Biedl: Pfliiger's Archiv, Bd. Ivii, H. 9 and 10, 1897.

220 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

effects on the muscular coat of the intestines is the result of
suprarenal overactivity induced by the current seems clear.
But these experimental data simultaneously show, since the
great splanchnic nerve includes branches from the fifth thoracic
ganglion and filaments which have been traced up to the first
ganglion, that the impulses to the adrenals were transmitted
from the upper thoracic region.

That the cervical ganglionic chain should be the normal
continuation upward seems obvious. Yet, the spinal and
cervical nerves, which likewise connect the portion of the
sympathetic above the ganglion from which the first branch
of the greater splanchnic is given off, with the cord, must also
be taken into account; otherwise the impulses might be
thought to originate in the latter. Section of the sympathetic
system in the neck, therefore, will alone demonstrate whether
it is totally independent of the medulla before the pituitary
lobe is reached.

Jaboulay's58 operation for exophthalmic goiter, in which
this procedure is resorted to, is instructive in this connection.
In his first case section of the nerve on one side at once caused
cessation not only of the excessive heart-action and of the
exophthalmos, but also of the trembling. But recurrence took
place within a few weeks. That such should be the case seems
normal if the pituitary plays a prominent part in the disease,
since the only result of the operation was to reduce the ex-
cessive activity of one of the adrenals while the still overactive
pituitary could throw the brunt of its stimulating energy upon
the remaining one. In a case operated by Gayot59 both nerves
were divided below the middle cervical ganglion on the left
side, and, above this ganglion, on the right. The exophthal-
mos completely disappeared on the same day and the cardiac
pulsations were markedly reduced.

Since then many operations have been performed with
more or less success. Anzilotti,60 for instance, in eleven cases,
in which the superior or middle ganglia were removed, always
obtained reduction of the exophthalmos, goiter, and tachycar-

68 Jaboulay: Lyon Medical, March 22, 1896.

«» Gayot: Lyon Medical, July 26, 1896.

*> Anzilotti: La clinica moderna, No. 7, 1898.

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 221

dia, with cure in some instances. Jaboulay,61 in a subsequent
paper, referred to eleven personal operations, and had reached
the conclusion that removal of the superior cervical ganglion
gave the best results. As the upper ganglion is the origin of
the carotid plexus, we have again reached the anterior pitui-
tary.

Some phases of the question, however, still require elucida-
tion. Why, for example, do the patients not succumb when
the bilateral operation is performed? It would seem, if the
anterior pituitary is the center of the suprarenal glands, as
if these organs should cease to functionate. Analysis of a
series of 61 cases, including 45 of epilepsy, 7 of glaucoma, and
8 of exophthalmic goiter, reported by Jonnesco,62 suggests a
solution which coincides with deductions previously referred
to in this work. Idiopathic epilepsy, we have seen, is mainly
due to accumulation in the organism of toxic products of
metabolism, which give rise to sudden exacerbations of supra-
renal activity. To sever the connection between the two over-
active organs must evidently reduce the morbid phenomena
witnessed. Jonnesco, out of the 45 cases above mentioned,
"carefully followed" the subsequent history of 19; of the rest,
6 died, while the others were either too recent or had passed
from observation. Of the 19 cases, he says that "10 are cured:
that is, no spasms have occurred for two years in 5 cases, for
nineteen months in 1 case, for eighteen to fifteen months in
3 cases, and for six months in 1 case." He then adds: "6 of
those upon whom I have operated are decidedly improved; 2
absolutely unchanged. To sum up, 55 per cent, of the opera-
tions resulted in cure, 28 per cent, in improvement, and 15
per cent, were without effect/763 We thus have evidence that
a fair proportion of cases may be benefited by the operation.

There is another side to this question, however. None of
the cases mentioned were operated before August, 1896, from
which month Jonnesco starts his series of 61 cases. The paper
in Medicine having been published in August, 1899, all the

ei Jaboulay: Presse Medicale, Feb. 22, 1898.

62 Jonnesco: Medicine, August, 1899.

63 Given verbatim as translated by Dr. Willard Bartlett for Medicine, August,
1899.

222 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

operations referred to, including those in epileptics, must have
been performed within three years. If the history of these
epileptics is studied from our standpoint, the 6 patients who
died "either in epileptic attacks or as a result of an inter-
current disease" are to be included in the series "carefully
followed," and we have as a result, 25 cases which, within three
years, showed a mortality of 24 per cent. In other words,
nearly one-fourth of the cases operated succumbed within that
time, and, as all -the operations were not performed during the
earlier months of the three years, it stands to reason that some
of the 6 must have died within a shorter time subsequent to
the surgical procedures. This in no way reflects upon Jon-
nesco's records, since he only refers, in keeping with the present
custom in this particular, to the immediate effects of the opera-
tion, while we are studying remote results from a new stand-
point. Why this great mortality?

Can we conclude that, in every series of 25 unoperated
cases of epilepsy, 6 die "in epileptic attacks or as a result of
an intercurrent disease" within such a short period, and say,
with Jonnesco, when referring to the remote effects of bilateral
resection of sympathetic ganglia, "there are none"? He can
legitimately say this, referring, as he does, to the trophic psy-
chical and general well-being of the patient immediately after
the operation; but, as is well known, such a mortality does not
attend idiopathic epilepsy. Although the occurrence of death
during attacks cannot be said to be rare, it is too infrequently
observed to enable us to ascribe the lethal results over and
above the usual ratio to this cause. Evidently the operation
must exert some morbid influence in the after-history of cases
in which it is performed.

This is further emphasized by the statistics of 37 operated
cases collected by G. Marchant,64 including 7 of his own. The
series showed 8 deaths: 5 immediate and 3 remote. Three of
the former are ascribed to "grippal pneumonia" or "pulmonary
congestion," the fourth to "erysipelas," and the fifth occurred
in a chronic drunkard, who died on the third day after show-
ing "extreme agitation." Two of the "remote" cases died

•* G. Marchant: Semaine M6dicale, Nov. 2,

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 223

within six weeks, and the third from chronic nephritis eight-
een months after the operation. In one of Jaboulay's cases
death occurred the sixth day; the necropsy also revealed con-
gestion of the base of the right lung. Peugniez65 also obtained
most satisfactory results, with every evidence of a permanent
and final cure, but a few weeks later the state of the patient
became rapidly worse, and death soon followed.

In the light of the views advanced in the present work,
not only are the beneficial results obtained accounted for, but
the cause of the unusual mortality also becomes clear. Jon-
nesco's deaths during epileptic paroxysms obviously point to a
further increase of toxic waste-products: i.e., to their incom-
plete oxidation through the aggravated suprarenal insufficiency
caused by dissociation of the adrenals from their overactive
center. This very dissociation, on the other hand, in cases
possessed of less vulnerable adrenals, or of a less active pitui-
tary, accounts for the reduction of the abnormal suprarenal
activity to a normal level: a feature which also obtains in the
other disorders in which the operation has been employed. We
have excessive suprarenal activity in exophthalmic goiter, for
example, and if the operation does not reduce this activity
Mow the normal, a result that greatly depends on the con-
dition of the adrenals themselves, a marked and perhaps last-
ing improvement as regards the disease itself may occur.

But the deaths during epileptic seizures, and the unusual
post-operative mortality due to intercurrent disorders, point to
a subsequent reduction of suprarenal efficiency and perhaps to
acquired vulnerability to the morbid effects of toxic agencies,
as a result of the operation. The "intercurrent acute diseases"
referred, to in Jonnesco's paper are not enumerated: a fact
suggesting variety and showing that no special disease (such as
"ether-pneumonia" occasionally observed when this anaesthetic
is employed) follows section or resection of the sympathetic
nerves. In the fatal cases referred to by Marchant, Jaboulay,
and Peugniez, grippal pneumonia, erysipelas, and chronic ne-
phritis appear as lethal maladies. These, added to epilepsy,
not only indicate the wide range of morbid conditions that may

"Peugniez: Gazette Medicale de Picardie, Nov.,

224 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

ensue, but they distinctly point to the fact that the entire list
of conditions collectively considered under the term "intoxica-
tions" of intrinsic or extrinsic origin is brought into action.
Indeed, there seems to be no line drawn, no particular morbid
field common to these operated cases except the one vast source
of suprarenal insufficiency represented by poisons in general,
bacteria and their toxins, toxic products of metabolism, etc.

The operation brings the cardiac action down to a remark-
able degree — 10 pulsations in a case reported by Combemale
and Gaudier.66 Berry,67 in a review of the literature of the
subject, refers to a case in which the patient died a few hours
after operation after having shown an "extremely rapid pulse."
That we are dealing with weakened and finally overpowered
suprarenal glands in post-operative cases is not only suggested
by the class of disorders witnessed, but it is also shown post-
mortem by the pulmonary congestive phenomena referred to:
a normal result of the vasodilation which marked reduction or
arrest of the suprarenal secretion entails.

The few other general affections in which sympathectomy
has been resorted to are all, if the views advanced in this work
are exact, expressions of excessive suprarenal activity. Exoph-
thalmic goiter, therefore, can serve as a type to illustrate the
course of events when the suprarenal glands are not able,
through inherent or acquired debility, to continue their func-
tions when separated from their center, the anterior pituitary
body. Peugniez's case of this disease, in which sympathectomy
was performed on both sides, being one of this kind, it can
serve as example. The patient, a girl 20 years of age, presented
the typical signs: goiter, exophthalmos, tachycardia, and ex-
ceedingly profuse sweating. The operation on the left side
was performed on October 28th; that on the right on Novem-
ber 20th. Less than two weeks after the latter operation the
goiter had completely disappeared; exophthalmos had become
greatly reduced; the pulse likewise; and the sweating had
ceased. The patient left the hospital on December 12th in a

68 Combemale and Gaudier: Gazette Hebdom. de M6decine et de Chirurgie,
April 24, 1898.

67 Berry: Trans. Edinburgh Medico-Chirurgical Society, Jan. 17, 1900.

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 225

most satisfactory condition, with every probability of a prompt
and final recovery. On January 4th — i.e., three weeks late?' —
Professor Peugniez, having visited her, was shocked at her
appearance. A few days had sufficed to bring her to the last
degree of emaciation; the lids were wide apart, so great was
the exophthalmos, and pus exuded from the conjunctival re-
cesses. "Galloping cachexia" supervened, soon ending in death.

If all these facts are collectively considered, they not only
show that a direct functional communication exists between
the anterior pituitary body and the adrenals through the cer-
vico-thoracic ganglionic chain of the sympathetic system, its
greater splanchnic nerve, and the semilunar ganglia, but that
the system thus formed is an autonomous one, of which the
suprarenal secretion in more or less great quantities is the
primary functional result.

The existence of such a system and its true importance
are further emphasized when the direct connection between
the adrenals and cardiac action is further analyzed. On the
other hand, the cause of the baneful effects of resection of the
sympathetic ganglia, and particularly its influence upon the
rapidity of the heart-beats, become apparent when we realize
that the heart primarily owes its activity to the secretion of
the adrenals. That cases survive the operation at all is due to
direct spino-adrenal nerve-paths, survivals of the earlier days
of life, as will be shown.

We have seen that when Schafer and Oliver injected supra-
renal extract intravenously a great increase in cardiac and
respiratory activity was noticed. Was this due to a local effect
upon the heart itself or to an action upon the cardiac nerve-
centers? The marked effect of suprarenal extract on muscular
tissue indicates that the heart itself must have been stimulated.
As previously shown, detached pieces of vascular walls com-
pletely disconnected from their nerve-centers undergo contrac-
tion when suprarenal extract is applied to them. Even dried
tissues, as observed by Oliver,68 respond to its action. After
using other extracts with little or no effect the latter investiga-
tor says: "The suprarenal extract invariably produced the

Oliver: Journal of Physiology, Nos. 4 and 5, March 12, 1897.

226 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

most decisive contractions, and one, moreover, which persisted
30 to 60 minutes/7

As to a direct action upon the heart during life, we will
recall the experiments of Biedl, who found that when, in test
animals, removal of the entire cord had brought the blood-
pressure down to almost nothing, the heart would respond with
vigor to injections of suprarenal extract, the pressure rising to
160 millimeters mercury. Oliver conducted similar experi-
ments, and, referring to vascular pressure, says: "The constric-
tion was equally pronounced whether the spinal cord remained
intact or was destroyed." We have conclusive testimony in
these facts to the effect that, if the cardiac tissues themselves
were to receive, during life, an injected dose of suprarenal
extract, they would instantly respond to its effects.

The topographical anatomy of the structures between the
adrenals and the lungs, and a review of facts previously re-
corded in this work, show how this is accomplished. The supra-
renal secretion, we have seen, reaches the inferior vena cava —
directly on the right side, and through the renal or phrenic
vein on the left. It is, therefore, poured into blood collected
from the kidneys, the pelvic organs, the lower extremities, etc.,
and deprived of the oxygen appropriated by these structures.
While venous blood, even in the right ventricle, still contains
oxygen, this gas is held by the haemoglobin of the corpuscles;
so that the plasma itself contains none. But we have previously
seen that various investigators — Cybulski, Biedl, Dreyer, among
others — have found secretory products in blood received from
the adrenals destined for the inferior vena cava. These two
facts — i.e., the absence of oxygen and the presence of supra-
renal secretion in the latter vessel — can lead to but one deduc-
tion: i.e., that the suprarenal secretion reaches the right ventricle
in its primary state, or at least very slightly modified in com-
position.69 The important role it must fulfill here becomes evi-

69 We say "slightly modified composition" because we have reason to believe
that the venous blood of the Inferior vena cava above the level of the adrenals
and up to the pulmonary air-cells is the seat of a special protective process, in
which the marked reducing power of the suprarenal secretion acts as a dis-
sociating agency. There is obviously no literature on this subject, and as this
work is to contain nothing that cannot be poised on experimental data, a mere
mention must suffice. — S.

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 227

dent when we realize how rapidly the cardiac functions are
impaired as soon as a violent toxic has brought on suprarenal
insufficiency: the source, we now know, of the phenomena
that portend a fatal issue.

Schmiedeberg, we have seen, found that the cardiac arrest
brought on by digitalis was "not of the nature of a paralysis,
but of a spasm"; that the brunt of the action of this drug is
exercised upon the right heart has been observed by several
able clinicians, Germain See among them. The meaning of
this fact is obvious: digitalis is probably the most perfect car-
diac stimulant of our pharmacopoeia, but only because better
than any drug it enhances the activity of the anterior pituitary
body, which, in turn, so stimulates the suprarenal glands as to
bring them to their highest functional possibilities. The
unusual amount of its secretion, dissolved in the plasma,
reaches the cardiac cavity, and there produces what experi-
mental physiology has shown it to always cause in muscular
tissues: i.e., contraction.

A review of known facts concerning the effects of digitalis
on the heart shows the active part played by the adrenals in
the phenomena witnessed. A large dose, one capable of bring-
ing on marked suprarenal overactivity, occasions an enormous
rise of vascular pressure. Wood says that the arterioles of
a frog's web or of the mesentery of a rabbit undergo such
marked contraction that their lumen is almost obliterated. The
cardiac systole is "abnormally strong," the ventricles becoming
white when the blood is being forced out. Germain See, von
Openchowski, and others have emphasized the fact that this
action is greatest on the right side of the heart. The pulse
is at first slowed, strengthened, and hardened; then becomes
dicrotic: a suggestive fact, — a primary warning, perhaps. At
this time, indeed, the stage of suprarenal insufficiency may
suddenly appear, — i.e., the supposed "cumulative" stage, — and
death occur — the result of exhaustion of the suprarenal center,
with arrest of the heart in diastole. If this does not occur at
once, "ventricles and auricles no longer beat together"; one
portion of the heart is dilated while the other contracts.
Wood70 says, in this connection: "In the 1'ast period of the poi-

70 Wood: Lot-, cit.

228 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

soiling the auriculo-ventricular arhythmia grows more pro-
nounced, and finally the cardiac contractions become entirely
irregular, until at last there is that condition which is some-
times spoken of as delirium cordis." But why this arhythmia
after the stage of insufficiency has begun? That the previously
overworked right ventricle had been the first to collapse — in
diastole — is evident.

It seems to us that all these facts warrant the deduction
that the suprarenal secretion, mixed with the Uood-plasma, reaches
the right ventricle in its primary state, and serves mainly to in-
crease its propulsive power in order to insure adequate distribution
of the Nood in the lungs."**

If the anterior pituitary body is the functional center
of the adrenals, exophthalmic goiter, due to overstimulation
of the former organ by an excess of thyroid secretion, should
show symptoms corresponding to those of digitalis, since we
have said that the adrenals were the mechanical source of these
symptoms. Again, as we have also stated that some of the
symptoms ascribed to the sympathetic system are of suprarenal
origin, both digitalis poisoning and exophthalmic goiter should
include in their symptomatology some signs usually attributed
to the sympathetic system. Any other drug might be selected
for the purpose, but digitalis alone approaches thyroid extract
in its power to stimulate the organs in question.

Exophthalmic goiter being a chronic disease, while the
symptoms of digitalis poisoning given are those of an acute
condition (the erethic stage being only referred to, since the
cachectic stage does not typify activity of the organs), the
comparison is evidently in no way calculated to favor our argu-
ment. But even then, and leaving out only symptoms essen-
tially associated with chronicity, a common anatomical source
is easily traceable for many phenomena, notwithstanding the
dissimilar pathogenic agencies to which the two morbid states
owe their existence. In both, for example, excessive cerebral
hypera3mia and oxidation are manifested by violent headache,
excitability, insomnia, hallucinations, etc. The muscular

71 Weakness of the right ventricle as a result oT suprarenal insufficiency is an
Important factor in the pathogenesis of pulmonary phthisis; its various phases
will be discussed when this disease is studied. — S.

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER.

229

twitchings of exophthalmic goiter are represented in digitalis
poisoning by painful contractions. In both appear the essen-
tially "sympathetic" or "vasomotor" phenomena, superficial
heat and flushings, dyspnoea, and suffocation. Even exoph-
thalmos is duplicated in digitalis poisoning. While prominence
of the eyeballs is witnessed in most grave cases, Wood72 says:
"More or less exophthalmos is said to have persisted for weeks
in some cases." Strychnine, atropine, alcohol, opium, quinine,
and a few other agents more or less actively reproduce these
and other signs of exophthalmic goiter when administered in
suitable doses. But none of these give rise to cardiac symp-
toms similar to those of digitalis, because none possess its
power to safely stimulate the anterior pituitary lobe to the
same extent. They induce exhaustion of its cellular elements
before its maximum resources have been utilized: i.e., they
paralyze it in the midst of its functions — the underlying cause
of suprarenal insufficiency.

If we now group all these facts, it will become apparent
that seemingly irrelevant data introduced merit the title of
confirmatory evidence. To demonstrate that the anterior
pituitary body was the functional center of the adrenals a
direct relationship had to be shown to exist between them. We
ascertained that this direct connection was established through
sympathetic ganglia and splanchnic nerves. It then became
necessary to isolate the bulbo-spinal center as direct causal
factor in the production of certain phenomena belonging to the
pituitero-suprarenal domain. This was done by demonstrating
that structures previously shown to be governed by the ante-
rior pituitary — i.e., the adrenals — could, through their secre-
tion, fully sustain cardio-vascular action when all spinal con-
nections had been severed. The aim was not, however, to show
that the bulbar centers were deprived of all influence over the
adrenals, — since we do not, as yet, know whether this is the
case or not, — but that some of the major functions ascribed
indirectly or directly to the bulb — cardiac action, respiration,
muscular activity, etc. — were primarily related to the newer
system referred to. This was also suggested by the fact that,

"Wood: Loc. cit., p. 310.

230 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

while the functions of the adrenals gradually ceased after their
isolation from the bulbo-spinal centers, cardio-vascular action
could be very actively maintained by injections of suprarenal
extract: a result which, as shown by the experiments of le
Gallois, Goltz, Strieker, and Ustimowitch, could not be reached
by other means.

The all-important direct action of the suprarenal secretion
on the heart was then introduced to further strengthen the
relationship between the anterior pituitary and the adrenals,
previously found to exist through the intermediary of sympa-
thetic structures. The function of the anterior pituitary body
then affirmed itself, since the active symptoms of digitalis were
found to include not only phenomena directly assignable to
inordinate suprarenal secretion, but others which experimental
physiology — including the experiments quoted herein — had
ascribed to bulbar influence. To finally confirm all these facts,
a chronic disease, previously shown to be due to excessive stim-
ulation of the anterior pituitary body, was compared symptom-
atically with acute digitalis poisoning, to ascertain whether two
conditions, so remote pathogenically according to our present
knowledge, could also show signs of kinship. We have seen
that even this severe test did not fail to point to a common
origin, the anterior pituitary body, for many of the cardinal
phenomena witnessed in both.

If to all this we now add the results of de Cyon's experi-
ments in horses, dogs, rabbits, and guinea-pigs, in which he
noted that the least pressure upon or electrical stimulation of
the pituitary caused sudden variations of vascular pressure and
of cardiac action precisely coinciding with the effects now so
often shown in this work to be those of suprarenal overactivity,
and also the fact that acromegaly, essentially a disease of the
anterior pituitary body, likewise presents this kinship with the
adrenals, including the "erethic" and "cachectic" stages, and
various vasomotor phenomena, the following deductions seem
warranted: —

1. The thyroid gland supplies the Hood with a secretion which
has for its object to sustain the functional activity of the anterior
pituitary body.

2. The anterior pituitary body is directly connected with the

THE ANTERIOR PITUITARY AS THE ADRENAL CENTER. 231

adrenals through the cervico-thoracic ganglia., the splanchnic nerves,
and the semilunar ganglia of the sympathetic nervous system.

3. The thyroid gland, the anterior pituitary body, and the
adrenals are functionally interdependent, and constitute a system
through which cardiac action, respiration, and general cellular
oxidation are maintained.

4. The thyroid gland sustains the normal functional activity
of the anterior pituitary body, while the latter in turn maintains
the normal activity of the adrenals.

5. The functional activity of the anterior pituitary body is
increased when the blood contains an excess of thyroid secretion or
sufficiently-active toxics: bacterial toxins, poisons, physiological
toxalbumins, etc., to compromise the general cellular integrity of
the organism.

6. The functional activity of the adrenals is increased pro-
portionally with that of the anterior pituitary body when the tatter's
activity is increased from any cause.

7. The functional activity of the anterior and posterior pitui-
tary bodies is PASSIVELY decreased when the blood contains an
insufficient proportion of thyroid secretion or is inadequately oxy-
genated, or when from any cause its intrinsic metabolism is reduced
or impaired through deficiency of any of its molecular constituents.

8. The functional activity of the anterior pituitary body is
ACTIVELY decreased when the blood contains a sufficiently active
toxic of any kind, bacterial toxin, poison, etc., to induce excessive
metabolism of its intrinsic cellular elements and thus cause ex-
haustion or molecular metamorphosis of the latter.

9. The functional activity of the adrenals is decreased pro-
portionally with that of the anterior pituitary body whether the
reduced activity of the latter be due to active or passive pathogenic
factors.

If all the facts so far recited in the present work prevail,
another deduction suggests itself regarding the part played
in the body hy the system thus formed by the anterior pituitary
and the adrenals through their connecting nerves (and which
we will now term, for the sake of brevity, the "adrenal sys-
tem"): i.e., that its primary function is to insure oxidation.

Again, the fact that its functional activity is increased,
with the result that oxidation processes are correspondingly

232 THE PITUITARY, THYROID AND ADRENALS AS A SYSTEM.

enhanced when poisons of any kind threaten the integrity of
the organism, also indicates that its secondary function is to
protect the organism against disease.

In other words, the "adrenal system" simultaneously sus-
tains life and aims to preserve it.

CHAPTER VI.

THE ADRENAL SYSTEM AND VASOMOTOR
FUNCTIONS.

THE OXIDIZING SUBSTANCE AND THE MOTOR NERVES IN
THEIR RELATION TO MUSCULAR CONTRACTION.

DIVISION of the spinal cord below the medulla oblongata
is followed by dilation of all the vessels of the organism, while
electrical stimulation of the lower cut segment of the cord
causes constriction of these blood-vessels and a general rise
of blood-pressure. Evidently constriction and dilation of the
vessels of the organism are regulated by centers located in the
medulla and pons, in accordance with the present teachings.
We are, therefore, referred to these centers for the impulse-
waves (transmitted through the vasomotor nerves) which gov-
ern the structures that co-operate with the adrenal system in
the performance of its physiological functions. What is the
nature of the relationship between the adrenal system and the
vasomotor system?

A cursory analysis of this question soon reveals an impor-
tant feature, namely: that the voluntary, or skeletal, muscular
system cannot be classed with the other organs in respect to
vasomotor functions. The sympathetic system is the essential,
perhaps the only, source of vasoconstrictor nerves, and yet this
system is not known to extend to the extremities. Again,
vasoconstrictors and vasodilators are said to accompany the
larger nerve-bundles, — the sciatic, for instance; but a survey
of the field distinctly shows that the evidence as to the ex-
istence of separate vasoconstrictors is purely inferential. Since
the sympathetic nerve does not appear to send subdivisions to
this class of muscles, the association of constrictors of another
source introduces an element of confusion, not only as regards
the peripheral structures themselves, but particularly in re-
spect to the central origin of the two systems classed under
the one single term of "vasomotors." As it is impossible to

(233)

234 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

proceed without clearing this question, we will first ascertain
whether the prevailing views as to the physiology of the cir-
culation in the muscular system may not, in the light of our
own conceptions, be subject to change.

THE OXIDIZING SUBSTANCE AND MYOSINOGEN. — In the
production of muscular contraction a nerve-impulse is of
course transmitted to the muscular elements; but how are this
impulse and the resulting contraction related to the functions
of the blood itself? This question is suggested by the role
assigned in the foregoing pages to the oxidizing substance.

Stewart1 refers to the thermal phenomena of muscular
contraction as follows: "When a muscle contracts, its tem-
perature rises; the production of heat in it is increased. This
is most distinct when the muscle is tetanized, but has also been
proved for single contractions. The change of temperature
can be detected by a delicate mercury- or air- thermometer;
and., indeed, a thermometer thrust among the thigh-muscles
of a dog may rise as much as 1° to 2° C. when the muscles
are thrown into tetanus/' That tetanus is a phenomenon of
hypcroxidation through suprarenal overactivity we have re-
peatedly seen when studying the action of drugs. This affords
a first clue: If the plasma contains an oxidizing substance, the
chemical changes in muscular tissue during contraction — i.e.,
absorption of oxygen, increased production of carbon dioxide,
change of reaction from neutral or alkaline to acid, and finally
the formation of sarcolactic acid — clearly suggest that the
contractile process and the mechanical energy utilized may
be due to an increased supply of oxygen through the agency
of the oxidizing substance. Indeed, Kronecker has shown
that "the injection of arterial blood or even of an oxidizing
agent like potassium permanganate into the vessels of an ex-
hausted muscle also causes restoration." If an agency so
remote in composition from the normal organic fluids can
i <More merely through its oxidizing power an exhausted mus-
cle, so eminently physiological a fluid as the blood-plasma,
with oxy-rn in loose combination, must surely p<>

active proi.-crii.-s. Indeed, the link seems to

Stewart: ••.M;un:;il of Physiolojry," p. 508.

THE OXIDIZING SUBSTANCE AND MYOSINOGEN. 'J.'J")

be a strong one if the full meaning of the following sentence
from Foster's "Physiology" (sixth edition) is gathered: "We
might compare a living muscle to a number of fine, trans-
parent, membranous tubes containing blood-plasma." If we
also recall the fact that capillaries do not possess contractile
fibers and that arterioles represent the ultimate subdivision
to which vasomotor nerves are distributed, it becomes clear
that we have all the mechanical elements necessary to account
for some unexplained phenomena that attend muscular con-
traction. An impulse capable of causing a change of caliber of
a peripheral arteriole would thus suddenly admit more arterial
blood — i.e., more oxygen-laden plasma — into the "fine, trans-
parent, membranous tubes," and contraction, an inherent
property of muscular tissue, would follow.

The prevailing views as to the nature of the process
through which the mechanical energy utilized during muscular
activity cause contraction or retraction may be illustrated by
selections from Professor Foster's text. Referring to the
chemical analogy between the axis-cylinder and muscle-tissue,
he says: "We have no satisfactory evidence that in a nerve
even repeated nervous impulses can give rise to an acid re-
action" . . . "nor have we satisfactory evidence that the
progress of a nervous impulse is accompanied by any setting
free of energy in the form of heat." In the summary, referring
to the terminal phenomena, he remarks: "This muscle-impulse,
of which we know hardly more than that it is marked by a
current of action, travels from each end-plate in both direc-
tions to the end of the fiber, where it appears to be lost; at
all events, we do not know what becomes of it. As this im-
pulse-wave, whose development takes place entirely within the
latent period, leaves the end-plate, it is followed by an explosive
decomposition of material, leading to a discharge of carbonic
acid, to the appearance of some substance or substances with
an acid reaction, and probably of other unknown things, with a
considerable development of heat. This explosive decomposi-
tion gives rise to the visible contraction-wave, which travels
behind the invisible muscle-impulse at about the same rate,
but with a vastly increased wave-length. The fiber, as the wave
passes over it, swells and shortens, and thus brings its two

236 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

ends nearer together. When repeated shocks are given, wave
follows wave of nervous impulse, muscle-impulse, and visible
contraction; but the last do not keep distinct; they are fused
into the continued shortening which we call tetanus/'

The last word, "tetanus," stands as the highest expression
of a rapid succession of nervous impulses; but, viewed from our
standpoint, this succession of impulses can as readily produce
successive variations of vascular caliber, and give rise to pre-
cisely the phenomena witnessed, by admitting the oxidizing sub-
stance of the blood-plasma into the fine, "membranous tubes."
The shock experienced when the current is turned "on" or "off"
further suggests that the latter process is the true one. "The
mere passage of a constant current of uniform intensity
through a nerve does not, under any circumstances," says
Professor Foster, "act as a stimulus generating a nervous im-
pulse; such an impulse is only set up when the current either
falls into or is shut off from the nerve. It is the entrance
or the exit of the current, and not the continuance of the
current, which is the stimulus." . . . "It is the sudden
change from one condition to another, and not the condition
itself, which causes the nervous impulse."2

The confusion that attends prevailing views as to the
manner in which muscular tissue is physiologically caused to
contract is readily accounted for when, in the light of the
newer conceptions outlined in the last chapter, we analytically
dissociate the various causal elements of muscular activity.
Indeed, we have seen that various phenomena ascribed to the
sympathetic system belonged to the domain of the suprarenal
glands, i.e., to the newer system described; we are again
brought to realize that in all organs certain functions must
likewise, and for the same reasons, be disconnected from
others as regards their immediate purpose in the tissues.
Thus, the fact that the muscle-impulse, which "travels from
each end-plate in both directions to the end of the fiber, where
it appears to be lost," is at present considered as an inherent,
though causal, element of the "explosive decomposition of
material, etc.," through its activity as a physiological stimulus.

8 All italics are our own.

THE OXIDIZING SUBSTANCE AND MYOSINOGEN.

237

But if we can separate these elements of the process into two
distinct parts, viz.: (1) a nervous impulse to the muscular
elements themselves, and (2)- a simultaneous change in the
caliber of the local arterioles, the fact that as the impulse leaves
the end-plate "it is followed by an explosive decomposition of
material, leading a discharge of carbonic acid," will stand as
the only result to be expected. Such a division becomes neces-
sary in the light of our conception of the process.

While the nerve-impulses only have for their purpose to
excite and govern the function, the blood — i.e., the blood-
plasma mainly — through its oxidizing substance becomes the
factor through which the chemical process to which contractile
work is due is suddenly awakened. A feature of this concep-
tion upon which particular stress must be laid — since it applies
to all organs — is that it dissociates from the oxidation process
per se a stimulus which does not belong to it and which, there-
fore, introduces elements of confusion. "We cannot tell," says
Stewart, "in what the 'natural' or 'physiological' stimulus to
muscular contraction in the intact body really consists, nor
how it differs from artificial stimuli." Eelieved of this au-
tonomous agency, the organic physico-chemical processes enter
within the limits of exact investigation.

Oxygen in other fields of thermochemistry is known to
constitute the reactionary agent through which "explosive de-
composition" is awakened and sustained. That it fulfills the
same role in this connection, some complex organic compound
in the muscular fibers constituting the primary source of en-
ergy or fuel, is probable. Under these circumstances the
passive "irritability" of a living muscle would be maintained
by a continuous reaction in which the reagents would be these
compounds — i.e., hydrocarbons — and the oxygen held in loose
combination in the blood, particularly the blood-plasma, which
penetrates the contractile elements themselves. This irrita-
bility would then become abruptly converted into contractility
when the blood-supply — i.e., the plasma in the contractile fibers
— would be increased through the arrival of more oxygen.

Considerable familiar evidence besides that already ad-
duced is available in support of this conception of the general
physiology of muscle-tissue. Although continuous muscular

238 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

contractility is generally thought to be associated with nerve-
impulse, destruction of all nervous connection with a muscle
does not cause it to lose its excitability. Its inherent property
in this particular is shown by the fact that, although the apex
of the heart contains no nerve or nerve-cells, it nevertheless
responds to stimulation. Even when detached from the body,
muscles preserve their contractility for a time under suitable
conditions. This would appear to eliminate the need of fur-
ther energy to account for the phenomena witnessed; but the
contrary is the case, since it shows why muscular tissue, owing
to its inherent irritability, responds to various stimuli: vital,
electrical, physico-chemical, and mechanical. Electricity, we
know, acts as a powerful stimulus, but heat alone acts in pre-
cisely the same manner if the temperature is adequate and is
raised rapidly; marked contraction may thus be caused when
30° C. is reached, and violent activity induced before the mus-
cle is heated to 45 degrees. Chemical stimuli will produce the
same effect, provided the reaction induced occurs with suffi-
cient rapidity.

That the nervous impulse is not the source of mechanical
energy utilized under these circumstances, is shown by the fact
that a chemical stimulus applied to a nerve, ammonia, for in-
stance, will not stimulate it though it will excite the muscle;
various acids, hydrochloric, acetic, etc., will give rise to the
same phenomena. "Certain poisons (curare) cause the motor
nerves to become completely incapable of action," says M.
Duval, "and, therefore, incapable of transmitting irritation to
a muscle; nevertheless, under these circumstances, the excited
muscle can directly pass from the state of rest to that of
activity (Claude Bernard, Kolliker); the ultimate and fine
nervous ramifications that they contain take no part in this
irritability, since the poisons referred to kill mainly the intra-
muscular endings of the nerves (Vulpian). A motor nerve
separated from the cerebro-spinal axis loses, after four days,
all excitability; the muscle, on the contrary, previously in-
nervated by this nerve remains directly excitable more than
three months (Longet)."

That muscle is directly and independently excitable by a
large number of stimuli is evident; that oxygen should,

THE OXIDIZING SUBSTANCE AND MYOSINOGEN. 239

through exacerbations of a continuous physico-chemical re-
action of which its tissues are the seat while in the passive
state, be able to suddenly awaken the active state is as clear.
When the muscle is in the passive state, the transformation
of energy incident upon the continuous reaction manifests it-
self as heat; while, when it is active, it manifests itself as
greater heat plus mechanical work. Armand Gautier has as-
certained that a working muscle took up nine times more blood
than a resting one, and that the ratio of carbonic acid given
off by it or transmitted to the venous blood was nearly one
hundred times greater. This raises the question as to whether
the conversion of chemical energy into the mechanical work
upon which contraction depends must first be transformed into
heat energy. A study of this question by Professor Gautier,
based on Carnot's investigations, showed that, just as in a
voltaic cell in which the chemical potential at once appears
under the form of electricity without passing through the
intermediate state of heat, so can intramuscular chemical
energy become directly transformed into work. Indeed, he
found that 65° C. (149° F.) would represent the final tempera-
ture of an active muscle, were it otherwise, and reached the
conclusion that "a muscle contracts and works owing to a
direct transformation of the chemical potential into elastic
tension, without ever requiring the intervention of the heat
which theoretically accounts for internal combustions."
These facts seem to us to warrant the deductions: —

1. That the mechanical energy utilized by living voluntary
muscles in the passive state is converted chemical energy, the result
of a reaction in the muscular contractile elements during which
various compounds, mainly hydrocarbons, are oxidized.

2. That active muscular work is the result of an exacerbation
of the activity of this mechanical process, attended with a direct
transformation of the passive potential: i.e., irritability, into the
active potential: i.e., contractility.

The suggestion that the reaction occurs in the living con-
tractile elements themselves cannot, for obvious reasons, be
demonstrated experimentally. But if we associate Foster's
comparison of a living muscle to "a number of fine, trans-
parent, membranous tubes containing blood-plasma" with our

240 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

conception of the nature of blood-plasma as an excipient for
an oxidizing agent of adreno-pulmonary origin, on the one
side, and, on the other, recall the view of Englemann, that a
fluid substance passes from the bright bands of the fiber —
i.e., the interstitial disks — into the dark bands — i.e., the con-
tractile disks, — the intimate process would be as follows: The
hydrocarbon compounds would occupy the contractile disks, while
the oxidizing substance would fill the interstitial disks, and on the
proportion of the latter entering the contractile disks would depend
the activity of the oxidation process.

Further evidence that the general process outlined pre-
vails may be obtained by tracing the identity of myosin: the
substance found in the muscles after death. "While dead
muscle contains myosin, albumin and other proteids, extractives,
and certain insoluble matters, together with gelatinous and
other substances not referable to the muscle-substance itself,"
says Professor Foster, "living muscle contains no myosin* but
some substance or substances which bear somewhat the same
relation to myosin that the antecedents of fibrin do to fibrin,
and which give rise to myosin upon the death of the muscle.
There are, indeed, reasons for thinking that the myosin arises
from the conversion of a previously existing body which may
be called myosinogen, and that the conversion takes place, or
may take place, by the action of a special ferment, the con-
version of myosinogen into myosin being very analogous to
the conversion of fibrinogen into fibrin. We may, in fact,
speak of rigor mortis as characterized by a coagulation of the
muscle-plasma comparable to the coagulation of blood-plasma,
but differing from it inasmuch as the product is not fibrin,
but myosin. The rigidity, the loss of suppleness, and the
diminished translucency appear to be, at all events, largely,
though probably not wholly, due to the change from the fluid
plasma to the solid myosin. We might compare a living muscle
to a number of fine transparent membranous tubes containing
blood-plasma. When this blood-plasma entered into the 'jelly'
stage of coagulation, the system of tubes would present many
of the phenomena of rigor mortis. They would lose much of

* All italics are our own.

THE OXIDIZING SUBSTANCE AND MYOSINOGEN.

241

their suppleness and translucency, and acquire a certain amount
of rigidity. There is, however, one very marked and impor-
tant difference between the rigor mortis of muscle and the
coagulation of blood. Blood during its coagulation undergoes
a slight change only in its reaction; but muscle during the
onset of rigor mortis becomes distinctly acid."

If myosinogen were the precursor of the myosin of rigor
mortis, what would its composition probably be and how would
it become metamorphosed into myosin?

We have submitted the data sustaining our view as to the
existence of the oxidizing principle, and have referred to it
as a body derived from the suprarenal glands, which, in pass-
ing through the lungs, entered into loose combination with
oxygen. The labors of Schmiedeberg, Salkowsky, Jaquet,
Abelous and Biarnes were quoted to show that such a prin-
ciple had also been found by chemical methods, though its
origin remained unknown to them.

If combustion of products of nuclein metabolism in the
blood-plasma, through the presence therein of oxidizing sub-
stance, can produce uric acid, it seems reasonable to conclude
that, if this same substance is also present in myosinogen, we
should find evidence of a similar action. Not only is this the
case, but the same products of metabolism are found in mus-
cle-serum: the liquid portion of muscle-plasma obtained by
rubbing up and expressing fresh muscle. Though obtained
only in very small quantities, the purin bases, creatin, xanthin,
hypoxanthin, and creatinin, are always found in addition to
their end-product, uric acid. Phosphoric acid — a combustion
product accounted for by the presence of the phosphate of
potassium — is another link between muscular plasma and that
of the general blood-stream. Of course, these various bodies
should not be considered as elements of muscular activity.
Their history indicates that, along with other albuminoids
found, they are mere passive hosts of the muscular plasma as
waste-products of muscular tissue-metabolism, destined to be
converted here, as elsewhere in the organism, into harmless
bodies, acids or others.

The active constituents of myosinogen, as far as muscular
irritability and contractility are concerned, must be of another

242 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

kind, and are perhaps specific to muscle. Especially must this
be the case since it possesses, we have seen, a special physical
attribute: i.e., the direct conversion of chemical energy into
mechanical work, without involving the corresponding evolution
of heat which oxidation elsewhere in the organism engenders.
The word "corresponding" is used because we must not lose
sight of the fact that considerable heat is produced during
muscular contraction, and, indeed, that it is subject to marked
variations under the influence of fatigue, tension, the state of
the blood, the work done, etc. Yet the heat evolved is not
commensurate with the muscular work done, and if we deduct
from the heat potential actually produced that which intra-
muscular combustion of waste-products incident upon increased
exertion entails — an unproductive factor as regards work — the
need of the direct conversion of chemical energy into mechan-
ical work — i.e., contraction of the muscle — will appear.

One of the constituents of myosinogen upon which its
physical function depends must be glycogen, since it is the
constituent of muscle which diminishes during activity, while
it accumulates during rest. This body was shown by Claude
Bernard in 1848 to be formed in the liver-cells from food,
especially from sugars and starches, derived in turn from
glucose: one of the products of digestion. Herbivorous ani-
mals, such as oxen, horses, etc., — i.e., those that only feed
upon substances that contain these hydrocarbons, — are ob-
viously endowed with great muscular power. It is evident,
therefore, that the source of the energy to be ultimately trans-
formed into mechanical work must be stored in these vegetable
substances to a very great extent. Glycogen may not, how-
ever, migrate as such toward the muscular elements — since it
would undergo oxidation in the blood; it is thought to be
retransformed into glucose by a ferment and distributed as
such to the muscular tissue, where it is again dehydrated
(C6H1206 — H20 = C6H1005) into glycogen, ready for func-
tional use. This question will be studied later on.

Outside the organism lactic acid is known to be a product
of fermentation of glucose, dextrin, and glycogen; hence the
conclusion that sarcolactic acid is formed during muscular con-
traction. According to prevailing views, however, the evidence

THE OXIDIZING SUBSTANCE AND MYOSINOGEN. 243

tends to show that such is not the case,, because sarcolactic
acid is produced during progressive rigor mortis, precisely as
it is during muscular contraction. If, however, the process is
interpreted from our standpoint, including the presence of an
oxidizing principle in the muscle-plasma, — i.e., the myosinogen,
— this negatory evidence is eliminated. According to classic
doctrines, the nervous impulse is a direct initial factor of mus-
cular contraction, whereas from our standpoint it is an indirect
initial factor, oxygen assuming the place now accorded the
nerves. The continuation of oxidation during the progress of
rigor mortis, therefore, becomes a normal outcome of the post-
mortem vascular dilation, the remaining oxygen entering into
combination with the hydrocarbons present, as long as the
myosinogen is sufficiently liquid to permit of it: i.e., before
it has assumed the state of myosin.

Considered from this point of view the many mooted
features of the process appear — it seems to us — under their
proper light. Glycogen is absolutely known, first, to diminish
during muscular contraction; second, to accumulate during
rest; third, to rapidly decrease when an unfed animal is made
to work. Notwithstanding these established facts, it is deemed
inadequate, as judged from the analysis of dead muscle, to
quantitatively satisfy the needs of the process. With oxygen
as the initial factor it becomes clear that dead muscle only
shows the residue of the combustion that has gone on during
the progress of rigor mortis, and that the glycogen ratio should
therefore include that of the sarcolactic acid, — to say nothing
of other products of combustion that may be present, — which
would bring the proportion of glycogen to a much higher
figure than analyses under present conditions furnish.

Can we say, however, that glycogen alone satisfies the
needs of the process? The fact that the most powerful of our
domestic animals — oxen, horses, camels, elephants, etc. — are
all herbivorous would suggest that such is the case. Again, it
is the one constituent that is positively known to diminish
during work and to accumulate during rest. All other sources,
even fats, which are probably entitled to a place among the
sources of muscular energy, have only been theoretically asso-
ciated with muscular work, while the fact that the amount

16

244 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

of urea is not materially increased during muscular exertion
tends to eliminate the proteids. Muscles from which glycogen
is absent are stated to respond to stimulus; but the inherent
irritability of muscle-tissue readily accounts for this. On the
whole, experimental evidence, if considered in the light of the
views herein advanced, tends to show that glycogen is the main
constituent of myosinogen with which the oxygen of the Hood-
plasma combines.

The absence of free oxygen in muscle has been adduced
as evidence to show that the carbonic acid evolved could not
be formed by direct combustion. It becomes clear that if the
oxygen is used up to the last — to such a degree that a muscle
will absorb oxygen from the surrounding atmosphere — none
will be obtained from its tissues, even with the air-pump.
The transition of a muscle from its normal neutral reaction to
an intensely acid one when the rigor mortis is fully established,
is also accounted for by the oxidation of glycogeu. Prolonged
tetanus likewise causes acidity of the muscle; we have seen
that this is due to excessive suprarenal activity: i.e., to hyper-
oxidation.

This subject is of such importance that we deem it ad-
visable to meet each mooted point as presented by Professor
Foster precisely as if the problems were placed before us for
solution: —

1. "At the outset of rigor mortis there is a very large and
sudden increase in the production of carbonic acid: in fact,
an outburst, as it were, of that gas."

The onset of rigor mortis also represents the moment when
vascular tonic contractions cease; the blood-vessels being sud-
denly dilated, a correspondingly great amount of oxidizing
substance is as suddenly brought into contact with the energy-
holding substances in the myosinogen, and an outburst of car-
bonic acid ensues.

2. "The increased production of carbonic acid during
rigor mortis is not accompanied by a corresponding increase
in the consumption of oxygen."

This conclusion, based on the consumption of oxygen in
which the dead experimental animal is placed, does not take
into account the oxygen stored in the animals' blood-plasma.

THE OXIDIZING SUBSTANCE AND MYOSINOGEN. 245

As shown in the first answer, the oxidizing substance in the
latter is fully able to give rise to the production of the car-
bonic acid observed.

3. "A muscle (of a frog, for instance) contains in itself
no free or loosely attached oxygen; when subjected to the
action of a mercurial air-pump it gives off no oxygen to a
vacuum, offering, in this respect, a marked contrast to blood."

A detached muscle is, as far as its vascular elements arc
concerned, similar to a muscle in which rigor mortis has begun.
Its oxygen is not in sufficiently loose combination to yield to
the dissociating action of the pump when stored in myosinogen,
owing to its affinity for various constituents of the latter.
While in extra corpore blood the oxidizing principle of the
plasma might yield its oxygen in vacuo, it is probable that it
will not, judging from recorded data, though it will do so to
salicylic aldehyde, benzol, and benzilic alcohol, as shown by
Schmiedeberg, Jaquet, Salkowsky, Abelous and Biarnes.

4. "When placed in an atmosphere free from oxygen it
will not only continue to give off carbonic acid while it remains
alive, but will also exhibit at the onset of rigor mortis the same
increased production of carbonic acid that is shown by a mus-
cle placed in an atmosphere containing oxygen. It is obvious
in such a case that carbonic acid does not arise from the direct
oxidation of the muscle-substance, for there is no oxygen
present at the time to carry on oxidation."

The oxidizing substance when brought into contact with
the myosinogen gives rise to an intramuscular reaction: one
which, therefore, may continue in any atmosphere whether
the latter contain oxygen or not.

Professor Foster then summarizes prevailing views as to
this subdivision of the general subject, as follows: "We are
driven to suppose that during rigor mortis, some complex body
containing in itself ready-formed carbonic acid, so to speak,
is split up, and thus carbonic acid is set free, the process of
oxidation by which that carbonic acid was formed out of the
carbon-holding constituents of the muscle having taken place
at some anterior date."

The process appears to us to be fully accounted for as
follows: The presence of the oxidizing principle which the supra-

246 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

renal glands indirectly furnish to the l>lood-plasma accounts for
the phenomena witnessed. The abrupt increase in the production
of carbonic acid after death is due to the sudden relaxation of the
normal tonic vascular contraction incident upon the lethal state
and to the equally sudden onslaught of oxidizing principle upon
the myosinogen thus induced. Myosinogen becomes myosin after
the intrinsic combustion processes have ceased.

But can functional activity be maintained in an organ
merely by an increase of the local blood-supply? That such
is the case may be shown by means of one of Claude Bernard's
experiments, — that in which he demonstrated the existence of
vasodilator nerves. Having severed the chorda tympani,— a
branch of the facial distributed to the submaxillary gland, —
he found that, when the peripheral segment of the cut nerve
— that leading to the gland — was electrically stimulated, its
normal function became manifest. Mathias Duval described
the phenomena that immediately ensue as follows: "While the
salivary secretion is thus increased, the blood-vessels of the
gland are seen to become greatly enlarged; previously invisible
arterioles become red and turgescent. If the main trunk of
the gland is exposed, it is seen to increase in size, while its
contained blood, blackish before the experiment, becomes as red
as arterial blood the moment the chorda tympani is stimulated;
indeed, if the vein is cut, the blood may be seen to flow in
rhythmic jets, as it does from an artery, while it merely drools
out when the gland is in the state of rest: i.e., when the
chorda tympani is not excited."

The organ selected for the illustration, the submaxillary
gland, is particularly advantageous for the purpose, because
its vasodilator nerve, the chorda tympani, is isolated from the
vasoconstrictor branch of the sympathetic, also distributed to
the gland: a feature of importance. Again, it is evident that
function occurs without the active participation of the nerve-
impulse per se, such as that associated with a "motor" nerve.
We have, in Professor DuvaPs presentation of the process, an
exact description of the mechanism of active function. There
is not only increase of blood, but increase of energizing blood:
i.e., blood that is not allowed to become venous in situ. The
carbonic acid evolved must at once be removed; hence the

MOTOR NERVES AND MUSCULAR CONTRACTION. 247

rapid flow; while the veins are for the time being, as long
as active functions continue, transformed into arterial chan-
nels. Briefly, more arterial blood means more work. As we
will see later on, this is the only process through which the
potential of any organ — i.e., its latent power to do work — is
maintained and its functional activity awakened when required.
Whether the structures involved be muscular, hepatic, gastric,
renal, cerebral, splenic, etc., the exciting factor of activity is
always — shall we say blood? No; all this evidence emphasizes
the fact that the oxidizing substance is the main factor of all
functional processes, and that the red corpuscles are but carriers
of oxygen intended to sustain the plasma's efficiency as an oxidiz-
ing body. We have seen that Salkowski was also led, but by
chemical methods, to deny the red corpuscles the all-important
role now ascribed to them.

THE MOTOR NERVES AND THEIR ROLE IN MUSCULAR
CONTRACTION. — We must now transfer our attention to the
"vasoconstrictor" side of the question. The sciatic nerve is
thought to be supplied with vasodilator and vasoconstrictor
fibers. Division of this nerve causes the usual widening of
the arteries, while electrical stimulation of the peripheral
nerve-end causes contraction of the dilated arteries. This
coincides with the experimental results of section of the cer-
vical sympathetic, the splanchnic, etc., already given. "But
sometimes a different result is obtained," says Foster, "on
stimulating the divided sciatic nerve: the vessels of the foot
are not restricted, but dilated — perhaps widely dilated": a
phenomenon which leads him to conclude "that the sciatic
nerve (and the same holds good for the brachial plexus) con-
tains both vasoconstrictor and vasodilator fibers," and to in-
terpret the varying results as due "to variations in the relative
irritability of the two sets of fibers."4 These remarks are only
intended by their author to convey, not a personal conclusion,
but an inferential deduction based on what testimony the ex-
periment referred to affords as to the existence, in the sciatic
and brachial plexuses, of both constrictor and dilator fibers.
It is the value of the testimony itself, and not the author's
deduction, therefore, that we are analyzing.

* The italics are our own.

248 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

A query that normally suggests itself is the following:
What is the experimental value of the current for the deter-
mination of the specific function of any nerve when its relative
irritability is a sufficiently prominent factor to cause it to in-
dicate, under the influence of this current, one function at
one time and the opposite function the next? Evidently the
variation in irritability must mean either — as is the case with
the nerves of the parotid gland — that the antagonistic nerves
are directly connected or juxtaposed or that one is sufficiently
metamorphosed organically as to modify its conductivity.
Framed in this manner, the query meets with a ready response:
Inasmuch as vasoconstrictor and vasodilator nerves accompany
the sciatic nerve, they become common conductors when the
circuit is closed, and any indication furnished, therefore, is of
no scientific value.

There is another possible explanation, however, viz.:
Either one of the dilator or constrictor nerves may be absent
in the structures supplied by the sciatic and the brachial
plexus. In other words, skeletal muscles may only be supplied
with one of these nerves. Yet there is no experimental differ-
ence between these and other structures of distribution; thus,
section causes vasodilation, while stimulation gives rise to con-
striction of the vessels, and, if either of the vasomotor nerves
is not supplied to these structures, their motor nerves must
fulfill the role of the absent system. We could readily enough
state, after eliminating the only evidence in favor of the ex-
istence of vasoconstrictors, that there are none in striated
muscles, all the positive evidence pointing only to the existence
of vasodilators. But we must not lose sight of the fact that
we have interpreted the experimental evidence at our disposal
in a different manner, and that our own views must also be
shown to be in accord with this evidence, if they are to merit
confidence.

From our standpoint, then, granting the existence of both
constrictor and dilator nerves, in direct relation with the
sciatic, what would be the result of electrical stimulation?
None, whatever, — diameter, structure, and peripheral elements
of the nerves being equal. Function depending on increased
blood-supply and perfect balance between vasodilation and con-

MOTOR NERVES AND MUSCULAR CONTRACTION. 249

striction being the fundamental requirement of normal activity,
the conductivity of both nerves must be equal; hence, this posi-
tion may be taken as a working basis. But quite another result
is to be expected when, as is actually the case, the sciatic is to
be considered as a factor of the problem. A large motor nerve
plus the constrictor plus the dilator no longer represents bal-
ance as to conductivity, and our analysis must now include, as
an element, the fact that the energy distributed to the vaso-
dilator nerve will, all else being equal, be as its circumference
is to that of the sciatic and the vasoconstrictor combined.
When the great size of the sciatic is recalled, it becomes evi-
dent that the dilator will at best receive an insignificant pro-
portion of the current. Under these circumstances what ex-
perimental results could we expect? Section would obviously
cause dilation, since the dilator nerves would be cut, and the
tonic contraction of the vessels would also be annulled through
section of the constrictor. Electrical stimulation of the pe-
ripheral stump of all the nerves, therefore, could have but one
result, — constriction, — since the dilators receive practically no
current. This agrees perfectly with observed facts. But why
the opposite result also observed? This renders it necessary
to analyze what evidence there is as to the actual existence
of vasoconstrictors in striated muscles.

"With regard to the vasoconstrictor fibers/' says Professor
Foster, "the only evidence that they exist in muscles is that
when the nerve of a muscle is divided the blood-vessels of the
muscle widen, somewhat like blood-vessels of the ear after
division of the cervical sympathetic. This suggests the pres-
ence of vasoconstrictor fibers carrying the kind of influence
which we called tonic, leading to an habitual moderate constric-
tion; it cannot, however, be regarded by itself as conclusive
evidence." We have seen that vascular constriction is unmis-
takably associated with the sympathetic system: its only source
elsewhere. No fibers of the sympathetic are associated with
skeletal muscular tissue. In fact, Professor Foster, referring
to the latter, says: "The presence of any vasoconstrictor fibers
at all has not at present been satisfactorily established. When
a muscle contracts there is always an increased flow of blood
through the muscle/' thus simultaneously suggesting the pos-

250 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

sible absence of vasoconstrictors and indirectly confirming the
presence of vasodilators.

The question, therefore, becomes an open one, and, if it is
considered from the standpoint of our conception of the process
of muscular contraction, — i.e., with the vasodilators as the in-
citing factor of the oxidation process that underlies muscular
activity, — the contradictory phenomenon referred to — i.e., dila-
tion under electrical stimulation — may be accounted for, pro-
vided, however, vasoconstrictor nerves are eliminated from the
function involved.

Foster states that "this vasodilator action is almost sure
to be manifested when the nerve is divided and the peripheral
stump stimulated some days after division, by which time com-
mencing degeneration has begun to interfere with the irri-
tability of the nerve. For example, if the sciatic be divided,
and some days afterward, by which time the flushing and in-
creased temperature of the foot following upon the section
has wholly or largely passed away, the peripheral stump be
stimulated with an interrupted current, a renewed flushing
and rise of temperature is the result." As we interpret this
result, the stimulation means vasodilation. But we have stated
that the sciatic, owing to its greater size, would practically
alone transmit the energy, leaving the vasodilator uninfluenced,
and, if we transfer to the sciatic the constrictor function, the
effect should be the opposite of that observed. That a better
conductor than the vasodilator is present is shown by the sen-
tence "the constrictor fibers also appear to be more readily
affected by a tetanizing current than the dilator fibers." The
sciatic itself being looked upon by us as the vasoconstrictor,
we can, therefore, connect the remark with this nerve. Bear-
ing this fact in mind, we will now inquire into the comparative
behavior of the sciatic as a motor-constrictor nerve with its
antagonist, the vasodilator, under the conditions mentioned:
i.e., section, followed some days later by stimulation, utilizing
quotations from Professor Fosters text as the basis of our
analysis.

Eef erring to the sciatic and brachial plexus, he says: "The
constrictor fibers appear to predominate in these nerves, and
hence constriction is the more common result of stimulation."

MOTOR NERVES AND MUSCULAR CONTRACTION. 251

Considered as motor constrictors these nerves would respond
to stimulation in precisely this manner. "Exposure to a low
temperature again seems to depress the constrictors more than
the dilators; hence, when the leg is placed in ice-cold water
stimulation of the sciatic even when the nerve has been but
recently divided, throws the dilator only into action, and pro-
duces flushing of the skin with blood." This demonstrates at
least an intimate association between motor and constrictor
functions. Again, since placing of the limb in ice-cold water
abolishes response, of the sciatic to stimulation, this nerve must
readily succumb functionally to untoward influences — evidently
sooner than the vasodilator. This is confirmed by the state-
ment: "The latter" (the vasodilators), "in contrast to ordinary
motor nerves, retain their irritability after section of the nerve
for very many days." Again does the link between the motor
and the constrictor element appear, and as they jointly suc-
cumb while the dilators retain their irritability, and the loss
of function under pathogenic influences begins much sooner
than in the latter, we are brought to recognize, first, that motor
and constrictor nerve-elements are either pathologically af-
fected in precisely the same manner, or that both functions
are attributes of the motor nerve; second, that we have in the
histological changes incident upon section of the latter, or the
nerves of the brachial plexus, the cause of vascular dilation
that ensues upon stimulation, when this experimental proced-
ure is not carried out at once.

And, indeed, the strength of this proposition appears if
we examine the histological structure of any nerve-bundle, and
particularly such organs as the sciatic. The many elements
that enter into their organization suggest immediate morbid
alterations on section, especially if our view that the blood-
plasma is the vehicle or excipient of the oxidizing substance
which maintains all functional processes is warranted. Under
these conditions, it is plain that cutting of the nerve should
at once initiate degenerations, the morbid process and the re-
sulting loss of functional powers progressing until, "at a certain
stage, a stimulus, such as the interrupted current, while it fails
to affect the constrictor fibers, readily throws into action the
dilator fibers."

252 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

But why do the dilator fibers not degenerate likewise?
Inasmuch as, quoting Professor Foster's words, "the presence
of any vasoconstrictor fibers at all has not at present been
satisfactorily established/' while "the only evidence of their
existence" is that, "when the nerve of a muscle is divided, the
blood-vessels of the muscle widen," we must admit, in the face
of the foregoing statements, that all the evidence now tends
the other way: i.e., to suggest that the sciatic and the brachial-
plexus nerves are not only motor, but "motor-constrictor"
nerves, and that dilators are autonomous structures — if they
exist at all.

Referring to the effects of severance of a nerve from the
central nervous system, Foster says: "When a nerve — such,
for instance, as the sciatic — is divided in situ, in the living
body, there is, first of all, observed a slight increase of irrita-
bility, noticeable especially near the cut end; but after awhile
the irritability diminishes and gradually disappears. Both the
slight initial increase and the subsequent decrease begin at the
cut end and advance centrifugally toward the peripheral ter-
minations. This centrifugal feature of the loss of irritability
is often spoken of as the Hitter- Valli law. In the mammal it
may be two or three days; in a frog, as many, or even more
weeks, before irritability has disappeared from the nerve-trunk.
It is maintained in the small (and especially in the intra-
muscular) branches for still longer periods." This obviously
suggests that the size of a nerve, all else being equal, is a gov-
erning factor in the degenerative process due to nerve-section,
precisely as indicated when the relative effects of the electric
current were referred to.

Still, such a governing principle would necessitate that a
large nerve be structurally similar to a small one, qualitatively
and quantitatively, to warrant our accepting it as the basis of
a final conclusion. Such is not the case, however, as is well
known. While the various structures that enter into their
formation are specific to nervous organs, they are not evenly
distributed. This is illustrated in the case of vasomotor nerves.
Though both constrictors and dilators are medullated, the
former lose their medulla early in their course, while the vaso-
dilators preserve theirs until the blood-vessels to which they

MOTOR NERVES AND MUSCULAR CONTRACTION. 253

are distributed are almost reached. We must also remember
that this medulla is an extremely complex body. "Being so
complex," says Professor Foster, "it is naturally very unstable,
and, indeed, in its stability resembles putrid matter. Hence,
probably, the reason why the medulla changes so rapidly and
so profoundly after the death of the nerve." Viewed from
our standpoint, this suggests that, inasmuch as the vaso-
dilator fibers preserve their medulla until the vessels to which
they are distributed are nearly reached, they should degenerate
before the constrictors, which lose theirs early in their course.
And such would be the case did any such nerves exist in the
sciatic or brachial-plexus nerves or any nerve of the skeletal
muscular system. Indeed, were there any, their functional
activity would outlive that of the vasodilators, which is not
the case. If this fact is now considered in association with
the other features of this analysis, it seems to us to suggest
that the voluntary muscular system is not supplied with separate
vasoconstrictor nerves, and that the functions of the motor nerves
distributed to these muscles include that of vasoconstriction.

Further evidence that this conclusion must represent the
actual state of things is afforded by the manner in which it
simplifies — provided, of course, previous conclusions are like-
wise admissible — the whole process which underlies voluntary
muscular activity, without in any way contradicting the data
sustained by experimental evidence. Indeed, vasoconstrictors
have never been found; an element of confusion is thus re-
moved which will probably enable us to ascertain the actual
effects of nerve-impulse on the voluntary muscular fibers and
their purpose. As to the vasodilators, another element of con-
fusion is removed through the fact that we now know from
data recorded in these pages that they need extend no farther
than the ultimate vascular subdivision, the walls of which con-
tain muscular elements: i.e., the arterioles. The fact that the
oxidizing substance of the blood-plasma reaches the muscular
elements themselves and can there exercise its life-sustaining
power and suddenly awaken activity also simplifies a very per-
plexing question. The capillaries which entwine the muscle-
fibers simply allow their plasma to ooze out through their
stomata, or endothelial-plate interstices, and to thus reach the

254 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

contractile substance through the latter's own investing mem-
brane. Increase of plasma means increase of work: i.e., mus-
cular contraction. Waste-materials are as rapidly returned
through efferent capillaries to the venules, thus leaving the
field clear for continuous function.

While we have perhaps simplified the processes mentioned,
we have complicated another, since we now find it necessary
to account for the functions implied by "voluntary," "motor,"
and "constrictor," all through the operation of one set of
nerves. And yet we are now in perfect accord with the ana-
tomical side of the question, since there is no evidence that
constrictor nerves exist. The only nerve distributed to a
voluntary or striped muscle proper, the motor nerve, enters
its sheath, breaks into numerous subdivisions, and thus sciul.s
one filament — occasionally two — to each muscular fiber. On
the surface of the latter, near the middle, an important ter-
minal arrangement prevails: i.e., each nerve-fiber develops its
"motor end-plate!" Its white matter of Schwann ceases and
its outer covering becomes continuous with that of the muscle,
so that its axis-cylinder alone penetrates to the muscular fiber.
Here it subdivides into numerous root-like processes, forming
a hillock, or motor end-plate, supported by a layer of granular
substance which contains a number of large nuclei. It is this
end-plate that the impulse first strikes when it reaches the
muscular fiber, and it travels from the center of the latter to
the two ends. All the elements of the muscle are so disposed
as to receive the impulse simultaneously.

Before analyzing the mechanical result of this impulse or
going further into the vasodilator question, a brief allusion to
the histology of the arterioles of voluntary muscle must be
made. The internal coat is composed, as elsewhere, of endo-
thelial cells; when the middle coat is cut transversely, how-
ever, it presents a peculiar conformation: its outline festooned.
Eanvier5 divides the middle coat into two layers: an internal
elastic lamina and a muscular layer. In his description of
these structures he says: "The internal elastic lamina, as is
the case with all parts formed of elastic substance, possesses

6Ranvier: quoted by H. Berdal, "Histologie Normale," 1894.

MOTOR NERVES AND MUSCULAR CONTRACTION. 255

but little elasticity, and, when it is compressed by the muscular
layer encircling it, it happens that the lowest limit of its elas-
ticity is surpassed and that, in order to accommodate itself to
the restricted space reserved for it, it forms folds. It is for
this reason that a transverse section causes it to appear as
if festooned, while longitudinal sections of these small arteries,
owing to folds formed during muscular retraction, give the
appearance of longitudinal strias." From our point of view
this is subject to another interpretation. Indeed, this festoon-
ing in longitudinal folds, — observed to a limited extent in all
small arteries, — coupled with the effects of muscular retrac-
tion, seems to us to distinctly point to the mechanical process
through which efficient changes in the caliber of the arterioles
are insured.

The impulse, we have seen, travels from the end-plate
toward the extremities of the muscular fiber and the muscle
contracts, according to our view, as the result of dilation of
the arterioles. While the sudden onset of oxidizing plasma,
by suddenly increasing the production of chemical energy,
which in turn is converted into contractile energy, accounts for
the latter, it does not account for the "voluntary" element of
the process, nor for the wonderful precision which character-
izes muscular movements — those of the fingers, for instance.
Indeed, myosinogen plus the oxidizing substance must be con-
sidered— if our doctrine prevails — as the only source of work,
but not as the intermediary through which the volition (con-
scious or unconscious) implied by the word "voluntary/5 and
the functional control that this implicates, is obeyed. In
other words, it constitutes what in the locomotive is repre-
sented by the combination of fire, water, and steam, but it
does not represent the throttle-valve, which is subject to the
will of the engineer. His "voluntary" act, transmitted through
the lever, regulates the quantity of steam admitted into the
cylinder — in which heat is transformed into work. In the
muscle each "fine, transparent, membranous tube" is a cylin-
der, but one in which the conversion of energy into work is
the result of a local process in which myosinogen plus the
oxidizing substance are the sources of energy. The throttle-
valve is obviously the arteriole, but so located as to admit — as

256 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

regards contraction — a surplus, not of fuel, but of the active
element which underlies the effects of "draught" in the engine:
i.e., oxygen, that contained in the "oxidizing" substance. The
fuel — myosinogen — is always present in our muscles — when
they are normal, and the activity of the combustion is regu-
lated there, as elsewhere in Nature, by the quantity of oxygen
admitted. Yet, how is the conscious or unconscious control
implied by the word "voluntary" carried out?

The muscular arteriole during complete muscular retrac-
tion is only just sufficiently patent to allow the passage of
enough blood-plasma containing the oxidizing substance to
sustain the nutrition of the muscular tissues, and other proc-
esses through which their functional efficiency is insured. But
the fact must not be overlooked, as emphasized by Foster, that
the relaxation is an essential part of the whole act; indeed,
no less important than the shortening itself. Again, a com-
pletely retracted muscle is not a relaxed muscle; it is precisely
in the opposite state, — i.e., in a condition of tension between
its insertions, — and if either one of the latter- be cut the mus-
cle recedes toward the other. This feature is well exemplified
after amputations. The biceps can contract unimpeded, for
example, three times the extent that its skeletal attachments
will normally allow; fractures of the olecranon or of the
patella are familiar examples, notwithstanding the fact that
the muscles thus liberated at one end are held partly retracted
by the surrounding structures. Indeed, a normal muscle can
aptly be compared to a piece of rubber stretched between two
fixed points, and contraction really represents a relaxation of
the stress. But there are variations in the resistance to which
this stress is submitted, and it is here that the identity of the
controlling concept appears as an independent factor, while
that of the motor mechanism also emphasizes itself by phe-
nomena that cannot logically be considered as elements of the
process through which the "voluntary" impulse is transmitted,
nor of the transmitting organs, the motor nerves.

If the arm is flexed, say, at an angle of 90 degrees, it can
be held in this position without fatigue for some time. But
if a sufficiently heavy weight be placed in the hand, the arm
remaining in precisely the same position, marked evidences of

MOTOR NERVES AND MUSCULAR CONTRACTION.

257

strain appear: the face becomes flushed, the superficial veins
enlarge, more or less sweating occurs, etc.: i.e., all the familiar
signs associated with continued effort assert themselves. Re-
sistance evidently underlies the whole process, and, as "resist-
ance" always implicates at least two contending forces, we are
led to divide the process itself into two parts: i.e., the weight
which tends to force the hand down and the muscular effort
exerted to hold it up. But if we analyze the muscular effort,
it soon becomes apparent that it is itself susceptible to a clearly
defined subdivision. Indeed, notwithstanding the weight, the
arm remains fixed in one position; and the entire organism
shows the effects of strain; muscles other than those of the
arm contribute work, the entire circulatory system (including
the heart, judging from its overaction) enter into a phase of
unusual activity, etc., — all laboring to the one end, viz.: to
mechanically satisfy, regardless of the aggregate of energy
converted into work, the needs of the voluntary act physically
impressed upon tlie muscle and transmitted to it from the brain
through the motor nerve. We thus have, on the one side, a
form of volitional energy through which the muscle is fixed in
the one position; and, on the other, an oxidation process,
through which muscular work is carried out, sustained, and
intensified to the highest possible degree compatible with the
body's strength.

That two distinct processes are present may be shown in
several ways. Professor Foster, referring to the "impulse-
wave" states, for example: "It is followed by an explosive de-
composition of material, leading to a discharge of carbonic
acid, etc." Not only does the active reaction occur after the
dispersion of the impulse, but Helmholtz ascertained that quite
a perceptible and computable period of time elapsed between
the two phenomena. By means of the Marey myograph this
"latent period" was found to occupy one-sixtieth of a second,
while the maximum contraction is only reached at the end
of about one-sixth of a second6 in an average muscle. A
radical difference is also evident in the relative ability of the
two kinds of energy — volitional and motor — to undergo fluct-

«M. Duval: Loc. cit., p. 151.

258 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

uations in what, for the sake of convenience, we may call
"intensity." The impulse-wave simply sets the muscle-elements
to a given vibratory rhythm, and they retain this, whatever
be the intensity of the exertion required. The oxidation proc-
ess, on the contrary, contributes whatever degree of mechan-
ical energy is necessary to fulfill the needs, not only of the
movement, but also of any additional work an increase of
resistance may demand. Thus, the impulse-wave may fix the
muscles of the flexed arm in a given position, but any fluctua-
tion in the power required to support different weights is at
the expense of the motor mechanism. This may be aptly
compared to the manner in which a note on a violin is made
loud or soft. The power with which the string is pressed upon
with the moving bow modifies the intensity of the sound; but
the note remains the same. This means that its pitch does
not vary, and if, for example, the lower C is given, we will
know that the sound-wave of that note represents 261 vibra-
tions per second. So may the impulse-wave transmitted by the
brain through a "motor" nerve be represented by a fixed num-
ber of vibrations. Retraction, the muscle being then most
tense, is therefore characterized by the greatest number of
vibrations. On receiving the impulse the muscle adjusts itself,
whether by contraction or retraction, to precisely the extent
which the number of vibrations transmitted will allow, and
remains fixed in the state of contractility assumed until the
impulse-wave itself is modified. The power or intensity of
sound and the variations in the work this implies are fully
typified by the motor process, through the enhanced circula-
tory activity and a corresponding increase in the rapidity with
which the oxidizing substance is brought into contact with
the myosinogen in the muscles. It is simply a question here
of more fuel and more draught.

Obviously, the rhythm transmitted to a voluntary muscle
is simultaneously communicated to the muscular walls of its
vessels by the same impulse. The lumen of each vessel — veins
as well as arteries, since the former also possess a muscular
coat, but much less important structurally and therefore less
active — varying synchronously with the muscle to which it is
distributed, the flow of blood through it is exactly adjusted

MOTOR NERVES AND MUSCULAR CONTRACTION. 259

to the needs of any degree of muscular contractility the vol-
untary (conscious or unconscious) movement requires. In
other words, the arteries, and to a certain extent the veins, become
constricted or dilated proportionately as the muscle is contracted
or retracted, and the activity of the motor mechanism is thus
concurrently adjusted to the functional requirements of the
moment.

If this conception is not erroneous, the general process
it represents certainly constitutes a marvelously simple way
of accomplishing many of the most important functions of
the organism, since those ascribed to both vasoconstrictor and
vasodilator nerves are thus performed without, indeed, leaving
a single reason for the presence of either of these nerves as in-
dependent entities.

This normally suggests the question: Do vasodilators
actually exist in muscular vessels? That there are vasodilators
in certain organs: the submaxillary and other salivary glands,
the tongue, the penis, etc., is thought to have been experi-
mentally demonstrated; but their existence in the muscular
vessels has not been shown, the evidence adduced, as was the
case with the constrictors, being purely inferential. We have
seen that section of the sciatic, followed by stimulation after
some time had elapsed, caused dilation of the vessels of the
extremities, while earlier it had caused constriction. Close
analysis also showed that actual dilation of the arteries could
be ascribed only to an active dilator action. The only remain-
ing feature that requires elucidation, therefore, is the manner
in which this is carried out. Does the above-described process
account for these contradictory phenomena as well as would
vasodilator nerves? That the elastic lamina of the vessel can
fulfill precisely the same function as the latter seems evident.

The impulse-wave being accepted as the governing factor,
each point of the muscular coat is caused to recede or approach
from the axial line of the vessel just sufficiently to bring the
caliber of that vessel to the required limits. Hence the pres-
ence of the muscular coat over the elastic lamina. The cause
and purposes of the latter^ longitudinal corrugations now be-
come apparent: while perfectly elastic, it is somewhat larger
in diameter than the muscular layer, and, lying, as it does,

17

260 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

within the latter, it forms the folds or "festooning" described
by Eanvier. Viewed from our standpoint, however, these
longitudinal folds play a very important part in the whole
mechanical process described, since it is upon variations of
their outline that the adjustment of the lumen of the vessel
mainly depends. Mere dilation of a circular vessel, of course,
involves an increase in the diameter of the stream passing
through it; but, if numerous folds that project into that
stream are simultaneously withdrawn by being leveled out, it
is evident that the free space within the vessel will be vastly
increased, and that a much greater range between dilation and
contraction will thus be available.

That such is the process through which a slight variation
of the peripheral pressure exerted by the muscular layer will
cause a relatively larger variation of the amount of blood to
pass through the vessel seems very probable, since it satisfies
all mechanical needs. As long as the characteristic impulse-
wave of a fixed degree of muscular contraction persists, the
vessels are simultaneously adjusted to the needs of this par-
ticular degree of contraction and allow just the necessary
amount of blood — i.e., oxidizing plasma — to pass.

Returning now to the contradictory results of stimulation
of the sciatic after section of that nerve, an important feature
must be referred to, which, if considered before, would have
but introduced confusion in the inquiry: i.e., the fact that
stimulation of this nerve immediately after section may either
be followed by dilation or constriction. Laryngologists are
quite familiar with the fact that one strength of current will
cause adduction of the vocal bands, — i.e., of their muscles, —
while another strength will cause the opposite condition — ab-
duction,— when the recurrent laryngeal nerve is cut and stim-
ulated. That the same controlling factor must prevail in the
case of the sciatic is very probable, if, as we have suggested,
the rhythm of the impulse-wave determines the degree of mus-
cular contraction. The certainty with which dilation is pro-
duced when the nerve is stimulated "some days after division"
is a phenomenon of another sort. The electric current does
not, like a normal nerve-impulse, select a physiological path;
it simply utilizes the channels that offer the least resistance.

MOTOR NERVES AND MUSCULAR CONTRACTION.

261

A diseased sciatic means impairment not only of its conductiv-
ity, but also of that of its subdivisions. The current may or
may not, under these conditions, continue to follow the nerve
stimulated after the segment buried in the tissues is reached;
selecting the best conductors, it will, if it follow the course of
the vessels, mainly stimulate the layer offering the least re-
sistance: i.e., the thickest and softest, as regards inherent pro-
portion of fluids. As this characterizes the elastic layer, it
cannot but receive the brunt of the stimulus. We are no
longer dealing with muscular vibrations, but with a corrugated
elastic tube the normal tendency of which is to expand, level
its folds, and increase its lumen. The current, by inducing
erethism, encourages this, and produces, by increasing the
caliber of the vessels, "flushing and increased temperature of
the foot/' Indeed, electricity is a poor substitute for the
physiological impulse-wave and sometimes a misleading one.

We can fully agree with Professor Foster, therefore, when
he says: "There is no adequate evidence that these vasodilator
fibers serve as channels for tonic dilating impulses or influ-
ences," and express our personal opinion that neither vasocon-
strictor nor vasodilator nerves exist as separate entities in volun-
tary muscles, loth functions being fulfilled through the agency of
their motor nerves.

The following general deductions seem to be warranted
by the facts presented: —

The functional activity of a voluntary muscle is dependent
upon the following correlated factors: —

1. As to nervous stimulus: an impulse-wave transmitted
from a cerebral center through motor nerves, which adjusts the mus-
cle to a fixed degree of contraction. As the vibratory rhythm of the
impulse and that of the muscle always correspond, any variation of
rhythm by the brain-center correspondingly modifies the muscular
contraction.

There are no independent vasoconstrictor or vasodilator nerves
in voluntary muscles, both functions being fulfilled by the motor
nerves through the filaments distributed to the muscular coat of
the vessels of these muscles, and under the influence of the same
impulse-wave that adjusts and fixes the tatter's contraction or
retraction.

262 THE ADRENAL, SYSTEM AND VASOMOTOR FUNCTIONS.

Source of muscular energy: an oxidation process in the
muscular contractile elements the chemical energy of which, after
conversion into mechanical energy, supplies the muscle during any
stage of contraction or retraction with the power-to-do-work required
to sustain either of the latter.

This oxidation process is subject to fluctuations of activity,
and occurs as the result of a reaction between two physiological
compounds: first, myosinogen, — i.e., Hood-plasma containing
various carbohydrates and immanent in the muscle-fiber, — as a
potential; second, an oxidizing substance, also contained in the
blood-plasma, but in that of the arteries, as reagent.

2. As to mechanical process: variations in the caliber of the
muscular vessels give rise to corresponding variations in the pro-
portion of oxidizing substance admitted to the myosinogen in the
muscular fiber and to correspondingly marked fluctuations in the
activity of the oxidation process.

The myosinogen is stored in the contractile disks while the
oxidizing plasma fills the interstitial disks, and an opening between
the two probably exists through which the oxidizing plasma is
forced when the impulse-wave adjusts the muscle to the required
contraction, the quantity of energy produced being thus simulta-
neously adjusted to the needs of that contraction.

THE OXIDIZING SUBSTANCE AND THE MOTOR NERVES IN
THEIR RELATION TO GLANDULAR SECRETION.

In the foregoing pages we have sought to elucidate the
manner in which the voluntary muscular system could be en-
dowed with vasomotor functions. The result has suggested
that such a system as the sympathetic does not exist as a
separate entity, and that the double chain of ganglia on each
side of the spinal column, and those situated in the head,
thorax, abdomen, and pelvis, their intercommunicating nerves
and plexuses are, in reality, but subdivisions of the motor
system. We have ascertained that a motor nerve was a vaso-
dilator or constrictor only in the sense that it adjusted the
organ's functions to a specific degree of activity, and simul-
taneously adjusted the lumen of its vessels to the needs of
this functional activity in order to admit precisely the amount
of blood — i.e., of oxidizing serum — required. Obviously, each

PHYSIOLOGY OF GLANDULAR SECRETION. 263

organ contains, as inherent source of energy, either endogenous
products with which the oxidizing substance combines, or cellu-
lar structures whose metabolism is sustained by the oxidizing
substance. This is a question, however, that will be taken up
as each organ is studied.

The classic subdivision into two great systems, cerebro-
spinal and sympathetic, seems to us, therefore, to be subject
to modification. Indeed this subdivision has always been an
artificial one, since at all times some connection or other with
the cerebro-spinal axis, whether it be associated with borrowed
or direct impulses, has always had to be considered as a factor
of its functions. This is well illustrated in a comprehensive
paper, in which the functions of the sympathetic system are
ably reviewed, by B. Onuf (Onufrowicz) and James Collins,7
who refer to tonic vascular contraction as follows: "It has been
shown that many nerves of the sympathetic system are under
the tonic influence of spinal or cerebral centers. Section of
the cervical sympathetic nerve is followed by dilation of the
blood-vessels of the head; section of the abdominal sympathetic
by dilation of the blood-vessels of the hind-paws; section of
both splanchnics by the same phenomena in the stomach and
the intestine. Severance of the nerves connecting the sub-
maxillary ganglion with its encephalic center gave rise to an
increasing continuous secretion of the submaxillary glands,
proving the regulatory influence of the cerebro-spinal system
upon the submaxillary ganglion (Claude Bernard)."

If we now recall the limitations of the adrenal system
described in the last chapter, — i.e., the triad: thyroid, anterior
pituitary, and adrenals, — and particularly the connection be-
tween the two latter organs through the chain of sympathetic
ganglia and the splanchnic nerves, the following remarks of
the same authors are especially interesting: "Regarding the
tonic influence of ganglia of the sympathetic itself, the views
still differ. . . . We know, however, that the heart re-
moved from the body still continues to beat, and that the
bladder deprived of motor nerves leading to it continues to
perform its functions." They also refer to the observations

7 B. Onuf and James Collins: Archives of Neurology and Psychology, vol.
iii, Nos. 1 and 2, 1900.

264 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

of Contejean, "according to which the secretion of gastric
juice continues after the stomach has been deprived of all its
nerve-connections/' The reason for this is now clear. Inas-
much as the motor nerves merely excite to action and regulate
this action through their impulses, severance of the nerve-
supply of an organ only annihilates this function, and, as the
agency that supplies it with working energy reaches its tissues
through the blood, it is plain that its functional activity should
continue, even when its motor nerves are severed.

As regards the tonic contraction of vessels ascribed to the
sympathetic vascular fibers, it is merely the result of the con-
tinuous, though passive, activity in which all muscular tissues
are held by the oxidation process, which continues as long as
blood flows in physiological channels. This includes the in-
creasing, though perhaps slower, filtration of oxidizing plasma
into the contractile elements of the muscular fibers of the
vascular walls, and its return to the blood-stream per se
charged with products of combustion. As previously stated,
these do not only represent the products of hydrocarbon com-
bustion, the specific source of muscular energy, but also those
resulting from metabolism of the cellular elements per se. In
other words, a relatively small amount of oxidizing plasma
is incessantly penetrating to the myosinogen and causing the
development of just sufficient energy to insure nutrition of the
tissues and to keep them in that potential state in which,
though not doing active work, they are ever ready to actively
respond to summonses: i.e., to "motor-nerve" impulses. A
skeletal muscle, held by its two insertions, is not free to con-
tract in obedience to what energy the continuous oxidation
process generates, and, not being at once converted into work,
this energy is dissipated as heat. But not so with the vas-
cular walls; having only the centrifugal resiliency of their
inner coat to contend with, they at once convert the chemical
energy generated by the reaction in their contractile elements
into work which manifests itself as "tonic" contraction.

We have stated that voluntary muscles possessed no vaso-
constrictor or vasodilator nerves per se, and that the functions
ascribed to such nerves were exercised through the agency of
the "motor" nerves. What is now termed a vasoconstrictor

PHYSIOLOGY OP GLANDULAR SECRETION. 265

nerve, therefore, is, according to our view, nothing but a motor
nerve distributed to the muscular coat of the vessel. Does this
also apply to the vascular supply of the internal organs? We
have ascertained that the existence of the vasomotor nerves
in the parts studied was purely inferential. If works on
anatomy are consulted — i.e., works in which actually-present
structures are described — no reference to a special set of nerves
endowed with vasomotor functions is made. The subdivisions
of the sympathetic are deemed to be the vasoconstrictors; as
to the vasodilators, apart from those distributed to the sub-
maxillary and parotid glands, the tongue and the auricles, all
still belong to the domain of conjecture.

If our view is based on a solid foundation, we must,
however, be able to show that all the nervous structures com-
prised under the name of "sympathetic" are component parts
of the general motor system and that they are not only capable
of causing constriction, as now generally believed, but also
dilation of the structures to which they are distributed. We
have seen, for example, that when the cervical sympathetic
chain is severed, the phenomena are those already referred
to dilation of the vessels of the ear, which can be overcome by
stimulation of the cephalic end of the cut nerve. We must also
account for the phenomena witnessed at least as well as they
are by the older doctrine. In this experiment it is plain that
the dilation of the vessels ensues owing to the kss of their
regulating nerve-impulse. The fact that the local temperature
rises shows that the oxidation process is independent of the
impulse, since it continues nevertheless. On the electric cur-
rent being applied the nerve-impulse is replaced, the re-
contracted vessel overcomes the exaggerated blood-flow, and
normal conditions are restored. Of course, we shall have to
introduce various phenomena, now attributed to the sympa-
thetic nerves, which belong to the domain of the suprarenal
glands and perhaps to the other organs of the system described
in the last chapter, since it is only by clearly defining the part
taken by each set of organs involved that we can, if not
elucidate the subject itself, at least make our position clear.

We are fortunate in having at our disposal in this con-
nection the article, previously referred to, by B. Onuf (Onu-

266 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

frowicz) and Joseph Collins,8 in which experimental researches
on the central localization of the sympathetic system are re-
lated. It contains, besides a critical review of the anatomy
and physiology of this system, several references to the morbid
conditions to which we have alluded.

After a very brief reference to the many observers who
have given the sympathetic system especial attention, includ-
ing Pourfour du Petit, Claude Bernard, Schiff, Vulpian, Dastre
and Morat, Luchsinger, Heidenhain, Gaskell, and Langley,
they outline its functions as follows: "It may safely be con-
cluded that it has, to a great extent, a controlling influence
over the secretion of most of the glands, the lacrymal, the
salivary, the sweat- glands, the glands of the stomach and
intestines, the liver, the kidney, etc.; that it presides over
the circulation by regulating the caliber of the blood-vessels
and the action of the heart; that it influences respiration; and
finally that all the involuntary muscles, those of the digestive
apparatus, of the genito-urinary system, of the hair-follicles
(pilomotor nerves) are under its control."

We shall successively review each of the functions re-
ferred to, beginning with those that present the simplest
mechanism, — i.e., the lacrymal, salivary, sudoriferous, and
mammary glands, — and seek to conciliate what new features
our work has so far suggested with what experimental data
we may be able to find. Whatever physiological teachings will
appear weak, — i.e., acknowledged to be so by physiologists, —
we shall ascertain whether our views do not furnish some clue
that may prove more satisfactory to them.

LACKYMAL GLANDS. — Present knowledge as to the in-
nervation of glands in general, judging from a perusal of its
literature, is well exemplified by Matthews, who, after a careful
study of the question, says: "Whether secretory nerves exist
or whether secretion is ever a function of the gland-cell must
be considered at present an open question."

To elucidate the connection between the sympathetic and
the lacrymal gland Onuf and Collins removed one stellate9

• B. Onuf and Joseph Collins: Archives of Neurology and Psychopathology,
Nos. 1 and 2, vol. iii, 1900.

• In the cat this ganglion constitutes what in man would be the three cer-
vical and the first thoracic ganglia coalesced.

FUNCTIONS OF THE LACRYMAL GLANDS. 267

ganglion from each of three cats, and reviewed their results
as follows: "In one of the cats (three and a half months old)
an injection of 1 centigramme of pilocarpine, given three weeks
after the operation, produced lacrymal secretion of the eye of
the normal side, while the eye of the operated side remained
dry. In the second cat (about two months old) 5 milligrammes
of pilocarpine were injected one month after the removal of
the left stellate ganglion. In this case the result was alto-
gether different. Both eyes wept, but the eye of the operated
side more profusely than the other. About an hour after the
injection there was still considerable lacrymal secretion from
the eye of the operated side, while the other eye was dry.
In the third cat (about six weeks old) an instillation of a 2-per-
cent, solution of pilocarpine was made in both eyes, four and
one-half months after the operation. The effect was an equal
amount of lacrymal secretion in both eyes." The authors then
close the subject with the following remarks: "These results
are rather contradictory, and further experimentation must be
made to harmonize them and to allow of a correct interpreta-
tion. It must be taken into consideration, of course, that the
age of the animals varied, as did also the period (after the
operation) at which the pilocarpine was administered. The
manner of administration of the poison was different also."

Viewed from our standpoint, these experiments do not
appear contradictory; indeed, they may enable us to ascertain
the identity of the nervous structures involved and the manner
in which the functions of the gland are carried out. Obviously,
removal of the stellate ganglion on the one side severed the
connection between the anterior pituitary lobe and the ad-
renal on that side. Pilocarpine injections, by stimulating the
anterior pituitary, caused the latter to transmit activating im-
pulses through the perfect ganglionic chain to the terminal
adrenal of that chain; but, the secretion of both adrenals being
poured into the one channel, the end-result of the injection
of pilocarpine, as regards its effects upon the lacrymal glands
per se, was merely a reduction of the intensity of the local
symptoms, through a corresponding reduction of the vascular-
pressure increase which both glands would have produced.
Still, judging from its effects upon the normal lacrymal gland,

268 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

the pilocarpine must certainly have stimulated the functional
activity of the organs through the blood. That the adrenals,
or at least the normal adrenal, were involved in the process is
suggested by the actual phenomena witnessed in the animals
and the gradual increase of power assumed by the adrenal
on the normal side, as time elapsed. In the first cat, for in-
stance, the injection was given three weeks after the operation,
and the eye on the operated side remained dry. In the second,
a younger one, one-half the dose given the first cat was ad-
ministered one month after the operation; this violently
stimulated the normal adrenal and so increased vascular press-
ure that lacrymation occurred on both sides — especially on the
operated side, since the vessels had lost their tonicity. The
muscular coats of these vessels in the first cat had not been
contracted, the dose given it having caused insufficiency of
the adrenals; but the smaller dose administered to the second
animal having given rise to stimulation of these organs, lacry-
mation occurred. In the third cat, the injection was given
four and one-half months after the operation. By that time
the normal adrenal had been so stimulated by the additional
labor imposed upon it that — aided perhaps by a collateral
nerve-supply — it assumed the functions of both. Hence "there
was an equal amount of lacrymal secretion in both eyes."

Assuming, then, that pilocarpine increased functional
activity by enhancing local blood-pressure, which means more
oxidizing plasma, and that the current typified the nerve-
impulse, thus reproducing the active process that prevails in
muscular functions, why should removal of the stellate gan-
glion markedly influence these effects? This involves the con-
sideration of an important feature of the problem: i.e., the
origin of the impulse-waves to which we ascribe all the func-
tions credited to the motor nerves, the sympathetic nerves,
and the vasomotor nerves. To simplify matters, however, we
will not trace the various nervous organs involved to their
primary source, but only to their common meeting-place: i.e.,
the medulla.

That this will suffice for the time being is well shown by
experimental transverse sections of the structure, on the one
hand, and simultaneous electrical stimulation of a peripheral

FUNCTIONS OP THE LACRYMAL GLANDS. 269

nerve, on the other. The reflex contraction produced in the
vessels and the consequent rise of blood-pressure continue as
long as the downward reduction of tissues by slicing progresses.
As soon as the medulla is reached, however, signs of impaired
activity appear: the blood-pressure becomes reduced, and
gradually sinks to naught when a certain level is reached.
Again, as is well known, division of the spinal cord immediately
below the medulla is followed by dilation of the entire vascu-
lar system and a corresponding decline of the blood-pressure,
while electrical stimulation of the cut surface of the lower seg-
ment is followed by general vascular contraction and a propor-
tionate rise in the blood-pressure. We can safely assume,
therefore, that removal of the stellate ganglion modified the
effects of the poison, because it severed the connection between
the terminal fibers in the lacrymal glands acting as vasocon-
strictors, and their center in the medulla.

That it was only under the influence of excessive stimula-
tion that the lacrymal glands showed their abnormal condi-
tion, however, is shown by the fact that in each of the three
animals the organ on the operated side remained normal when
not under the influence of the drug. And yet it would seem
as if, the vessels having lost on that side their tonic contrac-
tion, some morbid evidence of this fact should appear. That
it did not suggests that the sympathetic fibers are not dis-
tributed to the intraglandular vessels, but to the arteries and
arterioles outside the gland, as in the case of the muscular
fibers. Indeed, the vessels that are supplied with muscular
walls, small arteries, and arterioles, and to which nerve-fila-
ments are distributed, do not penetrate the glandules; dimin-
utive capillaries alone reach them, along with fine nervous
filaments. We thus have two distinct kinds of vascular supply
connected with the gland: an internal system of capillaries,
the walls of which, as elsewhere, contain no muscular fibers,
and an external system of small arteries or arterioles which
are supplied with a muscular coat. The fact that the gland
on the operated side remained normal in the experimental ani-
mals, unless submitted to great vascular pressure, coupled with
the principle submitted in the earlier chapters — i.e., that ves-
sels supplied with a muscular coat are antagonistic to capil-

270 . THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

laries in contraction and dilation — will now furnish us a clue
to the functional mechanism of the organ.

It seems clear that if, notwithstanding the dilation of
the vessels, the glandules did not become active it was because
these vessels were not directly connected with them; in other
words, because the secretory part of the organ was not situated
in the direct pathway of the blood-stream. Under these con-
ditions a gland would receive its blood-supply through an arte-
rial loop and only become active when the main channel would
be constricted. It would bear the same relation to the main
blood-path that a side-track bears to the main track of a rail-
road. Unused, the side-track typifies the passive state; used,
it represents the active state, the latter being assumed when
the main track is blocked. Unusual dilation of the main
blood-path, under these circumstances, would deplete the
gland, if it bore any influence upon it at all; a small dose of
pilocarpine, while causing lacrymation in the normal gland,
would hardly overcome the excessive vascular dilation of the
one on the operated side; a large dose, on the contrary, by
increasing general vascular pressure, would so engorge the
weakened vessels as to cause excessive lacrymation on the
corresponding side, as observed in Onuf and Collins7 s first two
animals.

The functional mechanism just referred to can be studied
with more precision in the next subject to be analyzed.

THE SALIVARY GLANDS. — When the effects of increased
blood-supply on the functional activity were reviewed, we saw
that when the chorda tympani was stimulated after section
the submaxillary gland assumed marked activity; its vessels
became greatly enlarged, and its main trunk, which gave
passage to blackish blood before the experiment, remained as
red as arterial blood as long as the chorda tympani was stim-
ulated. Evidently this nerve is the intermediary of the gland's
functions, and Professor Foster is inclined to even exclude
the sympathetic as an efferent nerve and to assign all the
attributes of such a nerve to the chorda tympani. Even from
our standpoint this view is tenable, since it not only distributes
filaments into the gland, but another besides, which reaches
the organ "along the small arteries" distributed to it. To the

FUNCTIONS OF THE SALIVARY GLANDS. 271

former may be ascribed the role of motor nerve, which conveys
impulse-waves that incite the gland to activity and govern the
latter, while the part of vasodilator would be fulfilled by the
vascular fibers. "We thus require nothing more to complete
the gland's functional mechanism.

Still, it is difficult to concede that the copious supply of
sympathetic fibers along the branches of the facial and lingual
that penetrate the organ should hold no place in the active
process, since their exclusion as efferent nerves simultaneously
eliminates them from the latter. If their influence on the
parotid gland can be taken as a standard, however, whatever
part they play, though perhaps not directly connected with
active function, must be directly concerned with the structural
integrity of the organ. Thus, Onuf and Collins state that
"when the parotid gland is thrown into an intense activity by
the cerebral secretory nerve so that it secretes from twelve
to thirteen cubic centimeters of saliva, the secretion scarcely
differs in its microscopical appearance from that of the gland
in a state of rest. If, on the other hand, it has secreted from
two to three cubic centimeters of saliva under the influence
of the sympathetic nerve, the character of the cells is changed
to such a degree that one thinks he has to deal with a com-
pletely new organ." They also refer to the experiments of von
Wittich, which showed that "excitation of the cervical sym-
pathetic nerve remained without effect upon the secretion of the
parotid gland, if the facial nerve of the same side had been
torn out from the cranial cavity either immediately or some
days before." All this suggests that the sympathetic fibers,
as is probably the case with the lacrymal glands, are not dis-
tributed directly to the glandular elements: a view empha-
sized by the experimental observations of Heidenhain, which
showed that the secretion obtained by excitation of the sym-
pathetic nerve (in dogs or rabbits) was very scarce. That
similar experiments would be followed by corresponding results
in the case of the submaxillary glands is very probable, inas-
much as their functions, nervous and vascular supply, and
general histological structure are similar to those of the
parotids.

Foster's belief that the chorda tympani is practically the

272 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

sole efferent nerve of the submaxillary gland is therefore justi-
fied. Indeed, using his words: "Section of that nerve, either
where the fibers pass from the lingual nerve and the submax-
illary ganglion to the gland or where it runs in the same sheath
as the lingual, or in any part of its course from the main
facial trunk to the lingual, puts an end, as far as we know,
to the possibility of any flow being excited by stimuli applied
to the sensory nerves or to the sentient surfaces of the mouth
or of other parts of the body." Referring to the fibers of the
chorda tympani when this nerve reaches the gland, he says:
"The fibers may be traced into the gland for some distance,
but, as we have said, their ultimate ending has not yet been
definitely made out.10 Along its whole course up to the gland,
the fibers of the chorda are very fine medullated fibers, but they
lose their medulla in the gland. The other set of nerve-fibers
reaches the gland along the small arteries of the gland/'

If the annexed engraving, taken from Professor Foster's
work, is carefully examined, however, it will become apparent
that the circulation of the organ and the sympathetic fibers
are intimately associated. The arteries are terminal subdi-
visions of the carotid, while the veins are primary channels
that ultimately lead to the jugular: features which emphasize
their functional importance. Over these are entwined sym-
pathetic fibers from the superior cervical ganglion, which fibers
are inclosed in a common sheath with the main sensory nerve
present, the vagus: further evidence that they must, in a
measure, govern the quantity of blood distributed to the
organ. In fact, this association with the vagus, sufficiently
intimate "to form what appears to be a single trunk/' almost
imposes the deduction that the arterial branches of the latter
nerve transmit the impulse-waves that emanate from the cen-
ters upon which the "nervousness" of speakers, actors, etc.,
depends as to the condition of "dry-mouth," or temporary
xerostomia, so frequently observed. Such an inosculation is
not due to mere hazard; it strongly suggests that the sympa-
thetic fibers form part of the mechanism through which the
intraglandular blood-pressure of the organ is governed: a fact

10 All italics are our own.

FUNCTIONS OP THE SALIVARY GLANDS.

273

confirmed by further inquiry into the mechanical attributes of
the organ.

Admitting, for the time being, that, as implied by the
word "vasodilator," the chorda tympani can dilate the walls of
the vessels to which its fibers are distributed, how could it do
so and so remarkably increase the blood-flow without the co-
operation of the sympathetic fibers? An answer — based

on

v.sym

a.car. aj.

a.sj/m.sm

r.sm.p.

ch.t.

DIAGRAMMATIC REPRESENTATION OF THE SUBMAXILLARY GLAND OF THE
Doa, WITH ITS NERVES AND BLOOD-VESSELS.

"The dissection has been on an animal lying on its back, but since all
the parts shown in the figure cannot be seen from any one point of view,
the figure does not give the exact anatomical relations of the several
structures.

"sm.gld., The submaxillary gland, into the duct (sm.d.) of which a
cannula has been tied. The sublingual gland and duct are now shown.
n.L, n.l.', The lingual branch of the fifth nerve; the part n.l. is going
to the tongue, ch.t., ch.t.", The chorda tympani. The part ch.t." is pro-
ceeding from the facial nerve; at ch.t.' it becomes conjoined with the
lingual (n.l.'), and afterward diverging passes as ch.t. to the gland along
the duct; the continuation of the nerve in company with the lingual
(n.t.) Is not shown, sm.gl., The submaxillary ganglion, with its several
roots, a.car., The carotid artery, two small branches of which (a.sm.a.
and r.sm.p.) pass to the anterior and posterior parts of the gland, v.sm.,
The anterior and posterior veins from the gland, falling into v.j., the
jugular vein, v.sym., The conjoined vagus and sympathetic trunks.
g.cer.s., The upper cervical ganglion, two branches of which, forming
a plexus (a.f.) over the facial artery, are distributed (n.sym.sm.) along
the two glandular arteries to the anterior and posterior portions of the
gland.

"The arrows indicate the direction taken by the nervous impulses
during reflex stimulation of the gland. They ascend to the brain by the
lingual and descend by the chorda tympani." (Foster.)

274 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

prevailing doctrines — at once suggests itself: When the gland
is in the passive state, the fibers of the chorda tympani "block"
the entrance of blood into the organ by causing constriction
of the intraglandular arterial subdivisions before the capil-
laries are reached; when the gland is to assume the active state,
they allow the "block" to relax and a correspondingly greater
amount of blood to pass. Indeed, present teachings do not
in any way grant constricting powers to the chorda tympani
but active dilating properties: i.e., it is thought to actually
dilate the vessel by relaxing its muscular coat, — the foundation
of the belief that vasodilators exist.

Is such a mechanical dilation of the arteries or arterioles
distributed to the gland possible? The intraglandular supply
is mainly composed of capillaries, which, of course, have no
muscular coat. The smaller arteries or arterioles end as such
soon after entering the organ; as the filaments of the chorda
tympani follow the course of these vessels we may surmise that
their terminal end-plates are attached to the muscle-fibers of
the arterioles; but, to avoid any error on this score, we will
consider that they end in the muscular layer of "the small
arteries" to which Professor Foster refers. Unless we can
ascribe to the nerve-endings themselves the lifting power re-
quired to relax the vessels, we must depend on some source
of expansile elasticity such as that shown to exist in the vessels
distributed to muscles, in the elastic festooned layer described
by Eanvier. That the vessels are not mechanically disposed so
as to forcibly dilate the vascular walls hardly needs mention.
Nor does an elastic expansile lamina under the vascular layer
exist in these vessels, which, besides their muscular coat, are
only endowed with an internal endothelial layer and an ex-
ternal adventitious coat. From the standpoint of mechanics,
therefore, there is nothing upon which active dilation of the
vessels could depend. In the light of the views submitted in
this work, therefore, and particularly since the sympathetic
and the chorda tympani are merely considered as subdivisions
of the one great motor system, we find ourselves obliged to
account for the functions of the submaxillary gland with two
vasoconstrictor nerves (sympathetic and chorda tympani) and
filaments of one of these as the transmitters of inciting and

FUNCTIONS OF THE SALIVARY GLANDS. 275

regulating impulses. As the three sets of terminal nerves thus
originate from the one general system, the same impulses must
furthermore satisfy the needs of all three — as we ascertained
was the case with muscles.

Before defining the manner in which we interpret the
functional process, a few quotations from Professor Foster's
work will serve to show that we are probably not on a wrong
path. As to dual function of the chorda tympani, he says,
referring to a series of experiments reviewed by him: "They
further lead us to suppose that the chorda contains two sets of
fibers, one of which we may call secretory fibers, acting directly
on the secreting structures only; and the other, vasodilator
fibers, acting on the blood-vessels only." Again, and what
seems to us to be a striking indirect confirmation of our views:
"When the chorda is stimulated, there pass down the nerve
in addition to impulses affecting the blood-supply, impulses
affecting directly the protoplasm of the secreting cells, and
calling it into action, just as similar impulses call into action
the contractility of the substance of a muscular fiber. Indeed,
the two things, secreting activity and contracting activity, are
very parallel."

The functional mechanism of the submaxillary gland, as
we view it, is as follows: —

Some fibers of the chorda tympani are distributed to the secret-
ing elements to excite and govern their metabolism; the remaining
fibers of the same nerve are distributed to some of the glandular
arterioles, but not to those which supply capillaries to the secreting
elements. While the gland is in the passive state the blood flows
equally through all arterioles.

When the gland is active, the chorda tympani constricts the
arterioles to which it supplies fibers, and thus forces the bulk of
the blood through the free arterioles and thence into the glandular
capillaries.

The rapidity of the blood-flow through the organ is concur-
rently increased through sympathetic constriction of the extra-
glandular arterial branches functionally connected with the gland.

The effect of stimulation of the chorda tympani as noted
by Professor Foster now seems clear: "The small arteries of
the gland become very much dilated, and the whole gland

18

276 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

becomes flushed." From our point of view, this applies to the
arteries deprived of chorda-tympani fibers, since those supplied
with these fibers are contracted and hidden to a greater degree
than before. "Before stimulation the blood trickles out in a
thin, slow stream of a dark, venous color; during stimulation
the blood rushes out in a full stream, often with a distinct
pulsation." Even during excessive glandular activity, the gen-
eral circulation remains unaffected; hence some local means
must intervene to greatly increase the blood-flow; a slight
increase of speed is doubtless afforded by the shifting of the
blood-stream into the glandular arterioles, but the passage of
the blood through the capillaries, glandular elements, etc., very
soon annuls this gain. Indeed, powerful pressure is required
to overcome these obstacles; hence the presence of vasocon-
strictor "sympathetic" fibers around the arteries, to reduce
their lumen and thus increase the vis a tergo power of the
blood-stream. These arteries being outside the gland, as com-
pared to those constricted by the chorda tympani, we will call
them "extrinsic" constrictor fibers in contradistinction to those
of the latter nerve, which we will call "intrinsic" The same
arrangement prevails in muscles to increase the general flow
of blood through them when incited to activity, and in addition
to the fibers distributed to the arterioles just before these give
off capillaries to the muscle-fibers.

SUDORIFEROUS GLANDS. — The confusion that the litera-
ture upon the secretion of sweat so plainly indicates in respect
to the mechanism of this function is easily accounted for when
we recall the important part taken in the process by practically
unknown organs: i.e., the adrenals and their consorts, the
anterior pituitary and the thyroid. We have seen that free
sweating attended the erethic stage of exophthalmic goiter,
and, furthermore, have ascertained that lacrymation could be
caused by pilocarpine as a result of the increase of blood-
pressure this alkaloid was able to produce. If we now recall
the fact that the sweating caused by it is attended with pe-
ripheral hyperaemia, — i.e., flushing, — the link with the first
stage of exophthalmic goiter, also essentially due to suprarenal
overactivity, along with its physiological sequela? (contracted
central vascular trunks, intense peripheral engorgement of the

FUNCTIONS OF THE SWEAT-GLANDS. 277

capillaries), will appear. This process implicates, however, the
participation of a certain — though limited — degree of mechan-
ical force, along with the enhanced metabolism brought about
by the quantity of oxidizing plasma present in the active local
process induced.

A brief summary of the histology of this system is neces-
sary, however, to illustrate the various features to be studied.
The capillaries form a close net-work around the coiled tubes,
and reach down to an extremely thin basement membrane,
which, in turn, surrounds the layer of muscular fibers that coil
around these tubes. An important feature of this muscular
layer, — which is only separated from the cavity or lumen of
the tube by the secreting epithelial cells and their endothelial
lining, — however, is that its ribbon-like fibers are spirally
wrapped round the tube, and in such a manner as to leave a
gap between their border, throughout their whole length. Not
only, therefore, is the thin basement membrane thus enabled
to reach the secreting cells through the gaps, but the former
actually project through the latter so as to touch the mem-
brane. Furthermore, the projecting cells are so related to one
another as to form canaliculi-like spaces, which extend from
the capillary-covered membrane completely through to the
lumen of the tube (Eanvier). The mechanism of the sweat-
secretion is not difficult to understand if these facts are borne
in mind: Contraction of the muscle not only shortens the tube
longitudinally, but causes it to contract when the oxidizing
plasma in the capillaries is increased through peripheral vas-
cular engorgement, whether this be due to constriction of the
arterioles from which the capillaries arise or to contraction of
the central vascular trunks. Both sources of peripheral blood-
pressure act in precisely the same manner: They engorge the
tubular capillaries, excite the functional metabolism of the
underlying muscles, and force the glandular secretion into the
tubular lumen and up along the duct to the cutaneous sur-
face. We can readily understand, therefore, why pilocarpine
should, by stimulating the anterior pituitary and through it
the adrenals, give rise to profuse sweating.

The experiments of Luchsinger, undertaken with other
phases of the problem in view, may also be used in this con-

278 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

nection: i.e., to illustrate the independence of the process from
the nerve-centers, when sweating is induced. This physiologist
cut the sciatic nerve of a young cat, then injected pilocarpine.
Sweating from the four paws occurred, the operation having
in no way interfered with the result. We have seen that
removal of the stellate ganglion in cats was followed by loss
of vascular tonicity in the head-supply, but it likewise does so
in the upper extremities. We also know that the adrenal on
the normal side, and probably collateral nerves connected with
that on the operated side, compensate, in a measure, for the
primarily isolated organ. Onuf and Collins removed the left
stellate ganglion of a cat and three months later injected pilo-
carpine. About ten minutes after the injection both front
paws were sweating; the left, however, less than the right;
six hours later all paws were still somewhat moist. In another
animal "instillation of a few drops of a 2-per-cent. solution of
pilocarpine into each eye produced sweating of all paws, ap-
parently no less of the forepaw of the side (right) on which
the stellate ganglion had been removed four and one-half
months previously." We are evidently dealing with a general
functional mechanism, the most active part of which is as-
cribable to the adrenals.

Another side of the question may be introduced by quot-
ing a passage from the paragraph immediately after that just
referred to. Alluding to the first cat (No. 2 in their series),
from which the left stellate ganglion had been removed, Onuf
and Collins say: "But yet we had to note the paradoxical
fact that, when, on a later occasion, we began the etherization
of cat No. 2 in order to perform another operation, the strug-
gles of the animal against being etherized produced consider-
able sweating of all paws except the left forepaw, which re-
mained perfectly dry." We are no longer dealing here with
induced diaphoresis, but with the purely physiological form
of sweating, — that due to excessive muscular activity, — and
involving primarily, therefore, active participation of the
nervous system. In the induced form, on the other hand,
sweating was incited inordinately through overaction of the
adrenals and through stimulation of the medullary centers.
Yet there is also involved in the process much of the same

FUNCTIONS OP THE SWEAT-GLANDS. 279

mechanical pressure present in induced sweating, — that to
which reference was made when excessive muscular activity
was studied: i.e., increased cardiac activity. \Yhen pilocar-
pine is given in sufficient doses to produce marked diaphoresis,
the heart-beat is increased in power, but lowered as to rhythm.
During the sweating from violent physical exercise the heart-
beats are increased in power, but quickened in rhythm. Hence
there is a more or less marked loss of balance between the
various functional features that contribute to the general
process when induced sweating occurs, while there is perfect
balance in all these when diaphoresis occurs physiologically as
it does during unusual physical exercise. It is only when the
centers are able to adequately utilize the two subdivisions of
the single efferent nerve that supplies glands concurrently with
perfect functional activity of the suprarenal system, that nor-
mal— i.e., physiological — diaphoresis may be said to occur.

In Onuf and Collinses cat No. 2 physiological sweating
supervened; but the centers could no longer transmit efferent
impulses to the secretion-exciting fibers nor to the arterioles
from which the tubular capillaries sprung. The functional
process therefore failed. Had it received the aid of the pow-
erful blood-pressure that pilocarpine procured through the
suprarenal overactivity, however, it would not have fallen
short. Nor did it when, in this same animal, the alkaloid was
put to the test.

In analyzing the manner in which the nervous supply of
the sweat-glands originates and its relationship with the tubuli
we will test the following postulate, suggested by our study of
the innervation of the muscles and submaxillary glands: —

1. All efferent nerves to the periphery and to voluntary mus-
cles are subdivisions of the one great motor system.

2. There are but two divisions of the great motor system: (1)
the "vasoconstrictor" nerves, and (2) the "excito-regulator" nerves,
which incite and govern the metabolism of the glandular elements.

In moribund cats, while the heart-action is growing
weaker, sweating of the toe-pads occurs; and if these are not
pigmented they become pale and exsanguine (M. Duval). This
corresponds with the profuse sweating of death-agony in human
beings, attended, of course, with great pallor or lividity. We

280 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

may recall the fact that several toxic drugs reviewed in one of
our earlier chapters — nicotine, for instance — produced identical
effects. We have also seen that sweating is a marked symptom
of exophthalmic goiter during its cachectic stage, and, indeed,
of many diseases when marasmus prevails. In all of these
pallor of the surface and of the mucous membranes points to
the prevailing mechanical feature, — i.e., engorgement of the
internal vascular trunks, — and therefore to suprarenal insuffi-
ciency. In the sweat-glands proper the opposite condition to
that observed after the use of pilocarpine obtains: The func-
tional metabolism of the acini and of the tubular muscles is re-
duced; the canaliculi between their edges are unusually patent;
the entire structure of the organ is relaxed and allows the secretion
to exude more freely through its elements.

How is this impairment of the sudoriparous functions
induced by suprarenal insufficiency? Section of the cervical
sympathetic in the horse is followed by profuse sweating on
the corresponding side of the head, owing to the relaxation
of the vessels: i.e., to loss of their tonic contraction. We also
know that section of the spinal cord below the medulla is
followed by the same loss of tonic vascular contraction through-
out the entire organism: experimental data which again refer
us to the medulla as the origin (apparent) of the impulse-
waves by means of which the sympathetic fibers govern the
vascular tone of the arteries and arterioles from which the
capillaries distributed to the sweat-glands are derived. We
are not only dealing, therefore, with a mechanical phenomenon
based upon reduced peripheral blood-pressure brought on by
the central engorgement, but with one in which the normal
functional activity of the centers is lowered just as it is low-
ered when the cord is cut below the medulla — the scalpel
being replaced by a reduction of its blood-supply. We, there-
fore, have two interdependent causes for the relaxation of the
peripheral blood-channels, viz.: accumulation of the blood in
the central vascular trunks and loss of tonic contraction of
the peripheral vessels through the lowered potentiality of the
impulse-waves transmitted to the latter via their sympathetic
filaments.

We have expressed the belief that there were but two

FUNCTIONS OF THE SWEAT-GLANDS. 281

divisions of the great motor system, the vasoconstrictor and
the excito-regulator nerves, and, furthermore, that all efferent
nerves were subdivisions of this system. If the sympathetic
nerves are the vasoconstrictor nerves, we are therefore bound
to account for any functional phenomenon witnessed attribu-
table to impulse-waves to the only remaining division: that
which we have termed "excito-regulator."

The question as to whether such excretory nerves exist at
all has been the source of considerable controversy. Vulpian
recognized the existence of "sweat-exciting fibers," but he was
logically led to conclude, in order to account for the fluctua-
tions of activity actually witnessed experimentally and during
morbid states, that "secretion-moderating fibers" likewise ex-
isted. Foster, referring to both these nervous elements, says:
"Though the idea of a double nervous mechanism, augmenting
and inhibitory, governing the activity of the sweat-glands, is
a tempting one, there are at present no satisfactory reasons
for adopting it." We have just seen that the amount of blood
allowed to reach the sudoriferous glands — or, to speak more
correctly in accordance with our views, the amount of blood-
plasma allowed to reach the secreting structures — greatly in-
fluenced their activity; we might, therefore, consider the sym-
pathetic fibers as the "moderating fibers." Still, they not only
moderate the intensity of the process, but also likewise in-
crease it. The same line of argument applies to the term
"sweat-exciting fibers," and we are, therefore, obliged to re-
frain from using these terms, much as we are desirous of
preserving all we can of the nomenclature introduced by such
investigators as Vulpian. Indeed, both peripheral subdivisions
belonging, from our standpoint, to a single system, we cannot
attribute to one subdivision a physiological governing influence
over the other. As we view it, fluctuations affect both divis-
ions equally, the one flow of impulse-waves governing all
functions under their domination, and we look upon any
variation in this functional parallelism, balance, or equipoise
as pathogenic, whatever be its cause.

That sympathetic fibers are distributed to these organs
is a recognized fact. All the experimental evidence adduced
— section of the sciatic, including its sympathetic fibers; Vul-

282 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

plan's, Luchsinger's, Onuf and Collins's experimental removal
of portions of the sympathetic ganglionic chain — attests to
this. The latter authors state that "some writers (Nawrocki
and Luchsinger, and Langley) go so far as to say that all
sweat-fibers destined for the limbs are derived indirectly — i.e.,
through the intermediation of the sympathetic nerve — from
the spinal cord." That the upper extremities and head are
also supplied with them has been emphasized in the foregoing
pages. We are warranted, therefore, in ascribing to these fibers
the functions of one of our divisions, the "vasoconstrictor,"
for the entire sudoriferous glandular system. Through these
vasoconstrictors the blood-plasma is ultimately brought to the
secreting structures, including the spiral muscles, furnishing
them with working energy and with the constituents, water
included, of the excretion itself.

If "excito-regulator" nerves exist, to which of the com-
ponent parts of the sweat-glands are they distributed? The
vasoconstrictor fibers, judging from their role in the voluntary
muscular system, may be considered as extrinsic to the sweat-
system itself, since they can, by constricting arterioles long
before the organ is reached by capillaries, regulate not only
the amount of blood allowed within the secreting elements
themselves, but also in the spiral muscles around the tubes.
We may, therefore, consider the vasoconstrictors as fully ac-
counted for topographically, and also as regards the nature of
their duties, which coincide with those found to be theirs in
the submaxillary gland. The "excito-regulator" nerves, there-
fore, must include within their area of influence the remain-
ing inherent factors of the local functional process: i.e., con-
traction of the spiral muscles and metabolism of the epithelial
secreting cells. It is evident that considerable analogy exists
between sudoriferous glands and salivary glands. In the sub-
maxillary gland we also had, besides the vasoconstrictors, to
account for two functions through the one nerve, the chorda
tympani, one subdivision of which went to muscular fibers
(those of the "blocking" vessels) and the other to the glandular
elements. That the excito-regulator division may dichotomize
— reach of the subdivisions being called upon to excite and
regulate a different, though functionally related, structure —
is evident.

FUNCTIONS OF THE SWEAT-GLANDS. 283

Can we conclude that such a system prevails in the sweat-
glands? Each glomerule of coiled tubes is surrounded by a
plexus of non-medullated fibers containing a number of nerve-
cells, while analogy renders it self-evident that the glandular
muscles must, as all muscles do, receive their stimulus through
nerve-filaments. The fact that they are of the smooth variety
does not modify this relationship, since Tschiriew showed that
"no essential morphological difference exists between nerve-
endings in striated muscles and those in smooth muscles."
Dejerine11 also states that "all nerves end in the form of free
arborizations, and the different modes of contraction of the
various kinds of muscle in no way depend upon the form of
their nerve-terminations/7 Finally, Onuf and Collins remark:
"For the sweat-glands of the head even Luchsinger admits both
a sympathetic (fibers of the cervical sympathetic nerve) and
a direct non-sympathetic nerve-supply, the latter being fur-
nished either by the spinal cord or the medulla." We have
seen that this also applies to the rest of the organism. Ke-
duced to its simplest expression, therefore, the functional
mechanism of the sweat-glands would be as follows: —

The efferent nerves of the sweat-glands are two in number,
loth divisions of the general motor system. One of these, the "in-
trinsic vasoconstrictor" is distributed to the glandular arterioles;
the other, the "excito-regulator," subdivides into two branches, one
of which is distributed to the spiral muscle of the tube and its coils,
and the other to the secreting elements.

When a sweat-gland is active, the "intrinsic vasoconstrictor"
nerve constricts the arterioles and thus forces more blood into
the glandular capillaries to supply sweat- constituents and work-
energy; one subdivision of the "excito-regulator" nerve incites
and governs the activity of the secreting elements, while the other
causes axial and centripetal contraction of the spiral muscle around
the coiled and straight tube.

The rapidity of the blood-flow through the organ is concur-
rently increased through the "extrinsic vasoconstrictor" nerves of
the extraglandular arterioles.

All this being carried on through the agency of a single
flow of impulses, the several elements of the process undergo

u Dejerine: "Anatomic des Centres Nerveux," p. 229, 1895.

284 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

functional fluctuations simultaneously, thus rendering antag-
onistic augmentor and inhibitor nerves unnecessary. Nor can
we deem applicable the term "vasomotor" nerves to regulate
the blood-supply, since it implies active vasodilation besides
vasoconstriction. We have seen that "vasodilation" could not
be active; hence "vasoconstrictor" alone denotes the true
function of such a nerve, vasodilation being either passive or
indirect. The term "secretory" appears as faulty from our
standpoint, since it also suggests that the nerve possesses,
besides its own attributes, — i.e., to excite and regulate gland-
ular activity, — the power to supply the energy required to
sustain the process, which is not the case.

That the foregoing views are sound is suggested by the
facility with which various familiar experiments are accounted
for. "If in the cat," says Foster, "the peripheral stump of the
divided sciatic nerve be stimulated with the interrupted cur-
rent, drops of sweat may readily be observed to gather on the
hairless soles of the foot on that side." The sciatic, as we view
it, supplies all the nerve-impulses of the organ; stimulation
will, therefore, furnish all the energy required for the entire
process. Again, he states: "The sweating is not due to any
increase of blood-supply, for it may be observed when the
cutaneous vessels are thrown into a state of constriction by
the stimulus. . . ." We have seen that this very constric-
tion is an important feature of the process, as we understand
it, since it insures rapid vis a tergo motion and increased
energy. Continuing the sentence, he adds: ". . . or even
when the aorta or crural artery is clamped previous to the
stimulating of the sciatic nerve of a recently amputated leg."
Even these factors should not prevent diaphoresis, if, as we
contend, the motor nerve — the sciatic, in this case — contains
both sets of functional fibers. The motor apparatus being
thus complete, the amputated limb is thus far better able to
respond normally to an artificial stimulus than would a system
embodying mutually antagonistic nerves, such as that now
thought to prevail. "Moreover," says Professor Foster, "when
atropine has been injected, the stimulation produces no sweat,
though vasomotor effects follow as usual." It is evident that
the drug caused this by inducing adrenal insufficiency, thus

FUNCTIONS OF THE MAMMARY GLANDS. 285

dilating the central vascular trunks and depleting the periph-
eral capillaries. While the other part of the sweat-gland mech-
anism may, therefore, act normally, the impulse-waves lose
their influence. Finally, he remarks: "The analogy between
the sweat-glands of the foot and such a gland as the submaxil-
lary is, in fact, very close; . . ." so close, we may add,
that the existence of a common source of energy, a common
channel for its transmission, and a common peripheral mech-
anism can scarcely be doubted.

MAMMARY GLANDS. — Foster refers to the influence of the
nervous system upon the functions of the mammary glands in
the following words: "That both the secretion and ejection
of milk are under the control of the nervous system is shown by
common experience, but the exact nervous mechanism has not
yet been fully worked out. While the erection of the nipple
ceases when the spinal nerves which supply the breast are
divided, the secretion continues, and is not arrested even when
the sympathetic as well as the spinal nerves are cut."

The nerves that supply these organs and the skin cover-
ing them are the intercostals from the second to the sixth,
inclusive; the thoracic branches of the brachial plexus; and
the descending branches of the cervical plexus, while sympa-
thetic filaments accompany all blood-vessels.

In this analysis we will, in a measure, cover two subjects,
since the mammary secretion is carried on in a manner similar
to that which prevails in sebaceous glands. The functional
process in the latter and the similarity referred to are well
illustrated in the following quotations from the work of W.
Eoger Williams.12 Eeferring to the sebaceous glands, this
author says: "Within the membrana propria of its secretory
part we find a stratum of small, irregularly-shaped epithelial
cells, each with a large nucleus (Fig. 1, &). The cells of this
region are constantly proliferating, and, as the products of the
process gradually shift toward the duct, they become changed
and gradually form the secretion." If the words that we have
italicized are placed in immediate sequence, they will be found
to exactly describe the histological arrangement of the sweat-
tubes from the delicate membrane to the lumen. "The steps

12 W. Roger Williams: "Diseases of the Breast," London, 1894.

286

THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

of the process are as follows: The cells next the marginal cells
(Fig. 1, b) increase in size and their nuclei dwindle. As they
approach the center of the acinus their nuclei disappear, and
the cells become distended with granules and oil-globules.
Finally they burst and their debris forms the secretion, which
is discharged." This also coincides with the manner in which
sudoriferous glands produce their secretion.

"Lactation is the outcome of a similar process," continues
Mr. Williams. "Milk must, therefore, be regarded as the
product of the deliquescence of successive degenerations of
epithelial cells which are destroyed in this process and replaced
by relays of new cells derived by division from other still active

FIG. 1.— HlSTOLOGICAL SECTION OF THE WALL OF A SEBACEOUS

CYST. (Cornil and Ranvier.)

a, Fibrous stratum with connective tissue corpuscles, b, Marginal
stratum, c, Hornifying cells, d, Sebaceous cells.

epithelial cells of the part. Thus we see that growth, devel-
opment, and secretion are but slightly varied manifestations
of cellular activity finding expression in different ways."
. . . "The complete degree of mammary function that
eventuates in lactation is only attained periodically, and the
process is always gradual. The following is a brief account of
Creighton's description of it: Subsidence of the function goes
hand in hand with undoing of structure, and revival of the
function with the building up of structure. Variations of
intensity in the secretory force are measured by its products
which correspond to changing aspects of the secreting acini.
The beginning of the rising function coincides with the be-

FUNCTIONS OF THE MAMMARY GLANDS.

287

ginning of pregnancy, and the process occupies the entire
period of gestation. During the intervals between its periods
of functional activity the breast remains in a quiescent func-
tionless state: the resting stage. In this condition the gland
is shrunken and surrounded by a considerable quantity of
fibre-fatty tissue. The acini are shriveled up. On micro-
scopical examination of sections of the gland in this stage
(Fig. 2) each acinus appears as an alveolar space bounded by
a thin layer of fibrous tissue, denuded of epithelium. Its con-
tents are irregularly-arranged, polymorphic, epithelial cells,
with large nuclei and scanty surrounding protoplasm. . . .
"During the rising function the size of the acini grad-

FlG. 2.

FIG. 3.

THE MAMMARY LOBULE NEAR THE RESTING STAGE (UPPER) AND
DURING FUNCTIONAL ACTIVITY. (Creighton.)

ually increases from that of the resting stage. The cells in-
crease in number and size and acquire more protoplasm. They
gradually arrange themselves so as to form a lining membrane
for the wall of the acinus (Fig. 3), which, as lactation ap-
proaches, is converted into a regular mosaic. The cells become
granular, irregularly shaped, excavated, and vacuolated, secret-
ing granular and mucous fluids. The milk of the first few days
is always somewhat crude, containing colostrum-cells, which
are the last of the long series of secretory products thrown off
during the period of rising function.

"The fully-expanded acinus (Fig. 4) in a state of active
secretion is at least four times as large as that of the resting

288 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

stage. Its contained cells are much more numerous than at
any other period, and they form a perfect mosaic, lining the
membrana propria. Each cell is flattened and of polyhedric
shape, and has a large nucleus surrounded by a broad zone of
protoplasm.

"During the period of subsiding function the organ grad-
ually reverts to the resting stage through the converse series
of changes. In this process the cells pass through a succession
of transformations, from the forms characteristic of the per-
fect mosaic of lactation to those peculiar to the various stages
of the subsiding process. These changes are accompanied by
constant destruction and renewal of the participating cells.

"With regard to the influence of the nervous system on

FIG. 4. — EXPANDED MAMMARY ACINUS, SHOWING THE ARRANGEMENT
OF EPITHELIAL MOSAIC. (Creighton.)

the mammary secretion, most of those who have studied the
subject are agreed that the secretion of milk is not directly
under its control. Laffont,13 however, maintains that the
mammaB possess vasodilator nerves which, when stimulated,
cause augmentation of the quantity of milk secreted; but de
Sinety,14 who has repeated his experiments, is unable to accept
his conclusions."

The foregoing review not only indicates the important
part cellular metabolism plays in the functions of the mam-
mary glands, but also that the blood is an important source
of active functional work. "The blood is the ultimate source

18 Laffont: Comptes-Rendus de l'Acad£mie des Sciences, vol. Ixxxix, 1879.
« De Sinety: Memoires de la Societe de Biologie, vol. i, 1879.

FUNCTIONS OF THE MAMMARY GLANDS. 289

of milk/' says Foster, "but it becomes milk only through the
activity of the cell, and that activity consists largely in a
metabolic manufacture by the cell, and in the cell, of the
common things brought by the blood into the special things
present in the milk. Experimental results tell the same tale."
Another feature which it places on a solid footing when asso-
ciated with Professor Foster's research, and one which we wish
particularly to emphasize, is the identity of the liquid which
holds the various constituents of milk in solution, viz.: blood-
plasma. This is also suggested by a statement of M. Duval's,
who, referring to the formation of cream, says: "The trans-
parent portion that remains at the bottom of the vessel repre-
sents the plasma of the milk: that is to say, the milk without
globules. We employ the word 'plasma' here to establish a
parallelism between the analysis of milk and that of the blood.
Skimmed milk corresponds to the liquor of the blood."

In the chapter on "Immunity" the true identity of blood-
plasma, owing to its inherent oxidizing substance, its alexins,
etc., as a prophylactic, and its role in this connection, will be
further studied. But, bearing directly upon the question in
point, — i.e., the functional mechanism, — the presence of plasma
in the milk forcibly indicates that an important vasoconstrictor
system must exist in the mammary gland. In fact, that so
careful an investigator as Laffont should have observed vaso-
dilation further emphasizes this, and tends to indicate that a
process similar to that described by us in our analysis of sub-
maxillary functions must prevail, — i.e., indirect vasodilation, —
a fact sustained by the counter-experiments of an equally com-
petent physiologist, de Sinety, who was unable to find vaso-
dilators per se. Laffont reached his deduction that vasodilation
occurred by measuring the blood-pressure in the mammary
artery of a bitch, during lactation, after severing the mammary
nerve and stimulating the peripheral segment of the latter.
Congestion of the gland and increase of milk-flow followed,
but after cessation of the artificial stimulation the flow, though
not arrested, was greatly reduced. This led Laffont to con-
clude inferentially that the mammary gland possessed typical
vasodilators similar to those thought to exist in the submax-
illary gland. We have shown that the phenomena upon which

290 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

such a deduction could be based, in respect to the latter organ,
could be accounted for without vasodilators and that active
dilation was a mechanical impossibility. Claude Bernard's own
testimony to this is indirectly afforded by the fact that the
"interference" or "inhibition" theory was introduced by him
to account for vasodilation: the existence of which he was
first — as he had been in the case of vasoconstriction — to dem-
onstrate.

The various data reviewed seem to us, when considered col-
lectively, to suggest modifications of generally accepted views.
In the mammary gland the secreting apparatus is formed, we
have seen, first, by an extremely thin basement membrane, and,
second, by a single layer of epithelial secretory cells. The
latter supply the milk-forming elements other than the liquid
per se, which liquid responds to various tests of blood-plasma
(Duval) and seems to replace the water secreted by the sweat,
salivary, and lacrymal glands. In all three of the latter organs,
however, the secreting structures are surrounded by a net-work
of capillaries. That such is also the case in the mammary
gland is evident, since Piersol,15 referring to the glandular
vessels, says: "From these vessels on the anterior surface of
the organ branches penetrate into the glandular mass and
pass between the lobules, giving off twigs which break up into
capillaries inclosing the alveoli.7' A net-work of nerve-fila-
ments are also traced to the glandular elements of salivary
and sudoriferous glands: a feature also reproduced in the
mammse. Thus, Bohm and von Davidoff,16 alluding to the
terminations of the nerves in the mammary glands, recall that
they have been studied by means of the methylene-blue method
by Dmitrewsky, who found that "the terminal branches form
epilamellar plexuses outside the basement membrane of the
alveoli, from which fine nerve-branches pass through the base-
ment membrane and end on the gland-cells in clusters of
terminal granules united by fine filaments." They also state
that "the vessels form capillary net-works surrounding the
alveoli." The ducts when nearing the nipple have an outer

15 Piersol: "Normal Histology," p. 241, seventh edition, 1900.
18 Bohm and von Davidoff: "Text-book of Histology," translated by Huber,
p. 361, 1900.

FUNCTIONS OF THE MAMMARY GLANDS. 291

layer of cellular tissue containing a large number of elastic
fibers and smooth muscular fibers which depart slightly from
the axial line in direction, though insufficiently so to be termed
"spiral" as in the case of the sweat-gland muscles. But, in
the mammary gland, suckling, by creating a vacuum and caus-
ing elongation of the nipple, fulfills the function of the latter.

"We thus have all the structural elements of the previously
studied glands present in these. Their peripheral mechanisms
should also correspond, however. As to the nervous supply,
we have seen that dilation of arteries was found to be con-
trolled by motor nerves, by Laffont, and that the presence of
vasomotors was denied by de Sinety. Hence, the vasodilation
must be due to indirect action, especially since Laffont caused
it by stimulating these nerves, precisely as Claude Bernard had
done in the case of the submaxillary glands. The stimulation
must, therefore, have caused this indirect vascular dilation
in the manner described when the chorda tympani was in
question: i.e., by causing constriction of some of the glandular
vessels. That this conception of the process is justified is
further sustained by the experiments of Rohrig,17 who found
that a motor nerve, the external spermatic, supplied constrictor
fibers to the glandular blood-vessels in the goat, and that
division of one branch of this nerve, the lower, enhanced secre-
tion (evidently due to relaxation of the vessels through loss
of their normal stimulus), while stimulation of the peripheral
end of this subdivision of the nerve decreased the secretion.
This clearly suggests that, just as is the case in the submax-
illary gland, each motor nerve of the mammary gland gives off
two subdivisions: one evidently to the vascular walls, the other,
as we have seen, to the glandular elements.

As to the sympathetic fibers, they are also stated by Eoger
Williams to "accompany the mammary blood-vessels"; and, as
section of a sympathetic nerve is always followed by dilation
of the arteries, they can only act as vasoconstrictors here as
elsewhere. That all efferent fibers distributed to the gland-
ular elements and to the blood-vessels originate from the
general motor system is evident when their relationship with

» Rohrig: Virchow's Archiv, vol. Ixvii, 1876.

19

292 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

the cord, and particularly the results of section immediately
below the medulla, are recalled. That a single stream of im-
pulses from the cerebral centers can sustain the entire function
— that is to say, that part of it under nervous control — scarcely
needs, under these conditions, to be emphasized.

An important characteristic of the functions of the mam-
mary glands, however, is that their dependence upon their
nervous supply is not as great as is the case with other organs.
This is readily accounted for when the identity of the liquid
portion of milk is realized. The blood-plasma must undergo
but little change during its conversion into milk-plasma; in-
deed, it is probably merely filtered through the membrana
propria and the epithelial layer of cells in the lobules and thus
becomes charged with their products. Leucocytes are the main
source of the latter; Kadkin18 found them both in the epithe-
lial lining and alveolar cavities, "wherein disintegration of
their nuclei supplies the milk with a proportion of its nuclein,
the remaining amount of the latter being furnished by the
epithelial cells." These bodies and the oxidizing substance of
the blood-plasma not only transfer to the milk their immuniz-
ing qualities, but the oxidizing substance is itself a source of
functional energy through which leucocytes and epithelial cells
are caused to endow the milk with its nutritive principles.
Much of the organ's work is therefore automatic.

While "the secretion continues and is not arrested even
when the sympathetic as well as the spinal nerves are cut,"
control experiments soon show that, as was the case with
Laffont's animal., the flow, though not arrested, is reduced even
when only one set of nerves is cut. This indicates, when con-
sidered along with the fact that stimulation of the mammary
end of the nerve increases the gland's activity, that the nervous
supply must not be disregarded, and it also suggests that the
sharp line drawn between "active" and "passive" activity, in
the case of other organs, and which mainly depends upon
nerve-impulses to secreting structures and vascular walls, is
scarcely applicable here. Indeed, we are doubtless dealing
with mere fluctuations of activity, called forth, during lacta-

18 Kadkin: Inaugural Dissertation, 1890.

CONCLUSIONS AS TO NATURE OF FUNCTIONAL ACTIVITY. 293

tion, by afferent impulses to the motor centers: a feature
which the rapid formation of milk after nursing and the in-
fluence of emotions upon its flow suggest. In framing our
summary of the functional mechanism of the mammary gland,
therefore, it is not the difference between active and passive
activity that we have in mind, but the manner in which fluct-
uations of activity are brought about. The actual process
involved, even here, however, is primarily a mechanical one,
since filtration of the blood-plasma into the secreting elements
represents no mean expense of force. As blood-pressure to-
tally independent of the normal systemic pressure must
account for this, we are relegated to the vessel-walls and their
nerve-supply as the intermediaries through which this is car-
ried out.

Fluctuations in the functional activity of the mammary
gland during lactation are brought about, if our views are well
founded, in the following manner: —

Each of the motor nerves distributed to the mammary glands
divides into two main branches. One branch, the "extrinsic vaso-
constrictor" (ex-sympathetic), is distributed to the arteries outside
the secreting structures. The other branch, the excito-regulator,
subdivides into two branches; one of these, the "excitor," supplies
fibers to the acini; the other, the "intrinsic constrictor" sends
fibers to the glandular arterioles, but not to those which supply
capillaries to the secreting elements.

During exacerbations of activity the branches distributed to
the arterioles, the "intrinsic constrictors," constrict the latter, thus
forcing the bulk of the blood through the free arterioles and thence
into the capillaries of the secreting acini, while the "excitor" branch
excites and governs the metabolism of the acini.

The rapidity of the blood-flow through the intrinsic blood-
supply — arterioles, capillaries — and through the secretory elements,
is concurrently augmented through increased contraction of the
extralobular mammary arteries by the "extrinsic vasoconstrictor"
(sympathetic) branches distributed to them.

GENERAL CONCLUSIONS AS TO THE MECHANISM OF FUNC-
TIONAL ACTIVITY. — A number of general questions have been
referred to in this chapter the discussion of which has to be

294 THE ADRENAL SYSTEM AND VASOMOTOR FUNCTIONS.

continued in the next, but the following deductions regarding
the several organs the physiology of which has been analyzed
appear warranted: —

1. The sympathetic system is structurally a part of the gen-
eral cerebro-spinal motor system, and is endowed with no function
other than that appertaining to the motor system: i.e., to transmit
efferent impulses.

2. All efferent nerves distributed to the voluntary muscles, to
the salivary, mammary, and cutaneous glands, are subdivisions of
the general cerebro-spinal motor system.

3. The general motor nerves distributed to the organs above
mentioned divide, when near their destination, into two branches:

(1) an "extrinsic vasoconstrictor" branch, which supplies filaments
to the arteries outside the contractile or secretory structures of the,
organ concerned, and increases the speed of the blood-flow through
the latter during activity by reducing the caliber of these arteries;

(2) an "excito-regulator" branch, which supplies the intrinsic
structures of the organ and governs their functional activity.

4. In voluntary muscles and in the salivary, mammary, and
cutaneous glands there are two sets of intrinsic arterioles: (1) a
set which supplies capillaries to the contractile or secretory ele-
ments; (2) a set that does not, but, instead, crosses over to the
venules before the contractile or secretory elements are reached.

5. In the glands mentioned the excito-regulator branch sub-
divides into two branches: one of these, the "excitor," supplies
filaments to the secretory elements and excites them to activity;
the other, the "intrinsic constrictor," is distributed to the intrinsic
arterioles that do not supply the secretory structures with capil-
laries, constricts them during activity, and thus increases the
blood-flow through those that do supply capillaries to the secretory
structures.

6. In muscles the excito-regulator branch also subdivides into
two branches: one of these, the "excitor," supplies filaments to the
muscle-fibers and excites them to activity; the other, the "intrinsic
constrictor," is distributed to the muscular arterioles that do not
supply the muscular fibers with capillaries, constricts them during
muscular contraction, and thus increases the blood-flow through
those that do supply capillaries to the contractile elements.

7. As all the nervous subdivisions referred to, including the

CONCLUSIONS AS TO NATURE OF FUNCTIONAL ACTIVITY. 295

subbranches and terminal filaments, originate from nerves derived
from the general cerebro-spinal motor system, a single stream of
efferent impulse-waves excites and regulates the functional activity
of the organs concerned ~by simultaneously stimulating all their
structural elements.

8. As the vibratory rhythm of the stream of impulses trans-
mitted by a nerve always corresponds with that of the structures
to which its terminal filaments are distributed, any variation of
vibratory rhythm transmitted from the cerebro-spinal centers by
the general motor nerves gives rise to a corresponding variation of
activity in the structures or organs supplied by these terminal
filaments.

9. In all the above-mentioned organs the oxidizing substance
— a combination of adrenal secretion and oxygen formed in the
lungs and of which the blood-plasma is the vehicle — is the physico-
chemical agency through which cellular metabolism is sustained
during PASSIVE functional activity, and increased during ACTIVE
functional activity.

CHAPTER VII.

THE ADRENAL SYSTEM, THE GENERAL MOTOR

SYSTEM, AND THE PNEUMO-

GASTRIC NERVE.

THE OXIDIZING SUBSTANCE AND THE DUAL NERVOUS
SUPPLY OF THE ORGANS OF DIGESTION.

THE oxidizing substance has already shown its ability to
subserve the physiological needs of several sets of organs; we
will now find it to assume similar functions in the stomach,
liver, heart, lungs, etc., notwithstanding the dissimilarity of
the functions of these organs. Here, however, the uncompli-
cated nervous mechanism we have described — all apparently
carried on, as far as efferent impulses are concerned, through
the agency of the single cerebro-spinal motor system — does not
suffice. A new and separate nervous supply seems to demand
recognition: i.e., that represented by the pneumogastric nerves.

THE STOMACH AND ITS PHYSICO-CHEMICAL FUNCTIONS. —
In an able review of the relationship between the nervous
system and the production of gastric secretion Howell1 intro-
duces the following remarks: "It has been very difficult to
obtain direct evidence of the existence of extrinsic secretory
nerves to the gastric glands. In the hands of most experi-
menters stimulation of the vagi and of the sympathetics has
given negative results, and, on the other hand, section of these
nerves does not seem to prevent entirely the formation of the
gastric secretion. There are on record, however, a number of
observations that point to a direct influence of the central
nervous system on the secretion. Thus, Bidder and Schmidt
found that in a hungry dog with a gastric fistula the mere
sight of food caused a flow of gastric juice, and Richet reports
a case of a man in whom the oesophagus was completely oc-
cluded and in whom a gastric fistula was established by sur-
gical operation: It was then found that savory foods chewed

1 Howell: "American Text-book of Physiology," second edition, 1900.

(296)

FUNCTIONS OF THE STOMACH. 297

in the mouth produced a marked now of gastric juice. There
would seem to be no clear way of explaining the secretions in
these cases except upon the supposition that they were caused
by a reflex stimulation of the gastric mucous membrane through
the central nervous system."

The Gastric Nervous Supply and the Formation of Gastric
Juice. — When the nervous supply of the stomach is closely
examined, a rather unusual state of affairs presents itself: i.e.,
it contains no lona fide motor nerves, unless we grant the many
sympathetic fibers distributed to it motor qualities, or, refusing
to recognize these, accept the vagus as the secretory nerve.
But, if we do this, to which nerve must we ascribe the afferent
impulses, which the ingestion of various substances that cause
nausea and other manifestations which clinicians so often wit-
ness induces? The sympathetic has everywhere shown itself
as an efferent nerve, and we have already furnished consider-
able evidence in favor of our view that all sympathetic nerves
are but subdivisions of the general motor system. Considered
from this standpoint, we could logically account for the phe-
nomena witnessed and relegate to the vagus the role of afferent
nerve which, judging from its recognized identity as a great
sensitive system, normally belongs to it. If, on the other hand,
we grant the vagus secretory functions, we have to transform
the sympathetic into an afferent nerve, and necessarily con-
trovert all the experimental evidence adduced.

Howell, continuing the remarks quote'd above, says:
"These cases are strongly supported by some recent experi-
mental work on dogs by Pawlow and Schumowa-Simanowskaja.
These observers used dogs in which a gastric fistula had been
established, and in which, moreover, the oesophagus had been
divided in the neck and the upper and lower cut surfaces
brought to the skin and sutured so as to make two fistulous
openings. In these animals, therefore, food taken into the
mouth and subsequently swallowed escaped to the exterior
through the upper cesophageal fistula without entering the
stomach. Nevertheless, this 'fictitious meal/ as the authors
designate it, brought about a secretion of gastric juice. If in
such animals the two vagi were cut, the 'fictitious meal' no
longer caused a secretion of the gastric juice, and this fact may

298 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

be considered as showing that the secretion obtained when the
vagi were intact was due to a reflex stimulation of the stomach
through these nerves. In later experiments2 from the same
laboratory the secretion caused in this way by the act of eating
is designated as a 'psychical secretion/ on the assumption, for
which considerable evidence is given, that the reflex must in-
volve psychical factors, such as the sensations accompanying
the provocation and gratification of the appetite. In favorable
cases the fictitious feeding was continued for as long as five to
six hours, with the production of a secretion of about 700 cubic
centimeters of pure gastric juice. Finally, these observers
were able to show that direct stimulation of the vagi3 under
proper conditions causes, after a long latent period (four and
a half to ten minutes), a marked secretion of gastric juice.
The long latent period is attributed to the simultaneous stim-
ulation of inhibitory fibers." Howell closes his review of this
subject by the remark: "Taking these results together, we
must believe that the vagi send secretory fibers to the gastric
glands, and that these fibers may be stimulated reflexly through
the sensory nerves of the mouth, and probably also by psychical
states/'

That oral sensory nerves and psychical states may reflexly
cause increase of secretion of gastric juice we deem demon-
strated, not only by experimental physiology, but also by the
teachings of clinical experience. As to the nature of the
stimuli through which this is caused, the newer conceptions
recorded in this work fully sustain the results referred to by
Howell when he says, in the foregoing review: "In the hands
of most experimenters stimulation of the vagi and of the sym-
pathetics has given negative results, and, on the other hand,
section of these nerves does not seem to prevent entirely the
formation of the gastric secretion." And, paradoxical as this
may seem, there is no ground to doubt the accuracy of Pawlow
and Schumowa-Simanowskaja's observation that electrical
stimulation of the vagus gave rise to a marked secretion of
gastric juice. Still, it seems to us that, had wire been dis-

1 Pawlow and Schumowa-Simanowskaja: "Die Arbeit der Verdauungsdrii-
," \Viesbaden, 1898.
• All italics are our own.

FUNCTIONS OP THE STOMACH.

299

tributed throughout the walls of the stomach and a free end
brought out to the exterior and the circuit closed under the
same conditions, an equally strong current being used, the
results would undoubtedly have been similar. The vagus may
have acted as a mere conductor for the transmission of a cur-
rent which would have simultaneously stimulated all the secre-
tory mechanism: glands, vessels, sympathetic fibers, and mus-
cles.

We know that application of the current to the skin causes
contraction of the underlying muscles; can we doubt that the
gastric tissue may be similarly affected when so perfectly 'dis-
tributed a conductor as the fibers of the vagus is employed
for its transmission? It is evident that a current may serve
a useful purpose as it did in Claude Bernard's experiments on
the submaxillary or in Laffont's on the mammary gland, after
vasodilation as a result of division of the nerve had previously
shown its physiological purpose; by merely restoring the nor-
mal state, it afforded confirmatory evidence and a basis for
logical deductions. In Pawlow's experiments it is given the
leading role, however, and, pending further elucidation, it may
prove wise to accept as basis of our analysis of the whole sub-
ject the following remark of Professor Howell's: "Our knowl-
edge of the means by which the flow of gastric secretion is
caused during normal digestion, and of the varying conditions
which influence the flow, is as yet quite incomplete," and to
build up the process with the aid of what newer factors our
own views may suggest.

We may assume, with the quantity of evidence already
adduced as groundwork, that the sympathetic fibers are inti-
mately connected with the functional mechanism of the organ.
As no true motor nerves have been traced to the stomach, and
as we have attributed to the sympathetic system motor func-
tions, may Auerbach's and Meissner^s plexuses — both sympa-
thetic structures — not supply all the efferent fibers required by
the glands and the muscular coats? Beginning with Auer-
bach's plexus, we know that after piercing the external serous
coat of the stomach its nerves pass between the circular and
longitudinal muscular layers, where they form a close net-
work strewn with ganglia, the whole constituting the plexus.

300 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

The terminal varicose fibers of this plexus are particularly in-
teresting to us, since they form in the muscular coat of the
stomach an i/i^mmuscular plexus which entwines, as it were,
the muscular fibers. Furthermore, this plexus gives off fila-
ments which, entering deeper into the wall of the stomach,
form another plexus, also containing many ganglia: i.e., Meiss-
ner's plexus. This net-work of sympathetic elements — fibers,
ganglia, cells, etc. — lies in the submucous coat, — i.e., imme-
diately under the muscularis mucosse, which separates the
latter from the secretory glands. Besides the many filaments
it distributes to the thin submucous muscular layer, it gives
off a large number that penetrate this layer. These, on reach-
ing the glands, form a close net-work in the connective-tissue
sheath surrounding them, which net-work gives off delicate
fibrils that enter into the glandular elements themselves.
They likewise supply terminal fibers to the neighboring mus-
cular elements and to their vascular supply.

The blood-vessels of the stomach are distributed in a very
similar manner. Piersol4 describes them as follows: "The
larger arteries, after penetrating the outer coats, divide within
the submucosa into smaller branches, one set of which pierces
the muscularis mucosae, to be distributed to the mucous mem-
brane, while the other enters the muscular and serous tunics.
The vessels supplying the mucosa form a rich subepithelial
capillary net-work as well as mesh-works surrounding the gastric
glands, the capillaries lying immediately beneath the base-
ment membrane in close proximity to the glandular epithelium.
The branches distributed to the outer layers form long-meshed
capillary net-works from which the muscle-bundles and fibrous
tissue derive their supply." A feature that requires emphasis
in this connection is the manner in which the vessels are finally
distributed to the mucous membrane: The small arteries or
arterioles do not themselves ascend between the glands, but
give off fine capillaries that do so. These, by anastomosing
with one another, form a very rich plexus which surrounds
each glandular tubule in a net-work of close hexagonal meshes.
The cellular secreting elements of the glands being covered

* Piersol: "Normal Histology," p. 166, 1900.

FUNCTIONS OF THE STOMACH. 301

by a delicate basement membrane, the capillaries are thus related
to the former precisely as we found them to be in the sweat-
glands. Indeed, if the intrinsic structures of the stomach are
compared with those of the organs reviewed, it soon becomes
evident that the mechanism to which the production of secre-
tions is due does not differ from them.

We cannot, however, say the same in respect to the ex-
trinsic vessels and nerves, and to this feature of the process
we wish to call especial attention. As is well known, the
vascular supply of the stomach is made up of the gastric,
pyloric, and right gastro-epiploic branches of the hepatic artery
and the left gastro-epiploic and vasa brevia from the splenic.
The important feature referred to is this: The gastric, hepatic,
and splenic arteries arise from the coeliac axis, and, as shown
in the earlier chapters, the cceliac axis is the first great arterial
trunk to receive the blood from the lungs: i.e., before the activity
of the oxidizing substance in the downward blood-stream has
in any way been reduced. Another very suggestive feature is
that the cceliac axis is surrounded by the cceliac plexus, a portion
of the solar plexus of the sympathetic, and that extensions of the
coeliac plexus — the gastric, hepatic, pyloric, gastro-duodenal,
and gastro-epiploic plexuses — follow the arteries of the same
name to the walls of the stomach. We thus have, though in a
much more imposing form, — one compatible with the impor-
tance of the function, — the two structures required by the ex-
trinsic mechanism: arteries with muscular walls and what we
have termed "extrinsic constrictor" nerves — since they are
sympathetic plexuses — to decrease their lumen and thus in-
crease the rapidity of the blood-stream through the gastric
walls, during functional activity.

Another feature requiring our attention is the formation
of the gastric secretion. In the blood-plasma we have sodium
and potassium chlorides; in the secretion of the stomach these
represent the most important and abundant salts, and consti-
tute the source of the hydrochloric acid in the gastric juice,
according to prevailing views. Has the oxidizing substance of
the plasma any influence upon the formation of this acid? The
marked affinity of chlorine for hydrogen seems able to fill the
want. It takes it up whether the gas be free or in vulnerable

302 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

combinations extra cor pore; it doubtless does the same in the
gastric structures. But here conditions are especially well
adapted for such a reaction, if we analyze the question with
the aid of thermochemistry. Equal volumes of chlorine and
hydrogen can only be kept in an absolutely dark place; diffuse
light causes them to slowly unite, while a bright light — sun-
light, for instance — brings on such an instantaneous combina-
tion of the two elementary bodies that the flask containing
them flies into pieces. The fact that this may also be brought
on with a magnesium light which, as is the case with sunlight,
is rich in chemical rays, .indicates that we are dealing with a
process in which heat plays a predominant part. Precisely as
the sun sends radiations which the earth transforms into heat,
so does it, in the experiment mentioned, send radiations which
the combined chlorine and hydrogen transform into heat; the
mixture absorbs the undulations of the ether and transforms
them into molecular energy: i.e., heat. But a multitude of
familiar every-day phenomena prove that increased molecular
energy, or heat, may be procured without light-rays, etc.; the
mere rubbing of a match against a dry surface will cause it to
light, for instance. That this occurs without in the least in-
volving the need of a chemical body on the substance against
which the match is rubbed to start the reaction indicates that
friction causes increased vibratory activity in the ingredients
of the match-tip, and, these only combining when a given tem-
perature is reached, heat must obviously be accepted as the
causative factor of the process. Now, a very significant feature
in connection with the formation of the gastric hydrochloric
acid is the fact that the combination temperature, when an im-
mediate reaction is obtained between chlorine and hydrogen, is
39.5° C. (103.1° F.), while that of the gastric cavity is about
38° 0. (1004° F.). The fact that the walls of the stomach,
the seat of the blood-flow, must show a higher temperature
than this (at least 2 degrees, that of the liver being 106 de-
grees) pointedly suggests that the formation of hydrochloric
acid only occurs when the stomach is brought up to the re-
quired temperature.

How this occurs may now easily be surmised: (1) the ex-
trinsic vascular supply, under the constrict ive influence of the

FUNCTIONS OF THE STOMACH. 303

coeliac-plexus extensions, hastens the speed of the Uood-flow
through the gastric tissues; (2) the oxidizing plasma, by enhanc-
ing metabolism, raises the temperature of the stomach at least the
1.5° C. required to render the formation of hydrochloric acid pos-
sible.

The acid is thus formed when needed: a feature quite
in accord with experimental data. The parietal cells of the
glands, which are the seats of its formation, are only active
during digestion, and then increase in size; they continue in
this condition as long as the stomach contains food, and then
return to their normal size. The following lines of Howell's
also tend to indicate that our conception of the process may
be the right one: "The chemistry of the production of free
HC1 also remains undetermined. No free acid occurs in the
blood or the lymph, and it follows, therefore, that it is manu-
factured in the secreting cells. It is quite evident, too, that
the source of the acid is the neutral chlorides of the blood;
these are in some way decomposed, the chlorine uniting with
hydrogen to form HC1, which is turned out upon the free
surface of the stomach, while the base remains behind and
probably passes back into the blood."

What is the role of the pneumogastric in this connection?
That it must be possessed of some regulative action upon the
circulation is shown by the fact that if, during digestion, — i.e.,
while the mucous membrane is congested and covered with
gastric juice, — the pneumogastric is cut on both sides, pallor
of the surfaces at once ensues and the secretion is arrested.
If the central end — i.e., that toward the brain — be stimulated,
the membrane resumes its former color and the secretion is
re-established, while stimulation of the stomach end of the
nerve produces no effect, according to some observers. Paw-
low, however, as previously stated, obtained a marked secretion
in this manner — probably by using a stronger current than did
his predecessors. We have previously suggested that the latter
result might have been due to the fact that the nerve acted
as a mere conductor; though an afferent nerve, the vagus must
thus have transmitted an electrical efferent impulse, while the
physiological impulse could not have been transmitted by it.
But this objection is removed when we link Pawlow's experi-

304 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

ment with the classic one just referred to, inasmuch as in the
latter we are dealing with an afferent impulse, followed ~by an
efferent impulse. The one experiment, therefore, confirms the
other, and we are brought to recognize that the vagus, as re-
gards its gastric functions, can transmit afferent impulses to
its center from the stomach and impulses from the center to
the stomach, the former being evidently sensory and the latter
motor. And, indeed, there is considerable testimony to the
identity of the vagus as a motor nerve, and, we may add, to
the presence of some exceedingly sensitive center in the region
mentioned, since marked excitement or emotion — fear, anger,
etc. — during digestion will sometimes arrest the latter: i.e.,
give rise to the effect observed after section of both vagi. As
the motor nerves (ex-sympathetic) are efferent nerves, we
therefore have two efferent systems connected with the stomach
besides the sensory portion of the vagus referred to.

What is the relationship between the vagus and the
plexuses overlying the cceliac axis? That the extrinsic vessels
are subject to contractile influences similar to those of the
organs already described is shown by the fact that, when all
nerves distributed to the stomach are cut, the secretion of
gastric juice becomes continuous. Relaxation of the vascular
supply having been induced, the secretion is doubtless due to
the ensuing engorgement of the blood-vessels and correspond-
ingly increased metabolism and temperature: a repetition of
the phenomena witnessed after section of the sympathetic else-
where. Again, that the intrinsic process in the mucous mem-
brane is also that witnessed in the organs referred to is shown
by the following lines by Professor Foster: "When the secre-
tion is very active, the blood flows from the capillaries into the
veins in a rapid stream without losing its bright arterial hue.
The secretion of gastric juice is, in fact, accompanied by vas-
cular dilation in the same way as is the secretion of saliva"
We can, therefore, assume that the cceliac-plexus extensions
fulfill precisely the same role that the sympathetic branches
we have termed "extrinsic vasoconstrictor" did in the other
organs, since they belong to the same motor system.

What is the relative function of the two sets of nerves
in the gastric structures? To analyze this question a brief

FUNCTIONS OF THE STOMACH. . 305

review of the topographical anatomy of the parts is neces-
sary. The following description by Professor Foster not only
furnishes anatomical data, but seems to strengthen the general
physiological process as we interpret it: "The stomach is sup-
plied with nerve-fibers from the two vagi nerves and from the
solar plexus of the splanchnic system. The two vagi, after
forming the cesophageal plexus on the oesophagus, are gath-
ered together again as two main trunks which run along the
oesophagus — the left in front, the right at the back — to the
stomach. The left, or anterior, nerve is distributed to the
smaller curvature and the front surface of the stomach, form-
ing a plexus in which nerve-cells are present; and branches
pass on to the liver and probably to the duodenum. The
right, or posterior, nerve is distributed to the hinder surface
of the stomach, but only to the extent of about one-third of
its fibers; about two-thirds of the fibers pass on to the solar
plexus. . . . From the solar plexus, nerves, arranged largely
in plexuses, pass in company with the divisions of the cceliac
artery, coronary artery of the stomach, and branches of the
hepatic artery, to the stomach. Though the two abdominal
splanchnic nerves which join the solar plexus (semilunar
ganglia) are chiefly composed of medullated fibers, the nerves
which pass from the plexus to the stomach are to a large
extent composed of non-medullated fibers. All these nerves,
both branches of the vagi and those from the solar plexus, lie
at first in company with the arteries on the surface of the
stomach beneath the peritoneum. From thence they pass in-
ward, still in company with arteries, and form, on the one hand,
a plexus containing nerve-cells between the longitudinal and
circular muscular coats corresponding to what in the intestine
we shall have to speak of as the plexus of Auerbach, whence
fibers are distributed to the two muscular coats; and, on the
other hand, a plexus in the submucous coat, also containing
nerve-cells, corresponding to what is known in the intestine
as Meissner's plexus. From this latter plexus fibers pass to
the mucous membrane; some of these end in the muscularis
mucosaB; whether any are connected with the gastric glands,
and, if so, how, is not at present known."

Immediately before reviewing these anatomical features

306 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

the author had referred to the physiological mechanism lead-
ing to the production of the secretion, in the following words:
"Seeing that, unlike the case of the salivary secretion, food is
brought into the immediate neighborhood of the secreting cells,
it is exceedingly probable that a great deal of the secretion is
the result of the working of a local mechanism; and this view
is supported by the fact that when a mechanical stimulus is
applied to one spot of the gastric membrane the secretion is
limited to the neighborhood of that spot and is not excited
in distant parts. This local mechanism may be nervous in
nature, or the effect of the stimulus may perhaps be conveyed
directly from cell to cell, from the mouth of the gland to its
extreme base, without the intervention of any nervous ele-
ments; but the vascular changes at least would seem to imply the
presence of a nervous mechanism" After the lines previously
quoted and referring to those just given, Professor Foster says:
"There are no facts which afford satisfactory evidence that any
part of this arrangement of nerves supplies such a local nerv-
ous mechanism as was suggested above. The importance,
however, of such a local mechanism, whatever its nature, and
the subordinate value of any connection between the gastric mem-
brane and the central nervous system, is further shown by the
fact that a secretion of quite normal gastric juice will go on
after both vagi, or the nerves from the solar plexus going to
the stomach, have been divided, and, indeed, when all the
nervous connections of the stomach are so far as possible
severed."

We have already emphasized the "subordinate value" re-
ferred to by showing that the oxidizing substance was, after
all, the functional principium energeticum, and that vascular
walls, nerves, ganglia, plexuses, etc., were accessories calculated
to bring this energizing principle and the cellular elements
together. In the cceliac-plexus extensions we have, as pre-
viously stated, "extrinsic vasoconstrictors/' but, if two-thirds
of the right vagus passes to the solar plexus, we must have a
duplication of motor functions in this location, and, as this
same nerve also passes on to the stomach, we have two kinds
of nerves distributed over the same structures in much the
same manner: an arrangement which extends to the Auer-

FUNCTIONS OF THE STOMACH. 307

bach and Meissner plexuses. The need of such an arrange-
ment at once suggests itself, however, when the influence of
stimulus applied to the membrane soon after ingestion of the
stimulating agency, as thought by Heidenhain, or some time
after, as thought by Pawlow, is recalled.

The sensory filaments of the vagus could alone, from our
point of view, produce such results, since we attribute only
efferent impulses to the other nerves which all belong to the
great motor system. This is sustained by the classical experi-
ment previously referred to, in which stimulation of the cen-
tral end of the cut vagus caused the secretion to reappear — a
fact which also demonstrates that the vagus is an autono-
mous system: i.e., endowed with afferent and efferent nerves.
Whether the branches distributed to the solar plexus and the
gastric extrinsic vessels are afferent or efferent nerves can now
easily be determined. As the functions of the stomach are
similar to those of the salivary glands, as previously shown,
the increase of secretion caused by stimulation of the stump
can only have been caused by conveying additional impulses
to the normal motor-constrictor impulses and to the rest -of
the motor functional mechanism: a feature which suggests
that the general motor mechanism (sympathetic) serves to main-
tain the tonic contraction of the gastric vascular supply and the
immanent potentiality of the stomach when it is in the passive
state, while the added impulses of the pneumogastric bring on
functional activity. In other words, the great motor system
officiates during the passive state, while the vagus system is
superadded during the active state.

We can now understand why section of both vagi produces
no effect: the motor nerves continue to maintain the tone of
the vessels and everything goes on as usual. If these motor
nerves are also severed, however, we have general relaxation,
as previously explained, and engorgement — secretion. Again,
we can better understand the effects of violent emotion upon
digestion when it becomes possible to ascribe to a single center
or area the effects of the morbid excitement. If the motor
system bore the brunt of such influences, these would in-
duce general vascular dilation by lowering functional activity,
since the said system sustains general vascular tone: again,

20

308 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

they would give rise, besides, to disturbances in all parts of
the organism to which its subdivisions are distributed. Any
practitioner is familiar with the fact that a violent emotion
immediately after a meal will arrest digestion, followed by its
attending phenomena, but give rise to no other symptoms.
The vagus center merely fails, under such circumstances, to
supply the added energy for the active function, and the
food lies in a passive stomach. We have seen that in the ex-
periments of Pawlow and Schumowa-Simanowskaja, referred
to by Howell, the "fictitious meal," though it passed out of
an artificial opening in the oesophagus, nevertheless caused in
dogs a "psychical" secretion of gastric juice. Cutting of the
two vagi in these animals, however, prevented its flow: strong
evidence in itself that the vagus system is the ruling one dur-
ing digestion. Finally, and even more to the point, are the
experiments of Contejean, referred to by Onuf and Collins in
the following words: "Contejean in experimenting upon frogs
found that the pneumogastric nerve has a stimulating influence
upon the secretion of gastric juice, the sympathetic having but
little effect in this direction." Alluding to the results of per-
sonal experiments, these investigators further say: "Inci-
dentally we may mention that this conclusion is in harmony
with the results obtained by Contejean on the stomach of
frogs."

A feature not to be overlooked in this connection is the
practical independence of the suprarenal system. Its vast im-
portance in the organism necessarily involves freedom from
individual organs. As regards the stomach, we can readily
see that the mere constriction of the extrinsic vessels is suffi-
cient to hasten the speed of the blood-flow and the metabolism
of the intramural structures.

This does not mean that all fibers of the motor system
are passive factors; indeed, it is probable that during peri-
staltic action the two nerves, by transmitting impulses of vary-
ing relative intensity, may underlie the motions observed. The
cardiac end of the stomach, for instance, is mainly supplied by
motor fibers.

Vomiting is an interesting symptom in this connection.
Toxics, we have seen, increase suprarenal activity to a more or

FUNCTIONS OP THE STOMACH. 309

less marked degree, and vomiting is a prominent symptom of
acute intoxications. The sudden appearance of a great amount
of suprarenal secretion and a corresponding increase of oxidiz-
ing substance in the blood would obviously cause not only
vomiting, but general gastric activity, were its penetration to
the walls of the stomach and the secretory structures not gov-
erned in some way. Whether there are both efferent and
afferent vagus fibers in the cceliac plexus it is at present im-
possible to tell; but, even if afferent filaments did not exist,
the enhanced activity of the vagus center incident upon the
increased local metabolism would act as an efficient controlling
factor, since it would assist the motor system — similarly over-
excited— in causing enhanced constriction of all the blood-
channels. The wealth of nervous structures over the coeliac
axis suggests that this protective effect is primarily exerted
in this location, thus preserving more or less — according to
the power of the toxic — the integrity of the stomach, liver,
pancreas, spleen, and other structures supplied through the
cceliac trunk.

When all these facts are considered and the kinship of
the functions involved with those of organs previously studied
is fully appreciated, the following deductions seem war-
ranted:—

1. The nerves of the stomach are derived from two auton-
omous sources: the general motor system (sympathetic) and the
vagus system.

(a) The general motor system supplies efferent nerves, which
serve to maintain tonic contraction of the arteries and to insure
the functional efficiency of all gastric structures during the passive,
or resting, period.

fb) The vagus system supplies loth sensory and motor nerves,
ivhich excite and govern the functions of the stomach during its
active period: i.e., digestion.

2. The extrinsic efferent nerves of the stomach, also derived
from the general motor and vagus systems, accompany the organ's
arterial supply and jointly constitute its extrinsic vasoconstrictor
system: i.e., that through which the Hood-flow in the organ is in-
creased.

3. The intrinsic efferent nerves are divided into two sets: (1)

310 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

branches of the "general motor system"; (2) branches of the vagus
system.

(a) Each branch of the "general motor system" subdivides
into two branches: one of these supplies the arterioles; the other
subdivides into two branches, one of which is distributed to the
muscles and the other to the glands.

(b) The branches of the vagus subdivide in the same manner
and inosculate with the general motor filaments and plexuses ex-
cept with those distributed to arterioles that supply capillaries to
the glands, and probably end in the muscularis mucosce.

4- When the stomach is in the resting state, the general motor
nerves alone transmit impulses to all the structures of the organ,
including the glands, which during this period elaborate their
secretory products.

5. When as a result of physical reflex or psychical stimuli the
stomach becomes functionally active, the vagus impulses impose
their rhythm upon the general motor nerves, and the vagus system
assumes control of the digestive process.

(a) The extrinsic arteries are constricted beyond their normal
tonic caliber; the speed of the blood-flow to the stomach-walls is
increased and peristaltic action excited.

(b) The intrinsic arteries that do not supply capillaries to
the glands are constricted also, thus forcing the blood into these
capillaries and inducing glandular activity and the production of
gastric juice.

(c) Pepsinogen (?) and rennin are secreted as a direct result
of increased metabolism in the central cells.

(d) Hydrochloric acid is secreted as a result of the rise of
temperature incident upon increased metabolism, the reaction be-
tween Cl and H — when HCl is formed in the parietal cells — only
occurring when 89.5° C. (103.1° F.) is reached: i.e., approxi-
mately the temperature of the gastric structures during functional
activity.

THE INTESTINES AND THEIR PROPHYLACTIC FUNCTIONS.
— The stomach is, in reality, but a dilated portion of the gen-
eral digestive tract. Its four coats — the mucous or glandular,
the submucous, the muscular, and the serous — are continued in
the intestinal walls, and what variations are present are limited
to the mucous and submucous layers and the glandular struct-

FUNCTIONS OF THE INTESTINES.

311

ures therein and according to their individual functions. To
emphasize the histological similarity between the stomach and
intestines referred to, the following description of the arterial
and nervous supplies, from the pen of Professor Piersol, is
submitted: "The blood-vessels supplying the intestines follow
the general arrangement of those of the stomach. The larger
vessels pierce the serous and muscular coats, giving off slender
twigs to supply the tissues of the tunics; upon reaching the
submucosa the vessels form a wide-meshed net-work. Numer-
ous branches then pass through the muscularis mucosae, to be
distributed to the deeper as well as to the more superficial
parts of the mucosa; narrow capillaries form net-works which
surround the tubular glands, while beneath the epithelium wider
capillaries encircle the mouths of the follicles. From this
superficial capillary net-work the veins arise and, passing be-
tween the follicles, join the deeper venous plexus, which, in
turn, empties into the larger vein of the submucosa. In those
parts of the intestine where villi exist special additional arteries
pass directly to the bases of the villi, when they expand into
capillary net-works, which run beneath the epithelium and
around the central lacteal as far as the ends of the villi. These
capillaries terminate in venous stems, which descend almost
perpendicularly into the mucosa, in their course receiving the
superficial capillaries encircling the glandular ducts. Brun-
ner's glands and the solitary and agminated follicles are sup-
plied from the submucosa by vessels which terminate in capil-
lary net-works distributed to the acini of the glands and to the
interior of the lymph-follicles." . . . "The nerves distrib-
uted to the intestines are arranged almost identically to those
of the stomach; they are composed largely of non-medullated
fibers, derived from the trunks which pass within the mesen-
tery from the larger abdominal sympathetic plexuses. After
giving off branches to the serous coat, the nerves pierce the
longitudinal muscular tunic to form the rich intramuscular
plexus of Auerbach. This is composed of a rich net-work of
delicate, pale fibers, at the nodal points of which microscopical
ganglia exist; after supplying the longitudinal and outer part
of the circular muscular coats the fibers obliquely pierce the
latter tunic to gain the submucous tissue, where they form the

312 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

plexus of Meissner, which closely resembles Auerbach's nervous
net-work within the muscularis, possessing, however, smaller
ganglia and somewhat closed meshes. From the plexus of the
submucous tunic fibers pass into the mucosa, to form net-works
about the glands and to send fibrillse into the villi."

In analyzing the functions of the intestinal tract it is im-
portant to note that two distinct sets of active structures are
present: (1) the secreting glands of Lieberkiihn and of Brun-
ner; (2) the villi of the agminated lymph-follicles (Peyer's
patches) and the solitary lymph-follicles.

Secreting Glands. — The glands, or crypts, of Lieberkiihn,
found in close array throughout the entire length of the intes-
tine, including the colon, are present only in the upper, or
mucous, layer. They are simple in construction and recall the
sweat-glands, minus the coils and muscle: i.e., a net-work of
capillaries and probably nerve-fibrils overlying a delicate base-
ment-membrane which in turn surrounds a single layer of
columnar epithelial cells. These cells radiate toward a com-
mon center and thus form a minute tube which opens upon the
mucous membrane between the villi. Their functional mech-
anism is doubtless that of all simple tubular glands. As sym-
pathetic fibers are alone found here, we are bound to accept
them as motor fibers. Yet only two sets of fibers are necessary:
a set to the glandular arterioles deprived of capillaries; an-
other to the secretory cells. During activity the first set (the
"extrinsic vasoconstrictors") reduces the caliber of the arte-
rioles, forcing more blood into the capillaries, while the second
set incites and governs the activity of the secreting cells.

Howell refers to the crypts of Lieberkiihn as follows:
"These structures resemble the gastric glands in general ap-
pearance, but not in the character of the epithelium.. The
epithelium lining the crypts is of two varieties: the goblet
cells, whose function is to form mucus, and columnar cells with
a characteristic striated border. . . . Whether or not the
crypts form a definite secretion has been much debated. Phys-
iologists are accustomed to speak of an intestinal juice, 'succus
entericus/ as being formed by the glands of Lieberkiihn; but
practically nothing is known as to the mechanism of the secre-
tion." We have seen that nerve-filaments are distributed to

FUNCTIONS OF THE INTESTINES. 313

the secreting cells of the intestines, as stated by Piersol. The
functional needs of these structures seem, therefore, to be satis-
fied. That they secrete mucus seems evident if their histolog-
ical attributes can be taken as guide. We must express the
belief, however, that they have functions other than those
theoretically ascribed to them.

Gastric juice does not only fulfill the role usually at-
tributed to it during digestion, but it is likewise a powerful
antiseptic. Howell refers to this property in the following
words: "One of the interesting facts about this secretion is
the way in which it withstands putrefaction. It may be kept
for a long time, for months even, without becoming putrid and
with very little change, if any, in its digestive action or in its
total acidity. This fact shows that the juice possesses anti-
septic properties, and it is usually supposed that the presence
of the free acid accounts for this quality/' This might serve
as evidence that beyond the pylorus further protection of this
sort is unnecessary: evidence of the care with which Nature
protects her organic creations. Every structural cell in any way
exposed seems to be surrounded not only with prophylactic
weapons, but also with second and even third lines of defense
to cope with what the first line may have failed to disarm.
Removal of the stomach in animals has been followed with
return to normal health; it seems plausible that the intestinal
tract should also be supplied with means for the protection of
its organs.

The material formed in the living crypt of Lieberkiihn
first presents the form of granules, then becomes transformed
into a transparent substance which accumulates in the spaces
of the cell-substance. This either constitutes the mucin found
in the secretion or represents an antecedent of this material.
The secretion proper is clear, viscid, yellowish, and alkaline.
That it may possess antiseptic properties is suggested by the
fact that a very similar fluid, — i.e., nasal "mucus," — thanks to
the labors of St. Clair Thomson and Hewlett,5 has been found
to prove bactericidal. Paget6 experimentally ascertained that

6 St. Clair Thomson and Hewlett: Medico-Chirurgical Transactions, vol.
Ixxviii.

6 Paget: Journal of Laryngology, Nov., 1896.

314 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

nasal "mucus" killed anthrax bacilli, that Klebs-Loeffler ba-
cilli were almost as actively destroyed by it, and that the viru-
lence of staphylococci and streptococci was reduced. Nasal
"mucus," however, is largely made up of serum: a feature
which also applies to the secretion of the glands of Lieberkiihn.

Brunner's glands, which occur in the duodenum, at the
portal of the intestinal canal, would seem to suggest, by their
situation and their general conformation, just such a function.
While they resemble in general structure the pyloric glands,
to which most authors compare them, they also present many
characteristics of the mammary lobules, especially in the man-
ner in which their interlobular ducts are disposed. The gland
proper is situated beneath the smaller crypts just described, —
i.e., in the submucous tissues, — its ducts penetrating to the
surface between the villi or into the crypts of Lieberkiihn: an
indication that there is considerable analogy between their
products. Indeed, their secretion is also serous: i.e., blood-
plasma relieved of its fibrin, globulins, etc.

The secretion of these two glands is termed "intestinal
juice," or "succus entericus," and is regarded by many as
capable of acting on starch, proteids, fats, etc., in connection
with intestinal digestion: all properties which might not con-
trovert any antiseptic power it might possess through the pres-
ence of oxidizing substance and alexins. Professor Foster,
however, referring to this supposed action on foods, says:
"Even at its best its actions are slow and feeble. Moreover,
many observers have obtained negative results; so that the
various statements are conflicting." And he adds: "We may,
therefore, conclude that at present, at all events, we have no
satisfactory reasons for supposing that the actual digestion of
food in the intestine is, to any great extent, aided by such a
juice."

These two glands are the only ones forming part of the
intestinal tissues per se to which the protective functions re-
ferred to could be ascribed. Hence, the facts that they both
produce a secretion so nearly identical to blood-plasma as to
be called "serous," — for the glands of Lieberkiihn are the
source of serous diarrhoea, and the rice-water discharges of
Asiatic cholera, a disease which, as we will show, is the most

FUNCTIONS OF THE INTESTINES. 315

acute expression of suprarenal insufficiency, — and that blood-
plasma is the normal excipient for chemical protective agencies,
suggest the following deduction: The glands of Lieberlcuhn and
the duodenal glands of Brunner supply a secretion having for its
object to asepticize, and prevent the putrefaction of, the intestinal
contents.

A kindred, though far more important, process is the pro-
tection afforded the organism where poisons of all kinds are
most likely to penetrate the blood-stream: i.e., the organs of
the intestinal wall connected with absorption.

Villi and Lymph- follicles. — The villi, the solitary lymph-
follicles, and the agminated lymph-follicles, or Peyer's patches,
are considered together, because they appear to us to represent
parts of a single system.

The structural similarity between the walls of the stomach
and those of the intestine must be set aside here, since the
function referred to, — i.e., absorption, — a predominating one
in connection with the intestines, can hardly be said to be
worth considering as a factor of gastric functions. Conversely,
the villi distributed throughout the whole small intestine are
especially adapted for this purpose. Besides the capillaries,
nerves, muscular tissue, basement membrane, and epithelium,
these structures contain a lymph-trunk, or lacteal, the purpose
of which is to take up nutritional agencies from the intestinal
contents as they pass along.

Each villus may be considered as a sort of "reversed"
gland, if a sweat-gland is taken as standard. The epithelium
is outside, — i.e., exposed in the intestinal canal, — while under
the epithelium lies the basement membrane. Combined, these
two constitute a glove-finger-like projection inside of which
are the structures that we found over the basement membrane
in the sweat-gland. The capillaries form a close-meshed net-
work not only in contact with the inside of the basement
membrane, but entwined with considerable connective tissue
strewn with leucocytes, the tissue and cells constituting "lym-
phoid tissue." We said "connective tissue," but at this point
we must emphasize the fact that it is not true connective tissue,
as met with elsewhere, but a fenestrated membrane made up
entirely of star-like cells that give off thin projections, or

316 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

pseudopodia, which by intermixing make up the tissue itself:
i.e., Kolliker's cytogenous tissue. The fenestra, or openings,
with which this cytogenous membrane is permeated accommo-
date the capillaries.

Another histological feature of special interest is the
presence of smooth muscular fibers which stand upright — a few
being horizontally disposed — and are interwoven among the
capillaries and cell-fibers previously referred to. We thus have
immediately under the villus's delicate basement membrane a

INTESTINAL, VILL.TJS; VENOUS RADICLE SHOWN AT o. (Cadiat.)

perfect, though minute, suction-pump which by alternately
contracting and relaxing causes the organ to absorb the pre-
viously asepticized intestinal fluids.

Next in order inwardly are the venous stems (one or two)
which carry the blood from the villous capillaries to the veins
in the deeper tissues. These vascular channels, which carry
the bulk of intestinal foodstuffs to veins which ultimately end
in the portal system, are well shown in the annexed cut, and
will again be referred to.

Last of all, in the middle of the organ, is the lacteal, — a

FUNCTIONS OF THE INTESTINES.

317

thick, club-like, sometimes double, lymphatic vessel, which
stands upright and reaches almost to the inside of the tip of
the villus, its own blind apex almost touching the former.
Each lacteal represents the origin of a lymphatic vessel. This
is illustrated in the second figure.

Lymph contains chyle — derived from the intestines — only
during intestinal digestion. At other times the fluid found
in the lacteal and neighboring structures is identical to that

INTESTINAL VILLI; INJECTED LACTEALS IN THE
MIDDLE OF EACH VILLUS. (Cadiat.)

found elsewhere in the organism. It is perhaps advisable to
emphasize the fact that lymph is very similar to blood-plasma,
and richer than this fluid, owing to the presence of leucocytes.
Indeed, it only differs from blood in the absence of red cor-
puscles. It undergoes coagulation and separates, as does
plasma, into serum and clot, the latter likewise containing
fibrin-globulins. It contains serum-globulin and serum-albu-
min in relative proportions similar to those in blood, though
in smaller quantity: a feature which accounts for its somewhat

318 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

lower specific gravity. Inorganic salts, the chlorides prepon-
derating, also correspond to those of the plasma. Being a
vehicle for various substances, its constituents are variable
quantities, and the conflicting analyses published are thus ac-
counted for. Stewart says, in this connection: "Lymph has
been defined as. blood without its red corpuscles (Johannes
Muller); it is, in fact, a dilute blood-plasma, containing leu-
cocytes, some of which (lymphocytes) are common to lymph
and blood, others (coarsely granular basophile cells) are absent
from the blood. The reason of this similarity appears when
it is recognized that the plasma of lymph is derived from the
plasma of blood by a process of physiological filtration (or
secretion) through the walls of the capillaries into the lymph-
spaces that everywhere occupy the interstices of areolar tissue.
But, in addition to the constituents of the plasma, lymph ap-
pears to contain certain toxic substances produced in the me-
tabolism of the tissues and destroyed in the lymphatic glands. 'r

It now seems probable that the intestinal tract, being one
of the two regions most exposed to toxics, the villi not only
have for their function to absorb chyle, but to protect the or-
ganism. The lacteal is the recognized absorption organ for
emulsified fats. As we view the process involved, the fat-con-
taining fluids, as soon as they reach the basement membrane,
are first submitted to the asepticizing influence of its endo-
thelial cells. They are then submitted to the next process of
epuration, and probably chemically transformed in the lym-
phoid layer — Kolliker's cytogenous layer — immediately be-
neath, in which leucocytes, and, therefore, antitoxic substances,
are constantly being formed. When it finally reaches the lacteal,
it again meets endothelial walls, and when through these and
in the lacteal, must run the gauntlet of an accumulated array
of fresh leucocytes from the cytogenpus layer. The chyle,
therefore, is met as soon as it enters the organism by all the
latter's protective resources: phagocytes, stellate or connective-
tissue cells, endothelial cells, and finally the oxidizing sub-
stance, the latter probably serving here to convert products of
local metabolism and other toxic materials into inert bodies.

The villi, which thus absorb all nutrient substances as-
similated by the organism whether by their venous stems or

FUNCTIONS OF THE INTESTINES.

319

their lactcals, are thickly distributed throughout the entire
length of the small intestine. In the duodenum and jejunum
they. doubtless fully satisfy the needs of the organism, both
as to absorption and prophylaxis. In the lower part of the
intestinal canal, however, more protection is required, owing
perhaps to continued exposure of the contents to a relatively
high temperature during the time elapsed since this material
has been submitted to powerful antiseptic treatment in the
stomach: i.e., several hours to a day, according to the meal.
A morning movement of the bowels, for instance, includes
products of the breakfast of the preceding day, thus repre-
senting twenty-four hours of exposure in the intestine to a
temperature averaging 39° C. (102.2° F.). This additional
precaution is represented by the solitary lymph-follicles and
the agminated lymph-follicles, or Peyer's patches. While the
solitary lymph-follicles are found throughout the entire canal,
small and large, they are by far most numerous in the lower
part of the ileum and in the first part of the colon. Peyer's
patches, or the agminated follicles, are likewise found in the
duodenum and jejunum, though rarely in the former; but their
site of predilection is also in the ileum, and, inasmuch as they
vary from one-half inch to four inches in length and are oval
or round, they cover an extensive area, though only twenty
to thirty in number. Especially is this the case since they are
practically limited to one side of the intestine: i.e., to the
portion facing the latter^s attachment to the mesentery. They
also frequently form a continuous layer in the vermiform ap-
pendix.

A single "solitary follicle" is typical of them all, includ-
ing those in Peyer's patches. A follicle consists, on the whole,
of a rounded mass lodged in the submucous tissue, a small part
of its upper portion appearing upon the free surface of the
latter, though the epithelium of the intestine also covers it.
The overlying layer of epithelium, however, is separated from
the follicle by a special delicate membrane perforated with a
multitude of holes that .surround its projecting portion and
communicate with the organ itself.

The structure of the body of the follicle will perhaps be
best understood if it is divided into three different parts, be-

320 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

ginning from the inner portion of the organ. A fine net-
work of capillary blood-vessels which acts as a supporting
fabric, furnished by underlying arterioles, is the central feat-
ure; this, in turn, is surrounded with a close net-work of
fibrils, in which "lymph-corpuscles, small round cells, with a
large nucleus and very little perinuclear protoplasm" so com-
pletely preponderate as to almost entirely obscure the net-
work.7 But there is a feature of special interest here which
will remind us of the cell-forming membrane of Kolliker found
in villi: i.e., a central nodule, described by Flemming, in which
some cells undergo active karyokinetic division, while others,
lymphocytes, are formed in continuous quantities. "In the
center of the nodule," say Bohm and von Davidoff,8 "the cells
often show numerous mitoses, and it is here that an active
proliferation of the cells takes place. The cells may either
remain in the lymph-follicle or the newly-formed cells are
pushed to the periphery of the nodule and are then swept into
the circulation by the slow lymph-current which circulates be-
tween the wide meshes of the reticular connective tissue." The
third portion is the interval referred to, a delicately partitioned
sinus which surrounds the follicle. To this sinus the lymph,
originally from the blood-capillaries, after it has permeated
the meshes and cell-spaces of the adenoid tissue and became
charged with the newly created cells, gravitates, to finally find
its way into the lymph-vessels of the submucous tissues be-
neath.

The physiological functions of the follicle seem plain when
we consider two salient features of its anatomical relations
with the mucous surface of the intestine and with the villi.
As to the relationship between the interior of the follicle and
the intestinal canal, it is suggested by the perforations to which
we have previously referred, but there seems to be no mech-
anism to insure absorption. The case is not the same, however,
in respect to the connection with the villi. Indeed, the lym-
phatic vessels which originate from the lacteals of the latter
constitute the afferent supply of the sinus, while the lymphatic
vessels of the submucous tissue represent its efferent system.

*Clarkson: "Histology," 1896.

8 Bohm and von Davidoff: Loo. cit.

FUNCTIONS OF THE INTESTINES.

321

Jt is very evident, therefore, that we have, in each follicle, a
powerful adjunct to the overlying villi, to add still another
prophylactic means to those already enumerated. While the
villi do not occur upon the portion of the follicle that projects
into the intestinal free surface, they are nevertheless present
around it, and their lacteals when below the level of the epithe-
lium break up into vessels which find their way to the lymph-
sinus. "When they reach the level of the closed follicles," says
Berdal,9 "the chyliferous vessels become united to the sinuses
of these follicles, of which they constitute the afferent vessels.
Crossing the muscularis mucosae, they form part of a varicose
capillary net-work in the submucosa. From this net-work
arise true lymphatic trunks supplied with valves that cross the
intestinal coats and then reach the subperitoneal lymphatic
net-work."

The intimate relationship between the villus and the lym-
phatic follicle is further emphasized by the similarity which
their mechanisms present. If the lymph-sinus of the latter is
considered as functionally encircling what in the villus has
been termed cytogenous tissue by Kolliker, including its net-
work of capillaries, this similarity becomes striking. Indeed,
the fact that the sinus is situated around the lymphoid tis-
sue instead of in its center, as it is in the villus, would tend
to indicate that the follicle does not absorb intestinal fluids,
since these would merely, before reaching the sinus, be sub-
jected to what epuration the epithelium and the fenestrated
membrane overlying the organ could afford. It is, therefore,
probable that the solitary follicle or organ does not include
absorption among its attributes. Indeed, unless possessed of
a suction mechanism such as that of the villi, it is evident that,
surrounded, as is its projecting part, by these minute pumps,
its usefulness would be very slight.

What can be the use, therefore, of the minute apertures
encircling the projecting part of the follicle and which con-
stitute the "fenestrated" subepithelial membrane? "These
orifices appear," says Berdal, "to afford passage to lymphatic
cells that emigrate from the follicle toward the cavity of the

• Berdal: "Histologie Normals," p. 365, 1894.

322 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

intestine/' — and to assist, if considered from our standpoint,
in asepticizing the contents of the lower end of the small intestine
by permeating it with mobile phagocytes and alexocytes. If we now
connect this fact with the predilection of Peyer's patches for
bacterial invasion in typhoid fever, it would seem as if func-
tional impairment of these organs would render possible the
pullulation of pathogenic organisms in the ileum. This would
normally lead to infection of the patches, and of the system
at large through the apertures.

Besides this first, and we may add, very important pro-
tective function, the follicular sinus, by serving as a secondary
passage for the chyle, appears to afford a supplemental pro-
tection to the organism of no mean power when we consider
that it serves not only as a channel for freshly-manufactured
leucocytes, but that the follicle simultaneously receives freshly-
oxidized blood directly from the great arterial trunks, through
the mesenteric arteries. This blood, which reaches the lym-
phoid tissue through the rich intrinsic capillary net-work to
which we have referred, doubtless furnishes it with the various
elements required for the metamorphoses — retrogressive and
progressive — :noted by Flemming and others, then forces its
way into the sinus, carrying with it not only the newly-created
cells, but also serum supplied with all the defensive agencies
which the blood affords. The accumulation of Peyer s patches
in the lower two-thirds of the ileum seems to directly point to
this as the most toxic part of the canal — and clinicians well
know how frequently this region becomes the seat of intestinal
disease.

It would thus appear as if in the duodenum, the jejunum,
and the upper part of the ileum, the gastric juice, the secretion
of the crypts of Lieberkiihn and that of the glands of Brunner,
in addition to the ultravillous process, would subserve the
protective process; and that beyond this, to the end of the
ileum, the follicles, either solitary or agminated in patches,
the villous process plus the folliculous process, including the
output of lymphocytes into the intestine, united to accom-
plish the same prophylactic purpose.

Solitary follicles are also very numerous in the caecum;
while in the vermiform appendix agminated follicles they are

FUNCTIONS OF THE INTESTINES.

323

sometimes so plentiful as to have suggested to some anatomists
the presence of a great Peyer patch. If the production of
lymphocytes through the upper fenestrated layer is a function
of the follicles here as it is in the ileum, the appendix would
have, as its physiological function, the production of quantities
of leucocytes intended to prevent the pullulation of bacteria
in the caecum: a region which, owing to its conformation,
must lend itself admirably to the accumulation of putrefactive
matter. The colon is deprived of villi, but plentifully supplied
with crypts of Lieberkiihn, while solitary glands, somewhat
larger than those in the ileum, are scattered throughout its
entire extent. The former doubtless furnish the mucus, while
the latter probably contribute the asepticizing lymphocytes.

These views, as far as they go, are sustained by experi-
mental data. We must state, however, that the sympathetic
system alone — our general motor system — does not account for
other phenomena to be studied elsewhere in this work. While
the tabular plan on the next page, illustrating the nervous
mechanism down to the adrenals, explains all effects ascribable
to efferent impulses, afferent impulses are as necessary here
as they are in the stomach to initiate the secretions of the
glandular structures and, if need be, augment them. The pres-
ence of vagal filaments can, therefore, be assumed pending the
presentation of confirmatory testimony.

After stating that "the influence of special nerves upon
the secretion of intestinal juice has not been studied as yet,"
Onuf and Collins refer as follows to the disturbances that re-
sult from extirpation of the stellate ganglion in cats: "They
consisted of diarrhoea and putrefaction of the faeces. The
faecal matter was semiconsistent, of yellow or dark-grayish-
brown color, and of exceedingly foul odor. This putrefaction
of the faeces 'was observed in two of the three animals from
which we removed the stellate ganglion. In the third cat
they were not noted; but it should be added that this cat was
killed before a time corresponding to that which had elapsed
antecedent to the occurrence of putrefaction in the first two
cats. The putrefactive symptoms made their appearance as
late as two or three months after the operation, and it was
noted that the

21

digestive disturbances had a tendency to in-

324 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

crease and persisted until the death of the animals, three and
four and one-half months, respectively, after the operation. In
one instance the autopsy revealed marked anaemia of the in-
testines."

ORGANS OP THE DIGESTIVE TRACT SUPPLIED BY THE SOLAR PLEXUS.
Diaphragm.

( a ) Phrenic plexus

Suprarenal glands. f ^ in{erior yena ^

Through its dia-

phragmatic ganglion

i Suprarenal capsules.

(6) Suprarenal plexus. (Also includes subdivis-
ions of the solar plexus, semilunar gan-
glion, phrenic, and great splanchnic.
Branches of this plexus are remarkable
for their large size.)

Suprarenal glands.

(c) Cceliac plexus

Coeliac axis.

Stomach.

Liver.

Spleen.

Pancreas.

Duodenum.

Epiploon.

(d) Superior mesenteric

Mesentery.
Pancreas.
Small intestine.
Part of colon.

(«) Aortic plexus

Mesentery.
Part of colon.
Sigmoid flexure.
Rectum.

We are dealing, in these experiments, less with the effects
of section of intestinal nervous supply on the local vascular
walls than with those of impaired suprarenal functions, the
connection between the adrenals and the anterior pituitary on
one side being removed. Decrease in the suprarenal substance
supplied to the blood, and therefore of oxidizing substance in
the plasma, was the main morbid factor. The functional en-
ergy of the intestinal crypts, glands, and follicles being im-

FUNCTIONS OF THE INTESTINES.

325

paired through loss of part of their pabulum energeticum in the
blood, the asepticizing secretion of the crypts of Lieberkiihn
and the glands of Brunner became reduced, the production of
lymphocytes by the follicles likewise, while the reduction of
oxidizing substance in the secretions per se contributed to fur-
ther impair their prophylactic qualities. Onuf and Collins also
refer to one of their animals operated in the same way, in
which diarrhoea developed in two weeks; the third week "the
animal began to be uncertain in gait, which increased to well-
marked staggering" . . . "within two days it died in col-
lapse." That these phenomena are of suprarenal origin needs
hardly to be emphasized.

The following deductions seem to us to be warranted by
the analysis submitted: —

The glands of Lieberkuhn and the duodenal glands of Brun-
ner supply a secretion the purpose of which is to asepticize the
intestinal contents.

The villi, through their venules and lacteals, absorb nutrient
and chyle-forming materials from the intestinal foodstuffs, and
the contents of the lacteals are submitted to a further asepticizing
process, mainly in Kolliker's cytogenic membrane.

The solitary and agminated lymph-follicles (Peyer's patches)
are cytogenic structures which further asepticize the materials ab-
sorbed by the surrounding villi, the efferent lymph-vessels of the
latter constituting the afferent lymph-vessels of the follicles, where
.both kinds of organs occur together: i.e., in the portion of the small
intestine in which pullulation of pathogenic bacteria is most likely
to occur, the ileum particularly.

The solitary and agminated lymph- follicles also supply leu-
cocytes to the intestinal cavity, which leucocytes are formed in
their cytogenic area (Flemming's central nodule) and pass out
through the fenestrated membrane overlying each follicle. The
purpose of some of these leucocytes is to insure the destruction of
pathogenic bacteria formed as a result of putrefaction of the in-
testinal contents or introduced into the intestine.

The ccecum, being particularly exposed to the accumulation of
putrefactive materials, is supplied with an organ in which agmin-
ated lymph-follicles are particularly numerous: i.e., the vermiform
appendix. The functions of this organ, therefore, appear to be to

326 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

supply the ccecum with bactericidal cells and their products: i.e.,
phagocytic leucocytes and alexocytes — in addition to those supplied
by the ccecal agminated follicles — and antitoxic blood-serum.

In the colon, the asepticizing process is fulfilled by a rich sup-
ply (1) of Lieberkiihn's crypts, which keep its walls bathed with
their muco-serous secretions; and (2) of irregularly scattered
solitary lymph-follicles, which supply the latter secretion with
bactericidal cells and their alexins.

The nervous supply of the intestines is derived from the gen-
eral motor system (ex-sympathetic nerves) and from the vagal sys-
tem, the distribution to the various intestinal coats being similar to
that of the branches of the same system in the stomach. The vagal
system probably alone excites and regulates intestinal functions
during digestion as well as during intervals,

THE LIVER AND ITS PHYSICO-CPIEMICAL FUNCTIONS. —
There is considerable evidence available to show that oxidation
is one of the most active factors of hepatic functions, and yet
it must be admitted that, according to prevailing views, there
is no blood-supply capable of accounting for this powerful
source of energy. To the portal vein, essentially a channel
for physiologically impotent blood, — i.e., blood replete with the
waste-products of four important organs and the oxygen of
which has been utilized in these organs, — is ascribed this pre-
ponderating role. On the other hand, the hepatic artery is
thought to supply the liver "with the blood of nutrition." Text-
books on physiology, therefore, seldom refer to this vessel;
works on histology hardly grant it more than two or three
lines, if they refer to it at all. In text-books on anatomy it
receives more attention, but only in its general topographical
bearing.

As viewed from our standpoint, the hepatic artery does not
only supply the liver with its nutritional blood, but simultaneously
with the blood upon which all its functions depend.

To develop this proposition a review of the histology of
the lobule is necessary. Clarkson10 gives the following com-
plete, though succinct, description of this wonderful little body

10 Clarkson: "Text-book of Histology," 1896.

FUNCTIONS OF THE LIVER. 327

— about one-twentieth of an inch in diameter — and which in
itself has been termed a "miniature liver": —

"A lobule of the liver is polygonal in shape, and is com-
posed chiefly of a number of gland-tubes, which radiate from
near the center of the lobule to the periphery, where they open
into their ducts. Thus, the blind terminal end of the tube is
turned toward the center of the lobule; the ducts at the pe-
riphery lie in the interlobular connective tissue, which to the
naked eye marks the boundaries of the lobule.

"The blood brought to the liver by the portal vein11 is
conveyed along its subdividing branches till the ultimate sub-
divisions are reached, which lie, together with the bile, in the
connective tissue surrounding the lobules. Here capillaries are
given off which pierce the lobule and pass between the radiat-
ing gland-tubes to reach the center, where they open into the
intralobular radicle of the efferent vein of the liver, the hepatic
vein. These small hepatic radicles open into the larger vessel,
— the sublobular vein, — and the sublobular veins unite to con-
tribute to the hepatic vein itself. The walls of the branches
of the hepatic vein are destitute of muscular fibers and the
adventitia is extremely thin. The radiating gland-tubes anas-
tomose laterally with each other, as do the capillaries also.
The meshes of the net-works are elongated in a radial direction.
Thus, a lobule is composed of a radiating system of gland-tubes
and a corresponding radiating system of capillaries lying be-
tween them. A very minute quantity of connective tissue
accompanies the capillaries as an adventitia and in this lym-
phatic channels are to be found separating the gland-tubule
from the blood-vessel.

"The lobule is surrounded (in part or whole) with con-
nective tissue supporting branches of the afferent portal vein,
— the feeder of the capillary net-work, — and the bile-ducts,
which receive the secretion of the gland-tubules. Thus, the
blood flows from the periphery to the center of the lobule; the
bile, from the center to the periphery.

"But in addition to the afferent portal vein and the bile-
ducts another vessel is found in the interlobular connective

11 The italics are our own.

328 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

tissue. This is the hepatic artery, which supplies blood for the
nutrition of the connective tissue of the organ, the vessel-walls,
etc. It ultimately terminates in the small portal veins, and
perhaps partly in the capillaries in the periphery of the lob-
ules."

There exists some uncertainty as to the manner in which
the subdivisions of the hepatic artery are related to the other
perilobular and intralobular vessels. Pick and Howden12 refer
to its terminal distribution as follows: "Finally, it gives off
interlobular branches, which form a plexus on the outer side
of each lobule, to supply its wall and the accompanying bile-
ducts. From this lobular branches enter the lobule and end in
the capillary net-work between the cells. Some anatomists,
however, doubt whether it transmits any blood directly to the
capillary net-work/' Harrison Allen13 says: "Each lobule is
a miniature liver having at its periphery between the lobules
branches of the portal vein and hepatic artery (interlobular
branches) which freely intercommunicate and form through the
lobule, between its periphery and center, a capillary net-work.
Directly at the center the venules of this net-work (intra-
lobular vessels) converge to form radicles of the hepatic vein."
Labadie-Lagrave14 states that, "as regards the divisions (of the
hepatic artery) destined for the lobules, they penetrate con-
jointly with interlobular veins, but without communicating with
them, in the interior of the lobule, in the form of capillaries
distributed to the central vein" In the presence of these di-
vergent views, which but exemplify those of other authors,
our only choice lies in the selection of the one region which
all authors seem to consider as reached by the artery: i.e., the
periphery of the lobule. But, as all concede, also, that the
arterial capillaries penetrate in one way or another to the
intralobular supply, we will adopt — though we believe that
Harrison Allen's definition is the true one — the more con-
servative distribution indicated in the annexed engraving by
Piersol, who, in accord with many histologists, describes the

"Pick and Howden: "Gray's Anatomy"; edition, 1901.
18 Harrison Allen: "Human Anatomy," 1884.
"Labadie-Lagrave: "Traite" des Maladies du Foie," 1892.

FUNCTIONS OF THE LIVER.

329

hepatic artery as "supplying nutrition to the interlobular
structures and terminating in the lobular capillary net-work."
A noteworthy feature of the capillary net-work envelop-
ing the cellular hodies is that each mesh does not merely cover
one cell, but several. Indeed, were it otherwise, the bile-
capillaries could not exist as individual channels and give an
uninterrupted free way to their contents without allowing the
bile to penetrate the blood-stream. To prevent this, and yet
simultaneously insure perfect exposure to the blood and lymph,
a very simple arrangement exists: i.e., three or more of the

SECTION OF LIVER SHOWING THE LOBULES, CELLS, AND THH
BLOOD-SUPPLY. (Piersol.)

P.V., Portal vein. H.A., Hepatic artery. H.V., Hepatic vein.

cells (usually polyhedral) are joined longitudinally, and, while
the narrow passage in the center of the group thus formed
serves as a bile-channel, the outside only is in contact with
the blood- and lymph- capillaries. When only two cells are
thus joined, the surfaces in contact have in their center a small
opening, which, being adjusted to that of the adjoining cell,
insures the continuity of the channel. It thus becomes clear
that the blood-plasma may penetrate the cell, undergo or in-
duce metabolism therein, and the product pass out through
the intercellular biliary passages or bile-capillaries. The cells

330 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

are so joined as to form continuous, though correlated, chan-
nels, which radiate from the center of the lobule to its periph-
ery, where they join the interlobular bile-channels.

The intimate structure of the hepatic cell is peculiar. It
possesses no limiting membrane; but its peripheral protoplasm
is more dense than that of its other parts and the pseudocov-
ering so formed serves as the outer wall for numerous cavities
or vacuoles which inosculate irregularly throughout its inte-
rior. All these vacuoles, however, more or less directly con-
verge toward the center, where they meet a protoplasmic mass,
which in turn contains one and sometimes two nuclei. The
cell, apart from its nucleus, suggests a miniature sponge the
cavities of which (secretion vacuoles) become tilled with

BILIARY CANALICULI. (Mathias Duval.)
a, A biliary canaliculus cut transversely, ft, Intercellular capillary.

glycogen. This substance seems to accumulate in the outer
vacuoles, which appear wider in this location than the inner
ones, when, by artificial means, the glycogen has been removed.
It is perhaps noteworthy that this substance accumulates in
the part of the cell nearest the blood-vessels and that the
droplets, or "granules," considered as bile are most abundant
in the opposite direction: i.e., near the bile-capillaries. These
"droplets" accumulate between periods of digestion and dimin-
ish during this process. A delicate canaliculus connects this
part of the cell with the biliary channel. The vacuoles in the
paraplasm, according to Kupffer, "play an important part in
the secretion of the cell, and are due to the confluence of
minute drops of bile into a large globule. As soon as the
vacuole has attained a certain size it tends to empty its con-

FUNCTIONS OF THE LIVER. 331

tents into the bile-capillary through a small tubule connecting
the vacuole with the bile-capillary." Kupffer's main vacuole
is thought by him to constitute an intracellular vesicle con-
nected with the bile-capillaries by means of delicate tubes.

The nerves of the liver enter the organ at the transverse
fissure and accompany the blood-vessels and lymph-vessels to
the interlobular spaces. That the sympathetic and the pneu-
mogastric supply these nerves and that "minute ganglia occur
along the interlobular trunk" represent about all the informa-
tion to be gleaned from classical books. Berkley traced several
divisions of the intrinsic nerves; "no doubt, the neuraxes of
sympathetic neurons," observe Bohm and von Davidoff, who
add: "The suggestion seems warranted that these terminal
fibrils are the endings of sensory nerves. Some of the nerve-
fibers following the bile-ducts may be traced into the hepatic
lobules. The intralobular plexus is formed, therefore, by the
terminal branches of the non-medullated nerve accompanying
the portal and hepatic vessels and the bile-ducts." Pfliiger
has contributed interesting complemental evidence, however,
which confirms the existence of the pericellular nervous net-
work that we have observed in all other glandular structures;
indeed, he not only noted the presence of a plexus around the
cell, but also ascertained that terminal filaments perforated
its protoplasmic peripheral thickening. On the other hand,
Nestorowski and Kolatschewski found a terminal plexus around
the intralobular capillaries, while Miura, who confirmed the
latter observation, also ascertained that this vascular plexus
could be traced to the intralobular vessels (Labadie-Lagrave15).
This establishes a connection with the extrinsic nerves, down
to the transverse fissure referred to at the beginning of this
paragraph, and indicates that the liver is innervated, as we
found the stomach and pancreas to be, by vagal and sympa-
thetic extensions from the coeliac plexus.

Our inquiry into the character and composition of the
substances that are transformed in the liver and of the secre-
tions of this organ must necessarily include the blood of the
portal vein, since it contains whatever products of metabolism

16 Labadie-Lagrave: Loc. cit.

332 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

the organ is thought to transform. We shall, therefore, begin
with this channel, which brings to the liver essentially venous
blood, since it contains that utilized by four organs — the
stomach and the intestines, the pancreas and the spleen — in
which the metabolic products include, besides those incident
upon ordinary tissue-waste, food metabolites, physiological
toxics, etc.

As is well known, there exist in the liver's secretions dis-
tinct evidences of association with splenic haematopoietic or
hasmolytic functions. The liver is known to modify the com-
position of the blood as it passes through it, but the purposes
of the alterations involved are not established.

The path from the spleen to the portal vein, through the
splenic vein, is a direct one, and the blood the spleen sends
to the liver is not, therefore, submitted to modifications in
transit by any other organ, though the splenic vein receives a
few branches from the pancreas and stomach. Still, these are
mere tributaries to a common channel, and, as the' arterial
supply comes directly from the cceliac plexus, we can say that
the spleen receives nothing but pure, freshly-oxygenated blood
in great quantities. Indeed, the splenic artery is remarkably
large for the dimensions of the organ, and we can easily account
for the so-called "ague-cake" and the temporary enlargement that
occurs during malarial and other fevers when we include supra-
renal overactivity in the pathogenesis of these phenomena.

To this we cannot ascribe, however, the post-prandial
splenic enlargement, which attains its maximum about five
hours after an ordinary meal, since we now know how inde-
pendently of suprarenal overactivity and merely through nerv-
ous influence an organ's function can be excited and governed;
indeed, sympathetic and pneumogastric again unite here to
account for a passive period and for an active period: that
of gradual enlargement. "The turgescence of the spleen
seems to be due to a relaxation both of the arteries and of
the muscular tissue of the capsule and of the trabecula?" says
Professor Foster: evidence that we are again dealing with
vasoconstriction of some arterioles to shift the blood-stream
into the functional areas, — a repetition of what we have found
to exist in other organs. Obviously the constriction and shift-

FUNCTIONS OF THE LIVER.

333

ing does not, as we have previously said, require an increase
of the quantity of blood distributed to an organ. A striking
confirmation of this fact occurs in the following lines of Pro-
fessor Foster's: "The pathway of the blood through the splenic
reticulum is peculiar; and increase or decrease in the volume
of the spleen means more or less blood held in the spleen-
pulp, not necessarily a greater or less flow of blood through
the organ."

That the organ is concerned with some process incident
upon blood-changes is evident. But what is this process? The
various points that may afford a clue are these: red blood-
corpuscles have been found in various stages of disorganization
in the organ, but in the interior of amoeboid cells buried in the
pulp. The spleen-pulp also contains an albuminoid proteid
rich in iron, and a pigment which shows considerable carbon.
That an active combustion process may go on in the organ is
suggested not only by the latter, but also by the presence of
various purin bases: xanthin, hypoxanthin, and their end-
product, uric acid. Various other acids — acetic, butyric,
formic, succinic, lactic, etc. — are also found in relatively large
quantities. This appears suggestive when we consider — if our
views are sound — the large quantity of oxidizing substance that
must course through the organ especially during post-prandial
activity.

The spleen also seems to be a leucocytogenic center, since
the splenic vein contains a much larger proportion of leuco-
cytes than the splenic artery. But as these leucocytes leave
the organ through the splenic vein, and ultimately, therefore,
reach the liver through the portal, they must either be con-
nected with some function in the liver or be destroyed there.
Again, the arterial blood has been found to lose one-half of its
red corpuscles; at least, blood from the spleen contains one-
half of those found in the blood of the splenic arteries.
Coupled with the finding of disorganized remnants of these
bodies in the splenic pulp, this certainly suggests, as is gen-
erally believed, that red blood-disks are disintegrated and white
corpuscles created in the spleen. Indeed, the portal blood is
poor in red disks. Yet, the hepatic vein is still poorer in them
in the sense that the proportion of red to white cells is as

334 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

four in the subhepatic vein is to one in the portal vein, after
the blood has been submitted to the effects of hepatic func-
tions. It seems clear, therefore, that red corpuscles are de-
stroyed both in the spleen and in the liver, and that, since
the spleen is possessed of no external duct, it is in the liver's
secretions that we should find proofs of this dissociation of
corpuscular elements. Indeed, we have in bilirubin, a bile-
pigment derived from haemoglobin, direct evidence of this fact.

The Hepatic Blood-pigments. — We have already analyzed
(in the second chapter) the process through which various
blood-pigments are transformed one into another. We will
now only refer, therefore, to the features which suggest the
purposes of the spleno-hepatic functions as regards these
bodies.

We ascertained that the changes undergone in the liver
represented but a portion of a cycle of which the intestines
were the starting-point, bilirubin (excepting that transformed
into urobilin and stercorin) being reabsorbed from the intes-
tine and again used in the building up of haemoglobin. Ex-
perimental evidence was adduced to show (Macallum) that in
an animal fed on albuminate of iron free leucocytes crowded
with iron-pigment could be traced in transit through the in-
testinal mucous membrane in the villi, and that similar leu-
cocytes had been found in the spleen and in the liver. But
can we conclude from this that the iron-laden leucocytes find
their way to the spleen and that this organ constitutes a part
of the cycle? The anatomical relations of the structures in-
volved show that, even if such an arrangement did exist, it
could serve no useful purpose, since the leucocytes would but
penetrate the splenic structures to again enter the portal cir-
culation. Obviously, the only pathway available anatomically
is the venous one, since Macallum found the "leucocytes
crowded with granules of iron-pigments" in the venules of the
villi.

The single venous channel at our disposal, therefore, is
that of the distribution of the villi, the ileum and jejunum
mainly, i.e., the superior mesenteric veins, — which again lead
us to the portal vein. This probably means that the iron thus
taken from the intestine is not ready for the circulation, and

THE LIVER AND BLOOD PIGMENTS. 335

that it must undergo a secondary process in the liver before
it can serve its physiological purpose in the arterial circula-
tion. This is sustained by the prevailing view as to the func-
tions of the spleen, i.e., that it disintegrates worn-out red
corpuscles, and also by the great increase of leucocytes ob-
served in the splenic vein as compared to the proportion of
these cells in the artery. It therefore seems logical to conclude
that both in the lymphatic structures of the intestine and in those
of the spleen leucocytes are formed which carry iron-pigments to
the portal vein; those from the intestine reach the latter by the
superior mesenteric vein, and those from the spleen by the splenic
vein. As Macallum observed iron-pigment leucocytes in the
spleen similar to those witnessed in the intestinal villi, and the
venules of the latter and the splenic vein ultimately transmit-
ting their blood to the portal vein, no other conclusion seems
possible.

The similarity of the general mechanism involved suggests
the presence of correlated functions. Thus, in the spleen the
leucocytes are formed in situ, pass out into the pulp-channels, and
take up the iron-pigment and carry it out to the liver; in the
intestine they are formed in a similar structure, — the follicle, —
pass out into the intestinal channel, take on a similar supply of
blood-pigment, re-enter through the villi into the venous system,
and also proceed to the liver. True, we have previously ascribed
bactericidal properties to the leucocytes produced by the intes-
tinal follicles; but the chemotactic property of the leucocytes,
the existence of which is shown by their ability to take up the
pigments, serves but to demonstrate that they must also be
endowed at least with phagocytic attributes.

We also ascertained, in the chapter referred to, that, while
the adrenals supply an oxidizable substance to the blood, in-
sufficiency of the adrenals leads to the formation of a com-
pound inferior to haemoglobin in oxygen-absorbing powers, —
i.e., methaemoglobin; and, furthermore, that haamatoporphyrin
is formed when the suprarenal insufficiency is still further ad-
vanced, haemoglobin being unable to hold itself together, as it
were, and to absorb oxygen. Again, we saw that haemoglobin
is reduced to haematin when the reaction with the reducing
agent occurs in the presence of oxygen. In the absence of oxygen

336 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

a haemochromogen is formed which slowly loses its iron, the
end-product being also haematoporphyrin.

It is evident that the integrity of the haemoglobin mole-
cule is dependent upon the quantity of secretion that the ad-
renals supply to the blood, and also upon the condition of that
molecule at a given time. In other words, while the adrenals
may be supplying their normal proportion of secretion, the
haemoglobin molecule in the red corpuscles of venous blood —
i.e., blood about to return to the vena cava for a fresh sup-
ply— may be compared to that of blood during insufficiency.
Even as haemoglobin, the blood-pigment is loosely combined;
when approaching the end of its systemic circle, it is still
nearer the state of disintegration — according to the activity of
the oxidation processes which it has subserved. Starting from
the lungs as oxyhaemoglobin, it may return to the heart as
haemoglobin or reduced haemoglobin, ready to at once absorb
another supply of suprarenal secretion and, once in the lungs,
take up its oxygen.

Blood from the head, extremities, and other structures in
which the drain upon its resources has not been excessive, re-
turns such a molecule to the heart; it is still efficient as an
oxygen-carrier. But not so with the blood from any organ directly
connected with the digestive system. As is well known, all the
blood from the organs of the alimentary tract — stomach, intes-
tine, pancreas, and spleen — is not returned to the heart before
it has been submitted to whatever action the liver may have
upon it; then only can it re-enter the circulation through the
hepatic veins, which carry the blood to the vena cava. But not
all the blood may thus be rejuvenated; some has gone beyond;
it has, indeed, almost reached the state of haematoporphyrin,
the last on the list of pigments, that which appears in the most
advanced stages of suprarenal insufficiency. We have seen
that haematoporphyrin and bilirubin are similar; and, as is
well known, it is bilirubin which passes out with the bile.

A salient feature of the haemoglobin molecule is missing
here, however, namely: the iron. As stated, a reducing agent,
if used in the presence of oxygen, will reduce haemoglobin in
the absence of oxygen; the primary product is a haemochro-
mogen which gradually parts with its iron, leaving as end-

THE LIVER AND BLOOD PIGMENTS.

337

product haematoporphyrin. As bilirubin and haematoporphyrin
are fundamentally identical, the presence of the former in the
bile must be the result of a similar process in the liver. That
such is the case is sustained by considerable collateral evidence,
first of which is the invulnerability of the haemoglobin mole-
cule.

Paradoxical as this statement appears, it nevertheless con-
stitutes the key-stone of the entire edifice, since it is only when
vulnerable that the molecule becomes the prey of disintegrating
influences. We have used the words "reducing agents" several
times; but the hemoglobin molecule does not yield to even
moderately-strong reagents of this nature; indeed, only a
powerful agent — sulphuric acid, for instance — will dissociate
it: an exemplification of the wonderful binding power which
the suprarenal secretion must exert upon all its constituent
parts. Still, we must not overlook the fact that the oxidizing
substance in the blood-plasma is identical to this binding com-
pound. Indeed, we have accumulated so much testimony
affirming the fact that the plasma per se is a potent source of
energy, while the red corpuscles always played so secondary a
role in the various intrinsic functional mechanisms, especially
those concerned with muscular and glandular elements, that
we have been led to conclude that the red disks are, after all,
but servants of the blood-plasma: pack-mules, as it were, from
which it can draw, as needed, enough oxidizing substance to
maintain its own functional potentiality as previously stated.

Under these circumstances we can readily see how the
haemoglobin molecule, gradually deprived of its binding oxidiz-
ing substance during the inordinate metabolism which the tis-
sues of the digestive organs undergo during their periods of
activity, should yield more readily to dissociating influences.
It is evident that a molecule so weakened, thrust in blood
such as that of the portal vein, — a vast sewer replete with
physiological waste-products and deoxidized blood-cells, all
bathing in a plasma itself despoiled of its oxidizing substance,
— should soon become dissociated. Transported through grad-
ually narrowing channels, the walls of which, like all tissues,
eagerly absorb any loose oxygen that it may contain, it must
inevitably undergo the transformation of haemoglobin referred

338 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

to, i.e., into the primary haemochromogen, which soon drops
its iron, leaving as end-product bilirubin.

We have here the identical process that occurs in the brain
or other structures when blood-clots are disorganized into
hasmatoidin preparatory to absorption. "The bile-pigments
originate from haemoglobin77 says Professor Howell; "this
origin was first indicated by the fact that in old blood-clots
or in extravasations there was found a crystalline product, the
so-called 'haematoidin/ which was undoubtedly derived from
haemoglobin, and which, upon more careful examination, was
proved to be identical with bilirubin. This origin, which has
since been made probable by other reactions, is now universally
adopted." That the influence of the suprarenal secretion rests
upon as solid a foundation is illustrated by the experiments
of Boinet, who found the blood of a large number of rats from
which he had removed the adrenals replete with "haematoidin."

To trace the itinerary of the two products, iron and bili-
rubin, through the liver, naturally brings the hepatic cell
within the scope of our inquiry, since we have to account for
the transfer of the former to the bile and the return of the
iron to the general circulation.

The functional importance of iron in the haemoglobin
molecule is generally recognized. Yet, the pigments, when
separated from it, are not unable to take up oxygen. Indeed,
we have ample evidence of this in the formulae of the very
products of which bilirubin is the primary compound. Thus,
while bilirubin is C16H18N203, biliverdin is C16H18N204, and
the latter can readily be prepared artificially from the former
by oxidation. "It is supposed that, when the blood-corpuscles
go to pieces in the circulation," says Howell, "the haemoglobin
is brought to the liver, and then, under the influence of the
liver-cells, is converted into an iron-free compound: bilirubin
or biliverdin. It is very significant to find that the iron sepa-
rated by this means from the haemoglobin is, for the most part,
retained in the liver, a small portion only being secreted in the
bile. It seems probable that the iron held back in the liver is
again used in some way to make new hcemoglobin in the haema-
topoietic organs." We have seen that it is not under the in-
fluence of the liver-cells, as now believed, that hcemoglobin is dis-

THE LIVER AND BLOOD PIGMENTS. 339

sociated: an important feature, since it removes the main ele-
ment of confusion from our path. Indeed, we can now easily
account for the retention of the greater part of bilirubin in the
liver, since we have at our disposal all the constituents for the
synthetic production within the portal capillaries of the hepatic
lobule of new haemoglobin, and particularly oxidizing substance,
brought there by the terminals of the hepatic artery.

On examining, on page 329, the illustration from Piersol's
work, the distribution of the hepatic artery's terminal arterioles
or capillaries will be found to be unusual. Immediately above
the margin of the lobule — i.e., where the portal or interlobular
vein breaks up into the capillary net-work of the lobule — the
hepatic arteriole may be seen to open into the portal capillary.
The inference is obvious. The hepatic artery coming directly
from the cceliac axis, brings freshly oxidized Hood, — i.e., oxidizing
substance, — which, mixing freely in the narrow channels of the
lobule with the portal blood, at once groups bilirubin and iron,
and builds up all the hcemoglobin that the constituents present
(including what iron the splenic leucocytes and those from the
intestinal follicles have brought) allow. What bilirubin cannot,
owing to deficiency of either of the other constituents, be utilized,
becomes an excretory product; and with many others it enters the
hepatic CELL and is passed out with the bile.

That deficiency of suprarenal-oxidizing substance can in-
crease the excretion of bilirubin has been repeatedly shown
herein. We may refer, for example, to the many forms of
acute poisoning and to the diseases attended with suprarenal
insufficiency in which there is increased excretion, either in the
urine or faeces, of haematoporphyrin, methaemoglobin, urobilin,
stercobilin, etc.: i.e., of some derivative of haemoglobin.

We have referred to the hepatic cell as a miniature sponge.
This comparison, due to Berdal, is especially warranted, since
Schafer16 noted the existence, within this cell, of canaliculi
which are in direct communication with the blood-capillaries.
Having injected carmine gelatin into the portal vein, the col-
ored substance filled this vessel and its subdivisions, besides
the canaliculi, but no other structure. It may, therefore, be

18 Schafer: Journal of Physiology, Jan. 31, 1902.

340 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

inferred, says Professor Schafer, "that the injection has passed
directly from the blood-vessels into the liver-cells; indeed, here
and there one can see what appear to be such direct commu-
nications." These can readily be seen in the annexed illustra-
tion. He refers to the conclusion reached by Browicz,17 based
on appearances, normal and pathological, "that there must
exist a net-work of nutritive canals, within the hepatic cells
which are in direct communication with lobular capillaries";
this he had not as yet, however, verified by injections.
Schafer' s observation probably accounts for the direct transfer
of the bilirubin to the biliary capillaries, along with other

LIVER OF RABBIT INJECTED FROM THE PORTAL VEIN. THE
INJECTION HAS PASSED INTO CANALICULI WITHIN THE LIVER-
CELLS. (E. A. Schafer.)

products of oxidation, to which we will refer later on. Indeed,
J. W. and E. H. Fraser18 are also stated to have found intra-
cellular passages communicating with the blood-vessels in the
hepatic cells of frogs. For the present it seems logical to con-
clude that one or more of the canaliculi may lead to the vacuole
previously referred to as nearest the bile-capillaries, and that
it is in this vacuole that bilirubin joins the bile. That even
this vacuole is supplied with a canaliculus we have already

"Browicz: Bulletin de 1'Acadgmie des Sciences de Cracovie, 1899.
» J. W. and E. H. Fraser: Journal of Anatomy and Physiology, vol. xxlx.
p. 240, 1895.

THE LIVER IN ITS RELATIONS TO BACTERIA. 341

seen; Kupffer found it to afford a direct channel between this
bile-reservoir and the bile-capillaries per se.

The Hepatic Tissues in their Relations to Bacteria. — A
prominent feature of the work so far done is the evidence
furnished that several physiological processes now ascribed to
the hepatic cell in no way involve this structure, and that the
portal vein itself and the intercellular19 capillaries are the seat
of several of these processes.

Before proceeding further, however, reference must be
made to the connection between bacteria and the normal liver.
We emphasize "normal" here, because we thus simultaneously
lay stress upon a feature which plays a predominating role in
disease: i.e., the fact that anatomically, as far as bacteria go,
there is no direct normal connection between the digestive
system and this organ. The liver, in fact, is essentially a
physiological organ in the sense that it is mainly intended to
rid the system of waste-products and to economize others that
may again prove useful, by preparing them for reabsorption
in the intestine.

We have seen that the venules of the villi allow iron-
pigment leucocytes to enter the mesenteric veins which carry
their blood to the portal. A depraved condition of all the
digestive structures — such as that induced by alcoholism, for
instance — can so lower the functional activity of these struct-
ures as to cause these venules to lose their normal turgescence
and afford passage to bacteria, alcohol in large doses being
known to impair metabolism. The intestinal venules under
these circumstances, surrounded by weakened protective struct-
ures, can well give passage to Adami's cirrhosis bacillus, for
instance, or any other capable of coping with what prophylactic
conditions may still prevail. "The portal vein can transport
to the liver morbid germs from the intestinal surface," says
Labadie-Lagrave. "One of the best established pathogenic
connections of this kind is the influence exerted upon the de-
velopment of hepatitis by dysentery; although this relation-
ship is not constant, all observers have noted it. Phlebitis

19 We find it necessary to give the terminals of the portal this name in order
to avoid confusion; they contain blood from both the portal and hepatic chan-
nels, and in reality form part of both as extensions.— S.

342 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

starting from an ulcerated area and directed toward an hepatic
focus has also been observed. When the primary portal struct-
ures are normal, transmission of the putrid material may occur
through the lymphatics. While this fact seems admissible, it
has not been verified." Again, pathological conditions of the
stomach, pancreas, or spleen may supply the portal vein with
pathogenic elements. In the normal subject, however, the
liver-tissues per se are totally isolated anatomically from any of
the structures that come into contact with exogenous bacteria, pre-
cisely as they are in other organs: the muscles, the heart, etc.
That its blood-stream affords protection from disease is un-
doubted, however, judging from the leucocytes that are con-
stantly entering the organ, and the perivascular lymphatic
channels. That the portal vein is also an important field for
the splitting of toxalbumins and their reduction to harmless
bodies we shall also see. But it seems quite clear that the liver
itself is not primarily a germ-killing organ, and that its at-
tributes are essentially chemical. This removes the hepatic
cell still further from the functions now attributed to it, and
suggests that the oxidizing substance in the lobular blood-
vessels may be the main source of the liver's functional activity.

This brings us to the consideration of the functions in
which the oxidizing substance in the blood-plasma acts as a
reagent. We have already reviewed, in this connection, the
synthesis of haemoglobin; we will now take up and consider
two equally important subjects: i.e., the origin of urea and the
conversion of sugar into glycogen.

Urea and its Formation. — We will first analyze an experi-
ment by Schroder20 in which the liver was taken from a freshly-
killed dog and irrigated through its blood-vessels by a supply
of blood taken from another animal. Howell refers to this
experiment in the following words: "If the supply of blood
was taken from a fasting animal, then circulating it through
the isolated liver was not accompanied by any increase in the
amount of urea contained in it. If, on the contrary, the blood
was obtained from a well-fed dog, the amount of urea con-

20 Schroder: Archiv fur exper. Pathol. und Pharm., Bd. xv aad xix, 1882 and
1885.

UREA AND ITS FORMATION.

343

tained in it was distinctly increased by passing it through
the liver,, thus indicating that the blood of an animal after
digestion contains something that the liver can convert to
urea."

Considered from our standpoint this experiment has an-
other meaning. During digestion, especially after copious feed-
ing, as stated above, the entire organism is, to a certain degree,
involved in the digestive process, as shown by the general sense
of heat often experienced under these conditions. As liver,
intestines, pancreas, and spleen, even after gastric digestion
has passed, are all operating together, the suprarenal activity
is doubtless enhanced. In other words, at such times the blood
contains either in its corpuscles or in its serum a more or less
marked increase of oxidizing substance. Conversely, the fast-
ing dog's blood — especially if the fasting has been prolonged
— is really abnormal blood, in which the oxidizing substance
is unusually low, since suprarenal activity is depressed with
that of the rest of the tissues. We have also seen that, under
these conditions, the tissues nevertheless continue to absorb
their normal supply of oxygen, the blood being thus actively
depleted while insufficiently oxygenated. It seems clear, there-
fore, that the blood of the well-fed dog contained more oxidiz-
ing substance than that of the fasting one.

That the injected blood taken from the well-fed animal
should have been the source of the urea-forming substance is
unlikely. Since the liver alone receives alimentary waste-
products, it is only with blood from the portal vein that such
substances could have been obtained. This is not specified.
The urea-forming agent must, therefore, have been in the
excised liver's portal channels, and the only available agency
capable of inducing the reactions involved appears to be the
oxidizing substance. Experimental evidence may be adduced
to show that such is the case. We consider the blood of the
hepatic artery, as previously stated, as the source of supply of
the oxidizing substance, since it is directly derived from the
cceliac axis. Stewart states that, "although the portal vein
carries a much greater supply of blood than the hepatic artery,
ligation of the latter causes a greater diminution in the ratio
of the amount of urea to the total nitrogen in the urine than

344 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

ligation of the former. This seems to indicate that oxidation
plays an important part in the formation of urea in the liver
(Doyon and Dufourt)."

That the substances thus oxidized reach the liver by the
portal vein needs hardly to be emphasized. But Foster says:
"The introduction of even a small quantity of proteid mate-
rial into the alimentary canal at once increases the urea in the
urine, and in the curve of the discharge of urea in the twenty-
four hours each meal is followed by a conspicuous rise. . . .
We have seen reason to think that the proteids of a meal are
absorbed not by the lacteals, but by the portal blood-vessels,
and such bodies as leucin probably take the same course. This
being so, all these bodies pass through the liver and are sub-
jected to such influences as may be exerted by the hepatic
cells."

Such bodies of leucin — one of the main products of nitrog-
enous dissociation — naturally follow the same course. Drech-
sel has suggested that all bodies of this class — i.e., leucin,
tyrosin, glycocoll, etc. — first undergo oxidation in the tissues,
and that their ammonia and carbonic acid then combine syn-
thetically, forming ammonium carbamate, this, in turn, being
carried to the liver and there transformed into urea.

It is clear that these ammonia compounds take the course
outlined by Foster: i.e., the venules of the villi, the mesenteric
veins, and finally the portal vein. That they undergo oxida-
tion in the blood of these vessels, however, is not likely, for
they contain probably the most watery blood of the organism,
and that most depleted of its oxygen.

Quite another field of activity is afforded, however, when
the hepatic lobule is reached; here the ammonia compounds
meet the oxidizing substance brought ~by the hepatic artery's capil-
laries. Taking the ammonium compound referred to by Drech-
sel for example, the series of reactions outlined by him seem
to follow in normal sequence: 1. In the portal vein: hydro-
lytic cleavage with the formation of amido-bodies, such as
leucin, tyrosin, aspartic acid, glycocoll, etc. 2. In the hepatic-
lobule capillaries and their oxidizing substance: oxidation,
with the formation of ammonia, carbonic acid, and water, fol-
lowed by the synthetic union of ammonia and carbonic acid,

UREA AND ITS FORMATION. 345

forming the carbamate of ammonium. This being dehydrated,
urea is formed, as shown in the following equation: —

That the conversion of ammonia compounds into urea does
occur in the liver is sustained by experimental physiology.
Ho well refers to the experiments of Schroder, in which this
is demonstrated as follows: "As further proof of the urea-
forming power of the liver, Schroder found that if ammonium
carbonate was added to the blood circulating through the liver
— to that from the fasting as well as from the well-nourished
animal — a very decided increase in the urea always followed.
It follows, from the last experiment, that the liver-cells are
able to convert carbonate of ammonium into urea. The re-
actions may be expressed by the equation: —

(NHJ2C03 — 2H20 = CON2H4."

The foregoing facts, considered collectively, indicate that
the formation of urea in the liver is probably accomplished in
the following manner, taking DrechseFs series of reactions as
standard of the numerous ones of the same class that must
occur in this organ: —

Granting that the nitrogenous bodies are absorbed by the
venules of the intestinal villi and transmitted by the mesen-
teric veins to the portal vein, the ramifications of which would
then carry them to the hepatic lobules, the first reaction would
occur in the preldbular portal vessels: i.e., the nitrogenous bodies
would undergo hydrolysis, with the formation of amides, leucin,
aspartic acid, tyrosin, etc. The second reaction would follow
as soon as these bodies reached the pericellular capillaries,
owing to the presence therein of the oxidizing substance sup-
plied by the terminal branches of the hepatic artery; in other
words, further reduction of these bodies by oxidation to ammonia,
carbonic acid, and water would occur in the pericellular capillaries
of the lobule. The third reaction would seem, like the first, to
require comparatively inert surroundings: i.e., a fluid not
charged with oxidizing substance as is the blood of the peri-
cellular capillaries. Such a medium we have, in all likelihood,

346 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

in the afferent venous channels, since it is very improbable
that any oxidizing substance, so precious in all physiological
functions (at least so it appears to us), should be wasted in
vessels ultimately ending, via the hepatic veins, in the inferior
vena cava. Hence, whether it involved a preliminary forma-
tion of an ammonic carbamate or proceed to immediate syn-
thesis, it appears as if the terminal reaction ending in the forma-
tion of urea occurred in the efferent venous hepatic channels.

The salient point of this series of reactions is the fact
that, contrary to the general belief, they all occur, not in the
hepatic cells, but in the blood-stream of the lobular capillaries.
The following facts show this to be the case: It is clear that,
if urea is formed in transit through the vessels of the organ,
it should appear as soon as, or at least soon after, its causative
agencies are introduced in the portal system. We will recall
the quotation from Professor Foster's text, in which he says:
"The introduction of even a small quantity of proteid mate-
rial into the alimentary canal at once increases the urea in
the urine, and in the curve of the . discharge of urea in the
twenty-four hours each meal is followed by a conspicuous rise,
etc." When we consider that the entire circulatory circuit
occupies but twenty-six seconds, the cause of the rapid appear-
ance of urea — heretofore unexplained — becomes apparent.

When the role of the oxidizing substance in the produc-
tion of uric* acid from the alloxuric bases was analyzed in the
third chapter, uric acid was considered as the end-product of
a series of reactions in which, according to modern views, these
toxic nuclein derivatives were converted into benign ones. All
nitrogenous products being transferred to the portal system,
it now seems clear that normally the reaction must occur in
the intercellular capillaries of the hepatic lobules, and that it
is when this oxidation process in the liver is inadequate that
the so-called "uric-acid diathesis" symptoms occur. As uric
acid leaves the organism, as does urea, by the urine, it is
evident that we are again dealing with a function totally dis-
connected from the hepatic cell per se. Again, we have re-
peatedly seen, in the preceding chapters, that the elimination
of phosphoric acid was increased by the administration of
suprarenal, pituitary, and other organic extracts and by various

GLYCOGEN AND ITS FORMATION.

347

drugs. As will be seen later on, the increased excretion due
to drugs always coincides with suprarenal overactivity, hence
with enhanced oxidation. It thus becomes apparent that many
constituents of the urine, normal and abnormal, the origin of
which is obscure, are due to variations in the oxidation processes
in the intercellular capillaries of the liver, caused by corresponding
fluctuations in the functional activity of the adrenals.

Glycogen and its Formation. — Glycogen obviously removes
our inquiry from the arteriole to the hepatic cell, since this
organ is that in which it accumulates; but we must not lose
sight of the important fact that two processes are involved in
the analysis, — (1) the formation of the glycogen and (2) its con-
version into dextrose, — and that the latter reactions must
occur in the vascular channels. Again, the first process seems
so bound up with the formation of the bile that it becomes
necessary to consider this subject simultaneously to avoid repe-
tition.

The sponge-like construction of the hepatic cell due to its
vacuoles, the delicate canals described by J. W. and E. H.
Fraser, Browicz, and Schafer, and finally, the bile-collecting
vacuole, or vesicle, leading through its own canaliculi to the
perilobular bile-capillaries, does not appear to afford much
room for protoplasm capable of undergoing functional metabo-
lism, since this would have to be embodied in the partitions
separating all these cavities. Yet, were it otherwise, the
nucleus — often duplicated, particularly in herbivorous animals,
almost one-third in size that of the entire cell, and containing
nucleoli — would represent a useless structure. It seems evi-
dent, judging by the appearance of the cell as a whole, there-
fore, that the nucleus, which, as we have seen, is surrounded
by a thin limiting layer of protoplasm, must impart its energy
to this layer. This, in turn, being the central terminal of all
the partitions, which, along with the cell's own pseudocovering,
are protoplasmic, the vacuoles become receptacles, as it were,
of the products of their walls.

Again, when we behold the minute canals so clearly shown
in Schafer's illustration (shown on page 340) a direct commu-
nication with parts external to the cell is evident in several
places, and it seems clear that, if his carmine gelatin could

348 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

penetrate through these, so could an equally viscid substance,
and with still greater ease, the blood-plasma. As "no injection
in the intercellular bile-canaliculi nor in the perivascular lym-
phatics nor between the cells" could be detected, the penetra-
tion of the gelatin can hardly be ascribed to undue stress.
"There being," also, "no diffusion of carmine nor any staining
of the cells or nuclei by carmine," the nucleo-mural net-work to
which we refer must be an independent structure, circumscrib-
ing two kinds of cavities: the canals and the vacuoles. The ca-
nals communicating with the exterior of the cell, they are prob-
ably the receiving cavities, while the vacuoles, their neighbors,
are the spaces in which the useful products of metabolism are
accumulated. The canals themselves, continuing until Kupf-
fer's vesicle is reached, would thus pour their excretory con-
tents— bile and its various constituents — into this cavity, and
this, in turn, would convey them to the intercellular bile-capil-
laries through its own canals.

Whether so direct a connection between the intercellular
capillaries and the bile-channels through the cell exists is a
point to be determined. Bile and the various bodies excreted
with it would be voided as are the intestinal contents, the
canalicular walls taking up certain elements, while physiolog-
ical substances would be mixed with the substances in transit
for definite purposes.

The first question that suggests itself is the following:
Is glycogen formed during the active functional activity of the
liver (during digestion) or during its passive state (between
meals)? We have seen that the production of urea is increased
immediately after a meal; we have evidence, therefore, that an
active state based upon increased oxidation processes must
prevail, and that it is during digestion that the substances out
of which glycogen is formed reach the liver, i.e., while the
oxidizing substance is present in the capillaries. This suggests
that the oxidizing substance must itself take part in the forma-
tion of glycogen, though perhaps indirectly, and also in the
elaboration of bile.

The main coloring constituent of bile, bilirubin, we have
previously considered as the product of a reaction in the inter-
cellular capillaries. As such it is probably eliminated with the

GLYCOGEN AND ITS FORMATION. 349

bile merely because its high oxygen constituent places it be-
yond the limits of further oxidation. Yet we have in another
component of bile, biliverdin, evidence that some oxidizing
process occurs during the passage of bilirubin through the
cell, under certain circumstances, — perhaps when more oxidiz-
ing substance is present, — for Howell says: "Biliverdin is sup-
posed to stand to bilirubin in the relation of an oxidation
product. Bilirubin is given the formula, C16H18!N"203, and
biliverdin, C16H18N204, the latter being prepared readily from
pure specimens of the former by oxidation."

With this evidence that oxidation does play some role
of the processes involved, it will facilitate our task to briefly
review the mutual relations of main biliary constituents. By
far the larger proportion of these is made up of the bile acids,
namely: the sodium salts of cholic acid, — i.e., glycocholic and
taurocholic acid. These are obtained from cholic acid derived
itself from sugars and fats (Voit). Now, Tappeiner21 found
that cholic acid yielded fatty acids on oxidation, and, since
taurocholic and glycocholic acids are fatty acids, this suggests
that they become such during their passage through the hepatic
cells and as the result of an oxidation process.

The various phases of the process in the hepatic cells
become clear when the oxidizing substance is included as one
of the intrinsic factors involved. The blood-plasma of the
portal vein contributes the sugars and fats (along with the
waste-products to be excreted), while the hepatic artery sup-
plies plasma containing the oxidizing substance. All three
active agents meeting in the canaliculi, a part of the sugar
(according to the proportion of oxidizing substance present)
and all the fat (if the proportion of oxidizing substance is not
abnormally reduced by suprarenal insufficiency) are oxidized
into cholic acid. But, as the blood also contains glycocoll
(probably collagen-cartilage, mucin, connective tissue, and
gelatin-waste), glycocholic acid is formed. Again, since the
blood likewise contains taurin (probably muscle and pulmonary-
tissue waste), taurocholic acid is formed. Just the amount of
oxidizing substance necessary being supplied by the hepatic

Tappeiner: Zeitschrift fttr Biologic, Bd. xii, S. 60, 1876.

350 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

artery to each lobule, to properly regulate the functions in-
volved, only the required sugar is burnt by the oxidizing sub-
stance. The rest, under the influence of the nuclei of the
hepatic cells and the mural protoplasm of the latter, is con-
verted into glycogen and collected in the adjoining alveoli.

But we must also account for the elimination of the many
waste-products that are found in bile. An interesting feature
connected with these fatty acids is that they can combine
synthetically with other bodies, even with proteids, while they
are simultaneously able to emulsify the more insoluble soaps
and other fatty acids and thus insure their elimination. Again,
cholesterin, mainly derived from the white matter of the
cerebro-spinal axis and nerves (Flint), in which it occurs in
abundance (Foster), was formerly considered as a fatty sub-
stance capable of undergoing saponification, but it is now
classed among alcohols: the only alcohol that occurs in the
organism in a free state. This body is not only soluble in
solutions of the biliary acids also, but it combines with acids,
including glycocholic acid. The importance of this fact appears
when it is recalled that insufficiency of glycocholic acid in this
connection — and also, perhaps, of oxidizing substance — is the
main source of gall-stones. The cholesterin being a constant
constituent of bile, when there is not enough glycocholic acid
present to take it up, it is precipitated in the gall-bladder and
there forms the calculi of which it is the main component.
Another body derived from nervous structures, but which, like
cholesterin, is to be found in other fluids, especially blood-
serum, is lecithin. This body, besides others not mentioned,
only occurs, however, in very limited proportions.

It is now evident that glycocholic acid and taurocholic
acid should be looked upon as functional acids, in the sense
that they are not only vehicles for waste-products of metabo-
lism, but are also capable of submitting them to dissociating
reactions under the influence of the oxidizing substance. They
are sources of energy precisely as myosinogen appears to be a
source of energy, and capable of becoming factors of combus-
tion phenomena when in contact with the latter substance.
They are also truly physiological in the sense that they serve
to recover or economize those products which can again be

GLYCOGBN AND ITS FORMATION. 351

used by the organism. Indeed, they (or at least a part of their
decomposition products) are again absorbed by the intestinal
mucous membrane, and, passing through the venous channels,
probably take up therein and transfer to the hepatic cells what
waste-matter they are to carry to the intestinal tract. We
thus have in the cellular canaliculi two acids endowed with
powerful affinities and an active reagent, the oxidizing sub-
stance, to account for the processes of a chemical nature con-
nected with the functions of the hepatic cell.

Of course, all this involves the necessity of showing, as a
controlling factor, that products of combustion are also pres-
ent. The following lines by Professor Howell give this feature
due emphasis; referring to bile, he says: "The secretion con-
tains also a considerable, though variable, quantity of C02 gas,
held in such loose combination that it can be extracted with a
gas-pump without the addition of acid. The presence of this
constituent serves as an indication of the extensive metabolic
changes occurring in the liver-cells."

Again, the element of nervous control implied when we
referred to the oxidizing substance contributed by the hepatic
artery must be shown. We have seen that the vagus was the
active nerve during functional activity of the stomach; that it
should likewise govern hepatic functions is obvious. That such
is the case is sustained by no less an authority than Claude
Bernard, to whom we owe the discovery of glycogen — one of
his greatest achievements — and whose conceptions have been
almost all sustained by all the labor bestowed upon them since.
He not only found that the vagus was the predominating nerve
in the liver, but that its section also suppressed its glycogenic
function.

The fate of glycogen, its conversion into sugar for the use
of muscular and other tissues, may now be analyzed with
greater facility.

Our analysis of muscular functions led us to the deduction
that the contractile elements contained a substance, myosino-
gen, which, when brought into contact with the oxidizing sub-
stance of the plasma, became the source of the muscle's work-
ing energy. Ample evidence was afforded to show that we
were dealing with an oxidation process, the intensity of which

352 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

was commensurate with the amount of blood that the arterioles
supplied to the contractile tubular elements. There seems to
be considerable analogy between this process and that which
prevails in the hepatic lobule. Howell alludes to this in the
following words, which well recall the fact that we referred to
glycogen as the main constituent of myosinogen: "The history
of glycogen is not complete without some reference to its oc-
currence in the muscles. Glycogen is, in fact, found in various
places in the body, and is widely distributed throughout the
animal kingdom. It occurs, for example, in leucocytes, in the
placenta, in the rapidly-growing tissues of the embryo, and in
considerable abundance in the oyster and other mollusks. But
in our bodies and in those of the mammals generally the most
significant occurrence of glycogen, outside the liver, is in the
voluntary muscles, of which glycogen forms a normal con-
stituent."

The similarity between muscular and hepatic sources of
energy is further emphasized when, in the following paragraph,
Howell says: "In accordance with the view given above of the
general value of glycogen — namely: that it is a temporary
reserve-supply of carbohydrate material that may be rapidly
converted into sugar and oxidized,22 with the liberation of energy
— it is found that the supply of glycogen is greatly affected by
conditions calling for increased metabolism in the body. Mus-
cular exercise will quickly exhaust the supply of muscle and
liver glycogen provided it is not renewed by new food. In a
starving animal glycogen will finally disappear, except perhaps
in traces; but this disappearance will occur much sooner if
the animal is made to use its muscles at the same time. It
has been shown also by Morat and Dufourt that, if a muscle
has been made to contract vigorously, it will take up much
more sugar from an artificial supply of blood sent through it
than a similar muscle which has been resting; on the other
hand, it has been found that, if the nerve of one leg is cut so
as to paralyze the muscles of that side of the body, the amount
of glycogen will increase rapidly in these muscles as compared

22 The italics are our own.

GLYCOGBN AND ITS FORMATION. 353

with those of the other leg, that have been contracting mean-
time and using up their glycogen."

These facts clearly indicate that oxidation processes are
not in order here, since glycogen is a source of energy, intended,
therefore, for subsequent oxidation wherever it is distributed.
Indeed, Professor Foster remarks, in this connection: "It was
formerly believed that this sugar underwent an immediate and
direct oxidation as it was circulating in the blood. ... It
is sufficient for us at the present to admit that the sugar is
made use of in some way or other." Referring to the physio-
logical uses of glycogen, he also says: "The main purpose of
the deposition of glycogen is to afford a store, either general
or local, of carbohydrate material, which can be packed away
without much trouble so long as it remains glycogen, but which
can be drawn upon as a source of soluble circulating sugar
whenever the needs of this or that tissue demand it." That
the oxidizing substance has nothing to do with the process is
clear.

The conversion of glycogen into sugar in the liver appears
as a wasted function, the carbohydrates having been already
split into dextrose or dextrose and levulose in the portal sys-
tem. Why they do not merely pass on to the several tissues
seems strange. But it soon becomes evident that, were it
otherwise, sugar would accumulate, then be excreted by the
kidneys, and lost, since there can only be a fixed and limited
(0.1 or 0.2 per cent.) amount of sugar in the circulation at a
given time. So useful a substance is, therefore, stored, after
dehydration, in the hepatic cell as glycogen, and converted into
sugar according to the needs of the organism.

Conversion of the liver glycogen into dextrose is generally
ascribed to a special ferment, thought to originate in the liver,
but the nature of which has remained undetermined. The
experiment of Claude Bernard, upon which this view is mainly
based, is the following, as related by Stewart: "A rabbit, after
a large carbohydrate meal — of carrots, for instance — is killed
and its liver rapidly excised, cut into small pieces, and thrown
into acidulated boiling water. After being boiled for a few
minutes the pieces of liver are rubbed up in a mortar and again
boiled in the same water. The opalescent aqueous extract is

354 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

filtered off from the coagulated proteids. Xo sugar, or only
traces of it, is found in the extract, but another carbohydrate
— glycogen, an isomer of starch, giving a port-wine color with
iodine and capable of ready conversion into sugar by amylolytic
ferments — is present in large amount. Again, the liver, after
the death of the animal, is left for a time in situ, or, if excised,
is kept at a temperature of 30° to 40° C. or for a longer period
at a lower temperature; it is then treated exactly as before,
but no glycogen, or comparatively little, can now be obtained
from it, although sugar (dextrose) is abundant. The infer-
ence plainly is that after death the hepatic glycogen is con-
verted into dextrose by some influence which is restrained or
destroyed by boiling. This influence may be due to an un-
formed ferment or to the direct action of the liver-cells, for both
unformed ferments and living tissue-elements are destroyed
at the temperature of boiling water."

Another explanation suggests itself to us if, instead of a
ferment of hepatic origin, we hypothetically use one of ex-
ternal origin: In the first procedure immediate immersion in
boiling water destroyed the ferment which happened to be in
the blood-vessels, while, in the second, the ferment was given
time to act. The difference in the conclusions vouchsafed is
simply this: no thought being given to the blood-vessels, the
ferment could only be considered as of cellular origin. We
have seen how many functions ascribed to the hepatic cells
really belonged to the intercellular blood-stream; this seems
to be an additional one.

Admitting that we are dealing with a ferment of external
origin, from which organ could we expect it to be derived?
Can we attribute the process to ferments from the salivary
glands or pancreas? If it is produced only by digestive fer-
ments,— i.e., amylolytic ferments poured out during digestion,
— why does glycosuria appear irrespective of any digestive
process when the floor of the fourth ventricle is punctured, as
shown by Claude Bernard? He also found that conversion of
glycogen into sugar was a continuous process, carried on to
subserve the needs of the organism: a perfectly logical con-
clusion if the liver is really a storehouse for this substance.
Again, the quantity of sugar in the blood, as we have seen,

GLYCOGEN AND ITS FORMATION. 355

is small, but constant. How could we account for these feat-
ures of the problem with ferments transmitted through the
digestive tract?

Finally, sugars thus produced — i.e., from amylolytic fer-
ments secreted by the digestive tract — do not seem to be
dextrose, the sugar produced by the supposed hepatic ferment.
Thus, Professor Foster says: "In the case of the amylolytic
ferment of saliva, pancreatic juice, intestinal juice, and, in-
deed, of all other amylolytic animal fluids, the sugar into which
starch or glycogen is converted is maltose. Now, the sugar
which appears in the liver after death is dextrose, identical,
as far at least as can at present be made out, with ordinary
dextrose." It is evident that a ferment other than the amy-
lopsin connected with the digestive process must be the active
one, and that it must reach the liver by a channel other than
the intestinal tract, the villi, etc. Again, it must be very
nearly similar to the salivary and pancreatic amylolytic fer-
ments. The salivary glands are so remote anatomically that
they can hardly be considered; we are brought, therefore, to
the pancreas as the only organ which could act as source of a
ferment or diastase having for its main function to convert
glycogen into dextrin.

As shown by von Mehring, Minkowski, and de Dominicis,
removal of the pancreas causes marked glycosuria, and this
persists whether the animal be given carbohydrates or not.
All the other symptoms of diabetes mellitus appear, — namely:
increased flow of urine, considerable urea, acetone, etc.; great
thirst and hunger, emaciation, marked muscular weakness, —
followed by death in two to four weeks. Indeed, we are vividly
reminded of the suprarenal glands, on ascertaining that graft-
ing of a piece of pancreas in the abdomen or skin will arrest
the glycosuria, and that, if a small portion of the organ is left,
the symptoms will disappear. Again, whether carbohydrates
are given as food or not, the glycogen disappears from the
liver. "We may believe, from these experiments," says Howell,
"that the pancreas produces a substance of some kind that is
given off to the blood or lymph, and is either necessary for
the normal consumption of sugar in the body or else, as is
held by some, normally restrains the output of sugar from the

356 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

liver and other sugar-producing tissues of the body. What
this material is and how it acts has not yet been determined
satisfactorily/7 That we are dealing with an internal secre-
tion is clear, and, such being the case, the secretion probably
passes out into the blood by the pancreatic vein, which "opens
into the splenic and mesenteric veins." As these open, in turn,
in the portal vein, the pancreas would then supply a special
ferment for the conversion of glycogen into a functional sugar.

If the foregoing symptoms are closely scrutinized, it soon
becomes apparent that the functions of the pancreas — as will
be shown in the next chapter — are far more important than is
generally believed. For the present, however, we will limit
our inquiry to the subject in point.

The fact that, notwithstanding the ingestion of carbo-
hydrates, the glycogen will totally disappear from the liver is
easily accounted for. A prominent function of the pancreas
during intestinal digestion is to transform starches into malt-
ose, to insure absorption of this sugar. When the organ is
removed, therefore, its amylopsin is no longer furnished to the
intestinal contents, starches are not properly converted, and
the portal vein carries no maltose to the hepatic lobule. The
production of glycogen, therefore, ceases. The fact, however,
that we can so easily account for this phenomenon suggests
that:—

1. The pancreas is the organ upon which all the preliminary
functions connected with the formation of glycogen depend.

2. Its amylopsin converts starches in the intestine to prepare
them for the elaboration of glycogen in the hepatic cell.

S. Its internal secretion, supplied to the portal system by way
of the splenic vein, converts glycogen into dextrose.

That we are on the right path is suggested by a series of
experiments by Croftan,23 in which the conversion of glyc-
ogen into sugar was obtained by means of injections of supra-
renal extract: "Incomplete as these experiments are," says
the author, "they reveal the fact that the injection of supra-
renal extract can cause the excretion of dextrose provided the
quantity injected is sufficiently large. Why in the case of one

Croftan: American Medicine, Jan. 18, 1902.

GLYCOGEN AND ITS FORMATION.

357

animal more must be given than in the case of another to pro-
duce approximately the same excretion is undecided and re-
mains to be determined." Dwelling upon the presence in the
adrenals of a diastatic ferment, he states that "two possibilities
may present themselves, viz.: either the suprarenals manu-
facture a diastatic ferment or they retain the diastatic ferment
that is formed elsewhere in the body (pancreas, salivary glands)
when it is carried to them in the blood- or lymph- stream."
The author also refers to the investigations of F. Blum,24 who,
"testing the effects of suprarenal extract empirically," discov-
ered "glycosuria in 22 out of 25 animals .that he operated on."
Our interpretation of the manner in which these investigators
reached their results is, of course, not that of Croftan, since,
as we view the process, the oxidizing substance constitutes the
active suprarenal agency as a compound of suprarenal secretion
and oxygen.

We are dealing with enhanced physiological activity some-
where. Indeed, Croftan says: "In order that hyperglycosuria
be produced the amount of sugar normally poured into the
blood must be increased, or the amount normally destroyed
must be decreased." That excessive activity was either pro-
cured by the injected extract or by overstimulation of the
adrenals, both leading to total insufficiency, is shown by the
brief history of one of the animals: "The second rabbit died
in one hour and ten minutes; here some spasmodic symptoms,
involving chiefly the posterior extremities, preceded the coma."
Referring to two rabbits, including the latter, the first having
died in two hours and forty minutes and to "all others to be
spoken of presently" (six, all told), he says: "Dextrose was
identified in the urine by its cupric-reducing powers and the
phenylhydrazin test; in one of the dogs in addition by circum-
polarization and yeast fermentation. The substance excreted
was undoubtedly dextrose. The amount excreted would be far
too large to be explainable by a splitting of the jecorin-like
substance mentioned above; it would, not, moreover, be pos-
sible for considerable quantities of dextrose derived from this
source to appear in the urine for several days after the injec-

24 F. Blum: Deutsche Archiv f. klin. Med., Oct. 31, 1901.

358 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

tion." Excessive stimulation by a great increase of oxidizing
substance in the blood evidently occurred. As soon as the
extract was injected it was carried to the lungs, and lost its
individuality immediately therein by taking up oxygen. It
could no longer, therefore, act as a diastase.

The question now to decide is this: General stimulation
enhanced the production of an amylolytic ferment either by
the liver or by the pancreas. To which organ can we ascribe
this function? Since oxidation destroys sugar, a great excess
of oxidizing substance in the blood would burn sugar actively
on all sides and produce the opposite of glycosuria: i.e., ex-
cessive combustion and rapid disappearance of the liver glyc-
ogen through abnormal use of it in the other organs. But
here we have, as a result of a great increase of oxidizing sub-
stance in the blood, marked glycosuria, and that evidently
without preliminary feeding, since this fact is not mentioned
by Croftan. As the oxidizing substance does not affect glyc-
ogen, that of the liver could not be converted by it into sugar;
hence the excessive production of the latter can only be ac-
counted for by an equally excessive production of amylolytic
ferment.

Claude Bernard showed that conversion of glycogen into
sugar took place more rapidly when the blood was made to
traverse the liver with unusual speed. Yet he attributed the
formation of the ferment to the liver, having obtained it from
pulp rubbed up and treated with glycerin, after the liver had
been washed out so as to remove the vascular contents. But it
seems clear that injections by the portal vein will hardly deplete
the liver of every particle of the ferment in its minute lobular
capillaries, while reduction of its substance to pulp and a three
days' immersion in glycerin will dissolve all that contained in
the latter. When we consider how readily conversion can be
produced, — even by traces of soluble albumin, according to
Seegen, — it is evident that upon the addition of water to the
glycerin solution the very small proportion that may have re-
mained imprisoned in some of the lobules will suffice for the
conversion of glycogen.

One of Claude Bernard's experiments seems to us to afford
proof that the amylolytic ferment reaches the liver through

GENERAL CONCLUSIONS. 359

the portal vein. By ligating the latter vessel he created a
collateral circulation, and shifted the portal-blood stream into
the general circulation. Ten or 12 grammes of sugar were
then given to the animal, and sugar was soon found in the
urine. In a normal dog, on the other hand, 50 to 80 grammes
had to be administered before this result was obtained (M.
Duval25). The absence of sugar in the latter animal's urine
until a very large quantity of sugar had been ingested dis-
tinctly shows that conversion of its glycogen only occurred
because its portal vein was open; in the other dog it was not
converted glycogen that passed into the urine, but maltose,
i.e., intestinal starch which had been submitted to the action
of the pancreas's intestinal ferment, — i.e., amylopsin. If we
now couple the fact that conversion of liver-glycogen only oc-
curs when the portal vein is free with Claude Bernard's ob-
servation that increased speed of the portal blood through the
liver causes the glycogen to be converted more rapidly, it seems
clear that the conversion process is not due to an hepatic ferment,
and that the pancreas supplies, as an internal secretion, the fer-
ment which converts glycogen into dextrose.

A perplexing feature of all this requires elucidation, how-
ever. If, as we have stated, the blood-plasma contains an
oxidizing substance, why is the sugar not oxidized on its way
to the tissues of distribution? Armand Gautier26 refers to the
investigations of Jaquet, which demonstrated that sugars
mixed with blood containing the oxidation ferment previously
referred to, and which we found to be of suprarenal origin,
did not become oxidized. He ascertained, however, that upon
adding to the blood a small quantity of fine pulp of muscle,
lung, or of any other organ, the oxygen was absorbed. This
obviously indicates that dextrose passes through the blood with-
out being destroyed, and it can only become oxidized after combin-
ing with bodies produced by the organs to which it is distributed.

General Functions of the Liver, Spleen, and Pancreas. — All
the facts reviewed in this chapter suggest the following conclu-
sions as to the functions of the liver, spleen, and pancreas: —

1. The hepatic artery, owing to the oxidizing substance that

25 M. Duval: Loc. cit., p. 378.

26 Armand Gautier: "La Chimie de la Cellule Vivante," p. 98.

360 THE ADRENAL, GENERAL MOTOR, AND VAGAL SYSTEMS.

its plasma contains and the mode of distribution of its terminal
capillaries, supplies the exogenous chemical energy which initiates
and sustains all reactions in the hepatic lobule that require oxygen.

2. The nervous supply of the liver is composed, first, of ter-
minal subdivisions of the general motor system (splanchnic-sym-
pathetic), which furnish nervous energy during the passive sta/je
of functional activity by insuring tonic contraction of all vessels,
and, second, of terminal subdivisions of the vagus, which excite and
govern the active stage of functional activity by regulating the cali-
ber of the hepatic arterioles and by supplying nervous energy to the
hepatic cells.

8. In the normal subject the liver is anatomically isolated
from structures that come into contact with bacteria, and protected
against their intrusion by the bactericidal products of the intestinal
glands and follicles.

4. The capillaries of the hepatic lobules, owing to the ad-
mixture therein of the hepatic artery's oxidizing substance with the
portal vein's waste-laden blood, are the seat of several functions
now ascribed to the hepatic cell.

5. Blood-pigments and iron, derived from the intestine and
spleen, simultaneously penetrate the hepatic lobule, and combine
with the oxidizing substance therein to form hcemoglobin. The un-
combined pigment is eliminated with the bile as bilirubin.

6. Urea is the end-product of three successive reactions, viz.:
(1) nitrogenous bodies are reduced to amides in the afferent veins,
— mesenteric and portal; (2) the amides are dissociated into
ammonia, carbonic acid, and water by the oxidizing substance in
the hepatic lobule; (3) urea is formed by synthesis in the efferent
veins, — hepatic and vena cava.

7. The hepatic cell contains, besides its vacuoles and nuclei,
numerous canaliculi (S chafer) and a vesicular vacuole which
opens into the bile-capillaries by a canaliculus (Kupffer); the
canaliculi and the vesicular vacuole are probably connected.

8. Glycocholic acid and taurocholic acid are functional acids,
inasmuch as they dissociate and appropriate waste-products, and,
under the influence of the oxidizing substance, convert them into
excrementitious products in the canaliculi of the hepatic cells.

9. The waste-products so converted by the biliary acids and
the latter themselves, constituting bile, are transferred, along with

GENERAL CONCLUSIONS.

361

other products for which the latter may serve as vehicle, — bilirubin,
earthy salts, etc., — to the vesicular vacuole of the cell and eliminated
by the canaliculus that opens into the bile-capillaries.

10. The liliary acids, blood-pigments, iron, and other bodies
or any of their components, that may prove useful to the organism
are, entirely or in part, reabsorbed by the intestinal venules and
returned to the portal circulation.

11. The sugars converted from intestinal foodstuffs in the
intestines are brought to the hepatic lobule with the portal blood,
and penetrate the canaliculi with the latter and with the oxidizing
substance. During the bile-forming reaction the sugars are de-
hydrated, and, probably with the assistance of the cellular proto-
plasm, converted into glycogen.

12. The liver glycogen is converted into dextrose by an amy-
lolytic ferment supplied by the pancreas as an internal secretion,
which enters the portal circulation by the splenic vein.

18. Dextrose is distributed to the organs in which it is used
as a source of energy by the blood, and only becomes vulnerable to
oxidation when combined with products of metabolism furnished
by those organs.

CHAPTER VIII.

THE INTERNAL SECRETIONS OF THE PANCREAS
AND SPLEEN.

GLYCOSUKIA AND OVEEACTIVITY OF THE ADRENAL SYSTEM.
— The pancreas and spleen are considered together because
there is considerable evidence in favor of the view that they
are functionally associated; and it is to give the analysis of
this question and its relationship with the ferments furnished
by the pancreas to the portal blood due prominence that we
have, under other headings, considered the better-known func-
tions of both organs.

To sustain our belief that liver glycogen is converted into
dextrose by an amylolytic ferment supplied by the pancreas
which penetrates the portal vein directly, — i.e., by way of the
splenic vein, — we were fortunate in having at our disposal the
experiments of Croftan, which showed that suprarenal over-
activity could so augment the functional activity of the fer-
ment-producing organ as to induce a very great increase in
the sugar eliminated. This feature requires further study,
since it will tend to elucidate other functions of the pancreas.

We believe that we have conclusively shown that drugs of
various kinds increase the functional activity of the adrenals.
The uniformity of the phenomena traceable to these glands
under the influence of such agencies seems to us to warrant
the conclusion that, if we can demonstrate that glycosuria is
also subject to the latter, its fluctuations following those of
the suprarenal activity or insufficiency induced by them, a
direct connection between glycosuria and suprarenal over-
activity will have been shown. Yet we must bear in mind, in
this connection, that all active drugs may have a primary
action upon tissues for which they possess a specific affinity
before the suprarenal protective functions are fully awakened.
We have seen that even electrical stimulation of the splanch-.
nic is only followed by vermicular motions of the intestinal
wall after some time has elapsed. But too much weight must
(362)

GLYCOSURIA AND ADRENAL OVERACTIVITY. 363

not be given this feature, inasmuch as we have personally seen
the typical symptoms of total suprarenal insufficiency occur
in a dog within twenty seconds after a fatal dose of hydro-
cyanide of potassium had been administered. Large quantities
of the less active drugs are more likely to reach the tissues
for which they possess a special predilection, bromide of
potassium, for instance, than such an agent as that pre-
viously mentioned. While, therefore, we cannot say that ex-
cessive formation of sugar, when drugs are given, is due only
to overstimulation of the adrenals, we can say that all drugs
can produce it when they stimulate suprarenal activity. Fur-
thermore, it seems probable that some drugs not only do this,
but they likewise, owing to their affinity for certain tissues,
enhance the production of sugar by increasing the functional
activity of the intimate structures of the organs concerned in
its production from ingested substances — thus stimulating two
different sets of organs simultaneously. Such an agent we
probably have in phloridzin.

In an able and exhaustive review of the subject of toxic
glycosuria, P. Cartier,1 of Paris, says: "The symptomatology of
phloridzin is very limited, seeing that it does not give rise to a
true intoxication. ... In man it is even possible to bring
on glycosuria, and maintain it a long time, without giving rise
to general disorders, provided a copious alimentation is in-
sured." We have evidence in the last sentence that the main
general result is an excessive formation of sugar, and, more
carbohydrates being required, it is to an excessive production
of the converting agent that we must ascribe this phenomenon.
Still, if general symptoms are absent, what becomes of the
suprarenal overactivity? Cartier answers this question when
he says: "Yet all authors who have studied phloridzin unite
in saying that the animal experimented upon becomes voracious,
and, if not overfed, rapidly wastes. . . . When alimenta-
tion is insufficient, grave phenomena appear. Phloridzinic
glycosuria has been obtained in animals entirely deprived of
hydrocarbons; under these circumstances general symptoms
analogous to those of diabetic coma have been observed."

1 F. Cartier: These de Paris, 1891.

364 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

Osier2 states that Frerichs recognized three groups of
cases; two of these are of special interest to us: (a) Those
in which after exertion the patients were suddenly attacked
with weakness, syncope, somnolence, and gradually deepen-
ing unconsciousness, death occurring in a few hours, (b)
Cases with preliminary gastric disturbance, such as nausea
and vomiting, or some local affection, as pharyngitis, phleg-
mon, or a pulmonary complication. In such cases the attack
begins with headache, delirium, great distress, and dyspnoea,
affecting both inspiration and expiration: a condition called
by Kussmaul air-hunger. Cyanosis may or may not be present.
If it is, the pulse becomes rapid and weak and the patient
gradually sinks into coma, the attack lasting from one to five
days. The need of a copious supply of carbohydrates ob-
viously points to increased oxidation. Indeed, complete ab-
sence of glycogen in the liver and muscles has been noted.
The voracious appetite and rapid wasting further sustain this
— and simultaneously, therefore, the presence of suprarenal
overactivity. The italicized words in the list of terminal
symptoms, on the other hand, as prominently point to the
gradually deepening suprarenal insufficiency.

Alluding to the effects of acids in the production of
glycosuria, Cartier refers to the experiments of Pavy3 with
phosphoric acid. An increase of sugar was noted in twenty
minutes; fifteen minutes later a large quantity was present.
In another strong, but fasting, dog the sugar was markedly
reduced by a smaller dose. HaBmorrhagic infiltration of the
gastric and intestinal tissues and haBmaturia were also noted.
These are all familiar landmarks of suprarenal origin. Strik-
ing, in this connection, are the observations of Stadelmann,4
who found that the production of C02 decreased in the rabbit
during acid intoxications as it does in diabetic coma. In a
foot-note Cartier says: "Voit and Pettenkofer and Gaethgens
have peremptorily shown, by means of most precise experi-
ments, that (1) the oxygen absorbed by a diabetic is much less
than by a normal man, and that it decreases progressively until

2 Osier: "Practice of Medicine," third edition.

8 Pavy: Guy's Hospital Reports, vol. of 1861.

4 Stadelmann: Deutsche med. Wochenschrift, Nov. 4, 1890.

GLYCOSURIA AND ADRENAL OVERACTIVITY. 365

the end of the disease, when it is hardly equal to half of the
normal quantity; (2) that the C02 exhaled is likewise reduced."
That this is essentially due to suprarenal insufficiency — i.e.,
reduced oxidation — is shown by the fact that, in a case of coma
due to meningitis witnessed by Stadelmann, the proportion of
C02 was 28.2 per cent.; while in diabetic coma the gradual
decline is that observed in Minkowski's rabbits, which, from the
normal 25 per cent., steadily dropped to 16, 8.8, then 2.9 per cent.

We have seen that tetanus was due to excessive suprarenal
activity. Cartier refers to the experiments of Claude Bernard,
which showed that strychnine produced glycosuria in dogs.
"It is unnecessary to reproduce here," says Cartier, "the symp-
toms of poisoning produced by this alkaloid; we will simply
say that nothing recalls tetanus to such a high degree as does
intoxication by it." We have another proof that it is due to
an excessive production of a ferment or some other agency
possessed of converting powers since Langendorff found that
"glycosuria only occurs in frogs when the liver contains glyc-
ogen. ... In the summer, when their liver contains none,
strychnine does not cause diabetes in these animals."

We are reminded of the disorganization of haemoglobin
produced by advanced suprarenal insufficiency when, referring
to curare glycosuria, Cartier says: "Others account for this
glycosuria by an insufficiency of the respiration and by slowing
of combustions. The dark coloration of curarized blood indi-
cates this asphyxia." Even the nervous distribution, as we
interpret it, including the connection between the anterior
pituitary body and the adrenals, finds itself sustained in a
remarkable manner by the following lines of Cartier's in ref-
erence to morphine glycosuria: "An extremely interesting
fact that all these investigations indicate is that one can
produce with a toxic substance exactly similar phenomena to
those recorded by Claude Bernard in his lessons at the .College
of France, and obtained by puncture of the medulla, and that
these toxic glycosurias can in most cases be arrested, as are
glycosurias of nervous origin, by severing the centrifugal nerve-
impulse conductors. Indeed, section of the pneumogastric
(centripetal nerve) does not prevent glycosuria caused either
by Bernard's puncture or by morphine; but, on the contrary,

366 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

section of the splanchnic nerves (centrifugal nerves) and of the
medulla above the origin of these nerves prevents both the
experimental diabetes of Claude Bernard and the toxic diabetes
caused by morphine."

The list of drugs that are able to produce glycosuria could
be indefinitely prolonged: it includes all those that produce
suprarenal overactivity. But this does not mean that the fer-
ment-producing organ is alone stimulated; glycosuria is but
one of the manifestations of the exaggerated general metabo-
lism induced, and oxidation processes are enhanced accord-
ingly. Toxic glycosuria, therefore, only represents the sur-
plus of sugar which oxidation processes have not consumed;,
the excess of sugar actually produced is probably far greater
than the surplus which the urine shows. Again, certain drugs
— phosphorus, for instance — do not produce glycosuria to any
marked degree; as soon as the dose capable of causing it is
reached, the adrenals lapse into insufficiency, and, if the dose
is pushed to any extent, even the normal ratio is reduced.
Antipyrin is now considerably employed in diabetes; we have
seen that this drug and acetanilid readily produced suprarenal
insufficiency and dissociation of the haemoglobin molecule.
This is sufficiently extensive sometimes to manifest itself a&
methaemoglobinuria or even hgematoporphyrinuria. All these
facts seem to us to indicate that toxic glycosuria is primarily
due to over stimulation of the adrenal system, the excessive func-
tional activity which increased oxidation produces giving rise to an
inordinate production of an agency that converts glycogen into sugar.
All these features will again be reviewed.

That the agency which converts glycogen into sugar is
the amylolytic ferment produced by the pancreas to which we
have referred is further sustained by the foregoing facts, espe-
cially in view of the amylolytic properties of the pancreatic
secretion in the intestine. Since the conversion into sugar
occurs during fasting as well as during digestion under the
effects of toxics, the reaction can only include the hepatic
glycogen and pancreatic ferment; and, there being nothing in
the intestine to convert during fasting, the ferment must nec-
essarily reach the glycogen by another channel. May this not
"be the more direct route afforded ly the splenic vein?

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 367

Yet there is a possibility that the flow of amylopsin in the
intestine, which the enhanced activity of the pancreas must
undoubtedly increase, may be reabsorbed by the venules, and,
being carried into the portal system, produce conversion of the
glycogen precisely as if it had entered the portal vein by the
way of the splenic vein. But we have seen that, while removal
of the pancreas is rapidly followed by death, very large por-
tions of the gland can be safely removed. Admitting that the
operators may have left the portions related with the pan-
creatic duct, how could we account for the effects of trans-
planted fragments in arresting the glycosuria caused by re-
moval of the pancreas, recorded by Minkowski5 and Hedon?6
As long as fragments transplanted subcutaneously remained
normal no glycosuria occurred; it reappeared, however, when
these fragments became histologically impaired. It is evident
that the only channel here for the amylolytic ferment produced
could be the blood. Thus carried to the heart, it then pene-
trated the liver by way of the hepatic artery, and reached the
intercellular capillaries and the glycogen precisely as if it had
penetrated the organ by way of the portal vein. Although but
a small quantity of the ferment could thus reach the liver, it
was evidently sufficient to convert the amount of glycogen
required to build up the very limited proportion of sugar found
in the normal blood, as previously shown. Again, we have
seen that the product of intestinal reduction is maltose, while
the urine of Crof tan's animals when stimulated with supra-
renal extract gave dextrose in very great quantities: a feature
denoting successive processes. This and the other facts ad-
duced appear to us to contribute additional evidence to the
view that the dextrose- forming ferment enters the portal system
by way of the splenic vein.

THE FUNCTIONAL KELATIONSHIP BETWEEN THE PANCREAS
AND SPLEEN.

The internal secretion of the pancreas and that of the
spleen may perhaps be best studied by submitting to a care-
ful analysis the hypothesis advanced by Schiff, sustained by

« Minkowski: Verhandl. d. XI Congr. flir Inn. Medicin, Wiesbaden, 1892.
8H6don: Archives de Physiologie norm, et path., vol. iv, 1900.

368 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

Herzen,7 and defended by Lepine8 and others that the spleen
supplies a ferment which, when added to pancreatic juice,
greatly increases its digestive energy. Schiff believed that the
splenic substance played an important part in the genesis of
the pancreatic proteolytic ferment, but Herzen attributed to
it the function of converting trypsinogen into trypsin, the
albumin-solving constituent of the pancreatic juice. This
subject was more recently studied experimentally by Gachet
and Pachon,9 who were led to conclude, as previously suggested
by Laguesse (1893) and Schafer (1895), that the spleen fur-
nishes a true internal secretion which possesses a special
affinity for the pancreas, the protrypsin of which it transforms
into trypsin, as suggested by Herzen. This substance loses its
properties at the boiling-point; is precipitated, when in aqueous
solution, by alcohol; and is, therefore, of the nature of a fer-
ment.

Lepine also confirmed Schiff's and Herzen's view by ex-
periments in vitro and by blood-analyses. He found that a
mixture of pancreas and spleen-pulp in glycerin possessed far
more active properties than pancreas alone similarly prepared.
On the jother hand, the blood of an animal deprived of its
spleen proved almost inert as a tryptic, while the blood of a
normal dog possessed distinct digestive powers. Analysis of
the experiments of these various authors distinctly indicates
that some function of the kind mentioned exists. The ana-
tomical relations of the organs involved, however, make it
impossible for the internal secretion referred to, to penetrate
the circulation without first passing through the liver with
the Hood of the splenic vein, which collects the pancreatic inter-
nal secretion and carries it to the portal vein. This fact seems
to suggest that, besides the amylolytic ferment, the portal
carries a ferment to the liver calculated to insure the tryptic
action upon albumins and kindred bodies. If we consider that
we have in the blood of the portal channels all the products
of digestion and that trypsin is "applied solely to albuminoid

7 Herzen: Revue G6nerales des Sciences pures et appl., vol., 1895.

8 Lepine: Societ6 des Sciences Medicales de Lyon, July, 1895.
» Gachet and Pachon: Archives de Physiologie, April, 1898.

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 369

conversions and changes" (Charles), the importance of the
spleen's internal secretion will appear.

Albuminoids, especially those ingested with food, are not
the inoffensive bodies that they appear to be; indeed, they
constitute the foundation of some of the most dangerous sub-
stances that enter the organism when their molecular structure
undergoes certain changes. Apart from any function of the
spleen in the direction mentioned, the pancreatic trypsin sup-
plied to the intestine — if we can judge by the manner in which
a small remnant of pancreas will prevent glycosuria — must
persist even when the pancreas is, in a state of advanced dis-
ease. We saw that one-twentieth of the functional area of
the adrenals sufficed to sustain the general oxidation processes.
That the pancreas possesses at least four times more functional
area than it absolutely needs has been experimentally demon-
strated. With proper — fresh, uncontaminated — food, a nor-
mal organism is practically invulnerable, so splendidly is it
armed against any chemico-physical decomposition that the
ingesta may undergo. But these physiological defenses may
be weakened through general or local adynamia, i.e., lowered
oxidation processes, and peptones, capable of yielding toxal-
lumins, leucomaines, ptomaines., — all albuminoids, — fail to un-
dergo further splitting in the intestinal canal. Again, and
under the same circumstances, notwithstanding the destructive
action of the gastric and intestinal secretions, bacteria and
their toxins may penetrate the debilitated villi and the portal
circulation. The blood-stream, furthermore, may be invaded
through peripheral organs not only by bacteria and their
toxins, but also by vegetable poisons and venoms: all albuminoid
substances, as previously emphasized. Even these do not rep-
resent all the sources of danger that a protective function, such
as that represented by the pancreatic and splenic secretions,
would have to meet, were they, as we believe, mainly intended
to fulfill such a mission.

If toxic albuminoids reach the portal vein by way of the
intestinal villi and the mesenteric veins, all conditions therein
are most advantageous for the action which trypsin is known
to exercise upon them: It acts with great energy in alkaline
media, and the presence of oxygen does not inhibit its action;

370 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

if, therefore, the venous blood of the afferent channels should
happen to contain an unusual amount of oxidizing substance
through suprarenal overactivity, the tryptic disruption of pep-
tones would not, to say the least, be prevented; in laboratory
experiments the need of an antiseptic when pancreatic juice
is used is well known; we have seen that in the afferent ves-
sels, the fluids derived from the intestines had been saturated
therein with the -antiseptic secretion of the glands of Brunner
and Lieberkiihn, and it is evident that their influence would
normally continue in the venous channels; finally, the action
of trypsin does not cease when the peptone stage is reached;
it converts these into leucin, tyrosin, aspartic acid, etc., the
fate of which derivatives we have traced down to urea, the
end-product eliminated in the urine.

The role played by the spleen in the pancreatic digestion
of proteids, and to which we add a prophylactic function, has
been so ably reviewed by H. F. Bellamy in a comparatively
recent number of the London Lancet10 that we will utilize the
greater part of his paper to illustrate the various features that
appear to us to furnish a solid foundation, not only for the
views of Schiff and Herzen, but also for our own.

The author reviews the history of the question as follows:
"Corvisart found that in dogs in full digestion there was for
a certain time a constant rise to maximum in the digestive
power of the pancreatic juice, succeeded by an equally constant
fall to minimum. The maximum was attained during the
eighth hour after the ingestion of a meal, the minimum from
the thirteenth to the eighteenth hours. Meissner announced
that in fasting animals the pancreatic juice possessed little or
no peptonizing power. Schiff, after a number of experiments
on such animals as rats, guinea-pigs, rabbits, and young dogs
or dogs of small breed, found that during fast the pancreas
really possessed almost no peptonizing power; the albumin
imprisoned in the duodenum remained there for whole hours
without dissolving, the infusion of the gland giving results
equally negative. On the other hand, in the case of ravens
and adult dogs of large breed the pancreas preserved during
fast a certain digestive power, even in animals in a condition

10 H. F. Bellamy: London Lancet, Oct. 27, 1900.

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 371

of complete fast which had digested a copious meal the day
before; under these circumstances, indeed, the infusion of the
whole pancreas of a large dog was capable of digesting from
50 to 60 grammes of albumin. In such dogs this condition
of weak digestion was maintained until toward the fourth hour
after the meal, after which time digestion proceeded very
much more rapidly, so that at the time of maximum the pan-
creatic infusion was capable of digesting from 50 to 60 grammes
of albumin. As regard cats and small dogs, he was able to
confirm the results of Corvisart. By these experiments, then,
the above-mentioned observers succeeded in establishing the
following two facts: (1) that the activity of the pancreatic
juice or of an infusion of the gland is not continuous, but in-
termittent, and (2) that maximal activity appears regularly
during the culmen of gastric digestion (from six to eight hours
after a meal), at which time it is very considerable."

Passing now, for the moment, from the pancreas to the
spleen, he proceeds briefly to examine the behavior of this
organ in relation to digestive phases. "Lauret and Lassaigne
in 1825 discovered that the spleen began to become congested
at the moment when the stomach discharged chyle abundantly
into the duodenum; that this is, however, merely a coincidence
is shown by the fact that the congestion also occurs after
ligature of the pylorus. Dobson in 1847 discovered that in a
dog three hours after a meal the spleen is still as small and
as anaemic as during fast; that it commences to dilate in the
fourth hour after a meal; that five hours after it has attained
its maximal turgescence, decreasing afterward from the sev-
enth hour to attain toward the twelfth its minimal volume.
Landois in the same year found that in the rabbit the relative
weight of the spleen to the body-weight of the animal was
the same two hours after a meal as after forty-eight hours of
fast; that it increased considerably from the fifth hour, re-
maining high until the twelfth hour. .....

"The striking synchronism in the splenic congestion and
the presence of trypsin in large quantity in the pancreatic
juice or in an infusion of the gland was observed by Schiff and
caused him to repeat all his former experiments on the tryptic
digestion of albumins, this time on animals in which the spleen

24

372 INTERNAL SECRETIONS OP PANCREAS AND SPLEEN.

had been for some time removed and on others in which it
was prevented from dilating by ligature of its hilum at the
time of the experiment. He experimented in this way upon
a very large number of dogs and cats; nearly all his experi-
ments were double: i.e., performed at the same time and in
the same manner on two animals selected so as to resemble
one another as much as possible, and in only one of which had
the spleen been extirpated or ligatured. These experiments
were of two kinds: (1) those conducted with pancreatic in-
fusions, and (2) those carried out in the living duodenum, the
following being typical examples: —

"/. Infusions. Ligature of the Hilum of the Spleen. — Two
cats, after fasting for 19 hours, received as much meat as they
would eat; 1 hour afterward they were etherized, and the
spleens, which were found to be in a state of contraction, were
brought out through a wound in the abdomen and their hila
were encircled by strong thread; in one of the animals the
hilum was firmly tied, but in the other it was simply encircled
and a knot was tied, leaving the splenic circulation perfectly
free (this was done in the endeavor to equalize traumatic con-
ditions as much as possible). The spleens were then replaced
in the abdominal cavity and the wound was sutured. On
recovering from the anesthesia the animals did not appear to
suffer. They were killed 6 hours later. Gastric digestion was
found to be more advanced in the animal in which the splenic
vessels were tied; the pancreas of both was cut up into small
fragments and infused with 100 cubic centimeters of water for
an hour at 35° C.; the liquid was afterward decanted and
returned to the warm chamber together with cubes of albumin.

"Result. — In 7 hours the pancreatic infusion of the cat in
which the hilum was not ligatured digested 17 grammes of
albumin; that of the other did not digest at all even at the
end of 12 hours.

"This experiment was performed on a large number of
cats and dogs and always gave the same result. In spite, how-
ever, of the perfection of gastric digestion in the operated
animals, it was possible to lay at the door of traumatism the
absence of duodenal digestion; to correct this the experiment
was repeated as follows: —

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 373

"Extirpation of the Spleen. — Two dogs — one normal, the
other having undergone splenectomy a month previously, but
at the time of the experiment in perfect health — were operated
upon, while fasting, as follows: Etherization, ligature of the
pylorus, injection into the stomach, per oesophagus laid bare
and opened, of 50 grammes of peptone and 2 grammes of dex-
trin; to allow drainage of swallowed saliva the oesophagus was
ligatured below the opening. Both animals were killed five
hours later, and each pancreas was infused for three-fourths of
an hour in 100 cubic centimeters of water at 35° C. Although
death had occurred before the most favorable moment for the
experiment, — i.e., in advance of the summit of the splenic
curve, — the infusion coming from the dog with the spleen
intact digested 17 grammes of albumin in 17 hours, while the
other digested nothing even in 18 hours. Numerous experi-
ments made in this manner always gave the same result. The
spleenless dogs had in many cases undergone splenectomy sev-
eral months before the experiment, and the determination in
them of perfect conditions of health was always a matter of
great care.

"II. Experiments in the Living Duodenum. Ligature of
the Duodenum at Both Ends. — Two dogs after fasting for 17
hours received as much meat as they would eat and immedi-
ately afterward were operated upon as follows: Etherization,
laparotomy, ligature of the pylorus and of the bile-duct, intro-
duction into the duodenum of from 30 to 40 grammes of albu-
min, and ligature of the jejunal end. In one of the animals
the splenic hilum was also ligatured. Both were killed 7 hours
later.

"Result. — In the dog with the splenic hilum tied the albu-
min was found to be intact; it had, however, disappeared in the
other.

"This experiment was also several times repeated on ani-
mals which had undergone splenectomy a long time previously,
and always yielded the same result; it is, of course, capable
of being combined with the preceding by making an infusion
of the pancreas after the death of the animals. Such infusions
give results in harmony with those furnished by the duodenum
itself. Further, it will be remembered that in the pancreatic

374 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

juice of dogs of large breed Schiff generally found, even while
fasting, a certain quantity of trypsin; when the same were
spleenless, however, he was unahle to find any.

"Digestion in the Normal Duodenum Provided with a Fist-
ula.— A duodenal fistula was established in a dog. After com-
plete recovery a measured and constant quantity of albumin
was introduced every day into the duodenum inclosed in a
small envelope of fibrous membrane fixed to the cannula by a
thread some centimeters long. The progress of digestion was
then observed, the following results being obtained: 1. When
the animal was fasting the albumin took from 5 to 6 hours
to become dissolved. 2. When the albumin was introduced
into the duodenum during the 2 to 3 hours immediately fol-
lowing the ingestion of a meal by the animal it remained un-
changed. 3. When introduced 4 hours after a meal it dis-
appeared very quickly, — in about half the time, in fact, occu-
pied during fast. These facts having been duly noted, the
spleen was' then extirpated, and after complete recovery the
same experiment was repeated; very different results were
now obtained. Whether fasting or in full digestion the time
taken for the digestion of the albumin was exactly the same,
viz.: from 5 to 6 hours. The acceleration in the peptonization
which had formerly appeared after the fourth hour of digestion,
and which coincided both with the appearance of trypsin in
the pancreatic juice and with the dilation of the spleen, was
now absent. The slow digestion (from 5 to 6 hours) in this
experiment was probably entirely due to the secretion of the
duodenal glands, which possess only a very feeble digestive
power; the active, rapid digestion was due to the appearance,
in large quantity, of trypsin in the pancreatic juice: a phe-
nomenon wanting in the spleenless animal. . . . Schiff
endeavored to interpret the facts by the following theory:
During the congestion of the spleen a substance is produced
within it which, carried away by the blood, gives to the pan-
creas the wherewithal to form its peptonizing ferment. . . .
In 1872, however, the theory of Schiff received a rude shock
through the great discovery of the zymogens by Heidenhain
and his pupils. From the researches of this observer it ap-
peared that, as the gastric mucous membrane forms at the

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 375

outset hardly any active pepsin., but a zymogen accumulating
in its glands in the intervals of digestion, so the pancreas does
not at once elaborate active trypsin, but a substance destined
to become trypsin under certain conditions and in a certain
phase of the digestive act, this substance being, of course, the
pancreatic zymogen trypsinogen, or protrypsin. The researches
of Heidenhain are well known, and it suffices to recall here
only one or more essential points: Thus from them we know
that the pancreas of a fasting dog contains little or no trypsin,
but merely trypsinogen; consequently its glycerin infusion
possesses little or no digestive power; the infusion, however,
of a dog in full digestion digests rapidly and copiously, because
it contains trypsin. If the pancreas of a fasting dog be divided
into two equal portions, one of which is infused at once and
the other only after an exposure of 24 hours to the air, the
first is found to be inactive, while the other is immediately and
energetically active, from which it is clear that the inert tryp-
sinogen which it contains becomes spontaneously transformed
into active trypsin; indeed, it suffices to pass a current of
oxygen through a pancreatic infusion, rich in trypsinogen and
poor in trypsin (an active infusion), to transform it into an
infusion possessing a digestive power. This transformation,
then, is an oxidation, trypsin being oxidized trypsinogen.

"The fact observed by Heidenhain of the continuous for-
mation and storing up of trypsinogen in the pancreas and its
subsequent transformation into trypsin during the culmen of
gastric digestion proved that the former substance at any rate
enjoyed an origin quite independent of all influence outside
the pancreas itself, and the hypothesis of Schiff as to the inter-
vention of the spleen seemed, in consequence, to be at fault.
But it was only the theory of Schiff which suffered by these
new revelations; as far as the experimental results of the two
observers were concerned, physiologists were face to face with
two series of apparently contradictory facts — apparently be-
cause facts properly observed can never stand in contradiction
with one another, and when they appear to do so it is merely
because the interpretation of them is either false or incom-
plete. It fell to the lot of M. Herzen to unravel the tangled
hypotheses. It appeared to him that, by modifying the hy-

376 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

pothesis of Schiff as to the manner in which the spleen acts as
a tryptogene, a fusion of the respective facts of Schiff and
Heidenhain could be brought about, and that, far from being
antagonistic, they could be shown to be reciprocally corrobora-
tive. He argued thus: since the zymogen, even in splenec-
tomized animals, is being continuously elaborated, and there-
fore independently of the spleen and its periodical congestion,
and that it accumulates in the gland-cells during fast, but that
it becomes rapidly and copiously transformed into trypsin only
in the presence of the spleen and in direct proportion to its
dilation, it would seem feasible that the spleen produces, by
'internal secretion' during its congestion, an unknown sub-
stance, which, carried away by the circulating blood, trans-
forms the inert zymogen already deposited in the pancreas into
active trypsin destined to pass into the secretion of the gland,
and that the influence exercised upon the zymogen by this
product of the spleen seemed to be a condition sine qua non
for the transformation of the former into trypsin, at least in
the living pancreas, since in the dead organ or its infusion it
is so transformed by direct oxidation. This hypothesis of
Herzen would seem to be further confirmed by the fact gleaned
from the researches of both Schiff and Heidenhain, to wit:
that the holding in zymogen of the pancreas at a given moment
either of fast or digestion is always in inverse ratio to its hold-
ing in trypsin, and vice versa, while the latter is always in
direct proportion to the spleen dilation.

"So far so good. But Herzen reasoned further. If the
spleen really produces, during its congestion, a substance which
brings about the transformation of the pancreatic zymogen
into trypsin, it would then be possible to seize upon this sub-
stance in the spleen itself while in its turgescent condition
(from 6 to 7 hours after a meal), and by at once making an
infusion of it and mixing a certain quantity of this splenic
infusion with pancreatic infusion made from the pancreas of
a fasting animal (very rich in zymogen and very poor in trypsin,
and consequently nearly inactive) there could be obtained in
vitro a rapid and copious formation of trypsin easily recogniz-
able by the amount of proteid digested in a given time. The
control experiment would also be very simple, consisting merely

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 377

in mixing with the same pancreatic infusion that of a contracted
and anaemic spleen, in order to observe whether it would have
the same effect as that of the spleen dilated and engorged with
blood. Artificial digestions actually carried out with these
infusions gave enormous differences: whereas the pancreatic
infusion alone, or that mixed with infusion of contracted spleen
digested nothing or almost nothing, the same pancreatic in-
fusion to which had been added infusion of engorged spleen
digested rapidly and copiously; indeed, it had often completely
digested its dose of proteid by the time that the other two, if
digesting at all, had barely commenced. The mixed infusions
thus behaved in the same way as a pancreatic infusion taken at
the culmen of digestion.

"A large number of similar experiments were made with
aqueous boric and glycerin infusions, each being double: i.e.,
performed in two separate series of vessels, the one containing
finely divided fibrin and the other equal-sized cubes of coagu-
lated albumin. The results were always the same. . . .

"At the German Congress of Medicine held at Strasburg
in 1886 Herzen exhibited several graduated flasks containing
the residua of fibrin and albumin in a number of his digestions,
the digesting liquid having been decanted and replaced by
alcohol. The physiologists who examined them all recognized
that the difference between the residua left by the pancreatic
infusions alone and those of the mixtures of the pancreatic and
splenic infusions were very obvious. In a private conversation
with Herzen, however, Heidenhain made the following criti-
cism: It is well known that the pancreatic zymogen is very
greedy of oxygen; on the other hand, the spleen during its
dilation is engorged with blood. The splenic infusions ex-
hibited were intensely colored by dissolved haemoglobin — ergo,
the undoubted and considerable acceleration in digestion ob-
tained by adding such a liquid to another containing tryp-
sinogen could be quite simply explained by the rapid oxidation
of the zymogen at the expense of the haemoglobin. This
objection disconcerted Herzen in no inconsiderable degree, and
he lost no time in making it the subject of experimental in-
quiry. He at length succeeded in disproving it by the following
excellent experiment: The pancreas of a normal fasting dog

378 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

was infused in pure glycerin and the infusion was divided into
eight equal portions. These eight portions were mixed with
eight samples of blood received directly into a double volume
of glycerin, of which four came from a fasting dog and four
from a dog in full digestion with the spleen greatly dilated.
The four samples were taken in both animals from (1) the
femoral artery, (2) the femoral vein, (3) the splenic artery,
and (4) a large splenic vein. The eight portions were then
given the usual dose of fibrin and placed at a temperature of
40° C. Now, it is evident that the femoral and splenic arte-
rial blood of the two animals contained more oxygen than
their venous blood; the former, then, according to Heidenhain,
should exercise a powerful influence on the digestion, equal
in the two dogs. On the other hand, according to Herzen, the
splenic venous blood alone should exercise this influence and
especially that of the digesting animal. The result of the
experiment was as follows: After one hour there was still
no trace of digestion under the influence of the femoral blood,
arterial or venous, nor of the splenic arterial blood of the fast-
ing dog; first traces of digestion were beginning to manifest
themselves under the influence of the splenic venous blood of
this animal. Digestion was rather advanced in the case of the
femoral arterial and venous blood and splenic arterial blood
of the digesting dog; the fibrin had almost entirely disappeared
under the influence of the splenic venous blood of the same
animal.

"The answer could not be clearer: the product of the
internal secretion of the spleen, borne therefrom by the cir-
culating blood, is present during the period of the dilation
of the spleen in feeble, but appreciable, quantity in the blood
of the general circulation and abundantly in the splenic venous
blood. The venous blood returning from the contracted spleen
only contains it in very small quantities. This experiment,
several times repeated, always gave the same result, showing
that it is not the blood as such which favors the transforma-
tion of pancreatic zymogen into trypsin, but that, by picking
up from the spleen the unknown substance possessing this
property, the blood becomes its vehicle and means of commu-
nication with the pancreas.

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. 379

"From the bulk of evidence collected by Herzen there thus
seems to be very little room for doubt that, apart from haema-
topoietic, and possibly allied., functions possessed by the spleen,
the organ furnishes a product of 'internal secretion' which
causes in the pancreas the transformation of its inert zymogen
into active trypsin."

Bellamy closes his article with a review of the criticisms
to which the researches of Schiff and Herzen have been sub-
mitted. In the experiments of Lussana, in 1868, the spleens
of three dogs were removed and the animals were subsequently
killed to ascertain whether the extract of their pancreas would
digest coagulated albumin. The pancreatic infusion of the
glands of two of the dogs digested 0.25 gramme of albumin in
24 hours; that of the third digested 1.10 grammes in the same
period of time. "The latter animal had, however, been killed
three hours after a meal: i.e., at a moment when, even had
it been in possession of its spleen, that organ would not yet
have commenced to become congested. The experiment, there-
fore, gave the result which might be expected, — viz.: no di-
gestion,— for nobody would accept seriously the digestion of
1.10 grammes, knowing that the pancreas of a dog when digest-
ing can dissolve from 50 to 60 grammes of albumin. . . ."
Indeed, the experiments of Lussana appear to us to be con-
firmatory of Schiff's and Herzen's views.

Carvallo and Pachon also reported negatively, but, errors
in their experimental procedures having been brought to their
attention by Herzen, subsequent experiments caused Pachon
and a new collaborator, Gachet, to reach the conclusions sus-
taining the views of Schiff and Herzen to which we have re-
ferred on page 368. "Nay, they did more," says Bellamy;
"they invented an entirely new experiment, at once original
and ingenious, which consisted in realizing in vivo what Herzen
had hitherto only done in vitro. This experiment was as fol-
lows: A dog, which a long time previously had undergone
splenectomy, was anaesthetized and half its pancreas was re-
moved and immediately infused; at the same time a normal
dog, in the height of digestion, was killed and its congested
spleen was infused in water, and this infusion was injected
into the venous system of the spleenless dog; from 15 to 20

380 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

minutes afterward the remaining half of the pancreas of the
latter dog was infused exactly like the first; of the two in-
fusions when given fibrin and albumin, the second- only digested
rapidly and copiously."

The investigations of Popelski are next reviewed. "In
both normal and splenectomized cats/' says Bellamy, "he col-
lected the pancreatic juice by means of a cannula introduced
into the duct of the gland, and was unable to find any differ-
ence in digestive activity. As, however, his cats had been
fasting since the day before, his experiments were made out-
side the digestive period during which the spleen, becoming
congested, furnishes abundantly its product of internal secre-
tion which transforms rapidly and copiously the zymogen into
trypsin." . . . "But Popelski also performed some anal-
ogous experiments on a dog with a permanent pancreatic fist-
ula, made according to the method of Pawloff. The pancreatic
juice of this animal was several times collected and examined
before and after splenectomy without any difference in activity
being demonstrable. This result, however, elicits no surprise
in view of the fact that in both instances the juice was always
collected immediately after a meal — i.e., — again to repeat it —
in advance of that digestive period during which the spleen
enters into function and the pancreas abounds in trypsin; so
that as well in this experiment as in that with his cats, Popelski
was placed in that position in which the presence or absence
of the spleen was a matter of perfect indifference. . . ."
The discussion of the various features in point have led to
considerable acrimony, but the impartial observer cannot fail
to consider that the position of Herzen, of those reviewed, is
the only tenable one.

In an article written since Bellamy's review was published
Popelski11 reiterates his views, and states that since it has
been demonstrated that there exist in the organism bodies in
the nature of ferments possessing oxidizing properties, which he
believes to be derived mainly from leucocytes, the results
obtained by Schiff, Herzen, Pachon and Gachet can all be
explained by their action. During the height of digestion

n Popelski: Vratch, Feb. 3, 1901.

FUNCTIONAL MECHANISM OP THE PANCREAS. 381

digestive leucocytosis prevails, and, an accompanying destruc-
tion of these cells yielding more oxidizing bodies, the latter,
he thinks, are the source of conversion of protrypsin or tryp-
sinogen into trypsin, which thus becomes a function of the
blood. Thus, the spleen would have nothing to do with the
process, the hyperaemia and dilation of this organ during the
formation of trypsin being regarded merely as concomitant
phenomena.

The only feature of interest to us in Popelski's last paper
is the fact that his experiments were performed in accordance
with the directions of Schiff. That he should be driven thereby
to ascribe all the phenomena witnessed to the action of
"oxidizing bodies" adds materially to the data contributed by
Schmiedeberg, Jaquet, Abelous and Biarnes, and Salkowski,
proving experimentally the existence of an oxidizing substance,
and is suggestive. Indeed, when, in addition to this, we realize
the strength of Heidenhain's position, the manner in which
it shook to its very foundation the equally strong position of
SchifFs views as developed by Herzen, by pointing to the in-
fluence of oxygen as another agency through which trypsin
could be developed from trypsinogen, "trypsin being oxidized
trypsinogen," the following query suggests itself: Are we not
dealing with two processes working in sequence, a part of the
trypsinogen secreted in the splenic vein being converted by
the splenic secretion for use in the portal vein, and the rest
being converted, when the arteries are reached, by the oxidiz-
ing substance?

To determine whether such a deduction is at all warranted
or whether it is subject to modifications through which the
various views submitted and our own can be conciliated, we
find it necessary to closely analyze the manner in which the
pancreas and the spleen are functionally governed.

THE FUNCTIONAL MECHANISM OF THE PANCKEAS. — The
pancreas will first receive our attention. Eef erring to this or-
gan, Howell says: "Until recently little direct evidence had
been obtained of the existence of secretory nerves. Stimulation
of the medulla was known to increase the flow of pancreatic
juice and to alter its composition as regards the organic constit-
uents, but direct stimulation of the vagus and the sympathetic

382 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

nerves gave only negative results. Lately, however, Pawlow
and some of his students have been able to overcome the
technical difficulties in the way, and have given what seems
to be perfectly satisfactory proof of the existence of distinct
secretory fibers comparable in their nature to those described
for the salivary glands. The results that they have obtained
may be briefly stated as follows: Stimulation of either the vagus
nerve or the sympathetic causes, after a considerable latent
period, a marked flow of pancreatic secretion. The failure of
other experimenters to get this result was due apparently to
the sensitiveness of the gland to variations in its Nood-supply.12
Either direct or reflex vasoconstriction of the pancreas pre-
vents the action of the secretory nerves upon it. Thus, stim-
ulation of the sympathetic gives usually no effect upon the
secretion, because vasoconstrictor fibers are stimulated at the
same time; but if the sympathetic nerve is cut five or six days
previously, so as to give the vasoconstrictor fibers time to de-
generate, stimulation will cause, after a long latent period, a
distinct secretion of the pancreatic juice. A similar result
may be obtained from stimulating the undegenerated nerve if
mechanical stimulation is substituted for the electrical. The
long latent period elapsing between the time of stimulation
and the effect upon the flow is not easily understood."

If the innervation of the stomach as we have interpreted
it is recalled, Howell's lines furnish several confirmatory data.
The fact that "stimulation of the medulla was known to in-
crease the flow of pancreatic juice" suggests that our previous
association of the vasomotor with the general motor system
(sympathetic) was well founded. The vagus being, from our
standpoint, the dominating nerve during pancreatic activity,
as it is in the case of the stomach, it must also have been
stimulated by its center at the proper time. Hence the secre-
tion. That the vagus, as we have stated, assumes charge only
during functional activity is further sustained by the state-
ments that "stimulation of the sympathetic gives usually no
effect upon the secretion" . . . "but if the sympathetic
nerve is cut five or six days previously, so as to give the vaso-

12 All italics are our own.

FUNCTIONAL MECHANISM OF THE PANCREAS. 383

constrictor fibers time to degenerate" . . . '"distinct se-
cretion of juice occurs." Inasmuch as the sympathetic fibers
are the vasoconstrictors, degeneration annulled their function
(limited to tonic vasoconstriction), and the current caused re-
action in the only normal nerves that remained, the vagi,
which, as we have seen, inosculate with the sympathetic fibers
around all vessels, and are the only ones capable of exciting
physiological activity. Still, Pawlow obtained secretion by
stimulating either nerve. The fact that "a considerable latent
period" elapsed before the flow appeared suggests the reason
for this; indeed — and it is very probable that earlier experi-
menters would also have obtained this result had they waited
long enough — stimulation of either the vagus or the sympa-
thetic was transmitted to the solar plexus, and, their own
plexuses inosculating over the arteries, the state of functional
activity was artificially brought on, though in a slow and de-
ficient manner.

"The secretion is evidently reflex," says M. Duval, "though
the nervous channels of this phenomenon are not exactly
known; it has been noticed, however, that section of the pneu-
mogastrics arrests the secretion of the pancreas." Conversely,
"stimulation of the medulla is effective after section of both
vagi," according to Foster. The solar plexus forming part of
the general motor system (sympathetic), stimulation of the
medulla is also transmitted to the pancreas, and the process
defined in the last paragraph then prevails. That the blood
alone may also sustain the organ's function is shown by the fact
that when all its nerves are severed the secretion continues.
But, initiated and governed by the vagus, this constitutes what
might properly be termed a pseudo-function.

Eef erring to the blood-vessels, Piersol says: "The larger
arterial branches run within the interlobular connective tissue,
sending off vessels which pass between the lobules and supply
the glandular parenchyma with twigs. These latter enter the
lobules and form net-works which inclose the individual acini
within the capillary reticulum. The capillaries lie beneath the
basement membrane in close relation with the glandular epi-
thelium. The veins accompany the arterial trunks within the
connective tissue." A similar arrangement prevails in the

0'S4 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

distribution of the nerve-terminals. According to Ramon y
Cajal and C. Sala, the pancreas contains many nerve-cells
and fibers of Remak. Some cells are found in the interacinous
spaces; others are in contact with the intrinsic vascular
walls, and their finer prolongations surround the glandular cells.
Those connected with the vessels form a plexus around them,
and send extremely fine filaments to the muscular elements.
Alluding to the nerve-cells, Ramon y Cajal says: "We may
consider this cell as a special cell, all the prolongations, or
almost all the prolongations, of which possess the meaning of
nervous prolongations contrary to the cells of the sympathetic
chain, that have two kinds of prolongations: a long one, or
fiber of Remak, for the viscera, and short prolongations com-
parable to the protoplasmic prolongations of cerebro-spinal
cells, destined to establish relations by contact between the
neighboring cells of a ganglion/' Berdal, who quotes the
above, therefore recognizes two varieties of nerve-fiber in the
pancreas: "1. The nerve-fibers formed by the cellular pro-
longations and which supply the periacinous and perivascular
plexuses. 2. The nerve-fibers derived from the sympathetic
nerves which penetrate into the pancreas with the vessels. These
nerves ramify between the lobules and contribute to the for-
mation of the periacinous plexus." He then adds: "In the
present state of the question it is impossible to say if the
latter nerves terminate in a manner different from that of
the former; and one cannot even indicate how they are related
with the nerve-cells of the pancreas."

With our conception of the innervation of the stomach as
guide, the relations between the two sets of nerves seem clear.
That sympathetic and vagus branches are distributed to the
organ, we have seen; it is evident that the fibers formed by
the cellular prolongations are those of the vagus, since the
others are recognized as sympathetic. The only path through
which vagal fibers could enter the organ is, as in the case of
the latter nerve, with the vessels. We have seen, when review-
ing the mechanism of the stomach, that two-thirds of the
fibers from the right vagus passed on to the solar plexus, and
that extensions from the latter, also arranged "largely in
plexuses," passed on "with the vessels" in company with the

FUNCTIONAL MECHANISM OF THE PANCREAS. 385

sympathetic fibers. The pancreas forming part of this same
system, the vascular as well as the nervous arrangement of
the latter are undoubtedly similar. Indeed, we can repeat
almost word for word the explanations given of the phenomena
observed under the same conditions when the stomach was in
question: i.e., the general motor mechanism (sympathetic) serves
only to maintain the tonic contraction of the vascular supply and
the immanent potentiality of the pancreas when it is in the passive
state, while the added impulses of the vagus excite and govern its
functional activity.

The functional mechanism of the pancreas would now be
as follows: —

The nerve-supply of the pancreas is derived from two auton-
omous sources: the general motor system (sympathetic) and the
vagus system.

The general motor system supplies efferent nerves, which only
serve to maintain tonic contraction of the arteries and to insure
the functional activity of all pancreatic structures during the
passive or resting period.

The vagus system supplies loth sensory and motor nerves,
which excite and govern the functions of the pancreas during its
active period.

The extrinsic efferent nerves of the pancreas, also derived
from the "general motor" and vagus systems, accompany the or-
gan's arterial supply and jointly constitute its extrinsic vasocon-
strictor system : i.e., that through which the Uood-flow in the organ
is increased.

The intrinsic efferent nerves are divided into two sets: (1)
branches of the general motor system; (2) branches of the vagus
system.

(a) Each branch of the general motor system subdivides into
two branches: one of these supplies the arterioles; the other sub-
divides into two branches, one of which is distributed to the mus-
cles and the other to the glands.

(b) The branches of the vagus subdivide in the same manner
and inosculate with the general motor filaments and plexuses ex-
cept with those distributed to arterioles that supply capillaries to
the glands.

When the pancreas is in the resting state, the general motor

386 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

nerves alone transmit impulses to all the structures of the organ,
including the glands which, during this period, elaborate their
secretory products.

When as a result of physical (reflex) or psychical stimuli the
pancreas becomes functionally active, the vagus impulses impose
their rhythm upon the general motor nerves, and the vagus system
assumes control of the secretory process. As a result,

(a) The extrinsic arteries are constricted beyond their nor-
mal tonic caliber and the speed of the blood-flow through the organ
is increased.

(b) The intrinsic arteries that do not supply capillaries to
the glands are also constricted, thus forcing the blood into these
capillaries and inducing glandular activity and the production of
pancreatic secretions.

FUNCTIONAL MECHANISM OF THE SPLEEN. — The innerva-
tion of the spleen includes, as a predominating feature, the
distribution of a fair proportion of the terminal fibers to the
muscular elements, which, in man, are mainly supplied to the
trabecula?. "We have evidence," says Professor Foster, "that
the muscular activity of the spleen, whether of the muscular
capsule and trabeculae and arteries combined, or of the latter
alone, is under the dominion of the nervous system. A rapid
contraction of the spleen may be brought about in a direct man-
ner by stimulation of the splanchnic or vagus nerves," . . .
"it may also be caused by stimulation of the medulla oblongata
with a galvanic current or by means of asphyxia. Though the
matter has not yet been fully worked out, we have already
sufficiently clear indications that the flow of blood through
the spleen is, through the agency of the nervous system,
varied to meet changing needs. At one time a small quantity
of blood is passing through or is being held by the organ and
the metabolic changes which it undergoes in the transit are
comparatively slight. At another time a larger quantity of
blood enters the organ and is let loose, so to speak, into the
splenic pulp, there to undergo more profound changes, and
afterward to be ejected by rhythmic contractions of the mus-
cular tra.beculaB."

That rapid contraction of the spleen should occur under
stimulation of the splanchnic nerve is now easily accounted

FUNCTIONAL MECHANISM OF THE SPLEEN. 387

for, when we recall the fact that, as shown by Biedl, Dreyer,
and others, suprarenal activity is thereby enhanced, as shown
by increased secretion. The marked muscular character of the
spleen obviously causes it to respond by contraction to the in-
creased amount of oxidizing substance suddenly thrown into
the circulation, especially when we consider its direct connec-
tion with the cceliac axis. The constrictive effect of stimula-
tion of the medulla on the arteries we have repeatedly seen;
as this is due to contraction of their muscular coats, the spleen
is evidently influenced in a manner similar to that following
stimulation of the splanchnic. Again, therefore, have we as
underlying cause of splenic contraction suprarenal overactivity.

But why should stimulation of the vagus also induce
splenic contraction? This requires an examination of the
distribution of the nerve-terminals. The innervation of the
spleen was studied by Kolliker in various animals,13 and his
observations, when viewed in the light of our conceptions of
the functional mechanism of glandular organs, are suggestive.
"The vasomotor nerves enter the organ with the large arteries.
In the walls of the large arteries the main trunks form a well-
marked superficial plexus with oblong meshes in the adventitia,
and a deep, more quadrate net-work in the tunica media; some
end in the little branched arborizations in this coat. The
smaller arteries and the trabeculae receive their nerves from
the rich maze of fibers in the pulp, consisting of axis-cylinders,
which, however, do not anastomose. Other fibers form a
plexus on the surface of the trabeeulaB, and from this fibrils
penetrate into the interior of the trabeculae (which contain
much smooth muscle) and end by free arborizations." Free
terminals, which Kolliker regards as sensory fibers, were also
found. When we consider that the trabeculse penetrate deeply
into the interior of the organ from the inner surface of the
capsule in every direction, thus forming a spongy frame-work,
it seems clear that stimulation of the nerves distributed to
these structures and to the vascular walls should produce gen-
eral contraction.

These data would not be sufficient to enable us to assimi-

18 Kolliker: Sitzungsbericht d. Wttrsb. Phys. med. Gesellschaft, No. 2, 1893.

388 INTERNAL SECRETIONS OP PANCREAS AND SPLEEN.

late the functional mechanism of the spleen to that of other
organs reviewed were it not that dilation of the latter can also
be produced by stimulating other nerves. Indeed, Howell
says: "The spleen is richly supplied with nerve-fibers which,
when stimulated either directly or reflexly, cause the organ
to diminish in volume. According to Schafer,14 these fibers
are contained in the splanchnic nerves, which carry also inhib-
itory fibers, whose stimulation produces a dilation of the spleen."
We have not so far found the need of such structures as
"inhibitory nerves," and it would seem as if this term were
applied, in this instance, to the fibers to which we have as-
cribed the mission of contracting the arterioles that govern
the intrinsic blood-supply of an organ. Especially does this
appear to be the case since these inhibitory fibers are described
as originating from the splanchnic: i.e., the sympathetic sys-
tem. The latter, if considered as forming part of the general
motor system, would precisely coincide with the origin of the
nerves which have appeared to us to cause contraction of these
small vessels and thus produce secondary dilation of the capil-
laries incident upon functional activity.

. The interpretation of the splenic functional mechanism
in accordance with our views is greatly facilitated when the
microscopical anatomy of the organ is considered in the light
of F. P. Mall's15 researches. The organ is divided, as is the
liver, into lobules, each of which is bounded by "interlobular"
trabeculas: those to which we have already referred. Each
lobule is about 1 millimeter in diameter, is partitioned into
about ten compartments by intralobular trabeculae, and receives
an artery which sends minute branches to each compartment.
There is also considerable analogy between each one of these
compartments and the hepatic lobule, the hepatic cells being
represented by masses of pulp, separated by venules, which
vessels carry back to the veins leading to the greater splenic
vein the various elements transferred to the liver. The pulp
itself is made up of an extremely delicate reticulum, in which
are found red corpuscles, lymphocytes, remains of corpuscles

"Schafer: "Proceedings of Royal Society," London, 1896, vol. lix, No. 365;
and Journal of Physiology, 1896, vol. xx.

«F. P. Mall: Johns Hopkins Hospital Bulletin, Sept., Oct., 1898.

FUNCTIONAL MECHANISM OF THE SPLEEN. 389

with or without pigment, etc. The arteries — which bring to
the organ oxidizing substance — soon after entering the organ
assume an unusual shape: their outer coat becomes lymphoid,
forming nodules similar to the solitary follicles of the intes-
tine,— i.e., the Malpighian corpuscles, — in which lymphocytes
are formed. When, after numerous subdivisions, their diam-
eter becomes greatly reduced, the arteries resume their normal
adventitia and on reaching the pulp in the compartments
break up into minute capillaries. The arrangement is, after
all, an uncomplicated one, and similar, in general plan, to that
of other organs reviewed.

The connection between the nervous supply of the spleen
and that of the other digestive organs becomes evident when
the distribution of the coeliac-plexus branches is recalled.
"The splenic plexus," say Pick and Howden,16 "is formed by
branches from the cceliac plexus, the left semilunar ganglia,
and from the right pneumogastric nerve. It accompanies the
splenic artery and its branches to the substance of the spleen,
giving off, in its course, filaments to the pancreas (pancreatic
plexus) and the left gastro-epiploic plexus, which accompanies
the gastro-epiploica sinistra artery along the convex border of
the stomach." If we append to this Kolliker's description of
the intrinsic nervous supply and the manner in which it is
connected with the blood-vessels, it will become apparent that
we have a counterpart of the vasculo-nervous mechanism of
the stomach, viz.: extensions of the general motor system
(sympathetic) and of the vagus, the former being probably
represented by the deep net-work in the tunica media, the
latter by the oblong meshes of the adventitia. We have here
the representatives of the extrinsic supply.

The functions of the Malpighian corpuscles around the
vessels would thus be insured by fibers from the vagus. In-
deed, Fusari17 traced nervous filaments within these bodies.
The pulp is also possessed of a "rich maze of fibers consisting
of axis-cylinders" — doubtless sensory structures. But here an
independent motor supply must also be present, since we also
have fibers that form "a plexus on the surface of the trabec-

16 Pick and Howden: "Gray's Anatomy," p. 806.

"Fusari: Archives Italiennes de Biologie, Turin, vol. xix, p. 288, 1894.

390 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

ulse," filaments from which penetrate into the trabeculae.
These, we have seen, contain much smooth muscle, and the
nerve-filaments are connected with them by "swellings"
(Fusari), evidently end-plates. Kupffer's bile-alveolus, with
its canaliculi, is recalled by a similar receptacle: i.e., Mall's
"intralobular venous spaces/' which form the starting-point
of the venules that ultimately end in the large trunks leading
to the splenic vein.

If we now trace the process from beginning to end, the
functional mechanism appears to us to be as follows: —

The nerve-supply of the spleen is derived from two auton-
omous sources: the general motor system (sympathetic) and the
vagus system.

The general motor system supplies efferent nerves, which serve
only to maintain tonic contraction of the arteries and of the tra-
becular muscles, thus sufficiently activating the flow of blood to
the Idbular compartments and to the Malpighian corpuscles to
maintain their functional efficiency during the passive period.

The vagus system supplies both the sensory and motor nerves
that excite and govern the functions of the organ during its active
period, which begins about the fourth hour of digestion.

The extrinsic efferent nerves of the spleen, also derived from
the general motor and vagus systems, accompany its arterial sup-
ply, and jointly constitute its extrinsic constrictor system: i.e.,
that through which the Hood-flow in the organ is governed.

The intrinsic efferent nerves are divided into two sets: (1)
branches of the general motor system; (2) branches of the vagus
system.

(a) Each branch of the general motor system subdivides into
two branches: one of these supplies the middle coat of the arteries
and arterioles (the so-called inhibitory nerves); the other is dis-
tributed to the muscular elements of the trabeculce.

(b) The branches of the vagus subdivide in the same manner:
one branch supplies the adventitious layer of the arteries, sends
offshoots to the Malpighian corpuscles, then passes on to the pulp,
where it forms a close net-work; the other forms another plexus on
the surface of the trabeculce which inosculates with that of the pulp.

When the spleen is in the passive state, the general motor
nerves alone transmit impulses to all the structures of the organ,

FUNCTIONAL MECHANISM OF THE SPLEEN. 391

to sustain the continuous functional work of the lobular and cor-
puscular (Malpighian) elements (destruction of erythrocytes, for-
mation of lymphocytes, formation of secretion, etc.) pending the
active stage.

When, as a result of reflex stimuli through the efferent gastro-
duodenal branches of the vagus, the spleen becomes functionally
active, the vagus impulses impose their rhythm upon the extrinsic
motor plexuses (extensions of the splenic plexus), and the vagus
system assumes control of splenic functions. As a result,

(a) The extrinsic arteries are constricted beyond their normal
tonic caliber; the speed of the blood-flow into the organ is increased
and the blood allowed to slowly accumulate therein (probably owing
to restricted caliber of the venous exit), thus causing its dilation.

(b) About the fourth hour of the digestive process the arterial
and venous calibers are equalized and the splenic products (secre-
tion, leucocytes, brolcen-down corpuscles, and pigments) are voided
into the splenic vein and increased rapidly. This continues for
two to four hours, when the calibers are readjusted by the vagus
and the organ resumes the passive state.

An incidental remark of Professor Mall's, in the contri-
bution previously referred to, goes far toward demonstrating
that we have not erred so far in ascribing to the blood-plasma
per se the active part in the blood's function. This constitutes
such a far-reaching feature of this entire work that the follow-
ing lines appear to us as timely: "The microscopical anatomy
shows that the ampullae and venous plexus have very porous
walls which permit fluids to pass through with great ease and
granules only with difficulty. In life the plasma constantly
flows through the intercellular spaces of the pulp-cords, while
the blood-corpuscles keep within fixed channels. Numerous phys-
iological experiments which I have made corroborate this
view." If this can occur in the spleen it is doubtless possible
elsewhere in the organism, especially when we consider that
red corpuscles average in diameter about 1/300o °f an inch,
while the lumen of the majority of functional capillaries is less
than one-half that size. Of course, corpuscles adjust them-
selves to the dimensions of the structures surrounding them;
but it is apparent that in many instances — the tortuous capil-
laries of pericellular net-works, for instance — such a system

392 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

could but compromise the free circulation of the fluids, and,
simultaneously, the functional efficiency of the organ itself.

THE SPLENO-PANCREATIC INTERNAL SECRETION. — Resum-
ing the consideration of the relationship between the functions
of the two organs, spleen and pancreas, it is evident that each
possesses its own complete mechanism, and that in both organs,
as elsewhere in the economy, the oxidizing substance or the blood
containing it is the source of functional activity.

Still, have we any reason to believe, with Popelski, that
it is through oxidation that the intrapancreatic trypsinogen be-
comes converted into trypsin? Can we say, for instance: the
intrapancreatic conversion of trypsinogen into trypsin is not
effected by the splenic ferment, but by the oxidizing substance,
when the efferent vagus nerves transmit appropriate impulses?
We think not, much as such a process would coincide with the
multiple functions that we have already ascribed to, the oxidiz-
ing substance.

We have seen that when the pancreas becomes function-
ally active the extrinsic arteries are constricted beyond their
tonic caliber, and that the speed of the blood-flow through the
organ is increased. Yet, while the net-work of capillaries is
very rich, these encircle the secreting lobules, and, though in
close relation with the glandular epithelium beneath the base-
ment membrane, they in no way, as in the spleen, break up
into reticulated tissue wherein their blood is poured; they
merely lapse, as elsewhere in the organism, into venules, which
ultimately carry the blood to the larger venous channels.
Blood and trypsinogen do not come into contact, therefore,
in the ducts of the typical pancreatic lobule: that which text-
books employ to illustrate the origin, centripetal migration,
and functional elimination of the zymogen granules. These
are lost in the lobular lumina and ultimately reach the greater
duct on its way to the intestine, without apparently having
come into contact with the oxidizing substance.

But, this being the case, how can we account for the ex-
perimental evidence adduced by Schiff and Herzen and other
physiologists who have confirmed their work? How can we
explain, for instance, the digestion of 17 grammes of albumin
in 7 hours with pancreas obtained from a normal cat and no

THE SPLENO-PANCREATIC INTERNAL SECRETION. 393

digestion in 12 hours with pancreas from one in which the
vessels of the splenic hilum had been ligated: an experiment
repeated many times, and always with identical results?

It is evident that, if — as believed by Schiff and Herzen —
the circulatory cycle must be traversed by the splenic ferment
before the pancreas can be influenced by it, this ferment will
merely pass through the pancreas without in any way convert-
ing trypsinogen into trypsin, and fruitlessly re-enter the splenic
venous current. There being no connection between blood-
stream and trypsinogen and none between the latter and the
splenic ferment, we are now reduced to either deny the need
of any converting agency, and simultaneously close our eyes
to all the experimental data adduced, — including Popelski's,
which sustain the existence of some process which has imposed
the necessity upon him of accounting for results witnessed, —
or seek elsewhere for an explanation of the phenomena re-
corded. Thanks especially to the labors of Langerhans,18
Laguesse,19 and Opie,20 this task will be greatly facilitated.

Laguesse having studied the islands of Langerhans in the
pancreas of an adult man (an executed criminal) and of a child
which had died several hours after birth without having taken
nourishment, and in the sheep, reached the following deduc-
tion, quoted from one of our own reviews of his work21: "Long
before the pancreas begins its function as a digestive gland
granules of secretion accumulate in the internal zones of the
cells; and, when these come into contact with the blood, a por-
tion of them appear as though dissolved, while in others the
granules are resorbed. It might be supposed, with some
reservations, that an internal secretion always exists in the
cell, — very much developed, however, and preceding the ex-
ternal secretion in the foetus. Later, each cellular group would
be first full, then acinous, furnishing alternately an internal
and an external secretion." Opie refers to the observations of
Kiihne and Lea22 in injected specimens, in which these in-

18 Langerhans: Inaugural Dissertation, Berlin, 1869.

19 Laguesse: Comptes-Rendus Hebdom. des stances et memoires de la Socle1 16
de biologie, Paris, No. 28, 1893.

20 Opie: Johns Hopkins Hospital Bulletin, Sept., 1900.

21 Laguesse: "Annual of the Universal Medical Sciences," vol. v, 1894.

22 Kiihne and Lea: Untersuch. a. d. Physiol. Inst. d. Univ. Heidelberg, ii,
488, 1882.

394 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

vestigators "found scattered through the organ glomerular
structures composed of dilated and tortuous capillaries, and
showed that these glomeruli correspond to the cell-groups
which Langerhans described. The islands are penetrated by
numerous wide, tortuous capillaries, which lie between cells,
forming irregular, anastomosing columns. Material injected
into the duct of the gland does not penetrate the islands."
The view that the islands of Langerhans furnish an internal
secretion is indirectly sustained, and the histological topography
outlined seems to furnish a clue to the mechanism involved:
i.e., the existence of two sets of glands capable of yielding similar
products, but adjusted individually, as regards distribution, to the
needs of two systems: the digestive system and the circulatory
system.

To develop this proposition and that on page 379, we
will employ the excellent paper of E. L. Opie,23 in which the
entire subject is not only reviewed, but also greatly elucidated
through personal investigations. The quotations from his
article will be limited, however, to the features bearing directly
or indirectly upon the question in point, as given in the above
italicized lines: —

"Schafer and Diamare think that the vascular islets prob-
ably furnish an internal secretion. The only evidence in sup-
port of this suggestion is contained in the short preliminary
notice of Ssobolew. He states that after feeding animals on
carbohydrates the cells of the islands become more granular.
After ligating the duct of Wirsung in dogs, the islands of
Langerhans, he finds, are not involved in the sclerotic process
which follows. He thinks that this fact explains the absence
of glycosuria after ligation of the pancreatic ducts. In human
cases I had observed after duct obstruction similar resistance
of the islands to the consequent inflammation. In pancreases
of two diabetics Ssobolew was unable to discover islands of
Langerhans.

"In the human pancreas the islands were found to be more
numerous in the splenic end, or tail, than elsewhere. To
obtain a numerical statement of their relative abundance, their

E. L. Opie: Loc. cit.

I

TABLE I.

HEAD.

11.0

II

30.0

Ill

4.0

IV

4.0

v

27.0

VI

25.0

VII

18.0

VIII

60

IX . .

44.0

x

140

THE SPLENO-PANCREATIC INTERNAL SECRETION. 395

number was determined in a sectional area of 0.5 square cen-
timeter. Sections about 10 millimeters thick were made from
the enlarged duodenal portion of the pancreas, or the head;
from the midportion, or body; and from the splenic end, or
tail. The following table gives their number in an area of
0.5 square centimeter in sections taken from the head, body,
and tail of ten normal organs: —

BODY. TAIL.

13.0 30.0

25.0 42.0

4.0 19.0

10.0 13.0

18.0 59.0

27.0 26.0

18.0 29.0

10.0 29.0

32.0 61.0

23.0 32.0

Average 18.3 18.0 34.0

"The table shows that the islands are more abundant in
the tail, or splenic end, than in the head and in the body,
where they are present in approximately equal number. They
are almost twice as numerous in sections from the tail as in
those from other parts. Since the number in only one plane
is recorded, in order to obtain their actual relative abundance
it is necessary to square these figures. They are then found
to be slightly less than three and a half times as numerous in
the tail as elsewhere.

"The cells composing the islands resemble those of the
acini. They have a large, round, occasionally oval, vesicular
nucleus and a conspicuous cell-body. The basal zone of the
secreting cell, as is well known, stains deeply with nuclear
dyes, — for example, haematoxylin or methylene blue, — while
the central portion, which contains zymogen granules, remains
unstained. The cells of the island, however, do not stain with
nuclear dyes, while with eosin their protoplasm takes a homo-
geneous bright-pink color. The nuclei differ but little from

396 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

those of neighboring acini. They vary considerably in size, and
not infrequently one finds very large round vesicular nuclei
whose diameter is two or more times that of those about.
Occasionally the cells, forming columns between which are the
anastomosing capillaries, are very closely packed together, and
nuclei are situated almost side by side; more frequently the
cells of the island are less numerous and the nuclei are less
closely crowded together.

"The outline of the island is usually round or oval, and
is not infrequently accentuated by a delicate circle of fibrous
tissue. In other instances the outline is less sharp, and the
body accommodates its shape to that of the neighboring acini.
Occasionally one sees, apparently within the island, cells ar-
ranged, as in the acini, about a central lumen, and, indeed,
in many instances it is difficult to convince one's self that they
do not form part of it. The impression is produced that the
columns of the island are in continuity with cells having an
acinar arrangement. Since the islands and the secreting acini
have a common origin, it is not inconceivable that they may
occasionally remain continuous in the adult organ. When the
fcetal pancreas is affected by congenital syphilis, the islands, I
have found, retain their continuity with the secreting struct-
ures.

"In the human pancreas the groups of acini about ter-
minal ducts are not sharply defined by connective tissue; so
that individual lobules, as in the human liver, are indistinctly
marked off and in places apparently fuse with one another.
In the pancreas of the cat the lobules, like those in the liver
of the pig, are much more sharply outlined by interstitial tis-
sue. Details of structure have been studied in the pancreas
of the cat.

"The parenchyma is divided by septa of fibrous tissue into
small polygonal areas in size and shape. When injected with
Berlin blue, a small ramification of the ducts is found to pene-
trate the isolated group of acini. These subdivisions, or lob-
ules, often appear completely isolated by fibrous tissue from
those near by, but when one of them is traced through a series
of sections its separation may be uniform, and in places one
finds the parenchyma of adjacent lobules in contact, the

THE SPLENO-PANCREATIC INTERNAL SECRETION. 397

dividing septa being incomplete. That these polygonal struct-
ures are actually independent of one another and represent
units of structure is readily demonstrated by causing an in-
flammatory increase of the interstitial tissue. If the pancreatic
ducts of a cat are ligated and the animal killed at the end of
two or three weeks, the gland is found to be the seat of a
chronic interstitial inflammation, characterized by an increase
of the interlobular tissue. The lobules are completely sepa-
rated from one another by narrow bands of firm, fibrous tissue,
and occur in sections as rounded, triangular, or polygonal
areas of parenchyma.

"The islands of Langerhans occupy a position near the
center of the lobule, and in the splenic end of the gland each
lobule contains an island. In a given section many lobules
whose limits are more or less distinctly outlined are seen to
contain islands situated near their center, while in neighbor-
ing lobules such structures may not be discoverable. If, how-
ever, serial sections are studied, every lobule is found to con-
tain an island. Its presence within the lobule is not constant
in other parts of the organ, and in the extremity of the de-
scending arm of the gland they are very few in number.

"The lobules are grouped about the medium-sized ducts.
The main ducts give off branches approximately at right angles
to their course. Branching one or more times, a duct forms
the center of a group of lobules, which is usually elongated in
form and tapers to a point at or near* the surface of the gland.
Such lobule groups are separated from one another by rela-
tively wide bands of areolar tissue much looser in texture than
that separating the individual lobules. The lobule groups in
the fresh state or in tissue macerated a few days in Muller's
fluid may be separated from one another by careful teasing.
In the loose tissue lie the larger ducts, arteries, veins, and
nerves. An artery and vein penetrate each lobule group in
company with the duct, and ramify between its lobules. The
smallest arteries occasionally penetrate the lobules, but usu-
ally branches, diminishing in size, give off capillaries which
enter the lobule and form a close net-work between the gland-
acini.

"The capillaries of the island of Langerhans form a

398 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

glomerulus of tortuous, freely-anastomosing vessels, much
thicker than those between the acini. A single afferent ves-
sel like that of the glomerulus of the kidney does not enter
this group of dilated capillaries, hut numerous anastomoses
make it continuous with the interacinar capillaries. When
Berlin blue is injected through the aorta into the arteries of
the pancreas, it not infrequently happens that in portions of
the gland which are poorly injected the vessels of the island

CAMERA-LUCIDA TRACING OP THE LOBULE BOUNDARIES IN
ONE OP A SERIES OP SECTIONS FROM THE SPLENIC END OP A
CAT'S PANCREAS.

The majority of the lobules are well defined. Those marked d,
e, f, g, and h are poorly outlined, but are found to be more readily
distinguishable when traced through the series of secretions. The
lobules, which are lettered (a to o), were traced through the
series, and each was found to contain an island of Langerhans sit-
uated near its center. The section passes through the island in
lobules a, e, i, j, and n. (Eugene L. Opie.)

are filled with the injected mass, while the surrounding capil-
laries are, for the most part, empty. If instead of soluble
Berlin blue a granular injection mass — for example, cinnabar
or ultramarine blue — is used, the islands may be injected, while
the interacinar capillaries contain little of the injected mate-
rial. The glomerular net-work is in very free communication
with the smallest arteries, and apparently has a richer blood-
supply than other parts of the lobule.

THE SPLENO-PANCREATIC INTERNAL SECRETION. 399

"In the human pancreas lobules and lobule groups are not
so regularly arranged as in the cat. But both structures are
more or less clearly definable. The lobules vary much in
size, and are usually not clearly separated from one another.
Though an island of Langerhans is often situated in the cen-
ter of a more or less clearly defined lobule, no constancy of
position is discoverable. The lobule groups are separated by
relatively wide bands of loose areolar tissue in which are con-
tained the medium-sized ducts, the blood-vessels, and the
nerves. Within a lobule group the arteries and veins, which
are side by side, do not, as in the cat, accompany the ducts."

The multiplicity of facts reviewed in the foregoing pages
and the intricacy of the whole question make it necessary to
collate and group in logical sequence the salient features of
.each subject discussed, in order to render a fruitful compari-
son of their merits possible. Not only are we required to
analyze the questions involved in the light of the solid data
that the last forty years have furnished, — i.e., since Schiff
first studied the relations between the spleen and the pancreas,
— but all these must likewise be sustained by, and be in accord
with, the functional mechanisms of the organs involved as we
interpret them, if our own views are well founded. If they are,
they must necessarily assist us greatly in elucidating the
various problems, physiological and pathological, to which ref-
erence has been made, since the very elements which they in-
troduce bear upon a predominating factor in all these proc-
esses: i.e., oxidation. To this subdivision of the subject we
will, therefore, turn our attention.

Can we ascribe to oxygen, or rather to the oxidizing sub-
stance of the blood, the conversion of pancreatic trypsinogen
into trypsin? We have seen that in both the spleen and pan-
creas the oxidizing substance seems, as elsewhere, to play the
main functional role; the extrinsic and intrinsic vessels are
disposed in a similar manner as regards their nervous rela-
tions, and vasoconstriction calculated to increase the flow of
blood through both organs is similar. Moreover, we have seen
that in the spleen the dilation incident upon malarial in-
toxication could be traced to the adrenals, — the primary source
of excessive oxidation, — while in toxic glycosuria we obtained

400 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

as clear evidence that overactivity of the pancreas could also
be ascribed to these organs. Again, the ease with which oxy-
gen is thought to convert trypsinogen into trypsin — a mere
current of oxygen through a solution of zymogen sufficing to
produce trypsin — has been fully emphasized. Besides Heiden-
hain's labors in this connection, we need but recall SchifFs ex-
periment with the two halves of a pancreas, one of which was
infused at once and the other left exposed to the air a day,
with the result that the latter alone proved active; and also
that of Herzen, in which an infusion of active spleen mixed
with an infusion of inactive (hence zymogen-laden) pancreas
proved very active, while a pancreatic infusion mixed with one
of inactive spleen digested nothing. Heidenhain ascribed to
oxidation the conversion into trypsin, in this experiment. In-
deed, when we consider the wealth of oxygen in the blood
supplied the pancreas, direct from the lungs via the cceliac
axis, it would seem as if it should be the predominating factor
of the conversion processes involved.

And yet, the oxidizing substance being a constituent of
the blood-plasma, it would have to penetrate into the ducts
per se and as oxidizing substance in order to carry out the
required reaction. There is no evidence that a direct chan-
nel, such as there is in the spleen, by means of which the
capillaries directly pour their blood into the secreting struct-
ures, exists. As may be seen in the annexed illustration, the
splenic vessels actually terminate in the latter; "their walls
become much attenuated, lose their tubular character, and the
cells of the lymphoid tissue of which they are composed be-
come altered, presenting a branched appearance and acquiring
processes which are directly connected with the processes of
the sustentacular cells of the pulp."24

Nor is there evidence that canaliculi such as those of the
hepatic cell exist by means of which the blood-plasma or its
contents may directly find their way to a structure correspond-
ing to bile-channels, which in the pancreas would be repre-
sented by the ducts. Langerhans long ago demonstrated that
canaliculi were present in the lobules between the epithelial

24 Pickering Pick and Howden: "Gray's Anatomy," 1901.

THE SPLENO-PANCREATIC INTERNAL SECRETION.

401

cells, but these, besides being pyriform, terminate as blind
pouches, with their orifice directed toward the glandular lumen.
Saviotti also found these minute, delicate, pouch-like chan-
nels. Eamon y Cajal, using the Golgi method, found that
they sent offshoots into the cells themselves, but that these
also ended as blind pouches, their ampullar dilations never
reaching beyond the line which separates the granular portion
of the cell from the clear area. It is evident that these con-
stitute collecting channels for the products of glandular metab-
olism: a further indication that no free channel between the
blood-stream and the ducts exists.

Indeed, experimental proof to this effect is available:
When the histological examinations of Kiihne and Opie were

TERMINATION OF SMALL BLOOD-VESSELS IN THE SPL,EEN. (Gray.)

a, Small artery. 6, Vessel undergoing lymphoid change, c, Vessel
continuous with supporting cells, d, Supporting cells.

mentioned on page 394, it was noted that material injected
into the duct of the gland did not penetrate the islands of
Langerhans. If, on the other hand, Opie's observation that
injections of Berlin blue often filled the vessels of the island
per se, leaving the majority of surrounding capillaries empty,
is considered in this connection, it is evident that there can
be no direct communication between ducts and blood-stream
through either the islands of Langerhans or the glandular
lobules that contain them. This involves an all-important
deduction, however, viz.: that the splenic ferment, as well as
the oxidizing substance, merely passes through the pancreas
in transit, the latter, in its usual capacity of reagent, being
intended only to activate function.

402 INTERNAL SECRETIONS OP PANCREAS AND SPLEEN.

But how, under these circumstances, can we account for
the experimental results reached by Schiff and Herzen, Heiden-
hain, Lepine, Pachon and Gachet, and Popelski? All these
observers in one way or another have unquestionably shown a
direct relationship between the blood-serum and trypsinogen,
Heidenhain and Popelski considering oxygen as the convert-
ing agency, with solid experimental data to sustain them;
Schiff, Herzen, and the other investigators mentioned attrib-
uting to the splenic ferment the same mission, with equally
strong experimental backing. How account, for example, for
the results observed in the following experiment of Herzen's?
Two fasting dogs, having received all the meat they could eat,
were at once submitted to ligation of the pylorus, bile-duct,
and jejunal end of the duodenum, and also, in one of the dogs,
of the hilum of the spleen. Albumin having been introduced
into the duodenum, both dogs were killed after seven hours.
In the dog with ligated splenic hilum the albumin was intact;
in that in which the splenic vessels were free, the albumin had
disappeared. This and other experiments to which we have
referred may, indeed, be said to prove — whichever be the pre-
vailing converting agency — that a communication between the
blood-channels and the ducts exists.

We have seen that there is no evidence to show that the
acini in direct communication with the ducts also open into
the blood-vessels; these, as elsewhere, form a close net-work
around the acini, but they do not open into the blind pouches
of the latter. Could the communicating channels traverse the
islands of Langerhans? That these organs do not possess such
channels or even ducts has been shown by Dogiel,25 who studied
this question in a well-preserved human pancreas treated by
the chrome-silver method, and in which the gland-ducts, "even
in their finest intra-alveolar branches, were well stained." Yet
these structures possess morphological characteristics that are
suggestive. Dogiel, for example, found that they possessed
relatively large capillaries located in the cellular trabeculae.
All investigators seem to agree upon the unusual size of those
vessels. Kiihne and Lea define the islands as "glomerular

Dogiel: Bb'hm and von Davidoff, loc. cit.

THE SPLENO-PANCREATIC INTERNAL SECRETION. 403

structures composed of dilated and tortuous capillaries." Opie
calls them "vascular islets" which are in "very free commu-
nication with the smallest arteries and apparently have a
richer blood-supply than other parts of the lobule." That
these dilated arteries are possessed of special functions is sug-
gested by the fact that, "if, instead of a solution of Berlin blue,
a granular injection mass — for example, cinnabar or ultra-
marine blue — is used, the islands may be injected, while the
intra-acinar capillaries contain little of the injected material."
They appear to constitute alveoli or ampullae rather than true
vascular channels, in which what blood passes through them is
submitted to some kind of process.

An interesting feature in this connection was noted by
Opie, viz.: the fact that the cells of the islands of Langerhans
are in some instances continuous with the regular glandular
elements of the organ, in such a manner as to prolong the
ducts of the latter by encircling them. "Occasionally," says
the author, "one sees, apparently within the islands, cells ar-
ranged, as in the acini, about a central lumen, and, indeed,
in many instances, it is difficult to convince one's self that they
do not form part of it." This intimate relationship between
the two sets of glandular elements is further emphasized by
the manner in which their capillaries are related. While the
smaller arteries or arterioles ramify between the lobules and
supply the net-work of capillaries to the acini, they also com-
municate with the tortuous and dilated vessels of the islands
of Langerhans; so that the latter, as regards their vascular
relations, really constitute glomerular expansions and offshoots
of the regular acini's blood-channels. We thus have two sets
of superposed glands around a common duct, the upper, or
common acini, pouring their own secretion (or granules) into it
through their microscopical ducts; the lower, those of the
islands — possessed of no ducts or other orifices — presenting
their dilated capillaries or alveolar walls so as to cause them
to face, and perhaps slightly project into its lumen. If we
now replace by an active circulation through all these vessels
the cinnabar or ultramarine-blue injections referred to above,
the accumulation of the latter in the islands distinctly points
to a similar process during life: i.e., accumulation of blood and

26

404 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

its normal result (with narrower blood-vessels at each end of
the glomerulus) : i.e., centrifugal pressure.

If we now conjoin Opie's remark — "the impression is pro-
duced that the columns of the island are in continuity with
cells having an acinar arrangement" — and Mall's observation,
in his study of the microscopical anatomy of the spleen, — that
"the ampullae and venous plexus have very porous walls which
permit fluids to pass through with great ease . . ." — it
seems probable that we hold the key to the situation. Indeed,
what have we in the dilated glomerules of capillaries of the
islands of Langerhans but vascular ampullae? Centrifugal
pressure under the circulatory conditions mentioned can have
but one result: i.e., filtration of the Hood- fluids through the am-
pullar walls and into the ducts.

It is, perhaps, unnecessary to point to the fact that, be-
sides being the only functional mechanism warranted by the
anatomical structures present, it also meets all the require-
ments of the well-founded experimental data adduced. The
precision with which it seems to harmonize the two seemingly
antagonistic features of the general function represented — i.e.,
the Schiff-Herzen spleno-pancreatic process and the Heiden-
hain zymogen-oxidation process — is also noticeable. If we also
realize that all these elements of the general function now fall
sequentially in the normal order of their physiological use-
fulness, it will become apparent that we must have reached a
solution worthy of confidence. This may be formulated as
follows: —

1. The splenic ferment secreted into the splenic vein is car-
ried to the portal vein through the liver, thence by the hepatic vein
to the inferior vena cava, and after passing through the cardio-
pulmonary circuit is distributed throughout the entire organism.

2. The quantity of splenic ferment distributed to the pancreas
is proportionate to the amount of Uood carried thereto by the pan-
creatic subdivisions of the splenic artery, and represents but a
fraction of that supplied to the general circulation.

3. The splenic ferment distributed to the pancreas follows the
course of its blood-channels, and is distributed to the cellular ele-
ments of the organ dissolved in the blood-plasma.

4. On reaching the cellular elements, the plasma, through its

THE SPLENO-PANCREATIC INTERNAL SECRETION.

405

oxidizing substance, insures functional metabolism of loth gland-
ular structures present, — the lolular acini and their immanent
structures, the islands of Langerhans, — which metabolism, during
the passive, or inactive, state of the organ, ends in the formation of
the secretion granules.

5. When at the end of the fourth hour of general digestion the
pancreatic ferments are required in the intestinal canal, the vagus
incites, sustains, and governs the functional activity of loth the
pancreas and the spleen, and thus insures their synchronous action
as long as the pancreatic ferments are needed.

6. Intrinsic-nerve constriction of the arterioles that supply
loth the pancreatic lolules and the islands of Langerhans with cap-
illaries constitutes, as elsewhere, the mechanism through which
glandular activity is sustained; lut, the islands' vascular ampullce
possessing no muscular layer, they lecome the seat, owing to their
large size, of sufficient Hood-pressure to cause the Hood-plasma and
its contained splenic ferment and oxidizing substance to filtrate
through their walls.

7. Some lolules are entirely composed of true secreting cells;
others contain, lesides, islands of Langerhans. In the latter lol-
ules the secretion, therefore, consists of two different lodies: the
granules of the true secreting cells and the Hood-plasma derived ly
filtration from the islands.

8. The true secreting cells and those of the island "being in
continuity and surrounding a common lumen (Opie), loth lodies
— (1) the zymogen, or trypsinogen-forming, granules, and (2) the
plasma containing the splenic ferment and the oxidizing substance
— meet in this common lumen, which connects with the terminal
ramifications of the pancreatic duct.

This is about as far as we can proceed at present, since we
can only surmise that, as soon as the products referred to meet
in the glandular lumen, the splenic ferment at once converts
the trypsinogen granules into liquid trypsin. Interesting in
this connection, however, is the fact, observed by Laguesse,
that 'long before the pancreas begins its function as a digestive
gland granules accumulate in the internal zones of the cells;
and when these come into contact with the blood a portion of
them appears as though dissolved/' As is well known, this is
precisely what happens even in true acini that do not belong to

406 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

lobules supplied with islands. When secretory activity occurs,
the granules of the inner zone of the cells simply disappear in
the central lumen; but how and in virtue of what agency they
are transformed into secretion at this point has not been de-
termined. In the lobules supplied with islands of Langerhans
the effused serum more than satisfies this feature, since it sup-
plies two agencies thought to be capable of converting the
granules into trypsin; but what of the lobules deprived of
islands? How are their granules converted?

To answer these questions we must first ascertain which
of the ferments credited to the pancreas can be shown to orig-
inate in the true acini. We have seen that, when the hilum
of the spleen is ligated and no splenic ferment can find its way
to the blood, the digestion of albumin ceases. It is, therefore,
evident that, in accordance with Herzen's view, the splenic
ferment is a sine qua non in the process through which tryp-
sinogen is converted into trypsin. But why does the oxidizing
substance not continue the conversion after ligation of the
splenic hilum? There is but one answer to this, viz.: zymogen
and trypsinogen are not similar bodies; while zymogen is converted
into some pancreatic ferment by oxygen, trypsinogen is not, and
always requires the splenic ferment.

To illustrate this fact we submit, in extenso, two of Gachet
and Pachon's experiments, performed to show that it was the
spleen's ferment, and not its haemoglobin, that converted pro-
trypsin, which they term "preferment." Believing that zymo-
gen, which, as shown by Heidenhain, is very greedy for oxygen,
and "preferment" are the same bodies, their aim is to prove
that, injected in arterial blood, pancreatic ferments cannot be
converted into trypsin therein. But, interpreted from our
standpoint, — since the blood contains oxidizing substance
which zymogen would readily take up, — these experiments
prove that zymogen and their proferment (trypsinogen) differ,
as stated.

"As the proferment of the pancreas becomes very easily
transformed into trypsin under the influence of oxygen," say
Gachet and Pachon, "it seems possible that splenic extracts,
intensely colored by the haemoglobin, should owe their tryp-
sinogenous power to the fixed oxygen of haemoglobin which

THE SPLENO-PANCRBATIC INTERNAL SECRETION. 407

they hold in solution. If such is the case, arterial blood, richer
in oxygen, should render a pancreatic infusion containing the
preferment more active than venous blood. A. Herzen has
already studied this question and antagonized it by means of
appropriate experiments. On our side, we have tried to ascer-
tain the value of this opinion in the following manner: —

''Experiment II. — The pancreas of a fasting dog was al-
lowed to macerate two hours in ten times its volume of a
saturated solution of boric acid. By decantation, 200 cubic
centimeters of the maceration liquid were taken and distrib-
uted among four flasks: A, B, C, and D.

"To A were added 20 cubic centimeters of defibrinated
arterial blood (obtained from the fasting dog).

"To B were added 20 cubic centimeters of defibrinated
venous blood (obtained from the fasting dog).

"To C were added 20 cubic centimeters of congested spleen
(aqueous maceration).

"To D were added 20 cubic centimeters of distilled water.

"These flasks, in each of which was introduced 1 cubic
centimeter of albumin, were then placed in the oven at 39° C.

*'At the end of 4 hours beginning digestion was observed
in flask C; villosities appeared on the surface of the cube of
albumin, which continued to be attacked in an energetic
manner.

"A and B, after remaining in the oven 24 hours, did not
show very clear traces of digestion. Their cubes of albumin
presented slightly less sharp projections, and their angles were
more rounded. The cube in flask D was slightly attacked.

"Experiment III. — The pancreas of a fasting dog was
divided into three parts and triturated: the first alone; the
second with 20 cubic centimeters of femoral arterial blood;
the third with 20 cubic centimeters of venous blood, taken,
as was the former, from a fasting dog. These were placed in
flasks A, B, and C, containing each 150 cubic centimeters of
boric-acid solution. After remaining 2 hours in the oven the
peptonizing power of the decantation liquids was tried. Their
proteolytic action was very slow; the first signs of digestion
had appeared: in A after 16 hours of oven; in B and C after
20 hours. Digestion was not further advanced in the flask

408 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

containing arterial blood than it was in that containing venous
blood.

"It can be seen that in these two experiments arterial
blood showed itself as inactive as venous blood. One cannot,
therefore, ascribe the unquestionable action of the extract of
congested spleen upon the pancreatic proferment to the oxy-
gen of splenic tissue."

There is one feature in this connection, however, which
requires elucidation: the influence that the use of fasting dogs
might have had on the experiments. We have seen that under
these conditions suprarenal activity becomes reduced; the
blood may, therefore, contain but a minimum of oxidizing
substance. Herzen performed an experiment which not only
confirms our conclusion that zymogen and trypsinogen are not
identical bodies, but also shows that fasting does not influence
the results just given. As Herzen's experiment has already
been reviewed at length, we will only reproduce its salient
points. The pancreas of a fasting dog (hence rich in tryp-
sinogen and other ferment-forming agencies) was infused in
glycerin, and this in turn was mixed with eight samples of
blood (bled directly in double its quantity of glycerin), four
being taken from a fasting dog and four from a dog in full
digestion with its spleen greatly dilated. The four samples
were taken in both animals from the femoral artery, the
femoral vein, the splenic artery, and the splenic vein. Fibrin
was then added to each sample. "After 1 hour there was still
no trace of digestion under the influence of the femoral blood,
arterial or venous, nor of the splenic arterial blood of the
fasting dog; first traces of digestion were beginning to mani-
fest themselves under the influence of the splenic venous blood
of this animal. Digestion was rather advanced in the case of
the femoral arterial and venous blood and splenic arterial
blood of the digesting dog; the fibrin had almost entirely dis-
appeared under the influence of the splenic venous blood of
the same animal." This seems to us to confirm not only the
view held by Herzen, that the splenic ferment is the only
agency capable of converting trypsinogen into trypsin, but
also that trypsinogen does not, like zymogen, possess affinity
for oxygen.

THE SPLENO-PANCREATIC INTERNAL SECRETION.

409

This may be further demonstrated by showing that oxygen
does exist in the blood, and that if we were dealing with
zymogen it would be oxidized therein. The oxidation of sugar
converted from glycogen, we have seen, represents the main
factor in the production of functional energy in the muscles
and other structures. That sugar occurs in the blood nor-
mally, but in small quantities, its combustion therein depend-
ing mainly — as in toxic glycosurias — upon suprarenal activity,
we have also seen. The more these organs produce of their
secretion, the greater is the proportion of oxidizing substance
in the blood, and suprarenal insufficiency means a correspond-
ing increase of sugar in the blood through imperfect oxidation.
Hence the oxidizing substance is a sugar-destroying agency.

That an agent capable of consuming sugar exists in the
blood was ascertained by Lepine in 1889, who named it "glyco-
lytic enzyme." Howell, referring to this substance, says: "It
has been asserted by Lepine and Barral that there is normally
present in the blood an enzyme capable of destroying sugar.
Their theory rests upon the undoubted fact that sugar added
to blood outside the body soon disappears" This obviously con-
stitutes another proof of the existence of oxidizing substance
in the blood.

Howell, referring also to the supposed source of Lepine's
glycolytic enzyme, says, referring to the pathogenesis of glyco-
suria: "The most plausible theory suggested is that the inter-
nal secretion produced contains a special enzyme, glycolytic
enzyme, whose presence in the blood is necessary for the con-
sumption of sugar. Such an enzyme may be obtained from the
blood, but it is not proved whether it is a normal constituent
or whether it is produced after the blood is shed by the dis-
integration of some of its corpuscular elements." . . . "It
is interesting and suggestive to state, in this connection, that
post-mortem examination in cases of diabetes mellitus in the
human being has shown that this disease is associated in some
instances with obvious alterations in the structure of the pan-
creas." That the glycolytic enzyme is, as oxidizing substance,
a normal constituent of the blood is obvious; but the inter-
esting feature to determine now is whether, as believed by
Lepine, the pancreas is the source of the ferment, since, if it

410 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

were, it would constitute an additional factor in this organ's
physiological functions.

To which of the two pancreatic active structures can we
hypothetically ascribe the formation of the glycolytic enzyme?
Laguesse26 has ascribed this function to the islands of Langer-
hans. That these structures underlie some physiological proc-
ess in addition to that already analyzed by us is undoubted.
The fact that they contain large nuclei shows that they are
physiologically active. "The cells composing the islands re-
semble those of the acini," says Opie; "they have a large,
round, occasionally oval, vesicular nucleus and a conspicuous
cell-body." They must produce some ferment or its zymogen,
for Ssobolew found that feeding animals on carbohydrates
caused them — i.e., their protoplasm — to become granular.
This is indirectly confirmed by the fact that these bodies are
often found diseased in diabetes. They had entirely disap-
peared in two of Ssobolew's cases. In a case of Opie's27 hyaline
metamorphosis was strictly limited to the islands of Langer-
hans, the glandular acini remaining intact. Flexner28 refers
to this cause of diabetes as follows: "That it depends upon an
internal secretion supplied by the pancreas to the blood is
highly probable. Whether this hypothetical secretion is the
product of the cells of the islands of Langerhans is unproven."

The data bearing upon this source of diabetes are very
few, — an unfortunate fact, since these particular structures
seem to us to play the predominating role in the production
of glycosurias of pancreatic origin, now that we have ascer-
tained that they are, through their ampullae, the only thor-
oughfares for the splenic ferment. Still, can we, with Laguesse,
now consider them as the source of a glycolytic ferment? Were
we to admit this possibility, we would find ourselves obliged
to concede that the pancreas supplies the intestinal tract with
a glycolytic ferment besides an amylolytic ferment, and we
would have, as a result, the formation of maltose from food-
starches and its immediate destruction by the glycolytic fer-

M Laguesse: Loc. cit.

27 Opie: Journal of Experimental Medicine, March 2o, 1901.

88 Flexner: University of Pennsylvania Medical Bulletin, Jan., 1902.

THE SPLENO-PANCREATIC INTERNAL SECRETION.

411

ment, thus annulling the very important functions of sugar in
the economy.

It is plain that the islands of Langerhans are not the
source of a glycolytic ferment. Of course, Professor Lepine
has never, that we know of, sustained this view, his contention
being simply that the normal pancreas contains a glycolytic
ferment which finds its way into the lymph and blood, in which
it controls the consumption of sugar by the tissues. And his
experimental evidence, in the light of our views, shows this
to be the case, since it all goes to prove that the oxidizing
substance which enters the pancreatic circulation is a glyco-
lytic body. This does not mean that it acts therein as such;
indeed, the organic cells at once take up its oxygen for their
own functional interchanges, the blood returning to the splenic
veins as venous blood. But it is nevertheless obvious that Lepine
should have experimentally found, as he says, a glycolytic fer-
ment in the pancreatic blood. All we show, therefore, is that
Lepine's glycolytic ferment is the oxidizing substance.

But why should disease of the pancreas under these cir-
cumstances increase the proportion of sugar in the urine: a
feature which Lepine ascribed to decrease of sugar destruction
and to the fact that "these lesions decrease the source of the
glycolytic ferment in the economy"? From our standpoint,
of course, the adrenals are the original source of the oxidizing
substance: i.e., adrenal secretion plus oxygen. But does this
account in an equally satisfactory manner for glycosuria?
This introduces a very important feature of the entire analysis,
one, indeed, bearing upon the pathogenesis of all forms of pan-
creatic diabetes.

We have previously referred to the fact that disease of
the islands of Langerhans had been found to be a prominent
causative factor of diabetes by various pathologists, and that
Opie had witnessed a case in which these islands alone were
diseased. This obviously points to the fact that, if in accord-
ance with our view the ampullce of the islands are the pathways of
the Schiff-Herzen splenic substance to the ducts, we are dealing
either with obstruction or impaired conversion of trypsinogen
into trypsin, or both simultaneously. If, bearing this feature
in mind, we review the list of pancreatic diseases that cause

412 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

glycosuria, it will become apparent that these two factors ac-
count for the phenomena observed in many cases: calculi,
lipomatosis, hypertrophy, tumors, induration, and periglandular
sclerosis. Atrophy, — a condition which in itself implies func-
tional impairment, — on the other hand, constitutes the major-
ity of the remaining pathological processes encountered post-
mortem in this organ.

But the question which now imposes itself is this: Why
and how does a condition that interferes with the conversion
of trypsinogen into trypsin or that impedes the passage of the
latter to the intestinal foodstuffs cause diabetes? The answer
now seems plain, viz.: because insufficiency of trypsin is fol-
lowed by imperfect reduction of proteids to simpler bodies, result-
ing in the formation or inadequate splitting of toxic albuminoids.
In other words, impaired pancreatic action of the kind men-
tioned gives rise to toxic glycosuria.

Our interpretation of the general subject seems again to
conciliate antagonistic views. Indeed, while Lepine29 has
affirmed that "the pancreas exercised a glycolytic influence,"
Chauveau and Kaufmann have held the opposite: i.e., that
"glycolysis is not diminished in diabetes, and that diabetes is
exclusively due to an increase in the production of glucose."
We have shown that the arterial blood of the pancreas does
contain a glycolytic body, — the oxidizing substance, — but we
have also — by our analysis of Cartier's paper and other data —
demonstrated that suprarenal overactivity was the underlying
cause of toxic glycosuria: i.e., & source of increased production
of sugar. To further sustain this fact, we may recall that the
coal-tar products, as already stated, possess a marked tendency
to give rise to suprarenal insufficiency, which sinks sometimes
to the stage of blood-disintegration. Lepine has himself ob-
served that methsemoglobinuria could follow the use of anti-
pyrin. This remedy is now classed among the most active
agents at our disposal for the reduction of glycosuria. A
remark of Professor Lepine's proves this to be the case in
another way. Referring to experiments conducted with the
collaboration of Porteret, he says, regarding the action of

28 L6pine: "Le Diab&te," Paris,

THE SPLENO-PANCREATIC INTERNAL SECRETION.

413

antipyrin, that, "in the cases in which it exercises an anti-
diabetic action, this substance acts, not by activating the
destruction of sugar, but by preventing its formation"30: the
result, we would add, of reduced suprarenal activity.

We have made considerable headway in the last few pages.
In the first place, we have ascertained (1) that zymogen and
trypsinogen were not identical; (2) that the Lepine glycolytic
enzyme and the oxidizing substance were the same thing, and,
this being the case, that (3) there was no ground for the
hypothesis that the islands of Langerhans were the source of
the glycolytic substance.

In view of these facts, what is the nature of the product
the existence of which the prominent nuclei and the granules
observed in the protoplasm of the islands indicate? This is
elucidated by two other features just brought out, namely: (4)
that glycosuria may be the result of intoxication by toxic
albuminoid bodies incident upon an insufficiency of trypsin,
and (5) that disease limited to the islands, as shown by Opie,
can cause glycosuria. It is plain that, in the latter case, the
permeability of the ampulla being alone compromised, the
pancreatic lobules that contain no islands are free as to the
elimination of their secretion into the ducts. If they produce
trypsinogen, — i.e., trypsin, — why are the functions of the latter
inhibited or absent as indicated by the glycosuria? The only
logical answer to this question is that the islands of Langerhans
alone secrete trypsinogen.

This fact, when added to others reviewed, normally leads
to another deduction: i.e., that, in addition to any other func-
tion it may possess, the spleen and the islands of Langerhans
are functionally united in the formation of a ferment, — trypsin, —
which is able to digest albuminoid bodies in the blood-stream.

We can now readily understand why the spleen and the
pancreas are so intimately connected through their nervous
supply. Indeed, this throws light upon a phenomenon which
we approach almost with diffidence: i.e., Claude Bernard's
experimental glycosuria obtained by puncturing the medulla
oblongata. "That pathological conditions of the central nerv-

80 The italics are Professor Lupine's.

414 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

ous system and perhaps of the sympathetic and larger periph-
eral nerves may give rise to glycosuria and diahetes is, of
course, established," says Flexner.31 "The number of neu-
ropathic conditions in which one or the other of these has
been found is now considerable. The one definite condition,
the effect of which is constant, is Claude Bernard's piqure, and,
as bearing out the physiological relationship existing between
certain unknown structures in the floor of the fourth ventricle
and the glycogen-store in the liver, may be cited the instances
of lesions (hemorrhages, softening, tumors) in man observed
in this situation with which glycosuria has been associated.
That cerebral and perhaps spinal disturbances other than those
in the region of the fourth ventricle may be associated with or
followed by diabetes many clinical cases prove. On the other
hand, there is no evidence that would show that it is the direct
influence of the central nervous system upon the carbohydrate
metabolism that produces hyperglycaemia and glycosuria. In-
deed, the experiments in which the splanchnics were sectioned
after piqure (Claude Bernard and others) without producing
glycosuria show the necessity of the interaction of other or-
gans."32

Eead in the light of all we have said, — particularly the
allusion to the relationship between the medulla and the
suprarenal glands through the splanchnic, — these lines, from
so competent an observer as Flexner, and which confirm those
of Cartier as to the action of section of the splanchnic, seem to
us to afford confirmatory evidence based upon the most solid
labors of the last half-century and to embody Claude Bernard's
own sanction. To analyze their far-reaching meaning would
involve the repetition of what has been said in all this volume.
Formulated as a deduction, the functional relationship between
the floor of the fourth ventricle and glycosuria would be as
follows: Puncture of the floor of the fourth ventricle (Claude
Bernard) causes glycosuria because the increased Nood-supply in
the injured area incident upon the local reparative process corre-
spondingly excites the normal structures around this area, which,

si Flexner: Loc. cit.

82 All italics are our own.

THE SPLENO-PANCREATIC INTERNAL SECRETION. 415

in turn, stimulate the adrenals through the communicating branches
between the cord and the ganglionic chain.

What we might term the intrinsic functions of the pan-
creas have now been analyzed; the importance — also in con-
junction with the spleen — of its extrinsic functions must now
be inquired into. Foster states that "a pancreas taken fresh
from the body, even during full digestion, contains but little
ready-made ferment, though there is present in it a body which,
by some kind of decomposition, gives birth to the ferment.33
. . . To this body, this mother of the ferment, which has
not at present been satisfactorily isolated, but which appears to
be a complex body, splitting up into the ferment, which, as
we have seen, is, at all events, not certainly a proteid body,
and into an undeniably proteid body, the name of zymogen
has been applied. But it is better to reserve the term zymogen
as a generic name for all such bodies as, not being themselves
actual ferments, may by internal changes give rise to ferments,
— for all 'mothers of ferment/ in fact, — and to give to the
particular mother of the pancreatic proteolytic ferment the
name trypsinogen." In other words, and in accord with pre-
vailing custom, each zymogen is named from the ferment it
produces: the zymogen of trypsin being "trypsinogen"; that
of pepsin, "pepsinogen," etc. It is therefore permissible to
use the term "amylopsinogen" as the main product of the true
lobular acini to differentiate it from trypsinogen, the product
of the islands of Langerhans, reserving the term zymogen as
a generic term for all pancreatic ferments. As "zymogen"
under these conditions, it preserves characteristics attributed
to it by Heidenhain; it is soluble in water, in which it is split,
after exposure to the air, into trypsin, etc. (Charles). The
conversion of trypsinogen into trypsin has been ascribed to
oxygen; but if our views are sound and the former is the
normal product of the islands, the portion distributed through
the pancreatic ducts is intimately combined with the splenic
ferment in the ampullae as fast as formed, so that it can never
be obtained as trypsinogen per se. Hence, oxygen will split
zymogen into trypsin, etc.; but trypsin is not, as stated, oxidized
trypsinogen.

83 These italics are the author's.

416 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

We have followed the course of the blood from the splenic
vein and back again to the splenic artery which supplies
branches to the pancreas, and we have seen that on its way
through the latter the arterial blood surrenders its oxygen to
the cells and its splenic substance to the islands. The domi-
nant feature of the extrinsic functions of the pancreas is its
power to destroy albuminoid toxic bodies, and it is evident
that the splenic ferment, the mission of which is merely to
unite with trypsinogen to form trypsin, cannot do this alone.
It is trypsin that constitutes the antitoxic body, and it is the
pancreas, therefore, that supplies it to the organism. How
does it penetrate the general blood-stream?

Now that we have ascertained that the islands of Langer-
hans are the seat of manufacture, as it were, of at least a part
of this antitoxic agency, and that it collects (combined) in the
ampullae, the manner in which the general circulation becomes
supplied with it is clear: i.e., the quantity that permeates
through the ampullar walls is but a portion of their contents,
and the rest is swept away with the blood and reaches the
splenic vein through the pancreatic veins. But this does not
mean that trypsinogen may not be carried alone in the same
manner to the splenic vein and therein combine with the
splenic ferment to form trypsin. In fact, this must constitute
the prevailing process, if the anatomical distribution of the
islands of Langerhans, as observed by Opie, can serve as guide.

As we have seen, Opie found that the islands of Langer-
hans were over three times as numerous in the splenic end
of the pancreas as elsewhere, and that the part of the organ
not in communication with the splenic vein — i.e., the extremity
of the descending arm — contained none. Moreover, each lob-
ule in the splenic end of the organ was found to contain an
island: a very suggestive fact. The tip of the pancreas, which
is almost in contact with the spleen, thus marks the starting-
point of the islands; so that trypsinogen begins to enter the
splenic vein almost at the hilum. Pancreas and splenic vein
being connected by several short venous radicles at about
regular intervals, the blood in the vein must become literally
saturated with trypsinogen, and its blood be replete with tryp-
sin when it reaches the portal vein, during the active stage of

THE SPLENO-PANCRBATIC INTERNAL SECRETION. 417

intestino-portal digestion. We have seen in Herzen's experi-
ment how rapidly albumin was digested with blood obtained
from the splenic vein during this stage.

That the amylolytic ferment derived from Heidenhain's
zymogen is also carried to the splenic vein is probable. We
have seen that it was through the effects of this ferment that
the liver glycogen was converted into sugar, and that the im-
portance of the latter, when distributed to the muscles and
other structures in which it is consumed, was very great. That
the conversion of glycogen into sugar is a continuous process
and that it is independent of digestion are recognized facts, —
and necessarily so, since the activity of the functions that
entail the use of glycogen may at any moment be increased,
the tissues requiring replenishment to a correspondingly great
degree at the expense of the liver reserve. How could this
predominating function be carried on in the perfect manner that
it is, were it connected with, or did it depend upon, any digestive
process? Again, if present views prevailed and the amylolytic
ferment were to only reach the liver after being secreted in
the duodenum by the pancreas, then absorbed by the venules-
of the villi, how could we account for the conversion of glyc-
ogen between the periods of active digestion? That the intes-
tinal tract is not the channel traversed by the portion of pan-
creatic amylopsin devolved to the conversion of glycogen into
sugar is also suggested by familiar experiments.

We have seen that the insertion of a piece of pancreas
into the tissues of an animal showing marked glycosuria, after
removal of the pancreas, will cause it to disappear. This ap-
parently constitutes a direct contradiction of all the foregoing
statements; but such is not the case in reality. Minkowski34
confirmed the fact, observed by other investigators, that glyc-
ogen quickly disappears after removal of the pancreas. This
indicates two important features: i.e., that glycogen is no
longer formed after removal of the pancreas, and that some
other agency converts it into sugar. Why removal of the pan-
creas should prevent the formation of glycogen may probably
be accounted for by the fact that the absence of trypsin causes

3*Minkowski: Berliner klin. Wochenschrift, No. 5, 1892.

418 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

the digestion of albumins in the duodenum to cease, as shown
in the Schiff-Herzen experiments. That the conversion of
food-starches into maltose is also, owing to the absence of
amylopsin, arrested, is evident. The only substitute for this
ferment available is ptyalin; but though the salivary secretion
— at least, its ptyalin — is quantitatively increased after removal
of the pancreas, it is inadequate to convert all the starch
required to compensate for the glycogen used. The glycogen,
gradually converted by what ptyalin is swallowed with the
saliva between meals, therefore disappears. The fact that
ptyalin converts starch partly into dextrose greatly hastens
the disappearance of the glycogen, the primary sugar of which
is mainly maltose. It would seem, therefore, that the glycosuria
following extirpation of the pancreas is due to the action of ptyalin
upon food-starches.

That the salivary secretion is gradually increased after
removal of the pancreas is sustained by experimental evidence.
Aldehoff35 observed that glycosuria only appeared from 24 to
48 hours after the operation in turtles; in frogs it only ap-
peared after four or five days, "slight at first, becoming more
intense later on." Minkowski36 found that it sets in after two
or three days in dogs, under the same conditions. Again, dur-
ing its passage through the stomach ptyalin acquires increased
energy as a ferment. Charles37 refers to this question as fol-
lows: "Chittenden and Griswold find that the presence of acid,
as hydrochloric acid, to the amount of 0.005 per cent, decidedly
increases the diastatic action, while an increase beyond this
diminishes it, the action stopping with solutions of acid from
0.1 to 0.4 per cent.; the diastatic action of the saliva would,
therefore, appear soon to cease in the stomach, but the peptones
in that organ exercise a decided influence on salivary digestion,
stimulating the ferment to increased action, particularly in
presence of acid, which by itself may completely prevent the
conversion of starch into sugar." Mering found that starch
acted on by saliva yielded dextrin and maltose at first, then
after some time grape-sugar.

M Aldehoff: Zeitschrift fur Biologie, Munich, Bd. xxviii, p. 293, 1892.
w> Minkowski: Loc. tit.
«7 Charles: Loc. tit.

THE SPLENO-PANCREATIC INTERNAL SECRETION. 419

Yet, glycosuria so produced may, we have seen, be pre-
vented by grafting a fragment of pancreas under the skin.
Minkowski38 grafted such fragments in the dog, cat, and pig,
removed from the pancreas of these animals. When the graft
had become adherent and functionally active, he removed the
rest of the pancreas. No glycosuria appeared until the grafted
portion itself had been removed. Besides indicating that
ptyalin glycosuria prevails after resection of the pancreas, the
fact that grafts can preserve normal functions clearly shows
that the intestinal canal is not the only region wherein split-
ting of carbohydrates and proteids may occur. Each graft
evidently received its blood through newly-formed vessels.
This blood doubtless contained splenic ferment, since, as pre-
viously stated, the greater portion of this ferment really enters
the general circulation via the liver, and ultimately reaches
the portal circulation, probably by the hepatic artery, in the
experimental animals. Such being the case, it is evident that
the splenic vein can, besides the intestinal villi, serve as a channel
for the transmission of the pancreatic and splenic ferments to the
liver.

Here, again, however, are we brought to realize that the
splenic ferment is not merely a local agency, but one which
during spleno-pancreatic activity forms part of the entire
blood-stream. We have given striking evidence of this in
Herzen's experiment with blood taken from various arteries
and veins. We saw that blood taken from the femoral vessels
(arterial and venous) of a dog in full splenic digestion proved
active in digesting albumin, and that the blood of the splenic
vein was exceedingly active. Indeed, the blood which is so
active in the pancreas originates from the cceliac axis, lungs,
heart, etc., — i.e., from the general circulation, — and only con-
tains the proportion of splenic ferment which the entire blood-
stream contains. But a question suggests itself here: If, by
the combination of trypsinogen and the splenic ferment, tryp-
sin is formed, is it not trypsin-laden blood that re-enters the
pancreas? Trypsin would re-enter this organ were the relative
proportions of the two bodies not regulated by the vagus. As

38 Minkowski: Loc. cit.

27

420 INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

we find that a slight excess of splenic ferment will serve the
physiological process in the pancreas, — to supply the intestinal
canal, — if we grant the vagus even one-tenth of the truly
wonderful prerogatives it seems to possess, we can readily as-
sume that, by regulating the quantities of either ferment al-
lowed to enter the blood-stream, it provides just the excess of
splenic ferment in the pancreas to insure perfect function
during the digestive process: all features which indicate that
trypsin is a constituent of the entire Uood-stream when albuminoids
are undergoing digestion in the alimentary channels.

The far-reaching meaning of all this is suggested in the
following deductions: —

1. The cleavage processes to which trypsin submits albumins
in the intestinal canal include the preliminary steps of a protective
function.

2. The spleno-pancreatic internal secretion is represented by
the trypsin which reaches the portal vein by way of the splenic
vein., and which continues in the blood-stream the cleavage processes
begun in the intestinal canal.

8. The main function of the spleno-pancreatic secretion,
trypsin, in the blood-stream is to protect the organism from the
effects of the toxic derivatives of albuminoid bodies.

CHAPTEE IX.

THE ADRENAL AND VAGAL SYSTEMS IN

THEIR RELATIONS TO CARDIAC AND

PULMONARY FUNCTIONS.

WE have repeatedly referred to the functional connection
between the secretion of the adrenals and the heart. Is this
connection direct or is it indirect? In other words, is it the
result of a direct stimulation of the heart-muscle such as is
produced by suprarenal extract, or of the stimulating effect
to which the increase of oxidizing processes, including those
of the cardiac cerebro-spinal centers, give rise? Analysis of
this question tends to show that both processes prevail simul-
taneously when from any cause the adrenals become over-
active.

THE ADRENAL SECRETION AS THE SOURCE OF THE FUNC-
TIONAL ACTIVITY OF THE RIGHT HEART.

As freshly-oxidized blood is constantly being supplied to
loth sides of the heart, the specific action of digitalis upon
the right heart to which we have referred cannot be ascribed
to the oxidizing substance. Again, it would seem that the
suprarenal secretion itself could hardly be credited with a
local stimulating action upon the cardiac walls when the thick-
ness of the myocardium is recalled, unless the latter be pro-
vided with channels calculated to insure the penetration of
the secretion to its deeper tissues. Not only do such chan-
nels exist, however, but they are so disposed as to enable the
adrenal active principle to permeate the entire myocardium
and be equally distributed among the contractile elements.
The channels to which we ascribe such important functions
have been known as the "foramina of Thebesius."

These canals are described in Gray's "Anatomy" as fol-
lows: "The foramina Thebesii are numerous minute apertures,
the mouths of small veins (venas cardis minimae), which open
on various parts of the inner surface of the auricle. They
return the blood directly from the muscular substance of the

(421)

422 THE DYNAMICS OF CARDIAC ACTION.

heart. Some of these foramina are minute depressions in the
walls of the heart, presenting a closed extremity."1 This in-
formation would afford but little light could we not supple-
ment it with an excellent paper by F. H. Pratt,2 in which the
nutrition of the heart through the vessels of Thebesius and
the coronary veins is studied. How much we are indebted to
the author for his investigations is suggested by the following
remarks: "So far as I have been able to determine, no experi-
mental physiological work has ever before been done on the
vessels of Thebesius; all opinion regarding their functional
importance has rested upon the assumption that they only
serve as veins, conveying a part of the venous blood from the
coronary capillaries through the foramina Thebesii into the
cavities of the heart."

After referring to the labors of Thebesius (1708), Vieus-
sens (1757), Haller (1786), and Abernethy (1798), the author
reviews the more modern investigations of Bochdalek,3 which
led to the conclusion "that the greater number of the small
openings on the inner surface of the right as well as the left
auricle, which from early times have borne the name of
foramina Thebesii, represent the mouths of little veins that,
often uniting into larger vessels, course with many branches
through the auricular walls.'7 Langer's researches4 on the
foramina of the human heart are next analyzed. "With the
aid of the blow-pipe, and by means of a watery injection-mass
colored with Berlin blue, he demonstrated these foramina in
all the cavities of the heart. He succeeded in injecting the
vessels of Thebesius not only from the coronary vessels, but
from the endocardial surfaces as well. Bochdalek's observa-
tions regarding the presence in both auricles of foramina
Thebesii were thus confirmed, and the fact of a communication
between the coronary vessels and each of the four cavities of
the heart was thoroughly established. The foramina which
Langer found on the endocardial surfaces of both ventricles
were similar to those in the auricles, but much smaller. They

i All italics are our own.

3 F. H. Pratt: American Journal of Physiology, vol. 1, p. 86, 1898.
s Bochdalek: Archiv fur Anat. u. Phys. u. wiss. Med., Leipzig, p. 314, 1868.
« Langer: Sitzb. der k. Akad. der Wissensch. zu Wien, 1880, Bd. Ixxxii. 3
Abth., p. 2u.

THE ADRENAL SECRETION AND THE HEART.

423

were most conspicuous on the papillary muscles and in the
neighborhood of the great vessels, being less easily seen in the
region of the apex, where they were obscured by the trabecular
net-work."

Very suggestive in connection with our own views are also
the observations of Gad5 on the vessels of Thebesius in the
ox, and to which Pratt refers in the following words: "In the
method which he describes for demonstrating the action of the
valves of the left heart, wherein water under pressure is made
to fill the ventricle and aorta, he noticed that water flowed
into the right heart from the foramina Thebesii. On illuminat-
ing the interior of the left ventricle he was enabled to see fine,
blood-stained streams issuing from the endocardial wall into
the clear water with which the cavity was filled." Finally he
reviews the labors of Magrath and Kennedy,6 who, "working
with artificial circulations of defibrinated blood on the isolated
heart of the cat, observed that a small portion of the coronary
"blood found its way into the left ventricle. The only possible
source of access other than from the vessels of Thebesius was
leakage past the aortic valves. This leakage, as shown by a
manometer-record of aortic pressure, did not occur." The
author closes his review of the literature of the subject with
the statement that "notwithstanding these painstaking ob-
servations, the vessels of Thebesius still occupy a very obscure
position in anatomical literature. Foramina Thebesii are re-
ferred to as constant in the right auricle, forming in part the
mouths of small veins. Their occurrence in the left auricle is
occasionally mentioned. But the fact that the vessels of Thebe-
sius open into all the chambers of the heart — ventricles as well
as auricles — is hardly recognized."7

In the author's own experiments, various agents were in-
jected at a constant pressure, through the coronaries of fresh,
often still living, hearts of the rabbit and dog. They showed
that liquids in these vessels penetrate into the heart cavities
through the endocardial foramina, thus verifying the foregoing

1897.

6 Gad: Archiv fur Pbysiologie, p. 380, 1886.

« Magrath and Kennedy: Journal of Experimental Medicine, vol. ii, p. 13,

7 All italics are our own.

424 THE DYNAMICS OF CARDIAC ACTION.

data. As the cannula was tied directly into the artery, the
liquid could only reach the cavities through the foramina, while
in all experiments care was taken to avoid high pressures. In
the heart of the ox the endocardial depressions were found
"regularly larger in the auricles than in the ventricles," while
in the right auricle "they may," he states, "be provided with
thin, single valves, especially about the origin of the great veins."
In the left auricle the depressions are fewer in number and
unprovided with valves. "Foramina Thebesii are never absent
from the ventricles," says Dr. Pratt. "In the right ventricle,
which is especially well provided with them, the larger number
are seen upon the septal wall. It is often much more difficult
to find them in the left ventricle, although a diligent search is
never without a reward" . . . "structures, accessory to
these ventricular foramina, which might in any way serve the
office of valves I have not seen." . . . "On the injection
of the vessels of Thebesius with air by means of the blow-pipe
applied to the foramina, characteristic, fine, subendocardial
ramifications, which very frequently conduct the air into other
Thebesian systems, or even into the great coronary veins will
seldom fail to appear." The latter point is also sustained by
experimental evidence.

The fact that the right side of the heart is endowed with
a more perfect system of canalization than the left is suggested
by the following remarks: "The ease with which injections
of air and blood could be made to demonstrate the connection
between the vessels of Thebesius and the coronary veins caused
me to doubt the opinion expressed by Langer that the foramina
Thebesii in the ventricles communicate with the veins by capil-
laries alone. To settle this point, I injected the coronary veins
of the ox with starch and celloidin masses, both too thick to
pass the capillaries, and found that even these emerged from
the foramina Thebesii. of the right ventricle. So intimate a
connection, however, between the coronary veins and the ves-
sels entering the left ventricle I have not yet been able to demon-
strate." The author also says: "By means of a very successful
corrosion preparation, made by injecting the veins of an ox-
heart with celloidin, I was able to trace the communication.
In this preparation the position of some of the foramina

THE ADRENAL SECRETION AND THE HEART. 425

Thebesii was marked by small disks of the hardened mass
formed by the oozing out of the celloidin upon the endocar-
dium. These foramina were shown to be connected with the
smaller coronary veins by fine branches. The still finer rami-
fications which, as Langer has demonstrated, lead from the
foramina and branch directly into capillaries were here unin-
jected; they would appear only when injected from the fora-
mina themselves."

The only connection between the vessels of Thebesius and
the coronary arteries that he could find, notwithstanding re-
peated attempts, was by capillaries. Bochdalek having ob-
served that the foramina of one auricle communicated with
those of the other, he was able by blow-pipe injection to verify
the correctness of this view, the air of one auricle having
passed out through a similar exit into the other.

To sustain his view that the nutrition of the heart may
be carried through the vessels of Thebesius some time after
the coronary arteries are absolutely obliterated, a number of
experiments are related. Thus, fluid introduced into the ven-
tricle of an isolated heart, by means of a cannula passed down
to this cavity, and tightly held in situ by a ligature passed
around the auriculo-ventricular groove, only found its way
through the vessels of Thebesius. Defibrinated blood, inserted
into the organ through this cannula, brought on, often within
one minute, "strongly marked, co-ordinated contraction of the
ventricle." As the blood thus introduced would become venous,
the action would become gradually reduced, but renewal of
the blood would at once cause the heart to resume its normal
action. "With a periodic supply of blood," says the author,
"and with favorable temperature and moisture this may con-
tinue several hours." That mere mechanical stimulation by
distension did not cause the phenomena witnessed is demon-
strated by the alternate use of Ringer's solution and defibrin-
ated blood. While the solution failed to sustain contractions,
blood always succeeded.

Another experiment served to demonstrate that a true
circulation could take place between the vessels of Thebesius
and the coronary veins. The organ being disposed as stated
above, two of the coronary veins were incised; "a small, but

426 THE DYNAMICS OF CARDIAC ACTION.

steady, stream of venous blood issued from them." Under the
same conditions the descending branch of the left coronary
artery was opened. "No flow of blood occurred from the artery,
although there was a free escape from an incision in an ac-
companying vein." In still another experiment the trunks of
both coronary arteries were ligated and the ligature around
the ventricles omitted. "The supply-cannula was tied into the
ventricle through the aorta. On the introduction of blood
the left ventricle alone began to beat strongly and regularly
. . . the blood found its way in part into the right ven-
tricle, coming of necessity through the walls. . . ." The
blood from the left ventricle had thus found its way into the
right one. Finally, he refers to the striking analogy which
this nutritional system presents to that of the frog and cat.
In the frog the heart is almost entirely nourished "through
the branching passages that carry the blood from the interior
of the heart nearly to the pericardial surface."

On the strength of all this evidence, Dr. Pratt concludes
(giving only the features that bear directly upon the question
we are analyzing) that: "1. The vessels of Thebesius open
from the ventricles and auricles into a system of fine branches
that communicate with the coronary arteries and veins by
means of capillaries, and with the veins — but not with the
arteries — by passages of somewhat larger size. 2. These vessels
are capable of bringing from the ventricular cavities to the
heart-muscle sufficient nutriment to maintain long-continued,
rhythmic contractions. 3. The heart may also be effectively
nourished by means of a flow of blood from the auricle back
into the coronary sinus and veins." The author concludes
with the very appropriate remark: "It is evident that the nu-
trition through the vessels of Thebesius and the coronary veins
must modify in no slight degree the existing views of the
nutrition of the mammalian heart, and of the manner in which
infarction of the heart takes place." The clinical features of
this question will be considered elsewhere.

Viewed from our standpoint, the vessels of Thebesius are
more concerned with the dynamics of the heart than with the nu-
trition of this organ, though the latter function is not to be
ignored, particularly in the sense emphasized by Pratt: i.e.,

THE ADRENAL SECRETION AND THE HEART.

427

as a source of compensation. That nutrition of the left heart,
auricle and ventricle, constantly filled with arterial blood, can
result from a flow of the latter through the Thebesian vessels
seems clear, but nutrition can hardly be associated with a
similar process in the right heart, with nothing but venous
blood to propel through the Thebesian channels. That nu-
trition, the recognized prerogative of arterial blood, owing to
its oxygen, cannot be the active factor here is evident.

The right heart seems, judging from the anatomical ar-
rangement of the parts concerned in the process, to play a
physiological function of a special kind. While the Thebesian
openings are larger in the auricles than in the ventricles, in
the left auricle they are also fewer than in the right; but even
more suggestive is the fact that, while some openings in the
right auricle are supplied with valves, none have been found
in those of the left. Again, both ventricles are supplied with
foramina; the right ventricle is particularly well provided with
them, while they are difficult to find in the left one. That the
septal wall should show them most clearly on the right side is
also suggestive. Evidently a similar condition exists between
the auricles, as suggested by Bochdalek and confirmed by
Pratt; but the fact that limited information supplied by works
on anatomy usually covers only those of the right auricle
points to greater prominence of the latter. Thus, Gray8
states that the venaB Thebesii open "on the inner surface of
the right auricle." Finally, the openings supplied with valves
are in the right auricle, as we have seen; but they are also
stated to be most conspicuous in the neighborhood of the
great vessels; hence it must only be the Thebesian openings
around the great vessels of the right auricle — the vense cava3
and the pulmonary artery — that are provided with valves.

If we can now ascertain whether the current which enters
the Thebesian vessels from the right auricle is shut out in this
location, or secured within the channels, according to the man-
ner in which the valves close, — i.e., inwardly or outwardly, —
we will be able to decide whether venous blood from the vense

«Gray: "Anatomy"; edition, 1901, p. 622.

428 THE DYNAMICS OF CARDIAC ACTION.

cavae or arterial blood from the lungs circulates in the Thebe-
sian system.

Bochdalek found that many of these openings in the
auricles "presented the appearance of blind depressions, since
they were often covered with single valves in such a way as
to resist investigation with the blow-pipe" . . . "some
were slit-like, resembling the mouths of the ureters; still
others were large, round depressions, with smaller openings at
the bottom." The first remark suggests that the openings
serve as exits into the auricle, while the second points to the
contrary, since it is difficult to conceive of a depression with
"openings at the bottom" as a valve calculated to resist liquids
exerting pressure on the concave side. From the left auricle
Gad caused water to pass out of the right and left ventricular
walls, but, as the auricular openings have no valves, this only
serves to emphasize the extensive canalization which the
Thebesian system represents. The system might, therefore,
be considered as essentially calculated to distribute venous
blood from the right auricle to the entire heart: a fact which
the free anastomosis with the venous channels would seem to
sustain.

Pratt states that he has seen "structures accessory to
these ventricular foramina which might in any way serve the
office of valves" . . . "the edge of the foramen is usually
sharply defined and may frequently exist as a partial, shelf-
like, covering, giving the impression perhaps of an attempt at
a membranous valve; but it is seldom more than this." A
shelf means a projection, and the fact that it is membranous
suggests that during ventricular contraction this valve is pressed
against the opening and closes it: a feature which involves
the possibility that during diastole a current — whether venous
or arterial — flows into the ventricle through its foramina.
That the latter and their valves open inwardly — i.e., in the
ventricle — is demonstrated by Pratt's experiment, in which he
injected the coronary veins with starch and celloidin and found
that even these passed into the ventricle. If, therefore, the
venous blood of the right heart at all enters the muscular
walls it is not through the foramina of the ventricle, i.e., from
below; it must be through the openings above, i.e., those in

THE ADRENAL, SECRETION AND THE HEART. 429

the right auricle. The experiment in which the cannula was
tied in the pulmonary artery, the blood being "allowed to
enter the right auricle through insufficiency of the tricuspid,"
appears to us to further sustain this fact. The heart continued
"its rhythmic contractions for eight hours: a period consid-
erably in excess of that observed in nutrition through the
vessels of Thebesius alone. It was inferred that blood had
gained access from the auricle to the coronary veins and had
thus aided materially in the nutrition." While this course
may have been taken by some of the blood in the experiment,
it is obviously not a normal one during life, and the unusual
duration of the contractions seems to us to indicate that the
blood that penetrated into the right auricle found its way into
the Thebesian system via the openings in this auricle, thus
approximating as nearly as possible normal conditions.

The relations between the coronary veins and the Thebe-
sian channels are self-evident, excepting, however, a theoretical
back-flow from the auricles into the veins suggested by Pratt,
which appears to us abnormal; at least it is not compatible
with our views of the process. The Thebesian vessels and
coronary veins were found to communicate freely on the right
side, but not on the left, with the ventricular foramina. The
septal foramina were also found to communicate with the
coronary vein at the end of the sinus. An interesting feature
is the fact that blood passed into the right ventricle flowed
freely from a cut vein of the left heart (experiment of April 3,
1897). On the other hand, the relations between the coronary
arteries and the Thebesian vessels are of a peculiar kind; thus
the communication between the left coronary artery and the
right ventricle seems as free as that between the same artery
and the left ventricle (through the Thebesian channel) is lim-
ited. The experiment in which a colored solution was passed
into the left coronary artery caused an accumulation of 400
cubic centimeters to flow from the right ventricle, while only
4 cubic centimeters flowed from the left, sufficiently empha-
sizes this fact. Haller, who had observed that injected sub-
stances flowed out freely from the surfaces of both ventricles,
states that "the passage from the arteries into the cavities of
the left side is more difficult."

430 THE DYNAMICS OF CARDIAC ACTION.

All these features seem to fully supply the needs of the
function with which the secretion of the suprarenal glands
must be connected, if the phenomena witnessed in many dis-
orders and after the use of most remedies have been correctly
interpreted. That we are in the presence of a dual process
of which the suprarenal secretion, operating in the right heart,
and the arterialized blood in the left heart are active factors
seems probable. Again, the marked power of arterial blood
— or rather of plasma — since the defibrinated blood filtered
through cotton was used — to sustain functional activity, even
when only poured into the ventricles, as shown by Pratt, cer-
tainly indicates that the blood must alone be able, during
life, to compensate, in case of need, for insufficiency of blood
furnished by the coronary arteries.

The contractions of the left heart seem to us to be greatly
assisted by the arterial blood that enters it, and mainly by
that which enters the cavities themselves. The experiments
of Pratt having shown that contraction could be produced by
contact with arterialized blood, the arrival into the auricle of
a normal quantity of this fluid must be fully capable, there-
fore, of causing contraction of the walls of that cavity. The
relations of the several structures and the mechanism involved
seems to us to be as follows: The main structures upon which
the arterial blood reacts are (1) the musculi pectinati and (2)
the sinus venosus and appendix auriculae, all of which are so
disposed as to offer as much surface as possible to the blood.
The walls of the cavities mentioned are provided with numer-
ous channels, the Thebesian "veins/' to satisfy this purpose.
The blood which enters the auricle when it is dilated pene-
trates all the circuitous areas around the musculi pectinati and
into the Thebesian vessels, and the ensuing contraction forces
the blood-plasma into the smaller subdivisions of these vessels,
from which they find their way into the auricular veins. When
the arterial blood reaches the ventricle, a process similar to the
preceding occurs. The columns carneas are disposed so as to
offer considerable surface to the blood, while the ventricular
walls are permeated with Thebesian channels, into which the
blood penetrates during diastole. The contraction induced
closes the apertures of these channels, and forces the blood-

THE ADRENAL SECRETION AND THE HEART. 431

plasma into their smaller ramifications and finally into the
veins. The larger channels carry the corpuscular elements to
the latter. The role of the coronary arteries will be referred
to later on.

The right heart, as we view the process, owes its functional
activity mainly to the suprarenal secretion brought to the
cavities by the vena cava. We have sufficiently emphasized
the power of this agent to restore cardiac action and sustain
it even when the entire spinal cord has been obliterated. The
manner in which it exercises its powers is similar to that of
the arterial blood on the left side. On penetrating the auricle
the contractile structures are submitted to its immediate ef-
fects; but the orifices of the Thebesian vessels or channels are
more numerous and larger than in the left auricle. The mem-
branous edges previously referred to as valves by the investi-
gators quoted do not appear to us to merit being considered
as such after careful examination of these structures in the
ox-heart. The aperture being closed by the least squeezing of
the tissues containing them, it seems evident that they should
as readily close under the powerful contraction of the auric-
ular tissues. The right ventricle also presents a very much
larger number of Thebesian orifices than the left, while its
walls, though thinner, plainly show the ramifications of these
channels. That the venous blood charged with suprarenal se-
cretion should at once penetrate the latter when the ventricle
begins to contract is self-evident. Return of the blood to the
circulation is effected in the same way as in the case of the
left heart: i.e., through the coronary veins.

The whole process is an exceedingly uncomplicated one,
but, as we will see later on, it simplifies many obscure prob-
lems, while affording, in connection with the coronary arterial
blood, a supply in keeping with the vital importance of the
organ itself. Again, Dr. Pratt' s experiment, in which blood
injected into the left auricle flowed freely from the right ven-
tricle, emphasized the possibility of compensation in case of
need. Thus, while under normal conditions, the pressure in
both ventricles must be equal, reduced contraction — of the
right ventricle, for example — through insufficiency of the ad-
renals would automatically cause the arrival into it, through

432 THE DYNAMICS OF CARDIAC ACTION.

the Thebesian foramina of the septum, of at least some arte-
rial blood. That this does not always suffice to maintain
interventricular equilibrium, however, is illustrated by the
dicrotic pulse, the pulsus paradoxus, and other kindred phe-
nomena.

Suggestive in this connection are the remarks of Professor
Porter in his review of the subject of cardiac innervation in
the "American Text-book of Physiology"9: "A positive dem-
onstration that the nerve-cells in the heart are not essential
to its contractions," says this observer, "is secured by remov-
ing the tip of the ventricle of the dog's heart and supplying
it with warm defibrinated blood through a cannula tied into
its nutrient artery. Long-continued, rhythmical, spontaneous
contractions are thus obtained (Porter10). As the part removed
contains no nerve-cells, the observed contractions can only
arise in the muscular tissue, provided we make the (at present)
safe assumption that the nerve-fibers do not originate im-
pulses capable of inducing rhythmic muscular contractions."
As will be shown, the cardiac nerve-fibers, as in all the organs
we have reviewed, merely impose upon the muscular fiber the
required vibratory rhythm. This is well illustrated by the fol-
lowing experiment: If the apex of a frog's heart "is suspended
in normal solution," says the same author, "and a constant
electric current kept passing through it, beats will appear
after a time, the frequency of pulsation increasing with the
strength of the current" (Langendorff11). But Porter also re-
marks, almost prophetically in the light of our views: "The
demonstration that the nerve-cells are not essential to con-
traction places us one step nearer the true cause of contrac-
tion. It is some agency acting on the contractile substance.12
Evidence is accumulating that this agent is a chemical substance,
or substances, brought to the contractile matter by the blood."

That the "chemical substance brought to the contractile
matter by the blood" is represented by the adrenal secretion
and the oxidizing substance seems clear.

• Porter: "American Text-book of Physiology," second edition, 1900.

10 Porter: Journal of Experimental Medicine, vol. ii, p. 391, 1897.

11 Langendorff: Archiv fur gesammte Physiol., Ixi, p. 336, 1895.
13 All italics are our own.

THE ADRENAL SECRETION AND THE HEART. 433

THE ACTION OF THE ADRENAL SECRETION AND THE OXIDIZING
SUBSTANCE UPON THE CARDIAC MUSCLE.

The histology of the myocardium still offers a broad field
for conjecture, notwithstanding the many investigations to
which it has been submitted by modern observers. The known
facts are briefly these: Its tissue is composed, in man, of
short, round fasciculi, or 'bundles, of striated fibers, possessed
of thick lateral projections. The latter directly connecting
with a similar projection of the adjoining bundles and being
cemented to it, a thick close-meshed net-work is formed: a
characteristic of the heart-muscle. But it differs from other
muscles in several other particulars; its fibers are one-third
smaller and their striae are much more faint; they possess no
sarcolemma and are, therefore, exposed to the immediate action
of a fluid that may surround them. The manner in which
the contractile structures are combined in bundles is also
peculiar: each bundle is made up of central prismatic fasciculi
of round fibers, in which nuclei (one or two) with their sur-
rounding protoplasmic area are imbedded, the whole being
surrounded with flat or ribbon-like columns of muscle-fibers.
The perinuclear protoplasm referred to generally contains fat-
droplets and minute pigment-granules which resemble haemo-
globin, and sends projections between the surrounding mus-
cular fibers so that each of the latter is connected with and
is only separated from its neighbor by a layer of protoplasm.
This arrangement does not in any way modify the manner in
which the sarcous elements are disposed, while the disks, clear
spaces, etc., are precisely as they are elsewhere in the organ-
ism. These muscular "primary" bundles form, by their union
with one or two of their neighbors, columns, or chains — or
"secondary" bundles, which are covered, as shown by Ranvier,
with a sheath of loose connective-tissue cells, which cells, in
turn, connect with one another by numerous projections, or
extensions. The primary fasciculi also contain connective-
tissue sheaths which invest the muscle-fibers and are likewise
supplied with connective-tissue cells. All this forms a close,
though permeable, net-work, which makes it possible for a
liquid to penetrate the muscular columns or chains and come
into direct contact with the bare, or exposed, muscle-fiber.

434 THE DYNAMICS OF CARDIAC ACTION.

Indeed, the intimate structure of the myocardium pre-
cisely supplies the required structure for the equable and free
distribution of such an agency as the suprarenal secretion rep-
resents. Fluids can penetrate through the maze of cellular
tissue to the bare muscular fibers; the sheaths that include
the columns or chains of muscular bundles afford a peculiar
system of canalization through which the liquids can easily
gain access to them. These canals — the lacunae of Henle —
are the intervals between the columns of secondary bundles, or
their sheaths, rather, which are placed in longitudinal apposi-
tion. Schweigger-Seidel and Eanvier having observed that
interstitial injections of colored substances penetrated the
lymphatic vessels, the lacunae have been considered as adjuncts,
or extensions, of the latter.

Renaut,13 however, concluded that the penetration of the
colored fluids into the lymphatics merely demonstrated the
weak resistance of the endothelial coat of the latter, and the
spaces, or lacunas, of Henle being unprovided with endothelial
walls, there was no ground for the prevailing belief that they
represented lymphatic vessels. He found that all the lym-
phatic capillaries of the myocardium are located on the surface
of the heart underneath the pericardium. They are large and
bosselated and form a mesh-work which covers the whole car-
diac surface, and send smaller blind pouches into the muscular
interstices. The spaces of Henle should be considered, he
thinks, "not as true lymphatic cavities analogous to those ob-
served around the pulmonary lobules of certain animals, but
as mere connective-tissue spaces, which represent, in fact,
pathways for lymph." In a foot-note Berdal states that the
spaces of Henle are crossed by "vessels," and in the text the
following remark as to the identity of this lymph appears:
"The muscular fibers of the heart are thus bathed in con-
nective-tissue spaces in which lymph easily circulates; but
this lymph is not that of the lymphatic vessels or capillaries,
but that of loose connective-tissue spaces (Kenaut)." It is
needless to state that this suggests the presence of blood-
plasma. Still, we can only consider this deduction as tentative.

13 Renaut: Trait6 d'Histologie pratique, p. 719; quoted by Berdal, loc. cit.,
p. 285.

THE ADRENAL SECRETION AND THE HEART. 435

The manner in which the blood-plasma, whether venous
or arterial, is distributed by the Thebesian channels is well
shown in a study of the vessels of the heart by Arthur V.
Meigs.14 The extreme paucity of literature on the Thebesian
channels has caused them to be overlooked by practically all
histologists; that they should be treated as capillaries in the
author's paper is, therefore, as normal as it is for text-books
to do so. "The capillaries of the human heart," says Dr.
Meigs, "differ in two ways from those of other parts of the
body: they penetrate the muscular fibers, and some of them
are larger than those found elsewhere, and of different ar-
rangement. . . . The accompanying illustrations are draw-
ings which were made with the camera lucida. They are from
sections of two human hearts. The first is from the heart of
a negro woman, 40 years old, who died of burns. Some pieces
of the organ were preserved in Fleming's solution, and others
in 70-per-cent. alcohol, and they were stained in bulk with
borax-carmine and imbedded in paraffin. The second heart is
that of a man, 30 years old, who died of lead encephalopathy.
When the post-mortem examination was made, the heart being
still quite fresh, there was injected through each of the two
coronary arteries as much as the blood-vessels would easily
receive of a solution of 3 grammes of Berlin blue (Griibler's)
in 600 cubic centimeters of water. Pieces of the organ of
suitable size were at once placed in preservative fluid, some in
70-per-cent. alcohol, and others in formaldehyde solution. The
tissue was afterward stained in bulk with borax-carmine and
imbedded in paraffin.

"The penetration of the muscular fibers by the capillaries
is made perfectly clear by the illustrations; it is shown as well
by the injected as by the uninjected heart. The two methods
of demonstration supplement one another, because, in injected
tissue which has been stained, the blood-vessels and their situa-
tion are made very obvious by the contrast of color, but the
details of the structure of the walls are obscured by the injec-
tion material, while, on the other hand, in the uninjected tissue,
the structure of the blood-vessels can be seen with the utmost
distinctness. In Figs. 1 to 4 the capillaries are easily recog-

14 Arthur V. Meigs: Journal of Anatomy and Physiology, Jan., 1899.

28

436 THE DYNAMICS OP CARDIAC ACTION.

nized. Their situations in relation to the muscular fibers are
very varied. Some are in the intermuscular fibers, others
slightly indent the sides of the fibers; still others are within
the fibers close to their peripheries, and sometimes the capil-
laries are in the very centers of the fibers. This penetration of
the muscular fibers of the human heart in the adult is a most

DESCRIPTION OF DR. MEIGS'S PLATE.

"Scales are included with the plate, showing the amplification. [The
amplification has been reduced about one-third in the reproduction herein pre-
sented.]

"Fig. 1.— x 420. From a man, 30 years old, who died of lead encephalop-
athy. A section of papillary muscle of the heart cut across the fibers. Ib are
injected capillaries, the one partially and the other entirely within the muscular
fibers, c, A capillary which remains uninjected; its nucleus is included.

"Fig. 2. — x 420. From the same tissue as Fig. 1. v, A vein stained by
the injection material. 66, Capillaries whose precise situation cannot be defined.
They cannot be said to be intermuscular spaces, nor to be entirely within fibers.
The effect is as if the fibers were coalescing.

"Fig. 3.— x 420. From the same tissue as Fig. 1. f, A capillary in a
fiber, g, A capillary in the center of a very small fiber. This is perhaps the
most convincing instance of the penetration of a muscular fiber by a capillary.

"Fig. 4. — x 420. A section of heart cut transversely to the muscular fibers,
from a negro woman, 40 years old, who died of burns. The muscular fibers are
of irregular shape, d, A capillary within a muscular fiber, its nucleus upon one
side producing a resemblance to a seal ring, e, A capillary within a muscular
fiber. /, A capillary in an intermuscular space; its nucleus being included, it
resembles a seal ring, g, A capillary in an intermuscular space; its endothelial
wall appears as a simple circle.

"Fig. 5. — x 115. From the same tissue as Fig. 4. A large capillary,
receiving many branches and surrounded by muscular tissue. The capillary and
its branches are almost filled with blood-corpuscles. The capillary walls are dis-
tinctly visible, containing many flattened endothelial nuclei.

"Fig. 6.— x 42. From the same tissue as Fig. 1. Not printed in two
colors, because the essentials show equally well in black, m, Muscular tissue,
a, An arteriole; the solid black within its caliber is injection material, v, The
accompanying vein to the arteriole, a; it also contained a little of the injection
material; these two vessels are in a connective-tissue interspace, c, A large
capillary; it contains a good deal of the blue injection material, which is rep-
resented by the heavily-shaded portions. These three vessels— arteriole, vein,
and capillary— give a good idea of the character of such vessels in the heart.
The great size of the capillary is the most striking feature."

striking and curious phenomenon, and it does not exist at an
early embryological stage. The condition is, therefore, one of
later development, but it is not yet known at how early an age
it does exist ..........

"Very large capillaries are found in the human heart, and
such vessels are shown by Figs. 5 and 6. It is not common to
find minute veins in company with the arterioles in the deepest

Fig. 1.

Fig. 9.

o

Fig. S.

Fig. 6.

CIRCULATION DF THE HUMAN HEART, [Arthur 17. Msigs.J

[Jo/iniu/ <>f Ainiloiny mill I'/ii/xio/oyi/.]

THE ADRENAL SECRETION AND THE HEART. 437

portions of the muscular substance of the heart, although it is
well known that, upon the surface and in the connective-tissue
interstices, arteries are found with their venae comites, just as
they are in other organs and tissues. The arrangement of the
vessels upon the surface and in the interstices is in marked
contrast with that found in the muscular substance proper.
Here, when an arteriole is accompanied by an efferent vessel,
this vessel is single coated and composed of endothelium, being
exactly like the smallest capillaries, except in size. These pecul-
iar large capillaries are found not only in company with arteri-
oles, and, therefore, when carrying on the function usually
performed by veins, but also alone. When they are alone, it
is impossible to be certain whether their function was afferent
or efferent. It may well be that arterioles are less numerous
in the heart than in other tissues, and that their place is taken
by the large capillaries. These capillaries are so numerous and
of such size that it seems likely they perform the function of
reservoirs. The presence of the large capillaries and the pene-
tration of the muscular fibers by the capillaries indicate a pro-
vision for the blood-supply of the heart even more bountiful
than that of the other organs."

That these vessels are the Thebesian channels is evident;
their mode of distribution and the peculiar endings of their
subdivisions is particularly well shown in Fig. 6, while the
outpouring of plasma for absorption by the muscle-elements is
suggested by Fig. 5.

The fact that the distribution of the Thebesian channels
is analogous to that observed in the heart of the frog has, we
have seen, been noted by Pratt. This had also been noticed
by Lannelongue, but this author considered the channels of the
human myocardium as vestiges of the batrachian system. Ber-
dal, who alludes to the latter, states that in the frog and in the
batrachian urodela there are no ordinary blood-vessels. "The
muscular fasciculi intercept cavernous spaces into which the
blood penetrates directly and from which they are only sepa-
rated by endothelium. The frog's heart is thus a true sponge the
structures of which, formed of muscular fibers, nourish themselves
~by imbibition. In mammals, on the contrary, the myocardium
contains distinct vessels. The capillaries form a net-work the

438 THE DYNAMICS OF CARDIAC ACTION.

meshes of which, elongated and parallel to the muscular fascic-
uli, are connected by short branches, which give each mesh the
appearance of a parallelogram. When these vessels cross the
spaces of Henle, they are covered, on the external surface, with
flat connective-tissue plates/' Pratt's observation not only in-
cludes the analogy between the human lung and that of the
frog, but also with that of the cat, a mammal. Under these
conditions, it becomes clear that in man, also, the heart-muscle
may be regarded as a sponge-like structure, the contractile elements
of which are nourished and supplied with working energy by
substances in the blood-plasma.

What is the role of the blood of the coronary arteries in
the functions of the heart? This may perhaps be traced by
analyzing the effects of ligation of these arteries upon these
functions. Porter15 refers as follows to the experimental work
in this connection: "The frequency of arrest after ligation is
in proportion to the size of the artery ligated, and hence to the
size of the area made anaemic, and is not in proportion to the
injury done in the preparation of the artery. The circumflex
and descendens may be prepared without injuring a single mus-
cle-fiber, yet their ligation frequently arrests the heart, while
the ligation of the arteria septi, which cannot be prepared with-
out injuring the muscle-substance, does not arrest the heart.
It is, moreover, possible to close a coronary artery without me-
chanical injury. Lycopodium-spores mixed with defibrinated
blood are injected into the arch of the aorta during the mo-
mentary closure of that vessel and are carried into the coronary
arteries: the only way left open for the blood. The lycopodium-
spores plug up the finer branches of the coronary vessels. The
coronary arteries are thus closed without the operator having
touched the heart. Prompt arrest, with tumultuous fibrillary
contraction, follows."

If the plasma that reaches the heart by way of the Thebe-
sian channels can sustain both its nutrition and its contractions,
how can such results as these be accounted for? The sudden
arrest of the heart's action by plugging the coronary arteries
certainly points to a predominating function, and, more than
this, to a function of which they are alone the sources of blood-

18 Porter: Loc. cit.

THE ADRENAL SECRETION AND THE HEART.

439

supply. That the role of the coronary blood is precisely that
which obtains elsewhere in the organism is forcibly suggested
by the experiments of Langendorff, who was able, according to
Porter, "by circulating warmed oxygenated defibrinated blood
through the coronary vessels, to maintain the hearts of rabbits,
cats, and dogs in activity after their total extirpation from the
body." It is clear that the blood-plasma can incite functional
activity when introduced through the coronaries as well as when
introduced into the ventricles. "Even pieces removed from the
ventricle will contract for hours," continues the author, "if fed
with blood through a cannula in the branch of the coronary
artery which supplies them (Porter16). It is evident, therefore,
that the cause of the rhythmic beat of the heart lies within the
heart itself, and not within the central nervous system."

The italicized words represent precisely the factor of the
problem which must be eliminated to enable us to differentiate
the role of the coronary plasma from that of the Thebesian
plasma, for blood will not alone induce contraction of the car-
diac walls; almost any irritant will under appropriate condi-
tions. Indeed, in the latter case it will sometimes undergo con-
tractions without any external irritation; thus, "a strip of
muscle cut from the apex of the tortoise ventricle and suspended
in a moist chamber begins in a few hours to beat apparently
of its own accord with a regular, but slow, rhythm, which has
been seen to continue as long as thirty hours. If the strip is
cut into pieces and placed on moistened glass slides, each piece
will contract rhythmically. Yet in the apex of the heart no
nerve-cells have been found" (Porter). Hence the power to
contract is inherent in the contractile tissues, and subject, as
elsewhere in the organism, to exacerbations of activity under
appropriate stimulus. This fact being now established, our in-
quiry is simplified, since we need only to inquire into the nature
of the processes through which it is utilized.

Analysis of the requirements of the right heart soon re-
veals the fact that the muscle-fibers require the same blood-
supply that any muscle of the body does. Indeed, we then
realize that the coronary arteries are their only source of oxy-

16 Porter: Journal of Experimental Medicine, vol. ii, p. 391, 1897.

440 THE DYNAMICS OP CARDIAC ACTION.

gen. The venous blood that reaches it through the Thebesian
channels has been depleted of this gas by the rest of the or-
ganism, and the suprarenal secretion, owing to its marked avid-
ity for it, must, while in transit through the inferior vena
cava, have deprived it of the little that might have remained
in loose combination. We have reviewed the ultimate distribu-
tion of the coronary arteries as given by Berdal. It does not
differ from that of other text-books. These generally concur
in stating that the larger branches are distributed to the con-
nective tissue between the large fasciculi, and once therein
divide into arterioles, which, in turn, subdivide into capillaries
that entwine the primary muscle-fasciculi. "The capillaries
of the myocardium are very numerous," say Bohm and von
Davidoff, "and so closely placed around the muscle-bundles that
each muscular fiber comes in contact with one or more capil-
laries." Do they serve here, as elsewhere, to supply the muscle-
fiber with its source of energy — i.e., the carbohydrates that enter
into the formation of the myosinogen — besides furnishing the
oxidizing substance which sustains the combustion processes
when brought into contact with this myosinogen? This is pre-
cisely where a difference between the muscular functions of the
heart and those of other muscular structures appears to us to
exist.

There is practically no passive period in the heart's action
when we consider that its stage of activity recurs every three-
fourths of a second; and the formation of myosinogen in its
contractile elements, were it to proceed as slowly as it does else-
where, would seem totally inadequate. Still, if the coronary
blood is not endowed with the mission of supplying the heart-
muscle with its source of energy, we are relegated to the venous
blood of the Thebesian vessels and its suprarenal secretion for
the myosinogen-forming products. A possible source of en-
ergy suggests itself when we consider that a carbohydrate
known to react under the effects of the oxidizing substance is
present in the hepatic veins, — i.e., dextrose, — and that this
sugar must pass through the right heart. As is well known,
these veins carry their sugar to the inferior vena cava. That
it is not used by the heart, however, was shown by a careful
analysis of the whole question. This is submitted in the twelfth

2 —

u

MECHANISM DF CARHIAC ACTION, [Sajous.]

1, Inferior ~y~ena Cava, the bland of which contains
SEcretian. 2, Hepatic "Wains, the blnod nf -w/hich. contains
granules /3 dErived from the Liver. 3, Right fiuricle, 4, Dne of
the Coronary UrtEriss. 5, Dne of the Coronary Vpins. B, One
cf the Foramina TnEbesii.

THE SOURCES OP THE HEART'S ENERGY. 441

chapter. Paradoxical as the statement may seem, we were led
to conclude that the minute granules referred to on page 433
were actually supplied to the heart through the intermediary
of leucocytes. These cells were found to migrate from the liver
(also through the hepatic veins) to the inferior vena cava, where
they meet the adrenal secretion and proceed with it to the
right ventricle. The evidence seems incontrovertible. The
subject is so far-reaching, however, that it had to be consid-
ered separately. We will, for the present only, refer to these
granules as "granules ft" (Ehrlich). We now have, it seems
to us, the elements necessary to account for the functional
phenomena witnessed, namely: —

1. The adrenal secretion, to contract the right auricle and
ventricle and thus insure the penetration of the Thebesian Mood into
the cardiac walls (which contraction venous blood or its con-
tained granules fi would not cause).

2. The granules fi, to account for the unusual and continuous
production of energy which the heart converts into work.

3. A continuous supply of oxidizing substance via the coro-
nary arteries to insure the combustion processes through which this
energy is liberated.

The annexed colored plate shows the manner in which the
adrenal secretion and the granules (3 simultaneously reach the
right auricle.

We can now understand why plugging of the coronary
arteries should, as stated by Porter, arrest cardiac action. Re-
ferring to the effects of embolism and thrombosis of these
arteries, this investigator also says: "That part of the heart-
wall supplied by the stopped artery speedily decays. The
bloodless area is of a dull-white color, often faintly tinged with
yellow; rarely it is red, being stained by hcenwglo'bin from the
neighboring capillaries. The cross-section is coarsely granular.
The nuclei of the muscle-cells have lost their power of staining.
The muscle-cells are dead, and connective tissue soon replaces
them. This loss of function and rapid decay of cardiac tissue
would not take place did anastomosis permit the establishment
of collateral circulation between the artery going to the part
and neighboring arteries. . . . The objection that one of
the coronary arteries can be injected from another, and that,

442 THE DYNAMICS OF CARDIAC ACTION.

therefore, they are not terminal, is based on the incorrect
premise that terminal arteries cannot be thus injected, and
has no weight against the positive evidence of the complete
failure of nutrition following closure." As we interpret the
process, the absence of anastomosis further suggests the exist-
ence of an additional source of energy; but the cardiac arrest
after ligation of the coronary also indicates that compensation
from the opposite heart can only be gradually established. On
the whole, the coronaries of the right side are as important
as if they alone supplied the needs of the functions of that
side. The granules fj and the adrenal secretion are furnished to
compensate for the absence of arterial blood in the right auric-
ulo-ventricular cavities and in their Thebesian channels; but,
the right coronaries being the only source of one of the three
necessary factors of the process, their obliteration means as
much as that of the left coronaries does to the left heart.

We can also understand why the contractile elements of
the primary fasciculi are bare. They are constantly bathed
in the plasma from which they obtain the granules (3 that
enter into the formation of their myosinogen. The absence
of oxygen in this fluid renders it perfectly harmless to the
delicate structures that surround the primary and secondary
bundles of muscle-fiber, and to the net-works of arterial capil-
laries that hug the bare fibers. The latter, by a rapid absorp-
tion,— which the presence of sarcolemma would counteract, —
are constantly forming their products of metabolism: i.e.,
myosinogen. The arterial capillaries, "coated, on their exter-
nal surface, with flat connective-tissue cells" (Berdal), when
they cross the spaces of Henle, being the only carriers of oxy-
gen, normally become the active factors of nutrition and func-
tion. Their blood is the normal excitant — as elsewhere. The
venous blood brings the granules £?; the adrenal secretion, by
contracting the cardiac walls, forces it into the Thebesian chan-
nels; the bare muscle-fibers absorb the granules and convert
them into their own particular kind of fuel, myosinogen; the
capillary blood supplies the energy for this metabolism — oxy-
gen— and simultaneously sustains, again with its oxygen, the
combustion processes upon which the continuous work of the
organ depends. Here, as elsewhere, the potential energy of

THE SOURCES OF THE HEART'S ENERGY. 443

the chemical agencies present becomes converted into mechan-
ical energy, which manifests itself as visible motion.

The left heart — the coronaries of which are larger than
those of the right — presents anatomical features which modify,
in a measure, the manner in which its physiological functions
are performed. Both its auricle and ventricle containing arte-
rial blood fresh from the heart, the Thebesian circulation does
not appear to fulfill the primary role it does in the right heart.
Indeed, the various experiments of Pratt and his predecessors
and our own careful examination of the ox-heart distinctly
show that the Thebesian circulation of the left heart, as regards
intraventricular orifices, is much less important than that of
the right heart. Still, the evident permeability of the inter-
ventricular septum and the histology of the left myocardium
suggest that the left heart must receive material aid from the
adrenal secretion and its granules ft. This feature will again
be referred to in the twelfth chapter.

A feature that may be considered as demonstrated, and
common to both sides, is the return of the blood, whether its
source be the Thebesian or coronary systems, by way of the
coronary veins. We have seen that Langer expressed the opin-
ion "that the foramina Thebesii in the ventricles communicate
with the veins by capillaries alone." Our conception of the
process involved would necessitate such an arrangement as re-
gards the right heart. Indeed, so direct is this connection that
even such viscid substances as starch and celloidin were found
by Pratt, when introduced into the coronary veins of the ox,
to emerge from the foramina Thebesii. Still, we could hardly
expect such a free transit on the left side of the organ, inas-
much as the presence here of arterial blood only would suggest
the presence of a structural organization similar to that of ordi-
nary muscles. Indeed, referring to the vascular connections
of the left heart, Pratt says: "So intimate a connection, how-
ever, between the coronary veins and the vessels entering the
left ventricle I have not yet been able to demonstrate." Again,
on the right side the connection with coronary veins must evi-
dently be a physiological one, since "a small, but steady, stream
of venous blood issued from them" when the veins were incised
after the right ventricle had been filled with defibrinated blood.

444

THE DYNAMICS OF CARDIAC ACTION.

But "no flow of blood occurred from the artery, although there
was a free escape from an incision in an accompanying vein" in
an experiment similar to that previously referred to, also per-
formed by Dr. Pratt. In fact, it appears to us very doubtful
whether even the capillary communication between coronary
arteries and the Thebesian vessels, referred to by the latter
observer in his conclusions, at all exists — at least in the walls
of the right heart. Even disregarding our views, it seems evi-
dent that the admixture of venous blood with the arterial blood
would greatly reduce and perhaps annul the functional efficacy
of the latter as an oxidizing agent.

We can now understand how the adrenal secretion so
greatly influences cardiac activity. An increase of it augments
the force of the contraction, but the heart does not dilate as
promptly nor perhaps as completely; hence its action is slower,
but more forcible; we have seen that this represents the primary
effect of all drugs sufficiently active to stimulate the adrenals.
A still greater quantity of adrenal secretion increases the vio-
lence of cardiac action; the vessels are tense, and ecchymoses,
haematuria, epistaxis, etc., may ensue. The heart acts normally,
however, in the sense that its diastole is almost complete. Con-
tinuous cardiac stimulation through excessive production of
adrenal secretion, due in turn to excessive production of iodo-
thyrin, as in exophthalmic goiter, causes the heart to contract
before it has exhausted its complete diastole and to work
within a narrower field. Its contractions are sharp, but rapid:
the type of the "cramped heart." Increase of adrenal activity
involves increase of oxidizing substance; hence the left heart
is correspondingly stimulated. When, however, adrenal insuffi-
ciency occurs, the phenomena follow an opposite course; when
total inhibition of the adrenal system ensues, the vascular walls,
losing all their functional stimuli, — the adrenal secretion, the
granules /$, and the oxidizing substance, — gradually cease their
contractions and lapse into diastole.

THE INNERVATION OF THE HEART.

We are again brought, by analysis, to the realization that
the afferent nerves distributed to the heart incite and govern
functional activity but contribute nothing to the continuation

THE INNERVATION OF THE HEART. 445

of vital processes per se. Indeed, in the heart they do naught
else than in other parts of the organism. The general motor
system (sympathetic) insures the tonic contraction of the coro-
naries and smaller vessels; the vagus, when need be, assumes
control, to increase or reduce the rapidity of the organ's con-
tractions. "The rich nervous supply of the heart is derived
from the coronary plexuses," says Piersol, "and includes numer-
ous medullated fibers coming from the pneumo gastric as well as
the non-medullated sympathetic fibers proceeding from the
•cervical ganglia. Numerous microscopical ganglia are found
along the course of the large nerve-trunks accompanying the
branches of the coronary arteries, especially in the longitudinal
interventricular and in the auriculo-ventricular furrows. Many
additional small groups of ganglion-cells occur within the mus-
cular tissue associated with the fibers supplying the intimate
structure."

The similarity between the innervation of the heart and
that of the organs of the digestive tract is recalled in the above
quotation by the conjoined sympathetic and vagus plexuses,
which form around the coronaries what we have termed the
"extrinsic" nerves: i.e., those that regulate the amount of blood
admitted into an organ. The analogy further asserts itself when
the distribution of the terminal fibers, as depicted by Langer-
hans and Eanvier, is reviewed. Berdal refers to this feature
-of the terminal supply as follows: "The nerve-fibers which
penetrate the depths of the cardiac muscle form, on the surface
of the fasciculi, a long-meshed plexus which sends into the
interior of these fasciculi still finer fibers. These fibers form
a second net-work, the elongated meshes of which present the
dimensions of a muscular fiber; but, instead of containing the
muscle-fibers in their meshes, the latter seem to traverse them
longitudinally."

We can, therefore, base our deductions, as regards the func-
tions of the terminal subdivisions of the sympathetic and vagus
nerves in the heart-muscle, upon the analogy which the func-
tions of these nerves in other organs suggest. Their similar
distribution, extrinsic and intrinsic, in all the organs that they
jointly supply, including the heart, seems to us to afford con-
siderable likelihood that their role is similar in the latter organ

446 THE DYNAMICS OF CARDIAC ACTION.

to that fulfilled by them in all others. Indeed, it is difficult
to conceive of a mechanism in which vasoconstriction and the
adjustment of functional activity to requirements could be dis-
pensed with. These factors, in addition to the normal attri-
butes of the afferent fibers of the vagus, — i.e., to transmit to the
vagal center impulses that will bring about reflexly the required
modification of functional activity, — constitute a simple, though
perfect, mechanism, when applied to the phenomena witnessed.
They satisfy equally well the needs of the functional activities
of the heart-muscle, when supplemented with the all-important
adrenal secretion of the Thebesian circulatory system.

There are two features of cardiac functions connected with
the nervous system, however, which appear to us to require
interpretations other than those that have been generally ac-
cepted: i.e., the "augmentor," or "accelerator," and the "in-
hibitor" phenomena.

"AlJGMENTOR," OR "ACCELERATOR," PHENOMENA. — These

consist of an increase of the rapidity of the heart-beats and the
force of the beat, "the diastole being shortened and the systole
strengthened": the type of cardiac action we have termed, when
exaggerated as it is in exophthalmic goiter, the "cramped heart."
In reviewing another subject Professor Foster says: "If we
stimulate the sympathetic in the neck,17 cutting the nerve below,
so as to block all impulses from passing downward, and only
allow impulses to pass up to the vagus and thence down the
mixed vagus trunk to the heart, we get very remarkable results.
The beat of the heart, instead of being inhibited, is augmented;
the beats are increased, either in frequency or in force, or most
generally both in frequency and in force. The effect is, per-
haps, best seen when the heart before stimulation is beating
slowly and feebly; upon stimulation of the cervical sympathetic
the beats at once improve in vigor and frequency; indeed, a
heart which, for one reason or another, has almost ceased to
beat may, by proper stimulation of the sympathetic, be called
back into vigorous activity." That we are dealing here with
stimulation of the adrenals seems probable.

Indeed, we have added a factor of marked importance to
those usually taken into consideration, — i.e., the anterior pitui-

17 All italics are our own.

THE INNERVATION OP THE HEART.

447

tary body, — which becomes itself activated, under these circum-
stances, through the carotid plexus. The- vagus is not alone
stimulated, therefore, but the suprarenal glands likewise: pre-
cisely the most effective means to bring about the effects
witnessed, — as we view the process. This is affirmed by the fol-
lowing remarks by the same author: "Last, the contrast is

Cr.

IX

-A.8b.

S.KC,

DIAGRAMMATIC REPRESENTATION OF THE COURSE OF CARDIAC

AUGMENTOR FIBERS IN THE FROG. (Foster.)

completed by the fact that the augmentation resulting from
the stimulation of the sympathetic is followed by a period of
reaction in which the beats are feebler; in other words, aug-
mentation is followed by exhaustion; and, indeed, by repeated
stimulation of these sympathetic fibers, a fairly vigorous blood-
less heart may be reduced to a very feeble condition."

448 THE DYNAMICS OF CARDIAC ACTION.

Again, the distribution of the nerve clearly points to the
adrenals as the source of the "augmentor phenomena." Pro-
fessor Foster states that it "may be traced from the spinal cord
by the anterior root of the third spinal nerve, through the
ramus communicans to the corresponding splanchnic ganglion
(G"')f and thence by the second ganglion (G" ), the annulus
of Vieussens, and the ganglion (G'J to the cervical sympathetic
(Sy), and so by the vagus trunk to the superior vena cava
(S. V. C.)" Indeed, he so accurately traces out, in the an-
nexed illustration, what to us appears to be the direct path-
way to the adrenals, in the frog, that his own words will serve
our purpose: "By watching the effects of stimulating the sym-
pathetic nerve at various points of its course we may trace these
augmentor fibers from their junction with the vagus down the
short sympathetic of the neck, through the first splanchnic or
sympathetic ganglion connected with the first spinal nerve ( Gr),
through one or both the loops of the annulus of Vieussens,
(An. V.), through the second ganglion connected with the
spinal nerve (G" ), to the third ganglion connected with the
spinal nerve (G'" ), and thence through the ramus communicans,
or visceral branch of that ganglion (r. c.), to the third spinal
nerve (III), by the anterior root of which they reach the
spinal cord." If, in the illustration, as above described, the
identity of G'" is noted, — i.e., the splanchnic ganglion, — the
fact that the "augmentor" stimuli follow the course outlined,
to the adrenals, will appear. We have already witnessed the
effects of lesions of the bulb in causing overactivity of the ad-
renals through this nervous path. Especially is it well illus-
trated by Claude Bernard's memorable experiment, during
which he discovered that puncture of the fourth ventricle gave
rise to glycosuria: a condition due, we have seen, to suprarenal
overactivity.

We must not lose sight of the fact, however, that "aug-
mentor" phenomena do not only include increase of the force
of the heart, — attributable, in our opinion, to the adrenal se-
cretion,— but also increase of the rapidity of the heart-beats.
It is evident that if the adrenals were the only sources of
energy involved in the process we would obtain increased force
and slowing of the heart's action. To what, therefore, can we

THE INNERVATION OP THE HEART. 449

ascribe the quickening of the heart-beats to which stimulation
of the augmentor fibers give rise? The answer is easily found
in the fact that the vagus fulfills in the heart the same functions
it does in other organs: i.e., it incites and governs the active
stage of its functional processes. Its prerogatives as governing
agency obviously include quickening, as well as slowing, of the
heart-beats, the former being the result, as previously stated, of
a more rapid vibratory rhythm, while the slowing results from
a slower rhythm of the impulses transmitted from the vagal
centers. When, therefore, stimulation of the adrenals is in-
duced through the augmentor fibers, the vagal centers are cor-
respondingly stimulated, — owing to the unusual activity of the
oxidation processes which the increase of oxidizing substance
in the blood engenders, — and the frequency of the heart-beats
is augmented in proportion. While the adrenal secretion there-
fore increases the power of the cardiac pulsations, the vagus
increases their number.

We wish to particularly emphasize this combined action
of the adrenals and the vagus, since it represents the functional
mechanism that underlies the production of fever.

That the first effect of stimulation of the augmentor fibers
is produced upon the adrenals, the vagal effects being secondary,
is strikingly emphasized by the following remark of Professor
Foster's in reference to "augmentor" phenomena: "In contrast
with the case of the vagus fibers, a somewhat stronger stimula-
tion is required to produce an effect; the time required for the
maximum effect to be produced is also remarkably long."

On the whole, it seems to us quite evident that stimulation
of the "augmentor" fibers increases the rapidity and the force of
the heart-beat by increasing the functional activity of the adrenals
and, as a result of the increased oxidation processes thus obtained,
that of the vagal centers. The excess of adrenal secretion increases
the force of the heart-beats, while the overactivity of the vagal cen-
ters increases their number.

"INHIBITOR" PHENOMENA. — We have previously stated
that we had not found, in the course of the inquiry to which
this work is devoted, the need of a subsidiary function such as
that generally understood by the word "inhibition": i.e., arrest,
partial or total (by a direct action upon tissues or by interfer-

450

THE DYNAMICS OF CARDIAC ACTION.

ence with other nerve-impulses), of the functional activity of
an organ. Indeed, direct "inhibition" does not appear to us
to prevail in the organism any more than does direct "vaso-
dilation." NOT do we find the need of such an action to account
for the "inhibition" phenomena witnessed in connection with
the heart — provided, of course, the functions we ascribe to the
vagus are considered as factors of the process through which
this organ is inhibited. It seems evident to us that, if this
nerve can quicken or moderate the pace of the cardiac contrac-
tions, arrest of these contractions must ensue if the impulses
transmitted through the nerve exceed in vibratory rhythm the
maximum rhythm of which the heart-muscle is capable. In
other words, there must obviously be a limit to the speed with
which the cardiac muscle can repeat its contractions within a
given time, and, excessive stimulation involving a greater num-
ber of heart-beats than the muscle can satisfy, cessation of the
organ's work normally follows.

"If while the beats of the heart of a frog are being care-
fully registered," says Professor Foster, "an interrupted cur-
rent of moderate strength be sent through one of the vagi, the
heart is seen to stop beating. It remains for a time in diastole
perfectly motionless and flaccid; all the muscular fibers of the
several chambers are, for the time being, in a state of relaxation.
The heart has been inhibited . . ." The overwhelming im-
portance of this simple experiment becomes emphasized when
the influence of excessive suprarenal activity upon the oxida-
tion processes of the vagal centers, to which we have just re-
ferred, are given their full meaning. Indeed, the cardiac arrest
that follows over stimulation of the adrenals under the influence of
toxics is due to excessive activity of the oxidation processes in a
certain proportion of cases.18

Whether cardiac inhibition be due to cessation of supra-
renal functions or to excessive vagal stimulation, the effect on
the heart is the same as regards the mode of arrest: i.e., in
diastole. We have just seen that it occurs in the frog when
the vagus is stimulated. We have also submitted evidence to

18 As such cases are clearly defined, — as we shall see in a subsequent chapter,
—their importance lies in their differentiation from cases in which the adrenals
are primarily arrested through excessive stimulation of their center: the an-
terior pituitary body.

THE INNERVATION OF THE HEART. 451

show that diastole was the type of cardiac arrest that followed
total suprarenal inhibition due to overstimulation. Even digi-
talis will arrest the heart in diastole.19 Arsenic, chloral, atro-
pine, the bromides, aconite, hyoscyamus, creosote, guaiacol,
antipyrin, acetanilid, iodoform — are types of the active drugs
used in practice which, when administered in adequate doses,
do what the current does through the vagus: i.e., inhibit the
heart. Even quinine, one of the safest suprarenal stimulants,
is capable of causing heart inhibition. "The evidence is con-
clusive," says Wood, "that both in man and in the lower ani-
mals quinine in sufficient amount is a powerful depressant to
the heart-muscle and ganglia."

"Both Schroff and Jerusalimsky noticed that the fall of
arterial pressure produced by quinine," continues Professor
Wood, "is preceded by a rise of pressure accompanied by an
increase of the cardiac action. This observation has been con-
firmed by G. See and Bochefontaine; but no observer seems
to have shown that the rise of pressure is more than a tem-
porary phenomenon." The kinship with vagal overstimulation
and the fact that it is but temporary are clearly defined in this
sentence.

The parallelism between excessive vagal action and the
action of drugs on the adrenals is further exemplified in the
following sentence of Professor Foster's: "With a current of
even moderate intensity — such a current, for instance, as would
produce a marked tetanus of a muscle-nerve preparation — the
stand-still is complete, — that is to say, a certain number of
beats are entirely dropped; but with a weak current the in-
hibition is partial only: the heart does not stand absolutely
still, but the beats are slowed, the intervals between them being
prolonged, or weakened only without much slowing, or both
slowed and weakened. Sometimes the slowing and sometimes
the weakening is the more conspicuous result." We have here,
again, the expression of the functional activity of both the
vagus and the suprarenal glands — with fluctuations in their
individual supremacy. This is further illustrated by the fol-
lowing experimental data: "It sometimes happens," says Pro-
fessor Foster, "that, when in the frog the vagus is stimulated

19 H. C. Wood: Loc. cit., 297.

452

THE DYNAMICS OF CARDIAC ACTION.

in the neck, the effect is very different from that just described,
for the beats are increased in frequency, though they may at
first be diminished in force. And, occasionally, the beats are
increased both in force and frequency; the result is augmenta-
tion, not inhibition."

This suggests that confusion must inevitably reign when
it becomes necessary to clinically determine the meaning of
danger-signals, but if the tendency of the adrenals to strengthen
and reduce the pulse-rate, while that of the vagus — under ex-
cessive oxidation — is to quid-en it, is borne in mind, and, fur-
thermore, that weakness of the heart-stroke portrays correspond-
ing weakness of suprarenal activity, no confusion need exist.
Of course, all this rests upon our assertion that oxidation proc-
esses when enhanced by overactivity of the adrenals correspond-
ingly increase the heart-beats. That such is the case may be
illustrated by the following sentence of Professor Wood's in his
section on the physiological action of quinine: "Jerusalimsky
attributes the increase of the pulse-rate to paralysis of the
inhibitory apparatus: a view which is supported by the asser-
tion of Cerna that previous section of the pneumogastric pre-
vents the quickening of the pulse-rate." Our interpretation
of the functions of the vagus does not, of course, harmonize
with the words "paralysis of the inhibitory apparatus," since a
far less complicated process — inordinate activity of the vagal
functions — accounts, according to our view, for the occurrence
of inhibition. Furthermore, we look upon this phenomenon
as pathological and absolutely removed from the physiological
purposes that the words "inhibitory apparatus" imply: a feature
which necessarily emphasizes our belief that no such apparatus
exists. Briefly, the phenomenon generally recognized under
the term "inhibition" appears to us to be accounted for in the
following deductions: —

1. No cardiac inhibitory apparatus exists as a physiological
entity.

2. Active inhibition of the heart may be caused ~by excessive
stimulation of the vagus.

3. Passive inhibition of the heart is primarily due to insuffi-
ciency of the adrenals.

The reasons for this are embodied in the following general

CONCLUSIONS AS TO THE CARDIAC MECHANISM. 453

summary of the functional mechanism of the heart as devel-
oped in the present chapter: —

1. The nervous supply of the heart is derived from the general
motor (sympathetic) and vagus systems.

2. The general motor plexuses and nerves maintain the nor-
mal tonic contraction of the coronaries and other cardiac vessels
and insure distribution of the blood among the muscular elements.

3. The vagal plexuses and nerves incite and govern the rhythm
of the heart, reducing or increasing its beats.

4. Increase of the vagal vibratory rhythm (impulses) causes
quickening of the heart-beats.

5. Excessive vibratory rhythm of the vagus (or spinal ac-
cessory) causes arrest of the heart-beats: i.e., inhibition.

6. Reduction of the vagal vibratory rhythm causes, when phys-
iological, slowing of the heart-beats.

7. Reduction of the vagal vibratory rhythm, when pathological,
especially when due to adrenal insufficiency, results in quickening
and weakening of the heart-beats, through loss of vagal control.

8. Cessation of the vagal vibratory rhythm (as after division
of the vagus on both sides) is followed by marked quickening and
weakening of the heart-beats, through loss of vagal control.

9. The mechanical energy upon which the right heart depends
is of two kinds: (1) the contractile action of the adrenal secretion
brought to it by the inferior vena cava; (2) the continuous action
of the oxidizing substance of the coronary arterial blood upon myo-
sinogen formed from granules fi, the latter being derived from the
liver.

10. The adrenal secretion and the granules (3 enter the right
auricle and the right ventricle with the blood of the vena cava.

11. The adrenal secretion, owing to its direct action on mus-
cular tissue, causes the walls of these cavities to contract alternately
upon their venous contents and to force a small quantity of the latter
into the Thebesian foramina and channels.

12. This blood then penetrates the interfibrillary spaces of
Eenle, — i.e., around the bare muscle-cells, — and its granules {$
are used by the latter to build up their myosinogen.

13. As the plasma of the coronary arteries and their terminals,
the pericellular capillaries of the muscle- elements, contain oxidizing

454

THE RESPIRATORY MECHANISM.

substance, contraction of the muscle-cells is induced as it is else-
where in the organism.

14- The adrenal secretion and the granules fi, which do not
enter the Thebesian channels, are carried to the lungs with the
venous blood of the right ventricle.

15. The mechanical energy of the left heart is supplied (1)
by the oxidizing substance of the arterial blood, which penetrates
its muscular structures and its cavities by the coronaries and the
pulmonary veins, and (2) by an additional supply of myosinogen-
building granules (3 , and perhaps of adrenal secretion, which find
their way to its myocardium through the Thebesian channels that
connect it with the right heart.

16. The manner in which the contractile process is carried
on in the walls of the left heart is similar to that which prevails in
the right heart.

THE ADRENAL AND VAGAL SYSTEMS IN THEIR RELATIONS
TO RESPIRATORY FUNCTIONS.

The role of the suprarenal secretion in respiration, and
particularly the process through which oxygen is taken up by
the blood, was reviewed in the second chapter. We believe that
the succeeding chapters, by affirming the importance of the
oxidizing substance in every part of the organism, have but
confirmed the conclusions reached concerning the process in
question. The fact that the interchange of oxygen and car-
bonic acid between the alveolar air and the blood by mere
diffusion was inadequate to account for the experimental results
of various investigators, particularly Bohr and Haldane and
Smith, has therefore been correspondingly emphasized. We
must also refer to the fact, however, that the belief of Ludwig,
Bohr, and others, that the alveolar tissues might be the seat
of functions capable of fulfilling the missing requirements
of the process, has not been sustained by our inquiry. On the
other hand, the role of the adrenal secretion in the lungs as
we have defined it seems to have supplied these requirements,
notwithstanding the severe tests to which it has been submitted
in previous chapters.

We have seen that the adrenal secretion, conveyed to the
lungs with the venous blood, is not only able to take up oxy-

THE INNERVATION OF THE LUNGS. 455

gen, but to form an oxidizing substance with the latter from
which haemoglobin can, in the lungs, become replenished with
oxygen. The entire set of analyses submitted in this work
so far, however, seem to us to have emphasized another fact:
i.e., that the plasma, and not the corpuscle, is the dispenser of
oxygen, the corpuscle being a mere carrier from which the
plasma itself becomes replenished as needed. As already stated,
this precisely coincides with the conclusion to which Jaquet
was led by chemical methods (see page 134) after Salkowski
(1881) had obtained oxidations from blood alone, which he
attributed, however, to the blood-corpuscles. Abelous and
Biarnes having obtained oxidation of salicylic aldehyde by
means of blood-serww, Salkowski modified his former view and
experimentally confirmed the results of the other investigators.

Finally, we were able to show how closely connected the
suprarenal secretion is with the integrity of the blood, and
how readily the haemoglobin molecule becomes dissociated in
proportion as the efficiency of the adrenals becomes weakened.
We have traced this dissociation down to the last cleavage-
product, haematoporphyrin or haematoidin, the coloring pigment
in bronzing, which corresponds with the lowest stage of adrenal
insufficiency.

The circulatory, nervous, and muscular mechanisms of the
lungs are the remaining features to be analyzed.

THE INNERVATION OF THE RESPIRATORY SYSTEM.

THE IDENTITY OF THE KESPIRATORY CENTER. — The abso-
lute independence of the suprarenal system — the adrenals
receiving their impulses from the anterior pituitary body — is
well illustrated by the following lines by Professor Foster:
"Observations show that under particular conditions, and espe-
cially in young animals, respiratory movements may be carried
out in the entire absence of the medulla oblongata. Thus, if,
in a kitten or puppy or young rabbit, after division of the
spinal cord below the medulla artificial respiration be kept up,
and then pauses be made in the artificial respiration, during
these pauses not only may what appear to be respiratory move-
ments be induced in a reflex manner, by pinching or by blow-
ing on the skin, but, especially if the excitability of the spinal

456 THE RESPIRATORY MECHANISM.

cord be heightened by small doses of strychnine, even spon-
taneous efforts of breathing may occasionally be observed."
. . . "Since in such cases the rhythmically repeated move-
ments of the respiratory muscles are sometimes accompanied
by rhythmic movements of the fore- and hind- limbs not re-
spiratory in nature, it may be doubted whether these experi-
ments really prove the existence of distinct respiratory centers
in the spinal cord/' That the data previously given further
tend to diminish the likelihood that any such center exists
seems obvious.

And still the existence of such a center seems to be sus-
tained by experimental evidence. Thus, division of the cord
below the seventh cervical nerve arrests costal respiration;
section below the medulla causes all thoracic movements to
cease; removal of the brain above the medulla, the seat of the
supposed center, does not stop respiration, while cessation of
this function occurs when the medulla is removed or exten-
sively injured, save in exceptional cases. After reviewing this
evidence Professor Foster adds: "Nay, more; if only a small
portion of the medulla — a tract whose limits have not been
clearly defined,20 but which may be described as lying below
the vasomotor center in the immediate neighborhood of the
nuclei of the vagus nerves — be removed or injured, respiration
ceases, and death at once ensues. Hence this portion of the
nervous system was called by Flourens the vital knot, or gan-
glion of life: noeud vital We shall speak of it as the respira-
tory center."

The first question that suggests itself is the following: Can
the respiratory center be a portion of the vagus center, in the
immediate neighborhood of which it is generally located?
Professor Foster remarks, in this connection: "In attempting
to decide this question we naturally turn to the pneumogastric
as being the nerve most likely to serve as the channel of
afferent impulses setting in action the respiratory center. If
both vagus nerves be divided, respiration still continues, though
in a modified form.21 This proves distinctly that afferent im-
pulses ascending those nerves are not the efficient cause of the

10 The italics are our own.
21 All italics are our own.

THE INNERVATION OF THE LUNGS. 457

respiratory movements/' . . . "One cranial nerve, as we
shall see, is especially concerned in respiration, viz.: the vagus
nerve; but if, after removal of the brain above the medulla,
both vagus nerves be divided, respiration still goes on; indeed,
the respiratory impulses proceeding from the center are, though
in a peculiar way, exaggerated." A feature of the experiments
referred to is that electricity is not in any way stated to have
been used; we are dealing, therefore, with positive facts,
which may be summed up in the statement that division of
the vagus does not arrest respiration. Such being the case, how
can the vagal center be considered as the respiratory center,
or as Flourens's no3ud vital? If removal or injury to the latter
suffice to arrest respiration, section of the vagi should do the
same. Since it does not, it seems obvious that the respiratory
center cannot be vagal, and that the "nceud vital" is not the
respiratory center.

The role of the vagus in pulmonary functions becomes
clear, however, if we grant this nerve functions similar to those
we have found it to fulfill elsewhere: i.e., as companion to the
general motor nerves, and intended to incite and govern the ex-
acerbations of functional activity assumed when from "passive"
the organ's work becomes "active," and to transmit to the bulb
the impulses that bring on the counter-impulses which main-
tain and regulate — temporarily and in lieu of its mate, the
general motor supply — these exacerbations of activity. It
might well be severed under these circumstances without ar-
resting respiration. The general motor fibers would merely
continue their work, though "in a peculiar, exaggerated" way.

If the vagal center is not that which presides over res-
piration, to which portion of the bulb can we ascribe this im-
portant function. With our limited array of nervous systems
to choose from,, we are led to consider the "general motor
center" in toto as a respiratory center. But a curious fact
appears when this question is closely studied: i.e., that what
has been called the "respiratory center" includes the parts of
the bulb which we consider as the "general motor center" and
"the vasomotor center," or rather the area to which the latter
term has been applied.

"The portion of the medulla the removal of which exerts

458 THE RESPIRATORY MECHANISM.

an influence on the blood-pressure, according to Owsjannikow,
extends from a point 4 to 5 millimeters above the point of the
calamus scriptorius to within 1 to 2 millimeters of the corpora
quadrigemina," says Professor Stewart,22 who also remarks
that other observers give narrower limits, and adds: "Stimula-
tion of the medulla causes a rise, destruction of this portion
of it a fall, of general blood-pressure. There is evidently in
this region a nervous center so intimately related, if not to all
the vasomotor nerves, at least to such very important tracts
as to deserve the name of vasomotor center. Experiment has
shown that it is much the most influential center, and it is
usually called the chief, or general, vasomotor center. But
there are subsidiary centers all along the cord, and, while a
very large number of the constrictor fibers are related to the
chief center of the medulla, some are either normally under
the control of subordinate centers or may in special circum-
stances come to be dominated by them." If the floor of the
fourth ventricle is examined, the area comprised between "a
point 4 to 5 millimeters above the point of the calamus scripto-
rius to within 1 to 2 of the corpora quadrigemina" will be
found to include practically all the bulbar nerve-centers, so
that the "vasomotor center" may be said to include the bulbar
origin of practically all nerves.

Again, it is manifest that the term "vasomotor" applies
to nerves distributed to vessels throughout the entire organism:
i.e., wherever terminal arterioles occur. If we now recall our
view that each general motor nerve distributed to a part sup-
plies it with its vasomotor fibers as well as with all others
distributed to it, — unless associated with a special nerve, such
as the vagus, — the deduction imposes itself upon us that the
vasomotor center in the medulla must coincidently be that of
the general motor nerves or at least the region where the
latter assume vasomotor functions.

Even reducing the area represented by the vasomotor
"center" to the narrowest limits recognized by physiologists, it
may conservatively be said to include at least one-half of the
fourth ventricle. If we now ascertain the nerves involved in
this area, the suggestive fact asserts itself that this upper half

a« Stewart: Loc. cit., p. 158.

THE INNERVATION OF THE LUNGS.

459

contains all nerves that possess motor properties. The fol-
lowing list of the seven cranial nerves in the upper half of
the medulla will illustrate the relationship: —

1st pair. Olfactory: No motor function; no bulbar connec-
tion.

2d pair. Optic: Filaments from 3d pair for iris and cil-
iary muscles.

3d pair. Motor oculi: Filaments from corpora quadri-
gemina; supplies collateral fibers to oph-
thalmic ganglion for iris and ciliary muscles.

4th pair. Patheticus: Fibers terminate in corpora quadri-
gemina; supplies fibers that govern superior
oblique muscle.

5th pair. Trigeminal: Upper part of floor and anterior
wall of fourth ventricle. Small root of mas-
ticatory muscles.

6th pair. Abducens: Upper part of floor of fourth ven-
tricle; supplies external rectus muscle.

7th pair. Facial: Upper part of floor of fourth ventricle;
supplies levator palati, azygos uvulae, tensor
tympani, stapedius, and the external mus-
cles of the ear, face, etc.

fc

Again, all nerves that anastomose with motor fibers or
require them in addition to their own are in some way con-
nected with the fourth ventricle: —

9th pair. Glossopharyngeal : Lower part of fourth ven-
tricle. Supplies palatal and pharyngeal mus-
cles, through anastomosis.

10th pair. Pneumogastric : Lower part of fourth ventricle.
Supplies oesophageal, cardiac, gastric, etc.,
muscles, through anastomosis.

llth pair. Spinal accessory: Lower part of fourth ventricle
and cord. Supplies laryngeal, deglutitory,
cardiac, and respiratory muscles.

12th pair. Hypoglossal: Lowest portion of fourth ventricle.
Supplies lingual, masticatory, deglutitory,
etc., muscles.

Still these only represent the motor nerves or motor anas-
tomoses. The t;asomotor connections are not referred to; but,
inasmuch as the vasomotor center has been experimentally
shown to be located in the medulla, it now behooves us to
account for the presence, besides the motor nerves just referred

460 THE RESPIRATORY MECHANISM.

to, of "sympathetic" fibers in some organs. Having totally dis-
connected the suprarenal system (the thyroid, the anterior
pituitary, the splanchnics, and the adrenals) from the vaso-
motor system, the latter, viewed from our standpoint, merely
represents subdivisions of the general motor system at all
times. We are, therefore, bound to point to a vasomotor func-
tion as an attribute of all motor nerves. Of course, the vaso-
motor center being admittedly located in the fourth ventricle
and the table just submitted showing that all motor nerves or
motor connections are related with the same structure, a step
in the elucidation of this point has been made; but we have
still to complete the list by showing that even these apparently
independent filaments also arise from the medulla or cord.

The nerves that receive filaments from the sympathetic
are the 3d, 4th, 5th, 6th, 10th, and 12th. The 3d, or motor
oculi, which supplies several eye-muscles, the circular fibers
of the iris, and the ciliary muscle, receives its sympathetic
filament from the cavernous plexus. The latter can only be
derived in this locality from one of two sources: either the
suprarenal system nervous connections or the spinal cord
through cervical or dorsal nerves (unless conjoined with the
vagal or glosso-pharyngeal roots, which is unlikely). Pupil-
dilating fibers were traced by Sherrington, in monkeys, and
by Langley, in cats and dogs, in the first and second and to
a less extent in the third and fourth dorsal nerves. Onuf and
Collins23 refer to the observations of Miiller in the case of
"a man in whom a lesion could be distinctly located in the
region of the first and second dorsal nerve-roots, and in this
case there was marked contraction of the pupil, ptosis, and
sinking in of the eyeball." They state that the results of in-
vestigators indicate that the pupil-dilating fibers occur with
the greatest constancy in the first dorsal and almost constantly
in the second dorsal, and refer to the fact that Salkowski
placed the origin of these fibers in the medulla oblongata.
Finally they express the opinion that, "although the evidence
is preponderatingly in favor of the existence of a cilio-spinal
center, yet the question has not been definitely settled."

The fourth pair, or patheticus, which governs the action

23 Onuf and Collins: Loc. cit., p. 90.

THE INNERVATION OF THE LUNGS. 401

of the superior oblique muscle, also receives filaments from
the cavernous plexus of the sympathetic; hence its connection
with the medulla through dorsal nerves is as likely as in the
case of the third nerve. The fifth pair, or trigeminal, receives
its sympathetic filaments from the carotid plexus: that con-
nected with the anterior pituitary lobe. Examination of this
communication, however, shows that the cavernous plexus is
the nearer one, and that the connections with it are direct
by two decussating embranchments. Though there would be
no difference as to its functional isolation and its probable
connection with the medulla, — except if electricity be used, —
were its fibers conjoined to those of the carotid plexus (dif-
ferent nerves often following the same path), it is probable
that the sympathetic filaments to the third pair are connected
with the cavernous plexus, and that they are also, therefore,
of medullary origin. The sixth, or abducens, is also stated
to receive its sympathetic filaments from the carotid plexus
through the Vidian, but again is it found on examination that
the Vidian is connected, not with the carotid plexus, but
primarily through a branch which in turn decussates from the
main trunk, — the so-called superior ganglion of the sympa-
thetic,— from which also originates the cavernous plexus. The
twelfth, or hypoglossal, receives its sympathetic branch from
a spot below this and evidently from the same trunk. Hence
the 4th, 5th, 6th, and 12th may be said to be traceable to a
common — and adjoining — source through the original source
of the cavernous plexus: i.e., the cord. Finally the tenth, or
pneumogastric, receives the three cardiac "sympathetic" nerves,
which contribute to the formation of the cardiac plexus. The
origin of these nerves and their motor functions we have
already reviewed.

All these facts seem to us to completely establish the gen-
eral motor system as a functional entity, and to centralize in
the medulla and the cord all the sources of functional motor
activity that depend upon nervous impulses. Inasmuch as it
includes within its manifestations of activity all vasomotor
functions, it seems clear to us that to remove or destroy this
vasomotor area means simply to remove or destroy — what we
may call for the time being — the centers of functional activity

462 THE RESPIRATORY MECHANISM.

of the medulla and upper cord. Still, we have seen that the
vagus cannot be considered as the respiratory center; what
then is there in the medulla that can be termed such? A
moment's reflection will now suggest that there is no such a
center as the respiratory center, and that the morbid phe-
nomena witnessed after section of the medulla are really due
to interruption of the general stream of motor impulses that
the bulb serves to transmit. Neither is the general vasodilation
that is invariably witnessed after section of the medulla due
to interruption of vasomotor impulses per se. There is no
such a "vasomotor" center; and vasodilation is also due to
interruption of the functions of all motor nerves, since it is
these which throughout the entire organism maintain tonic
contraction of the vessels.

We can further sustain this by analyzing the prevailing
view that the "respiratory center" may be stimulated by the
presence of carbonic acid in the blood, and that the vasomotor
center is also directly stimulated by a highly venous blood.
"When by reason either of any hindrance to the entrance of air
into the chest," says Professor Foster, "or other interference
with the due interchange between the blood and the pulmonary
air or of a greater respiratory activity of the tissues, as dur-
ing muscular exertion, the blood becomes less arterial, more
venous, — i.e., with a smaller charge of oxygen and more heavily
laden with carbonic acid, — the respiration, from being normal,
becomes labored. We may speak of normal breathing as
eupncea, and say that this, when the blood is insufficiently
arterialized, passes into dyspnoea, . . ."

The pathogenesis of dyspnoea was referred to a few pages
back. The following lines by the same author will recall some
of the features then referred to: "When a muscle contracts,
its consumption of oxygen and production of carbonic acid,
especially the latter, are increased; the blood leaving the mus-
cle is more venous then usual. Hence, when many muscles
are contracting powerfully, the blood carried to the right side
of the heart is more venous than usual; and we might expect
that it is this unusually venous blood failing to be adequately
arterialized in the lungs, and hence reaching the medulla from
the left side of the heart in a more venous, less completely

CONCLUSIONS AS TO THE RESPIRATORY MECHANISM. 463

arterialized condition than usual, which stirs up the respiratory
center to increased activity. On examination, however, it is
found that the blood leaving the left side of the heart in such
cases is not the less arterialized, but, if anything, more arte-
rialized than usual." . . . "Obviously the blood coming
from the tetanized muscles affects the respiratory center by
virtue of some quality which, unlike that due to the deficiency
of oxygen or excess of carbonic acid, is not immediately affected
by the passage through the lungs. Whether the quality in
question be dependent on an excess of sarcolactic acid, or on
some other product or products of muscular metabolism, we
do not as yet know." It is very clear, from all this, that it
is not the venous blood that reaches the medullary centers
which gives rise to the phenomena witnessed, but the products
of metabolism themselves, which react upon the anterior pitui-
tary body, and through it upon the adrenals, as do other poisons.
Indeed, if we consider the course of events in cases of
asphyxia, — the "general convulsions of the whole body, which,
however, have to a certain extent an expiratory character," fol-
lowed by "exhaustion," which "begins to set in," the rhythm
becoming "slower than proportionate to the weakening of the
individual movements," — the part played by the suprarenal sys-
tem affirms itself, combined with and aggravated by the gradual
decline of all physiological processes that depend upon proper
aeration of the blood. Again, therefore, does the "respiratory
center" in the medulla show itself unable to stand analysis.
Asphyxia, moreover, is not due, evidently, to the action of
C02 upon a medullary center; its active symptoms are due to
intoxication by products of metabolism, while its passive phe-
nomena— air-hunger, cyanosis, etc. — are the result of gradually
declining functional activity. On the whole, the following con-
clusions seem warranted: —

1. There is no individual center in the medulla oblongata to
which the term "respiratory center" can be applied.

2. The morbid phenomena witnessed after section of the me-
dulla are due to interruption of the stream of general motor im-
pulses which the medulla serves to transmit.

3. There is no individual center in the medulla oblongata to
which the term "vasomotor center" can be applied.

464 THE RESPIRATORY MECHANISM.

4- The general vasodilation witnessed after section of the
medulla is due to the interruption of the stream of general motor
impulses through which tonic contraction of the arteries is main-
tained, and which the medulla serves to transmit.

THE INNERVATION OF THE RESPIRATORY MUSCLES.

How, in the absence of a respiratory center, are the re-
spiratory movements governed?

After reviewing the part played hy the muscles involved
in the respiratory mechanism, Foster says: "It is impossible
that all these so carefully co-ordinated muscular contractions
should be brought about in any other way than by co-ordinate
nervous impulses descending along efferent nerves from a co-
ordinating nervous center. By experiment we find this to be
the case. When in a rabbit the trunk of a phrenic nerve is
cut, the diaphragm on that side remains motionless, and res-
piration goes on without it. When both nerves are cut, the
whole diaphragm remains quiescent, though the costal respira-
tion becomes excessively labored."

Even did a "respiratory center" exist, the co-ordinating
impulses upon which the diaphragm depends for its rhythmic
contractions would not be accounted for unless we grant the
phrenic nerve vagal properties: i.e., afferent, as well as efferent,
fibers. The origin of this nerve in no way indicates this to
be the case. In fact, it appears to us only as a secondary nerve,
such as any subdivision of the brachial plexus would be, since
it only arises from a branch of the third, fourth, and fifth
cervical nerves. Yet this very subdivision seems suggestive,
for, if the origin of the phrenic — i.e., its connection with the
third cervical — be closely examined, it will be found to meet,
or inosculate with, a communicating branch of the hypoglossal.
This would place the diaphragm on the same plane, as regards
nervous supply, as the lungs themselves, since it would then
be supplied (1) with general motor fibers, and (2) with hypo-
glossal fibers which immediately adjoin, in the fourth ventricle,
the origin of the vagus. This would fully account for the
co-ordination referred to, and which the phrenic as a mere
motor nerve would not explain were even a respiratory center
present.

THE NERVES OF THE RESPIRATORY MUSCLES. 465

The same dual supply should prevail, however, in the ex-
ternal respiratory muscles. "When an intercostal nerve is cut,"
continues Professor Foster, "no active respiratory movements
are seen in the intercostal muscles of the corresponding space,
and, when the spinal cord is divided below the origin of the
seventh cervical spinal nerve, — that is, below the exits of the
roots of the phrenic nerves, — costal respiration ceases, though
the diaphragm continues to act, and that with increased vigor/7
Again is the co-ordinating factor absent. The twelve inter-
costal nerves are now considered as mere motor nerves and
lack afferent fibers capable of accounting for the impulses that
call forth counter-co-ordination impulses from the bulb. Each
nerve, however, is thought to be accompanied by a filament
from the sympathetic — also an efferent nerve — and occasion-
ally (only on the left side, according to Swan) with commu-
nicating branches from the hypoglossal. We have not met, as
yet, muscles supplied with two motor nerves — excepting when
the associate nerve was vagal. On the other hand, so important
a function as adjustment of the intercostal muscles to corre-
sponding functions would hardly be satisfied by a set of "occa-
sionally present" filaments. We are, therefore, inclined to
consider what is now thought to be "sympathetic" filaments
as themselves hypoglossal filaments, to which the adventitious
ones would stand as anomalous duplications.

Indeed, close examination reveals the following facts:
each intercostal artery receives a vasomotor filament from the
ganglion immediately above it, while each intercostal nerve
receives two thicker branches from the ganglion below it. The
manner in which the decussations occur and the way in which
their distribution is disposed suggest that two nerves, as is the
case higher up, are insheathed in each ganglion. Under these
circumstances, hypoglossal fibers from the medulla would insure
the co-ordinating attributes to the muscles, in conjunction with
the latter7 s recognized general motor nerves, the intercostals —
thus normally accounting for the precision with which the
latter fulfill their functions, which otherwise remains unex-
plained.

That considerable confusion now exists regarding the part
taken by ganglionic branches of communication is suggested

466 THE RESPIRATORY MECHANISM.

by the following quotation from Onuf and Collins's article24:
"According to Gaskell, most of the motor fibers of the rami
communicantes are cerebro-spinal; those of the gray rami com-
municantes, for the most part, sympathetic. Nothing definite
is yet known concerning the mode of origin of the sensory fibers
of the sympathetic system nor of the manner of their connec-
tion with the cerebro-spinal system. Kolliker claims that all
sensory fibers of the sympathetic originate from cells of the
spinal ganglia in exactly the same manner as the sensory fibers
of the cerebro-spinal system."

While a study of the vasomotor functions connected with
the sympathetic nerves, as portrayed in the literature based
on experimental evidence, distinctly indicates that they in-
variably transmit efferent impulses, it is evident that some
fibers supplied by the ganglia experimentally furnish afferent
impulses, — such as their identity as hypoglossal nerves would
involve, — otherwise such authoritative observers as Gaskell and
Kolliker could not have referred to them as sensory fibers.
That the hypoglossal must be the medullary nerve involved is
further shown by the fact, referred to by Foster in the last
quotation, that section of the cord below the origin of the
phrenic nerve — which, as we have just shown, is conjoined with
the hypoglossal — causes costal respiration to cease. As the
hypoglossal, for us, is similar, functionally, to the vagus, the
entire active nervous supply of these muscles had thus been
interrupted.

"When the cord is divided just below the medulla all
thoracic movements cease, but the respiratory actions of the
nostrils and glottis still continue. These, however, disappear
when the facial and recurrent laryngeal nerves are divided."
The co-ordinative attributes of the larynx are self-evident,
since the recurrent laryngeal is a branch of the vagus; but
through what agency are they insured in the case of the
nostrils? The facial is a general motor nerve which acquires
sensory filaments from the vagus and from the fifth pair.
Unless we eliminate the levator anguli oris et alae nasi from
the co-ordinated structures, filaments from the vagus must

2* Onuf and Collins: Loc. cit., p. 13.

THE NERVES OP THE RESPIRATORY MUSCLES. 467

be traced to it, or the nasal branch of the fifth which supplies
the levator muscle must be considered as a factor of the co-
ordinating system. As the latter's motor and sensory roots
are situated in the medulla, there is nothing to militate against
its being considered precisely as is the vagus elsewhere. In-
deed, we are led, by the strict delineations established between
various parts of the organism by the older anatomists, to at-
tach undue importance to names, and the nerve in question
may, while being called "trigeminus," — merely because of its
physical attributes, — be an inherent portion of a general sys-
tem of which other subdivisions called pneumogastric, hypo-
glossal, etc., may form part.

The fact that "when the cord is divided just below the
medulla all thoracic movements cease" implicates all the mus-
cles of the neck and thorax, besides the intercostals, in the
co-ordinative process. The usual separation of these muscles
into two classes, — one for normal respiratory movements, an-
other for excessive respiratory effort, the latter being brought
into action to reinforce the former, — affirms the existence,
beyond mere co-ordination, of a function such as we have
ascribed to the vagus in various organs. The prevailing views
as to the way these muscles take part in the respiratory process
give no clue to the manner in which their functions are ad-
justed to the fluctuating needs of this process, the "respiratory
center" being supposed to supply the required impulses when
need be.

The relationship we have suggested between the phrenic
nerve and the hypoglossal, in the case of the diaphragm, again
shows itself in this connection. As is well known, the phrenic
nerve is also termed the "internal respiratory" nerve by Bell.
If the origin of the "external respiratory nerve of Bell" (the
posterior thoracic) is examined, it will also be found so related
with its mate, particularly at its junction with the fifth cer-
vical, as to clearly indicate a common origin. It is an extensive
nerve, and supplies filaments to each digitation of the serratus
magnus: a "reinforcement" muscle. That ample communica-
tion with the medulla to satisfy the needs of perfect co-ordi-
nation exists is further shown by the fact that communications
also appear through a vagal branch (first cervical), three hypo-
so

468

THE RESPIRATORY MECHANISM.

glossal branches (first, second, and third cervical), and two
spinal accessory branches (second and fourth cervical).

Summarized, the innervation of the muscles of respiration
appears to us to be as follows: —

1. The nervous supply of the respiratory muscles is composed
(1) of divisions of the general motor system, and (2) of divisions
of the vagal system.

2. The divisions of the general motor system are (1) the
phrenic (the internal respiratory nerve of Bell), distributed to the
diaphragm; (2) the intercostals, distributed to the parietes of the
thorax and abdomen; and (3) the posterior thoracic (the external
respiratory nerve of Bell), distributed to the serrati magni.

3. The divisions of the vagal system are (1) the hypoglossal,
distributed to the diaphragm (conjoined to the phrenic) and to the
intercostal and external respiratory muscles (instead of sympa-
thetic); (2) the inferior laryngeal, distributed to the muscles of
the larynx (except the cricothyroid) ; and (3) the superior laryn-
geal, distributed to the cricothyroid muscle.

4. The divisions of the general motor system maintain tonic
vascular contraction in, and nutrition of, the respiratory muscles,
while the divisions of the vagal system incite and govern their
functional and co-ordinative activity.

5. The mechanical energy of the respiratory muscles is the
result, as in all muscular tissues, of a chemical action of the
oxidizing substance of the Hood-plasma upon the myosinogen of
the muscle-cells.

THE NERVO- VASCULAR MECHANISM OF THE LUNGS.

The pulmonary circulation as regards general distribution
is succinctly portrayed in the following description by Miller,25
as given by Bohm and von Davidoff26: "The pulmonary artery
follows closely the bronchi through their entire length. An
arterial branch enters each lobule of the lung at its apex, in
close proximity to the bronchus. After entering the lobule
the artery divides quite abruptly, a branch going to each in-
fundibulum; from these branches the small arterioles arise
which supply the alveoli of the lung. 'On reaching the air-sac

2« Miller: Journal of Morphology, vol. viii, p. 165, 1893.
28 Bohm and von Davidoff: Loc. cit.

THE NERVO-VASCULAR SUPPLY OF THE LUNGS. 469

the artery breaks up into small radicles, which pass to the
central side of the sac in the sulci between the air-cells, and
are finally lost in the rich system of capillaries to which they
give rise. This net-work surrounds the whole air-sac and com-
municates freely with that of the surrounding sacs/ This
capillary net-work is exceedingly fine, and is shrunken into the
epithelium of the air-sacs; so that between the epithelium and
the capillary there is only the extremely delicate basement mem-
brane. The infundibula, the alveolar ducts and their alveoli,
and the alveoli of the respiratory bronchioles are supplied with
similar capillary net-works. The veins collecting the blood
from the lobules lie at the periphery of the lobules in the inter-
lobular connective tissue, and are as far distant from the in-
tralobular arteries as possible. These veins unite to form the
larger pulmonary veins. The bronchi, both large and small,
as well as the bronchioles, derive their blood-supply from the
bronchial arteries, which also partly supply the lung itself.
Capillaries derived from these arteries surround the bronchial
system, their caliber varying according to the structure they
supply: finer and more closely arranged in the mucous mem-
brane, and coarser in the connective-tissue walls. In the neigh-
borhood of the terminal bronchial tubes the capillary nets
anastomose freely with those of the respiratory capillary sys-
tem." To avoid confusion we may recall the fact that, while
the pulmonary artery and its branches contain venous blood,
and the bronchial arteries and their branches carry arterial
blood, the pulmonary veins, on the contrary, contain arterial
blood. When, therefore, bronchial capillaries are said to empty
into the pulmonary veins, it is not used, or venous, blood that
is transferred to the latter, but arterial blood originally derived
from the thoracic aorta or its primary branches.

The innervation of the lungs, as in the extrapulmonary
respiratory structures, consists of vagal and the general motor
nerves. These unite to form plexuses, the anterior and posterior,
which enter the organs with the bronchial tubes and accompany
them along their ramifications. The anterior pulmonary plexus,
made up of vagal and sympathetic filaments, overlies the pul-
monary artery, while the richer posterior pulmonary plexus,
composed also of vagal filaments, intermixed with sympathetic

470

THE RESPIRATORY MECHANISM.

fibers from the second, third, and fourth thoracic ganglia, fol-
lows the bronchi to their ultimate subdivisions. We have em-
phasized the fact that in the heart the vagal fibers served to
regulate the pace of cardiac contractions, and that, while feeble
galvanization or increased adrenal activity, by stimulating the
oxidation processes of the vagal bulbar centers, quickened the
heart-beats, powerful stimulation arrested them. The same
phenomena are obtained under similar conditions in the case
of the lungs. As is well known, section of the vagi in the
neck causes the respirations to fall to four or five a minute;
feeble galvanization accelerates their number, while a suffi-
ciently strong current will arrest the respiratory movements.
Barring the special functional attributes of the heart, which in
certain particulars influence experimental results, all phe-
nomena strictly ascribable to the vagal supply are repeated in
the lungs: a fact which pointedly attests to the similarity of
the nervous supplies of the two organs and to a common origin.
Still, we must not lose sight of the fact that the peripheral
respiratory muscles are the main factors in these phenomena,
and that those with which the lungs per se are concerned have
other objects in view.

In the light of all we have said so far concerning the
active functional role assumed by the vasomotor terminal
branches of general motor nerves, the distribution of vaso-
motor fibers to the terminal arterioles must play a predomi-
nant part in pulmonary functions: one, indeed, of consider-
able clinical importance. Thus, the plexus which overlies the
pulmonary artery and is intermixed with vagal fibers becomes,
when considered from our standpoint, the regulative system
as regards the amount of venous blood allowed to penetrate
the lung. As this blood contains the adrenal secretion, this
vessel becomes, therefore, one of the most important pathways
of the general circulation. This asserts itself when we realize
that it is upon the amount of venous blood driven into the
lungs by the right ventricle, besides the character of this blood,
that the efficiency of the respiratory functions depends. Ex-
cessive activity of the adrenals increases the power of the
heart and vascular tension, the speed of the stream which
traverses the lungs is correspondingly augmented, and con-

THE NERVO-VASCULAR SUPPLY OF THE LUNGS. 471

gestive turgescence of all its vessels must follow. Notwith-
standing the fact that not a drop of blood is added to that
contained in the system, dyspnoea occurs. Dyspnoea also fol-
lows insufficiency of the adrenals, — i.e., of its secretion, — be-
cause this involves in direct sequence imperfect oxygenation
of the pulmonary blood, inadequate oxidation of the cerebro-
spinal centers, relaxation of the vascular channels, etc. Con-
traction and dilation of the vascular channels being of su-
prarenal origin, the vasomotor terminals obviously become
prominent elements of the mechanism. In fact, it is partly
through the intermediary of vasomotor nerves that excessive
or inadequate activity of the adrenals is felt in all parts of
the organism.

That the suprarenal secretion, through which the right
heart is contracted, underlies dyspnoea is well illustrated by
the effects of all drugs that are sufficiently active to markedly
affect adrenal functions. The action of venoms even more
strikingly shows the morbid connection that exists between
the impairment of suprarenal activity and pulmonary func-
tions, even the stage of blood-disintegration being sometimes
reached. Noe,27 for instance, refers to the many observers
who have reported intense respiratory phenomena after cobra-
bites. Viper-venom was also found by Phisalix to produce at
first "accelerated respiration," then "somnolence, with slowing
of respiration." Bee-venom in sufficient quantity gives rise
to dyspnoea, according to Paul Bert, black Wood being found
in the vessels. Toad-, salamander-, scorpion-, and eel- venoms
were found to affect respiration in a similar manner. Mosso
noted that the process of death varied with the dose: medium
doses first arrest respiration, then the heart; stronger doses
arrest both simultaneously. Paralysis of the motor end-plates
had evidently nothing to do with this process, since Mosso
found the thoracic nerves responsive to the induced current.

Eemoval of the adrenals under these conditions should
give rise to phenomena similar to a violent dose of venom.
Cybulski not only observed,28 under these conditions, marked
dyspnoea, a fall of the vascular pressure to zero, and haemo-

27 No6: LOG. cit.

28 Cybulski: Gazeta Lekarska, March 23, 1895.

472 THE RESPIRATORY MECHANISM.

globinuria, but also found that the injection into the veins
of an aqueous 10-per-cent. solution of suprarenal extract "im-
mediately caused these phenomena to disappear." Boinet29
states that after removal of both organs in a large number
of rats the respiration became "slow, painful, and difficult."
Black pigment, ascertained to be similar to that found in the
skin in Addison's disease, was found in large quantities in the
great majority of the animals examined.

Again, the opposite procedure — i.e., the introduction of
suprarenal extract into the circulation — should increase the
activity of the cardiac and respiratory functions. Mankow-
sky30 noted "a great increase in blood-pressure and stimulation
of the cardiac and respiratory centers." This occurred "even
when the animals (dogs) were under the influence of chloro-
form, morphine, or chloral hydrate." "In cats," says Swale
Vincent,31 "by far the most noticeable feature was an enor-
mous rapidity of the respiratory movements in the early stage."
The two — now familiar — stages that occur under the influence
of toxic doses of suprarenal extract, as well as under that of
other poisons, are well illustrated in the following observation
by the same investigator: "In the early stage of poisoning
respiration is quick and shallow and the heart is excited. Sub-
sequently the breathing and heart-beats become feeble, and
finally the respiration is deep and infrequent." Finally, the
fact that all these phenomena are independent of the cord
has been shown by Biedl,32 who, as we have seen, obtained
marked increase of blood-pressure after injections of supra-
renal extract, notwithstanding the fact that all the spinal
structures had been removed. These few illustrations, to which
many could be added, seem to us to conclusively show that in
general toxaemias dyspnoea is primarily due to impaired activity
of the adrenals.

The evidence available that vasomotor nerves are present
in the lungs is exceedingly limited as compared to that re-
corded in relation to their presence in other organs. And still

29 Boinet: Loc. cit.

80 Mankowsky: Russian Archives of Pathol., etc., March,

81 Swale Vincent: Jour, of Physiol., Feb. 17, 1898.

82 Biedl: Wiener klin. Wochenschrift, ix. 1896.

THE NERVO-VASCULAR SUPPLY OF THE LUNGS. 473

the fact that, as in the latter, vagal and sympathetic fibers
are stated by all anatomists to form plexuses as they jointly
enter the lungs obviously suggests that these organs are on
the same plane in respect to our conceptions as any of the
thoracic viscera studied. So generally, in fact, have we found
this inosculation to mean combined and correlated function
that we have been led to believe that in all organs within the
vagal domain general motor functions invariably aim to pre-
serve tonic contraction of arteries and insure adequate nutri-
tion, while vagal functions are as universally intended to incite
and govern the active stage of these functions.

Clinical evidence tends to sustain this view. It seems to
account, for instance, for the following results of section of
both vagi in the neck, as outlined by Sappey33: "Section of
both pneumogastrics in the median portion of the neck not
only abolishes the sensibility of the respiratory mucous mem-
brane and paralyzes the internal respiratory muscles; it also
involves as consequence a mucous effusion into the bronchi,
engorgement of the lungs, emphysema of these organs, and a
very sensible diminution in the number of inspirations/' In-
deed, the three functions we have ascribed to the vagus, sen-
sory, excitomotor, and vasoconstrictor (while its mate, the
general motor, only preserves tonic contraction during passive
function, and thus insures nutrition), are shown to actually
prevail by the results summarized in these few lines. If we
now carry this line of inquiry one step further, and recall the
sudden overwhelming effusions that sometimes appear in pneu-
monia, and also — viewing the question from our standpoint —
the vasodilating effects of declining oxidation processes of vagal
and general motor centers, due, in turn, to rapidly increasing
failure of adrenal functions, it will become apparent that both
systems must be concerned in vasoconstriction. Again, if the
anatomical coalescence of both sets of nerves into plexuses
here as elsewhere indicates correlated functions, the fact that
the sympathetic fibers do exercise vasomotor influence in the
lungs seems suggestive.

The question as to whether vasomotor phenomena actually

83 Sappey: "Traite d'Anatomie Descriptive," vol. iii, p. 397.

474 THE RESPIRATORY MECHANISM.

occur in the lungs remained doubtful notwithstanding the
labors of Brown-Sequard, Hofmokl, Lichtheim, and others,
until 1881, when Frangois-Franck was able to demonstrate a
vasoconstrictor action of the sympathetic nerves distributed to
this organ. Since then Cavazzani, Henriquez, and Rose Brad-
ford and Dean have confirmed the latter investigator's observa-
tions. The experiments of Franc, ois-Franck34 consisted in
stimulating the sympathetic fibers at their entrance into the
organ: i.e., the fibers to which we have applied the term "ex-
trinsic." This investigator found that increase of pressure
occurred above the area stimulated, while decrease of pressure
simultaneously became manifest below the latter. This test,
as is well known, is used to determine the existence of vaso-
motors in other organs. Again, he noted that moderate stimu-
lation of the sympathetic cardio-pulmonary filaments caused
lowering of the pressure in the left auricle and increase in the
pulmonary artery: a result indicating a vasoconstrictor action
upon the intervening vessels.

Further testimony appears when in accord with previously
recorded facts we connect the effects observed, not with the
sympathetic ganglionic chain per se, — the conducting path
from the anterior pituitary to the adrenals, — but with the
spinal cord. The experiments of Eose Bradford and Dean35
are thus referred to by Frangois-Franck: "They carefully
sought the points of emergence, from the cord, of the filaments
which cause elevation of pulmonary pressure and lowering of
aortic pressure: that is to say, pulmonary vasoconstriction.
These were located from the second to sixth dorsal, and, in
respect to maximum effects, on a level with the third, fourth,
and fifth nerves. The pulmonary vasoconstrictors ascend the
chain up to the first thoracic ganglion, where they become de-
tached, to reach the pulmonary plexuses." A suggestive feat-
ure of the topography of these nerves is that the lower limit
of the ganglionic chain through which they pass happens to
be the upper limit of the ganglia from which the splanchnic

84 FranCois-Franck: Lalesque, These de Paris, 1881; and Archives de Phy-
siologic, Oct., 1895.

86 Rose Bradford and Dean: Journal of Physiology, p. 57, 1894.

THE NERVO-VASCULAR SUPPLY OP THE LUNGS. 475

nerves that ultimately carry impulses to the adrenals are given
off..

We thus have considerable testimony, clinical and experi-
mental, in support of the view that the lungs contain vaso-
motor nerves. It behooves us now to delineate, if possible, the
extent to which each system — general motor and vagal — takes
part in the process. The experimental evidence, as we have
seen, only refers to the sympathetic fibers as vasomotors, and
this coincides with anatomical data. Sappey36 studied the dis-
tribution of vagal nerves in the lungs of mammals, including
particularly those of man, the ox, and horse, and reached the
following conclusions: "1. They follow the subdivisions of the
air-tree to their terminal extremities; they do not leave these
subdivisions and follow them to the lobules. 2. All those that
leave the anterior pulmonary plexus and the much greater
number given off by the posterior pulmonary plexus preserve
their plexiform arrangement throughout their entire distribu-
tion; their meshes are elongated only in the line of their axis,
each thus constituting an elongated ellipse. 3. Their ramifica-
tions, essentially destined for the muscular coat of the bronchi
and respiratory mucous membrane, have no connection with
the blood-vessels." Berdal, on the other hand, confirms this,
and indicates the role of the sympathetic terminals in the fol-
lowing lines: "The branches of the pneumogastric are destined
for the bronchi; the branches of the great sympathetic are lost
in the walls of the arteries."

This represents the actual anatomical conditions present,
in the light of available evidence, and there is no ground, even
from the standpoint of our conceptions, to modify them. It
is only when we inquire into the manner in which the two
systems of nerves affect function that present teachings and
our own views differ. Indeed, we have seen that section of
the vagi in the neck caused loss of sensation in the respiratory
mucous membrane, paralyzed the bronchial muscles, and gave
rise to effusion of mucus into the bronchi and engorgement of
the lungs. How can all these phenomena be accounted for
without granting sensory, motor, and vasomotor functions to

86 Sappey: Loc. cit., p. 391.

476

THE RESPIRATORY MECHANISM.

the vagal supply? Loss of sensation points to inhibited func-
tion, and not to engorgement of the bronchial mucous mem-
brane. And yet we may have engorgement without functional
erethism, if it is due, not to the presence of blood fully charged
with oxygen, but to blood which, through the very fact of
being dammed up in the vascular channels, is reduced therein
to practically the condition of venous blood. The effusion of
mucus into the bronchi and pulmonary engorgement would
occur as normal consequences of such a state of things. But
how account for this vascular dilation without granting vaso-
motor attributes to the vagal plexuses? We might incriminate
sympathetic filaments were it not in the neck — i.e., above the
spinal embranchments — that the vagus was cut. But no error
is possible; section of the vagus alone gives rise to the phe-
nomena mentioned. It is the terminals of this nerve, there-
fore, that are alone in question, and the loss of the impulses
which they transmit to the subepithelial vessels is accountable
for their occurrence.

Again, one of the results of section is "paralysis of the
bronchial muscles." Vasomotor nerves, even apart from our
own views, are recognized factors of the circulation of any tis-
sue. We have proof of vasodilation in the effusion and pul-
monary engorgement as a result of the vagal section. Now,
coupling this with the mass of evidence we have submitted
that vasoconstriction is the primary factor of functional ac-
tivity, how can we account for the paralysis of the bronchial
muscles without granting the vagus terminals vasoconstrictor
functions? Again, the fact that cutting of both nerves in the
neck gave rise to paralysis of these muscles points to another
suggestive feature, namely: that the vagus must incite and
govern the motor impulses to these muscles, besides presiding
over the functional variations of caliber of their vessels. If
we now add to these manifestations of efferent nervous activity
those of afferent activity suggested by the loss of sensation
over the bronchial mucous membrane, it seems clear that we
have in the vagal nerves referred to an autonomous supply espe-
cially devoted to the functions of the bronchial tubes and their
ramifications down to — but not including — the pulmonary lobule.
The importance of this fact asserts itself when we realize that

THE NERVO-VASCULAR SUPPLY OP THE LUNGS. 477

it accounts for the complete isolation of bronchial affections
from those of the parenchyma, and gives us a clue to their
original cause, as we will see later on.

That the structures beyond the domain of the vagus have
their own independent mechanism hardly needs to be empha-
sized by physiological experimentation, so great is the differ-
ence between the clinical phenomena witnessed when the lob-
ules themselves are involved in the morbid processes. The
old and dreaded "capillary bronchitis" normally assumed a
pathological status in nomenclature more in keeping with its
true identity when it became known as "broncho-pneumonia/'
Even this term may become obsolete when the link with its
next of kin, lobar pneumonia, will be better understood.

Again, a familiar histological fact will serve to show — in
the light of our views — how definite is the association between
physiological function and disease as manifested in this lobular
individual system: The infundibuli, as is well known, are fre-
quently clearly denned by blood-pigment deposits in the con-
nective tissue that separates the lobules. This is because, as
we have shown, this is the region where the haemoglobin con-
stituents find their binding substance: the suprarenal secre-
tion. We have seen the effects of violent toxics — venoms, for
instance, — on the blood. The Martinique fer-de-lance viper so
thoroughly overcomes suprarenal functions as to give the blood
the appearance of "prune-juice." What have we in the "rusty,"
or "prune-juice," expectoration but signs of impaired activity
of the adrenals? We shall see that each has its meaning in
this particular, and that each represents a stage in the morbid
process, but a stage in which the adrenals play the leading
part. And so can the hyperleucocytosis, the fibrinous "exuda-
tion," the oedema to which we have referred, etc., be traced to
the adrenals: overactive at first, then insufficient and perhaps
altogether arrested when the general toxemia — not alone that
due to toxins derived from the Friedlander pneumococcus, but
to any other germ capable of sufficiently undermining supra-
renal functions, through its toxins — has reached an advanced
stage.

If, therefore, we have isolated the vagal field, it is all the
better to emphasize the overwhelming importance of that part

478 THE RESPIRATORY MECHANISM.

of the pulmonary structures which belongs to the domain of
the suprarenal glands — and to the vasoconstrictor nerves that
govern the flow of venous blood which carries their secretion
to the pulmonary lobules.

If we now retrace our steps, a corresponding identity of
the two blood-systems, the bronchial and the respiratory, will
assert itself. The bronchial arteries follow the subdivisions of
the bronchi, but only as far as the lobular bronchiole. The
terminal arteriole does not penetrate the lobule, but furnishes
branches to the pulmonary connective tissue, to the lymphatic
ganglia, and to the pleura. This appears to us as an impor-
tant feature in pathogenesis: The bronchial arteries supply
the blood upon which the parenchyma depends for its oxidiz-
ing substance. Insufficiency of the adrenals, therefore, by re-
ducing the oxidation processes correspondingly reduces the nu-
trition of the pulmonary tissues: a predominating feature of
phthisis.

The pulmonary artery — that containing the adrenal secre-
tion in its venous blood — also closely follows the bronchi and
their subdivisions, and only leaves them at the terminal bron-
chiole, where the alveolar ducts begin and subdivide into the
capillary net-works which closely enmesh the alveoli. The net-
works thus formed are the closest in the organism. The re-
turn arterialized blood passes into the venules, which carry it
to the pulmonary veins: the channels directly connected with
the left auricle.

The veins of the bronchial system, however, do not return
their blood, as do similar vessels in other parts of the organism,
along the path of their arteries. The capillaries which are
distributed to the connective tissue and lymphatic structures
between the lobules, etc., return their blood to the superior
vena cava by the bronchial veins of the venas azygos, but those
which end at the alveoli anastomose with capillaries derived
from the pulmonary venous tree. Their blood is thus mixed
with that of the lobular capillaries, and is returned to the heart
with the — now arterial — blood of the pulmonary vein.

We thus have two distinct vascular systems: the bron-
chial, the arteries of which supply blood to the bronchial and
peribronchial structures; and the respiratory, the vessels of

THE NERVO-VASCULAR SUPPLY OF THE LUNGS. 479

which solely subserve the process through which venous blood
is converted into arterial blood and are therefore distributed
to the lobules.

If we now inquire into the nature of the nervous mech-
anism through which their functions are governed, we are led
— in the light of our own views — to an interpretation similar
to that found to satisfy the needs of other organs. The com-
parison of a pulmonary lobule to a racemose gland is some-
times met with in text-books; examination of a lobule soon
shows that its structures sufficiently correspond to that of the
glandular organs we have studied to enable us by analogy to
ascertain the nature of its relations with nerve-terminals.
Miller, we have seen, refers to the "exceedingly fine capillary
net-work shrunken into the epithelium of the air-sacs so that
between the epithelium and the capillary there is only the
extremely delicate basement membrane" Again, he refers to
the subdivision of the pulmonary artery "which divides quite
abruptly, a branch going to each infundibulum"; from the
latter "small arterioles arise which supply the alveoli/7 while
these on reaching the air-sac are said to culminate in "the rich
system of capillaries to which they give rise." The italicized
words but repeat what we have emphasized elsewhere as the
integral constituents of all glands. As will be shown later on,
however, the alveoli present histological features which further
emphasize their identity as parts of an autonomous system.

There is but one feature wanting to complete the mechan-
ism common to glandular structures: i.e., the delicate nerve-
terminals distributed to the lobular cells. "The final ter-
mination of the nerve-filaments within the pulmonary tissue
is still undetermined," says Piersol; but under precisely similar
morphological conditions elsewhere in the organism terminal
fibrils have been clearly discerned. That the pulmonary lobule
should represent an exception to the rule is hardly probable:
a view indirectly sustained by the prevailing belief that the
mucous surfaces contain "secretory fibers." We have seen
that Frangois-Franck, Cavazzani, Henriquez, Rose Bradford,
and Dean have ascertained that vasomotor phenomena pre-
vailed in the lungs under stimulation. The implied presence
of this class of nerves completes the list of structures that

480 THE RESPIRATORY MECHANISM.

enter into the functional mechanism of other organs; it seems
to us to warrant the deduction that the pulmonary lobules
do not differ from the latter either in the manner in which
their functional activity is governed or in the processes through
which they are supplied with mechanical energy.

But we must lay special stress upon the important func-
tional connection that exists between the pulmonary lobule
and the right heart. Indeed, we must not lose sight of the
fact that venous blood is distributed to the lobules. This
venous blood, brought to them by the pulmonary capillaries,
only contains adrenal secretion, obviously incapable of insuring
functional metabolism of the lobular epithelium. But how,
then, is this secured? The answer is not difficult to find after
all we have said regarding the processes that obtain in the
right myocardium. Indeed, we have in the pulmonary alveolar
walls precisely the conditions that prevail in the cardiac wall:
i.e., the granules ft and the oxidizing substance of arterial blood.
While the granules ft also emanate from the liver, and repre-
sent the bulk of those unused in the right heart, the oxidizing
substance, instead of being supplied by the coronary, as in the
heart, originates from the vessels to which we have already
referred: i.e., the bronchial terminal arterioles. This anastomo-
sis between the bronchial and pulmonary systems is a generally
recognized fact; but its vast importance does not seem to us
to have ever been suspected.

May the secretion of the adrenals also produce contractile
effects upon the lobular walls? The wealth of elastic fibers
in the latter suggests that such might be the case, the purpose
being to maintain their tone and insure resiliency after unusual
dilation. As we will see in the twelfth chapter, the adrenal
secretion is active in various ways in this location.

Collectively considered, however, the various elements of
the process may be said to distinctly show that respiration, as
regards its chemical phenomena, starts in the adrenals and
ends in the pulmonary lobules, with the inferior vena cava, the
right heart, and the pulmonary artery as mechanical inter-
mediaries, and thus constitutes an autonomous system.

The following deductions appear to us to embody the
principal facts developed in the present chapter as regards the

THE NERVO-VASCULAR SUPPLY OP THE LUNGS. 481

nervo-vascular mechanism of the lungs and the respiratory
process: —

1. The nervo-vascular functional mechanism of the lungs
consists of two autonomous, though correlated, systems: the re-
spiratory and bronchial.

2. The respiratory nervo-vascular system is composed of: —

(a) The pulmonary lobules, in the walls of which the blood
is oxygenated.

(b) The pulmonary artery and its subdivisions, which bring
venous blood, adrenal secretion, and granules (3 to the capillaries
of the lobules.

(c) The pulmonary venules and veins, which return the
arterialized blood to the heart.

(d) The general motor nerves and plexuses (sympathetic),
which govern the functions of the foregoing structures and the vaso-
constriction of all vessels of the pneumo-respiratory system.

8. The bronchial nervo-vascular system is composed of: —

(a) The bronchial arteries, which, by their oxidizing sub-
stance, sustain functional energy and metabolism in: (I) the in-
terlobular cellular tissue and its lymphatic vessels and glands, the
blood thus used passing to the vence azygos, by the bronchial veins,
thence to the superior vena cava; (II) the bronchi, the terminal
ramifications of which only reach to the exterior of the lobules, but
anastomose with the pulmonary capillaries of the latter.

(b) Vagal nerves and plexuses, which supply sensation to the
bronchial mucous membrane, incite and govern its secretion and
the vasoconstriction of all vessels of the bronchial system.

4- The process through which functional energy is supplied
to the lobular structures (epithelium, basement membrane, and
vascular walls of the lobules) to compensate for the absence of
oxygen in the blood brought to them by the pulmonary artery is
as follows: The oxidizing substance in the blood of the bronchial
terminal branches which anastomose with the lobular capillaries,
meets the granules ft contained in the blood of the latter; oxida-
tion of the granules ensuing, functional energy is liberated, as it is
elsewhere in the organism.

5. The functional oxidation process through which the right
heart is supplied with mechanical energy is repeated in the pulmo-
nary lobules, and there is some ground for the belief that the con-

482 THE RESPIRATORY MECHANISM.

tractile effects of the adrenal secretion on the myocardium are
reproduced in the pulmonary lobules, the abundant elastic filters
of the latter acting as contractile elements.

6. The respiratory interchanges that occur in the lobules rep-
resent the end-result of a process which includes: —

(a) The production of the adrenal secretion, which provides
the blood with its affinity for oxygen.

(b) The admixture of granules f$ to the venous blood of
the inferior vena cava, to insure, with the arterial blood of the
coronaries, the oxidation processes through which the right heart
acquires its mechanical energy.

(c) The motor functions of the right heart.

(d) The vasomotor functions of the pulmonary artery and
its ramifications.

(e) The admixture of the arterial blood of the bronchial ter-
minal artery to the venous blood of the pulmonary capillaries as
these reach the lobule.

(f) The oxidation of the granules ft in the pulmonary cap-
illaries by the oxidizing substance in the blood derived from the
bronchial vessels.

(g) Conversion of the venous blood, as it courses through the
lobular capillaries, into arterial blood.

CHAPTER X.

THE POSTERIOR PITUITARY AS THE FUNCTIONAL
CENTER OF THE NERVOUS SYSTEM, AND
AS THE ANTERIOR PITUITARY'S CO-
CENTER IN SUSTAINING THE
VITAL PROCESSES.

THE IDENTITY OF THE LOWER BRAIN, OR CENTRAL
NERVOUS SYSTEM.

IN the ninth chapter we ventured to suggest that none of
the medullary nervous centers could be considered as "inhib-
itory" or "respiratory" in the physiological sense now accorded
these terms, and we stated that the phenomena ascribed to
these centers were regarded by us as (1) the result of excessive
(and therefore pathological) stimulation of the vagus as re-
gards cardiac inhibition, and (2) of the interruption of general
motor impulses which the medulla serves to transmit, in re-
spect to the respiratory phenomena. Paradoxical as the state-
ment may seem, our views are confirmed by the investigations
of the brothers Weber (1845), who first suggested that the
heart could be "inhibited" by stimulation of a corresponding
medullary center. Their experiments differed from those we
have reviewed in that the cerebro-spinal structures themselves
were submitted to the effects of the current, thus concentrat-
ing the latter upon the areas in which the "inhibitory" centers
were supposed to exist. One pole having been placed in the
nasal cavity of a frog and the other on the spinal cord over
the fourth or fifth vertebra, the heart's action momentarily
ceased, then gradually resumed its normal activity. Approxi-
mation of the poles upon the cerebral hemispheres and stimu-
lation of the cord produced no effect upon the heart. "Not
until the medulla oblongata between the corpora quadrigemina
and the lower end of the calamus scriptorius was stimulated,"
says Professor Porter, "did the arrest take place. Cutting
away the spinal cord and the remainder of the brain did not
alter the result." Our views are likewise sustained by the
effects of experimental injury of the medullary area which
Flourens termed le nceud vital, or "ganglion of life."

si (483)

484 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

Galen had already noticed that death ensued when a cer-
tain spot in the floor of the fourth ventricle close to that
which is now known as the center of the vagus was injured.
But Legallois and Flourens have added much to our knowl-
edge of its physiological relations, and the spot in question,
as we have seen, is still considered as the respiratory center.
"The results of various investigations show, however," says
Eeichert,1 "that Flourens's area, as well as certain other parts
of the medulla oblongata that have been looked upon by others
as being respiratory centers, are not such, but are largely or
wholly collections of nerve-fibers which arise chiefly in the
roots of the vagal, spinal accessory, glosso-pharyngeal, and
trigeminal nerves, and which, therefore, are probably nerve-
paths to and from the respiratory center. Moreover, excita-
tion of the "nceud vital" does not excite respiratory movements,
but simply increases the tonicity of the diaphragm; nor is the
destruction of the area always followed by a cessation of res-
piration. While the precise location of the center is still in
doubt, there is abundant evidence to justify the belief in its
existence in the lower portion of the spinal bulb." That we
are again dealing with the aggregate of centers to which we
have referred as the "vagal system" is clear. Indeed, Flourens
located his "vital knot" in an area five millimeters wide be-
tween the nuclei of the vagus and spinal accessory nerves —
again in the lower end of the calamus scriptorius : i.e., a region
comprised in the area to which the Weber brothers applied
one electrode, the other being in the nose, when cardiac arrest
or inhibition was first observed by them.

An interesting relationship seems to us to exist between
these two sets of experimental results. Indeed, the area to
which we refer as that of the "vagal system" thus becomes the
source of antagonistic effects involving the same structures: i.e.,
the Weber brothers caused arrest of the heart by overstimula-
tion (not "inhibition" considered as a physiological function)
in the manner defined in the preceding chapter, while the le-
sion produced by Flourens in the same area, when sufficiently
severe, arrested the flow of impulses to and from the heart.

1 Reichert: Loc. cit., p. 456.

THE LOWER BRAIN.

485

Flourens's noeud vital, therefore, is no more the respiratory
center than the area traversed by the current can be called
an "inhibitory" area. We are simply dealing with the results
of two morbid factors: overstimulation (Weber) and inter-
ruption (Flourens) of physiological — and therefore functional
— impulses transmitted through the medulla and the cord.

In the fifth chapter reference was made to the fact that
the posterior pituitary lobe alone, as shown by Howell, con-
tained an active principle. This lobe, the "infundibular," has
long been termed the "neural" portion of the whole organ,
and appears to us to anatomically present features that sug-
gest a direct connection between it and the cerebro-spinal
centers. Hence the use of the words "physiological impulses
transmitted through the medulla and the cord." The question
becomes all the more worthy of a searching inquiry inasmuch
as a casual examination of the mutual relations, anatomical
and physiological, of the cerebral structures traversed by the
current in the experiment of the Weber brothers suffices to
show that the elements thus submitted to excessive stimulation
coincide with those which would normally fall under the in-
fluence of the posterior pituitary body.

The physiological characteristics of the parts influenced
by the current must first be ascertained. In the frog, the dis-
tance between the nose and the medulla being very short, a
current would implicate all elements in its direct path, con-
sidering the character of the structures traversed. In this
animal, the lizard, etc., the nasal nervous terminals, the tissues
about the floor of the median ventricle and the habendula,
appear to us as the paths that would be involved. In man the
distance between the olfactory area or the nasal subdivisions
of the fifth pair and the medulla is also relatively limited, and
the intervening structures are of such a nature as to also allow
the current to pass uninterruptedly in a straight path. But the
floor of the median or third ventricle, which in its anterior
portion overlies the base of the skull and is very thin, becomes
what appears to us the inevitable path of free conduction, owing
to this proximity of the olfactory bulb and the trigeminal nasal
terminals, to the medullary centers. Of special interest to us,
however, is the fact that in man (and to a great extent in the

486 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

frog) the first structure reached by the current after the nasal
structures would be the infundibular portion of the third ven-
tricle: i.e., that connected with the posterior pituitary lobe.
Again, and very suggestive, is the fact that these structures and
all those falling in the line of the current form part of what
Professor Foster terms "in point of origin the oldest part of
the brain" and "the central gray matter" which "seems to
serve chiefly as a bed for the development of the nuclei of
the cranial nerves." Indeed, we might add that, according
to Eeichert,2 "one center has been located in the rabbit in the
tuber cinereum, which has been named a polypnceic center
because, when excited, the respirations are rendered extremely
frequent." . . . "Another area has been located in the
optic thalamus, in the floor of the third ventricle; this center,"
says the author, "is believed to be excited by impulses carried
by the nerves of sight and hearing, and when irritated causes
an acceleration of the respiratory rate."

The more dorsal portion of the current would strike a
no less important physiological region. "Next to the central
gray matter," says Professor Foster, "and more or less asso-
ciated with it, comes what is called the tegmental region, of
which the reticular formation coming into prominence in the
bulb and continued on to the subthalamic region, forms, as it
were, the core. Belonging to the tegmental system are nu-
merous masses of gray matter from the conspicuous optic
thalamus and the red nucleus in front to the several nuclei of
the bulb behind. This complex tegmental system, which may,
perhaps, be regarded as a more or less continuous column of
.gray matter, comparable to the gray matter of the spinal cord,
serves as a sort of 'backbone to the rest of the central nervous
system"

The morbid effects of the current become normal conse-
quences when we consider that the structures traversed by it
include those that even emotions will disturb. Referring to
the posterior portion of the pons, that adjoining the tissues
that form the fourth ventricle and which represents the down-
ward continuation of the tegmentum, Professor Duval says:
"It is, indeed, to the pons that we seem to be authorized to

3 Reichert: Loc. cit., p. 457.

THE LOWER BRAIN.

487

attribute the most important role in the greater emotional
expressions, laughing and weeping, cries of pain: in a word,
involuntary manifestations." That the structures such as
those penetrated by the current should be suddenly jarred and
forcibly thrown into vibratory conditions entirely foreign to
their normal vibratory rhythm is manifest. That such jarring,
especially when the current follows axially a direction opposite
to that of a physiological stream of impulses, should so per-
vert its normal influence upon the organs to which these im-
pulses are normally distributed — heart, lungs, stomach, etc. —
as to temporarily or permanently arrest their functions is not
only logical, but in accord with the known effects of electricity
upon the more highly developed structures.

And we can also doubtless better understand why respira-
tion still continues very much as usual after removal of the
brain above the medulla, and why, indeed, all nervous mani-
festations other than ideation can persist after such mutilation.
While there is no "nceud vital" or ganglion of life, in the sense
given these words by Flourens, — i.e., in the spot of the medulla
where injury arrests respiration, — and the area so injured is
not "the mysterious seat of the unknown principle of life,"
there is, nevertheless, in this location, not a locus minus
resistentice, but an aggregation of nervous paths from all di-
rections, which an injury can functionally impair or destroy,
according to the quantity of tissue involved and the kind of
lesion produced. Flourens doubtless caused death; but in
looking for death in his experimental animals he doubtless did
not treat the "nceud vital" with the gentleness of a dove.
Death ensued — the result of conditions similar to those pro-
duced by the Weber brothers with electricity in the sense that
molecular disturbance was produced. Yet the Weber brothers
only jarred the naso-bulbar structures, and produced temporary
inhibition of cardiac action; being more diffuse, the current
spread over greater bulbar surface and did less injury. Flou-
rens's puncture, on the contrary, produced an organic lesion,
capable not only of destroying the tissues involved, but also of
annulling, by the circumferential compression of the neighbor-
ing elements caused, the functions over which the latter preside.
Even the process of repair, which at once begins under such

488 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

conditions, may lead to a fatal issue, the infiltration throttling,
as it were, the paths to and from organs through which life is
sustained. When we consider the small relative size of the
fourth ventricle, and the fact that the so-called "vital knot"
is located in an area which may be computed only by a few
millimeters; when we furthermore recognize that such an
injury would thus include the vagal, spinal accessory, glosso-
pharyngeal, and hypoglossal within its radius of morbid in-
fluence, death as an injury to the spot becomes a normal con-
sequence. The heart and the entire respiratory system — to
refer only to those directly concerned with life's processes — •
are the mechanisms first functionally arrested.

And yet while obstruction of these few square millimeters
of bulbar elements will rapidly destroy life, it is possible, says
Professor Foster, in the case of some animals "to remove the
cerebral hemispheres and to keep the animal not only alive,
but in good health for a long time — days, weeks, or even months
after the operation!"

There must prevail in this connection, however, another
contradictory interpretation of experimental phenomena. In-
deed, how can we reconcile the presence of motor centers in
the cerebral cortex with the ability of an animal from which
both hemispheres have been removed to execute the motions
ascribed to these areas? That an animal deprived of its
hemispheres will do this is graphically shown in the following
lines of Professor Foster's: "We may, perhaps, broadly de-
scribe the behavior of a frog from which the cerebral hemi-
spheres only have been removed by saying that such an animal,
though exhibiting no spontaneous movements, can by the ap-
plication of appropriate stimuli be induced to perform all, or
nearly all, the movements which an entire frog is capable of
executing. It can be made to swim, to leap, and to crawl.
Left to itself, it assumes what may be called the natural
posture of a frog, with the forelimbs erect, and the hind-limbs
flexed, so that the line of the body makes an angle with the
surface on which it is resting. When placed on its back, it
immediately regains its natural posture. When placed on a
board, it does not fall from the board when the latter is
tilted up so as to displace the animal's center of gravity; it

THE LOWER BRAIN.

489

crawls up the board until it gains a new position in which its
center of gravity is restored to its proper place. Its movements
are exactly those of an entire frog except that they need an
external stimulus to call them forth/' It is quite clear that
all motor phenomena are carried out, notwithstanding the ab-
sence of parts of the brain which have been undeniably shown
by experiments in animals, pathological conditions of the
human hemispheres, etc., capable of inciting them. The familiar
convulsive movements in various parts of the body, trunk, leg,
arm, etc., when certain motor areas are stimulated would mean
nothing to us if the use of electricity for this purpose were the
basis of this doctrine, but lesions in these areas have unquestion-
ably proven that they do preside over motor functions, not only
in a general way, but in the sense implied by "cerebral localiza-
tion." How account for the self-evident discrepancy which the
entire absence of these structures indicates in present concep-
tions of the processes involved?

We are brought nearer to a solution when the removal of
cerebral tissues — those to which we have referred as jarred
by the electric current passed by the Weber brothers between
the nose and the bulb — is continued downward until the cord
only is left. "Very marked is the contrast," says Professor
Foster, "between the behavior of such a frog which, though
deprived of its cerebral hemispheres, still retains the other
parts of the brain, and that of a frog which possesses a spinal
cord only. The latter when placed on its back makes no at-
tempt to regain its normal posture; in fact, it may be said
to have completely lost its normal posture, for even when
placed on its belly it does not stand with its forefeet erect, as
does the other animal, but lies flat on the ground. When
thrown into water, instead of swimming it sinks like a lump
of lead. . . . When a board on which it is placed is in-
clined sufficiently to displace its center of gravity it makes
no effort to regain its balance, but falls off the board like a
lifeless mass." Such a frog moves its limbs irregularly, but
one has but to witness such motions to at once conclude that
they are aimless, mere random expressions of the inherent
power to contract possessed by all muscular tissues, and which
even persist some time after death, especially in the case of

490 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

the heart-muscle. Very marked is the contrast, indeed, be-
tween this animal and one still endowed with the tissues of
the base of the brain. "Pigeons, for instance, have been kept
alive for five or six weeks," says the same author, "after com-
plete removal of the cerebral hemisphere with the exception
of portions of the crura and corpora striata immediately sur-
rounding the optic thalami." . . . "In warm-blooded ani-
mals, as in the more lowly cold-blooded frog, the parts of the
brain below or behind the cerebral hemispheres constitute a
nervous machinery by which all the bodily movements are car-
ried out/'3

That this mechanism is located below the hemispheres in
man has also been illustrated by many cases reported, among
which may be cited the famous crow-bar case, in which, "by
a premature explosion of gunpowder, an iron bar three and
a half feet long, one and a quarter inches in diameter, and
weighing thirteen and a quarter pounds, was shot completely
through a man's head, and perforated his brain. This man
walked up a flight of stairs after the accident, and gave his
account of how it happened. Although his life was naturally
despaired of for some time, he developed no paralysis; nor did
marked impairment of his intellectual faculties follow conva-
lescence. Eventually he recovered his health. Twelve years
elapsed before his death, during which time he was a laborer
on a farm."4 It is thus evident that, in the entire animal scale,
the hemispheres are functionally dependent upon some comple-
mental function located in the base of the brain — in the region
through which the Weber brothers passed their heart-inhibiting cur-
rent: i.e., the central gray matter lining the neural canal.

A remark which in this connection is of particular inter-
est to us is that of Professor Duval, when, referring to the
meaning of bulbar functions, according to modern conceptions,
he says: "For the physiologist, the medulla extends above the
limits of the vertebral column into the cranium and about up
to the sella turcica." We would say into the sella turcica, for
it seems clear to us that the posterior pituitary lobe presents
the functional characteristic that would fulfill the requirements of

« The italics are our own.

* A. B. Ranney: "Lectures on Nervous Diseases."

MEDIAN AND VERTICAL SECTION CF A THREE
MONTHS' EMBRYO, [Ue]erine,]

1, .aqueduct of Sylvius. 2, Medulla Dblongata. 3, Central
Canal, 4, Infundibulum and Pituitary Ha dies [the latter have
been added to the original], 5, Optic Thalamus, B, Fourth
Ventricle,

THE LOWER BRAIN.

491

the complemental processes that the functions of the hemispheres
demand.

The annexed colored plate, which represents a median and
vertical section of the encephalon and bulb of a three months'
embryo, distinctly indicates the direct continuation of the
cord up to the posterior or infundibular pituitary lobe. The
tract connected with the posterior pituitary is colored bluish
gray. The pituitary has been added to the infundibular ex-
tremity of the original illustration. The relations of the
structures which ultimately become the corpora quadrigemina
by meeting the posterior part of the third ventricle are well
shown.

That our views in this connection are based on a solid
foundation is further sustained by the painstaking investiga-
tions of Andriezen,5 who traced a direct connection between
the pituitary and the medullary and other more anterior struct-
ures through the various phylogenetic stages of vertebrates.
The following statements and the table appended are quoted
from his paper: "A survey and investigation based on all
classes of vertebrates show that the hypophysis occupies the
position and relationship to the other structures which may
be condensed in the following table: —

"RELATION OF PITUITARY TO OTHER NERVE-CENTERS AND
HEAD- STRUCTURES IN ORDER FROM BEFORE BACK.

Nerve-center.

Olfactory center.

Posterior lobe of
pituitary.

The bulbo-spinal
centers.

Nerves.

Olfactory nerves.

Hypophyseal
nerves.

Bulbo-spinal
nerves.

Distribution.

Epithelium of na-
sal sac.

Pituitary duct
gland (anterior
lobe).

Buccal, etc., and
general subcu-
taneous.

Body-region.

Pre-oral fprosto-
mial).

Oral.

Post-oral (bran-
chial, etc.) and
general body."

•Andriezen: British Medical Journal, Jan. 13, 1894.

492 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

Of course, this applies to both pituitary bodies, but we
have shown that the anterior pituitary as the source of the
nervous impulses transmitted through the splanchnics was in
reality a nerve-center; and we have further referred to the
fact that the pituitary as a whole has long been associated
with the nervous system by anatomists, and particularly with
the "sympathetic" system by Bourgery and Hirschfeld. That
the investigations of Andriezen should have borne but little
fruit, so far, is probably accounted for by his statement that
"variations in weight bring it under the Darwinian law of
panmixia; if so, the indication being, what study of lower
vertebrates shows, namely: that it has probably passed the
acme of its activity and in man is functioning less vigorously."

We must express our belief, however, that, when man is
in question, cessation of natural selection may not always mean
that an organ has become useless, but instead that it has
reached the acme of perfection. Loss of functional vigor may
denote, in this connection, what it denotes in the human hand
as compared to that of the gorilla: i.e., gain in functional
precision and delicacy.

In the embryo, the posterior pituitary body opens directly
into the third ventricle through the infundibulum. If during
uterine existence "the whole life-achievement of myriads of
generations of living things" is represented, the phylogenetic
history of this organ should show traces of its ultimate func-
tions. Andriezen found that in the amphioxus its analogue
is represented by "a subneural glandular organ, a duct lined
by ciliated epithelium which affords a communication between
the buccal and neural cavities, and a group of nerve-cells
around and at the back of the upper opening where the duct
widens into the ventricular cavity." We have here the main
primitive structures of the pituitary in man.

Referring to Andriezen's investigations, Berkley6 says:
"He has farther shown that particles of carmine, suspended
in the water surrounding the animals, will be taken up with
the water passing through the infundibular duct and carried
by ciliary action into the ventricle, and thence into the central

« Berkley: Brain, Winter, 1894.

HISTOLOGY OF THE POSTERIOR PITUITARY. 493

canal of the cord; finally the particles of carmine may be traced
right up to the free end of the canal, where the spinal cord
opens into the exterior by the blastopore; therefore it is made
manifest that the infundibular duct carries a stream of oxygen-
bearing water for the nutrition of the tissues and the carrying
off of their effete products." Alluding to personal studies to
which we will presently refer, Berkley then adds: "It is quite
curious to find essentially the same structures preserved in as
high a vertebrate as the dog, and descending to so low a zoolog-
ical order as amphioxus, though, as Miiller remarks, the pitui-
tary is practically the same from myxine to man" Yet in man
the infundibular orifice is closed, and the posterior pituitary,
during its evolution, must, therefore, have assumed some func-
tion other than that possessed by the organ during the earlier
phases of its career and of which the earlier forms should also
show traces.

We have seen that oxygenation of the blood, the highest
development of the function carried out by the water-vascular
system in the amphioxus, belongs to the domain of the ante-
rior pituitary. The remaining inference afforded by the
phylogenetic history of the organ, therefore, is that the pro-
spective posterior pituitary body is represented in the amphioxus
and amoccetes by the group of nerve-cells around and at the ~back
of the upper opening, where the duct widens into the ventricular
cavity.

We must state that we consider this perfect concordance
between the functions of the anterior and posterior pituitaries
as we have conceived them and those found throughout the
entire evolutional scale of zoological forms as far back as the
amphioxus by Andriezen as very strong evidence that our views
are sound.

THE HISTOLOGY AND PHYSIOLOGY OF THE POSTERIOR
PITUITARY BODY.

What is the physiological relationship between the two
lobes? Dejerine7 states that vertical and horizontal sections
of both organs show that they are absolutely distinct and sepa-

7D6jerine: "Anatomic des Centres Nerveux," vol. i, 1895.

494 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

rated by a fibrous lamina; and, furthermore, that "the poste-
rior lobe alone is connected with the infundibulum." . . .
"It is developed from the brain" and "is a dependence of the
middle ventricle." The anterior lobe is only connected with
the cerebral structures through vessels which, according to
Berkley,8 "directly pass into it from the substance of the in-
fundibulum." The blood-supply of the posterior lobe is also
derived from the same source, but it is less rich, though suffi-
ciently so to satisfy the needs of an active function. Indeed,
the organs differ mainly in the character and wealth of their
nerve-supply — much to the advantage of the posterior lobe,
however. The development of the anterior lobe from the
ectoderm of the primary oral cavity, instead of, as in the case
of the posterior lobe, from the embryonic brain, accounts for
what anatomical dissimilarities prevail.

The histological characteristics of the posterior lobe also
suggest that it is the seat of some nervous function of a high
order. This is well illustrated by the exhaustive study by
H. J. Berkley9 after an examination of some two thousand five
hundred slides. A summary of such a work hardly does it
justice; we must therefore refer the reader to the original
paper for details other than those that we will presently sub-
mit.

The outer layer of the organ was found by Luschka and
Miiller to be composed of gray matter similar to that found
over the infundibulum. Berkley refers to this layer as com-
posed of slightly irregular ependymal cells three or four deep,
through which rather thick ball-tipped filaments penetrate to
the second anatomical subdivision of the lobe. This outer
coating of cells does not extend around the entire lobe, how-
ever, but covers only its free, or posterior, surface. Its ante-
rior portion, that nearest the partition between the two lobes,
has no such covering, so that its elements appear to be in con-
tact with the partition itself or to be only separated from it
by its capsule. The second subdivision of the posterior organ
occupies, judging from Berkley's drawings, about one-third of
its mass, and recalls, as to structure, that of the anterior lobe.

•Berkley: Brain, Winter, 1894.
» Ibid.

M

VERTICAL SECTION DF THE POSTERIOR PITUITARY
BODY, [Berkley.]

Somewhat diagrammatic to indicate various types of cells.
Its normal size is that of a small pea.

[Brain.]

HISTOLOGY OP THE POSTERIOR PITUITARY. 495

Again do we find the closed glands, or alveoli, including the
colloid substance. Again are the glandular elements supported
by connective-tissue trabeculaB permeated with capillaries,
though the caliber of the larger vessels is somewhat smaller.
Yet — a feature which seems to us important — the colloid
alveoli are always most numerous near the outer edge of the
ependymal cells, that portion farthest away from the inter-
lobular partition, while the space between these structures and
the partition is occupied by cellular elements of an entirely
different kind.

The third portion may be said to occupy nearly two-thirds
of the entire lobe: a perfect maze of nervous elements, some
of which have not so far been found elsewhere in the organism.
Yet connective-tissue partitions carrying blood-vessels are dis-
cernible throughout this entire area: a feature which suggests
that an orderly subdivision exists. Its nervous elements vary
greatly in form, but they may be divided into three general
classes: 1. Cells that give off protoplasmic extensions, neu-
raxons, etc., that are not sufficiently long to reach the upper,
anterior region of the lobe: t.0., the infundibular region. 2.
Cells the extensions of which reach this region. 3. Cells that
are found mainly or only in this portion of the organ.

The first class includes flask-like cells with knot-tipped
fibers that recall those of the anterior lobe (Fig. A, Plate I,
and Fig. a, Plate II). These bodies are widely distributed,
but their multitude of ramifications end freely among neigh-
boring structures. Similar, though smaller, cells (Fig. B, Plate
I, and Fig. &, Plate II) are found chiefly in the center, and
have processes that extend upward a considerable distance and
there often terminate in a brush-like figure. In this class may
be included peculiar oval bodies (Fig. (7, Plate I, and Fig. c,
Plate II), mainly found in the center of the organ, that recall
closed follicles. They give off axis-cylinders that coil about
them irregularly, and fibers which terminate either in irreg-
ular figures resembling combs with knob-tipped teeth or in
cat-o'-nine-tail-like tufts. Neuroglia cells, especially those of
the mossy kind, are shown in Fig. d, Plate II, while spider-
cells (Fig. E, Plate I, and Fig. e, Plate II) are mainly found
where the nerve-cells are very numerous: i.e., the anterior third

496 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

of the lobe. The spider-cells, however, which only differ from
those found in the cerebral tissues by their larger size in pro-
portion to the length of their tentacles, outnumber the other
cells as the upper infundibular region of the lobe is reached.

The cells included in the second class are all, as stated,
distinguished by one or more protoplasmic extensions, which
insinuate themselves between all the elements intervening be-
tween their starting-point and the infundibular area referred
to, where they break up into figures. The lowermost of
these, the ganglion-cells shown in Fig. F, Plate I, and Fig. /,
Plate II, exemplify this type very well, since their extensions
traverse the entire organ in an upward direction and end in
the upper infundibular area. Higher up in the organ large
pyramidal and oval cells are found (Fig. G, Plate I; Fig. g,
Plate II; and g, Plate III), the terminal subdivisions of which
break up into exceedingly fine feathery filaments. The only
axis-cylinder of this cell, after distributing a few branches to
neighboring elements, continues upward and subdivides, when
near the upper margin of the infundibular region, into a com-
plex net-work which entwines the alveoli found there. A third
type, characterized by short dendrites and many hair-like
processes (Fig. jET, Plate I, and Fig. h, Plate III), is found
throughout the entire nervous area and also gives off one long
dendrite, which extends a long distance upward and forward;
this extension may possibly reach the infundibular region or
its neighborhood. Coming from every direction, these long
dendrites seem, at any rate, to point all toward this one region.
The other dendrites are short and distinguished by the pres-
ence of more or less numerous hairy processes, while some of
the terminal ramifications are ball-tipped — suggesting a pos-
sible identity as collectors of energy, which, transformed in the
body of the cell, is directed upward by the long dendrites.

In the infundibular region of the lobe — i.e., the cellular
elements of the third class — the final ramifications of the long
dendrites form an extremely complex aggregation of tufted
figures, wavy threads, and feathery protoplasmic ramifications.
In the midst of this maze of nervous elements certain cells are
to be found, the like of which Berkley has not been able to
detect in any part of the central or peripheral nervous system.

VARIOUS TYPES DF CELLS IN THE POSTERIOR
PITUITARY HOUY, [Berkley,]

[Brain.]

HISTOLOGY OP THE POSTERIOR PITUITARY. 497

They are small and round, and give off strong dendrites, which
appear knotted or covered with thorns, giving them a "prickly
appearance" (Fig. J, Plate I, and Fig. /, Plate III). Another
variety found in abundance in this region is a small cell with
a rich, apical tuft of fine, wavy processes. They are also dis-
tributed in the midst of a net-work of varicose nerve-fibers
(Fig. K, Plate I, and Fig. fc, Plate III) in the upper and near
the anterior border of the lobe "along the space formerly occu-
pied by the infundibular duct." As already stated, the spider-
cell is to be found in great abundance in this locality, which,
added to the other two varieties of cell, gives us three main
cellular elements as representatives of the class of cells found
mainly or only in the upper infundibular region of the organ.

What is the nature of the organ's functions? That it is
not a secreting organ seems obvious; there is no evidence that
it contains ducts. May it produce an internal secretion? The
vascular channels, intrinsic and extrinsic, are smaller than
those of the anterior lobe, and the latter does not produce an
internal secretion. Such being the case, — notwithstanding its
far greater vascular supply and a much less complex nervous
organization, — it is not likely that its mate, the posterior lobe,
should be the seat of such a secretory function. Indeed, the
embryological development of the latter and its anatomical
relations disprove this completely, while they pointedly sug-
gest a marked kinship with the anterior lobe as to intrinsic
function: i.e., as a center for the conversion of chemical energy
into mechanical energy, — a perfectly logical deduction when we
note the presence of the same closed glands, or alveoli, includ-
ing the colloid substance, and their close anatomical relation-
ship. Indeed, everything tends to suggest that, what the ante-
rior pituitary body is to the adrenals, the posterior pituitary
body is to the general nervous system.

And, yet, what is the connecting structure between the
posterior pituitary body and the parts to which, under such
conditions, its energy would be supplied? There is no evi-
dence, according to Berkley, that any of the nervous elements
of the infundibular lobe itself pass beyond its limits into the
infundibulum. His histological work shows that, while "all
the axis-cylinder processes and the long dendrites have a gen-

498 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

eral tendency upward and forward, both dendrites and neu-
raxons branching as they proceed onward, all traces of the
dendrites of the inferior and median cells of the lobe are lost
some little distance below the superior edge." After an allu-
sion to the vessels and fibrillated tissues that connect the in-
fundibulum with the posterior lobe, he says, "the whole ar-
rangement of the structures of the infundibulum" is "here
altered"; then, referring to both lobes, — i.e., the hypophysis,
— remarks, "elsewhere it shows no break in the described ar-
rangement, the line of differentiation between hypophysis and
infundibulum being sharply drawn, a layer of coarse connective-
tissue bundles being placed between and separating the gland-
ular and other structures of the pituitary from the tissues of
the infundibulum." It is clear that discontinuity of tissue is
a necessity in this location: a suggestive point in itself, since
Nature does not take such pains to isolate adjoining structures
without an object.

Notwithstanding this striking autonomy of the organ,
there are several features in its histological make-up that may
enable us to detect the connecting-link between it and the in-
fundibular structures. Berkley refers to the "outer lamina
of slightly irregular ependymal cells (Fig. M, Plate I) three
or four deep, arranged after the manner of the cuticular epi-
thelium"™ This lamina, which older anatomists considered
as a continuation of the ventricular gray substance, only covers,
we have seen, the free portion of the posterior lobe and is not
continuous with the infundibular ependyma. Again, "there
are seen, extending from the thin capsule surrounding it"
(here Berkley alludes to the capsule that surrounds the entire
posterior lobe), "numbers of rather thick varicose threads, all
unbranched, and invariably ending, when their terminations
can be discovered, in a ball-shaped figure, at a definite line in
the substance of the body, usually at the inward ending of the
first layer of epithelial cells, at the line of separation from
the more centrally situated elements. These knobby threads,"
he says, "strongly resemble the ependymal glia-cells of em-
bryonic life, and possibly may be related to them; but, as their

10 All italics are our own.

tfARIDUS TYPES DF CELLS IN THE ANTERIOR AND
POSTERIOR PITUITARY BODIES, {Berkley.]

Figs, h, ], k, and g : Cells in the Posterior Pituitary Body, Fig.l: Portion
of Glandular Elements of the Anterior Pituitary Body,

{Krai,,.}

HISTOLOGY OF THE POSTERIOR PITUITARY. 499

basal end is shrouded in a blackened aggregation of cellular
masses, their histological origin must remain a matter of some
uncertainty."

If, with these histological data before us, we examine
Plate I, a suggestive fact asserts itself: i.e., that the lamina
of ependymal cells referred to forms a skull-cap-like covering
for the second, or secretory, portion of the posterior lobe. The
glandular alveoli of the latter, with their colloid substance,
are, therefore, in the best possible position for the reception
of any nervous impulse that the ependymal cells may be able
to transmit outwardly. This is emphasized in Plate I, which
shows that this layer exactly covers the entire surface of the
secretory region without reaching beyond its limits. The se-
cretory region of the posterior lobe thus seems to be held in
the grasp, as it were, of its ependymal covering, which in turn
contains the nervous, "rather thick, varicose threads." This
suggests that the capsule may not be the insignificant structure
it is now thought to be. Even the fragmentary data we have
concerning it tend to indicate that it plays an important role
in the functions of the organ.

Mere protective structures are usually detached without
much difficulty from the underlying tissues; Berkley states,
referring to the posterior body: "This lobe is so strongly ad-
herent to the dura that it pulls out of the rest of the pituitary
body in removing this with the brain, unless the membrane
is dissected with it from the base of the skull." Since the
capsule is the part of the lobe so strongly connected with the
dura, it must as firmly adhere to the layer of ependymal cells
beneath; otherwise efforts at removal would tear it away from
the latter. This firm hold of the capsule on the cellular layer
is fully accounted for by the thin, fibrous partitions the former
sends through the latter, but this in itself suggests an intimate
relationship between capsule and cellular layer, especially since
the "blackened aggregation of cellular masses," referred to
by Berkley, which form the basal extremities of the nervous
"threads," all terminate in what appears to be, in his draw-
ings, thickenings in the capsule proper. That such a relation-
ship between the capsule and the nervous elements must exist
is further shown by his reference, in the descriptive text of the

32

500 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

illustration, to the "capsule of the lobe thickened in places,
•from which extend threads that end in knobs," etc. That the
varicose threads and the capsule are structurally continuous,
the latter thus dipping, through a multitude of protoplasmic
projections, into the deeper elements of the lobe is evident.

We have, we think, firmly established the relationship
between the anterior pituitary and the adrenals, through nerves
at present considered as appurtenances of the sympathetic sys-
tem. That the anterior lobe contains but one kind of nerve
connected with this function — besides its vasoconstrictors — is
shown by the following statement of Berkley's: "In the gland-
ular portion of the body, nerves, other than those belonging
to the sympathetic system, are not found. They are very
fine varicose fibers, with numerous ramifications and branchlets
coming off from the main stems at a right or slightly obtuse
angle." These fibers must, therefore, represent, considering
their relation with the suprarenal system, not terminals of the
connecting nerves and distributors of energy, but collectors of
energy, which the organ's cells have converted into mechanical
energy: i.e., impulses for the adrenals. If Fig. I in Plate III,
which represents a section of the glandular portion of the
anterior lobe, is consulted, it will be seen that these nerves
present the two main characteristics of the capsular threads
of the posterior lobe: i.e., they are also varicose and their tips
are likewise knobbed. Since, therefore, the nerves so disposed
in the anterior pituitary are collectors of energy, the varicose
and knobbed threads of the capsules of the posterior pituitary
must also ~be collectors of energy. This is further sustained by
the analogy between the two organs to which reference has
already been made.

That a direct nervous connection between the posterior
pituitary and the infundibular tissues, etc., exists by way of
the capsule of the former is apparent. This makes it possible
for impulses generated in the depths of the lobe to reach the
ventricular structures, irrespective of the sharply defined con-
nective-tissue separation between the lobe proper and the in-
fundibulum. Indeed, such a, separation seems a necessity, in-
asmuch as an impulse, transmitted through the intermediary
of the capsule must, owing to the skull-cap shape of the latter,

PHYSIOLOGY OF THE POSTERIOR PITUITARY. 501

come from every part of the underlying structures and only
reach the cerebral elements through paths that are continuous
with the capsule's tissues. Again, the organ's vessels penetrate
it by way of the infundibulum; the vasomotor supply of these
vessels requires protection from the powerful stream of im-
pulses to which the organ's intrinsic structures give rise. That
a profuse padding of cellular tissue is Nature's resource under
such conditions is well illustrated by the following remark of
Dejerine's: "The vessels of the central nervous system are
surrounded by two sheaths of a different kind: the internal
is connective in nature and belongs to the mesodermic layer;
the external, neurogliar in nature, is developed at the expense
of the external, or ectodermic, layer."

Berkley, referring to the various cellular structures in the
deeper portion of the lobe supplied with long extensions, says:
"The axis-cylinder extensions of all the cells in the inferior
portion of the lobe turn upward. . . . Those belonging
to the larger proportion of the smaller cells of the superior
border turn upward and intermingle with the marginal fiber
net-work. . . . All the axis-cylinder processes and the
long dendrites have a general tendency upward and forward,
both dendrites and neuraxons branching as they proceed on-
ward: but all traces of the dendrites of the inferior and median
cells of the lobe are lost some little distance below the superior
edge, and then the neurons only are intermingled with the
extensions of the smaller superficial cells, passing them, how-
ever, before the border is finally reached, where they spread
out into a most extensive fret-work of fine varicose fibers, still
retaining something of their previous longitudinal arrange-
ment from the threads of the uptending fibers being coarser
than the lateral and intermingling branches. It is doubtful
whether any of these fibers pass beyond the limit of the lobe
into the infundibulum; our sections give no evidence of such
an arrangement." This upward tendency of all cells, and the
evident concentration of their functional activity at the upper
extremity, seem to us to further emphasize the identity of the
posterior lobe as a powerful source of energy. Its junction
with the end of the infundibulum becomes, under these cir-
cumstances, the normal pathway for all the energy that the

502 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

organ can accumulate. Capsule and protoplasmic extensions
or processes all serve a similar purpose, but the neck of the
organ is its own functional limit.

We must not lose sight of the fact, however, that other
nerves penetrate the organ. Berkley says, in this connection:
"while, on the other hand, the nerve-fibers accompanying the
larger arteries are sometimes distinctly seen coming from the
infundibular tract into the body of the posterior lobe of the
gland and ramifying through it." That there is no connection
between these and the nervous structures previously described,
however, is shown by the additional statement: "Connections
between the fibers of the vascular supply and the nerve-cells
of the organ we have never been able to observe. That these
are the nerves through which the organ receives its own func-
tional energy — i.e., the impulses to its vessels and alveoli, —
as in the case of other organs, is probable."

The prevailing view that the embryonal supporting sub-
stance of the brain and spinal cord, the ependymal neuroglia,
almost entirely atrophies and disappears in the adult mammal
would tend to counteract our belief that the capsule and its
underlying structures are important factors of the posterior
lobe's functions. Berkley, alluding to the writings of various
observers in this connection, and referring to the infundibulum
and other tissues of the third ventricle which he had just
described, says: "After reading these statements, it was some-
thing of a surprise to find the above-described beautiful spec-
imens of several types of ependymal neuroglia extending from
all portions of the middle and inferior regions of fhe cavity of
the third ventricle and reaching to the periphery, all portions,
bodies, branches, tentacles, and subpial endings being readily
distinguishable. The region examined is, therefore, very in-
teresting not only from the great variety of neuroglia-cells
that may be seen within a very limited area, but from the
fact that varieties of the ependymal neuroglia-cells, previously
supposed to have entirely disappeared from the central nervous
system in the adult mammal, are found present in perfect con-
dition in the brain of a very high order of animal, and are not
confined, as has previously been supposed, to those of adult reptiles,
amphibia, and fishes"

. PHYSIOLOGY OP THE POSTERIOR PITUITARY. 503

If all the data we have submitted are considered collect-
ively, it seems to us that the following conclusion is warranted:
Removal of the hemispheres in an animal does not arrest its power
to execute normal bodily movements under external stimulation,
because these movements are dependent upon functional structures
situated in the lower part of the brain and in the spinal cord and
which the posterior pituitary body governs.

Of course, this appears to contradict at once a great mass
of experimental and clinical testimony, but the contradiction
is only apparent. Eemoval of the motor region in the rabbit
gives rise to no detectable differences in the movements; the
injured animal is similar to an intact one. In the dog, the
same procedure, says Professor Foster, causes "loss or diminu-
tion of voluntary movement in the corresponding part of the
body"; but this is only temporary, and the animal may re-
cover to such a degree that the temporarily paralyzed limb
cannot be told from the normal one. Careful examination of
the brain. after death shows that no regeneration of the lost part
had occurred. Even removal of the whole motor area causes
no appreciable difference between the movements of the two
sides of the body to a casual observer. In the monkey the
results have been unequal: "While in some instances recovery
of the movement has, in the monkey, as in the dog, after awhile
taken place, in other instances the 'paralysis' has appeared to
be permanent." . . . "The facts, however, within our
knowledge relating to the permanence of the effect are neither
numerous nor exact enough to justify at present a definite
conclusion," says Professor Foster. "On the other hand, the
positive cases, where recovery has taken place, are of more
value than the negative ones, since in the latter the recovery
may have been hindered by concomitant events of a nature
which we may call accidental." We might add that a single
case of recovery in the monkey, when the motor area has been
completely removed, demonstrates that, generally speaking,
the structures are functionally similar in all higher animals,
including man, judging from such instances as the crow-bar
case, or one reported by Brown-Sequard,11 in which an entire

"Brown-Sequard: SocigtS de Biologic, 1876.

504 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

lobe was destroyed and in which the only symptoms were
amaurosis and slight headache. This emphasizes the identity
of the cerebral hemispheres as an aggregate of centers which
record impressions and are the seat of reason, intelligence, and
volition, but it also suggests that the word "motor" is only
applicable in its literal sense to the areas in the lower cerebral
mechanism: i.e., the intermediary through which the mandates
from the hemispheres are executed.

We have previously referred to the misleading information
afforded by the use of electrical stimulation. Nowhere in the
organism does this seem to be more applicable than to the
brain. This feature and the complexity of the processes in-
volved are fully emphasized in the following lines of Professor
Foster: "Some writers appear to entertain the conception that
in a voluntary movement, such as that of the forelimb, all
that takes place is that the 'will' stimulates certain cells in
the cortical area, causing the discharge of motor impulses along
the pyramidal fibers connected with those cells, and that these
motor impulses travel straight down the pyramidal tract to
the motor fibers of the appropriate nerves, undergoing pos-
sibly some change at the place in the cord where the pyramidal
fiber makes junction with the fiber of the anterior root, but
deriving their chief, if not their whole, co-ordination from the
cortex itself: that is to say, being co-ordinated at their
starting-point. That such a view is untenable and that the
simplicity of the electrical phenomena is misleading are shown
by the following two considerations, among others: On the
one hand, as was shown in a previous section, the co-ordination
of movements may be carried out apart from the cortex,
namely: in the absence of the hemispheres; and we can hardly
suppose that there should be two quite distinct systems of co-
ordination to carry out the same movement: one employed
when volition was the moving cause, and the other when some-
thing else led to the movement. On the other hand, the
analogy of speech justifies us in concluding that the cortical
processes do take advantage of co-ordination effected by the
action of other parts of the nervous system."

Referring directly to the general character of the processes
involved, Professor Foster says: "Hence, while admitting, as

PHYSIOLOGY OF THE POSTERIOR PITUITARY. 505

we must do, that in the intact animal the cortical area and
pyramidal tract play their part in carrying out voluntary
movements, their action is not of that simple character sup-
posed by the view referred to above. On the contrary, we are
driven to regard them rather as links — important links, it is
true, but still links — in a complex chain. As we have already
urged, we may probably speak of the changes taking place in
the pyramidal fibers as being, on the whole, of the nature of
efferent impulses; but we would go beyond ike evidence if we
concluded that they were identical with the ordinary efferent im-
pulses of motor nerves"™ All the features emphasized in
these quotations, especially in the last lines, appear to us to
isolate the hemispheres from the source of motor impulses per
se, and to confirm what experimental evidence obtained after
removal of the hemispheres had suggested: i.e., that the lower
cerebro-spinal structures constitute the executive intermediary
through which the cortical mandates are actively realized.
Yet, as is well known, these lower structures, in turn, manifest
their activity through the centers imbedded in them; what is
there to replace the energy in the form of motor impulses
which is erroneously supposed to be awakened by the "will" in
"certain cells of the cortical area"?

Professor Foster partially answers this question when he
says: "The discussion in a previous section has shown that
much of the co-ordination of the body is carried out by the
middle portions of the brain, and on these the motor area
must .have its hold as on the spinal mechanisms. The details
of the nature of that hold are at present unknown to us." It
would appear from the facts reviewed that what might be
termed the central brain and the spinal cord constitute an
entity — a mechanical entity, perhaps — made up of working
centers, beginning with the olfactory bulb and the other nerv-
ous structures distributed to the nasal mucous membrane
anteriorly, and terminating with the end of the spinal cord:
i.e., the neural tract of lower forms. Motility, unconscious co-
ordination, and sensation — but only, in the case of the latter,
to the extent of transmitting sensory impressions to their re-

13 The italics are our own.

506 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

spective perception-centers — would enter within the scope of
this central brain.

As to the source of the transmitted energy or impulses, —
apart from the sensory connections with underlying structures
which the cortex possesses, — the predilection of most writers
to ascrihe to the cortical areas motor functions but demon-
strates the need of such an agency to logically account for the
phenomena witnessed. To ascribe to the central brain or its
centers per se attributes of a similar kind would simply amount
to shifting to it a convenient, but unknown, quantity, and a
fictitious one besides, in the sense that it supplies nothing to
account for something. In the only nervous system that we
have so far traced to its origin, that of the suprarenal glands,
the conversion of chemical energy into nervous impulses was
found to be a functional attribute of the anterior pituitary
body. That so extensive a system as that represented by the
central brain and cord should likewise need a center such as
that represented by the posterior pituitary body for the con-
version of some form of energy of external source to satisfy
the needs not only of its efferent, but also its afferent, im-
pulses seems clear.

That the middle brain is the source of the motor phe-
nomena witnessed is not only suggested by the fact that nor-
mal muscular contractility promptly recurs after removal of
the hemispheres, but also by the following experiment by
Professor M. Duval: "If a part of the gray substance of the
cortex designated as the center of certain movements is cau-
terized, the same movements are obtained when the electrodes
are applied upon the eschar thus produced. . . . This
experiment shows," says the author, "that the gray cortical
substance is not a necessary experimental condition for the
production of localized movements." Indeed, he states that
the underlying white substance of certain parts will also cause
circumscribed motions in certain groups of muscles, etc.

Can the removal of the cortex of one side be followed by
the assumption of compensative functions by the opposite side ?
After the usual period of paralysis, due to shock, the normal
motions promptly recurred, precisely as they had on the other
side. To ascertain whether the cortex at all possessed motor

PHYSIOLOGY OF THE POSTERIOR PITUITARY. 507

attributes Vulpian passed an electrode through it, that part
in contact with the cortex being insulated. The underlying
white substance was thus alone stimulated. He found that
the latter was far more easily excited than the cortex. It
seems clear that in these experiments the increased excitability
was due to the closer proximity of the central brain. "All the
functions of the brain can persist," says Brown-Sequard, "after
the complete destruction of an entire lobe."13 Experimental
and clinical evidence, however, only eliminate motility and co-
ordination from the hemispheres. The cortex, as regards cere-
bral localization, merely loses the "motor" attribute suggested
by the term "motor area," and is shown, by its functional
relations with the underlying structures, to be a vast sensitive
surface, to the "areas" of which the term "sensory" might be
more fittingly applied.

The practical bearing of this may be illustrated by an
experiment that will recall some of the familiar features of
the earlier portions of this work and at the same time point
to the central brain as the source of motor phenomena. This
experiment, referred to by Professor Foster, is as follows: "It
has been observed that in certain stages of the influence of
morphine the cortex and the rest of the nervous system are
in such a condition that the application of even a momentary
stimulus to an area leads not to a simple movement, but to a
long-continued tonic contraction of the appropriate muscles."
This, we now know, is due to suprarenal overactivity induced
by the drug. Cerebral hyperaemia, we have seen, is the source
of the majority of phenomena that follow the ingestion of
drugs that are sufficiently active to stimulate the adrenals.
The intense headache of quinine and other agents is obviously
due to this congestion of the cerebral vessels; muscular con-
tractions, tetany, etc., are also familiar results of suprarenal
overactivity; indeed, digitalis, one of the most active supra-
renal stimulants, is particularly active in predisposing muscles
to contraction and in experimental animals suitably dosed a
minimal current without the drug will produce maximum effects

"M. Duval: Loc. cit., p. 115.

508 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

— prolonged tetany — with it. Strychnine is even more pow-
erful in this particular, as is well known.

In the course of the statements to which we have referred,
Foster, after ascribing the temporary paralysis observed after
operative interference to a condition "of the nature of shock,"
remarks: "But, even giving full weight to this consideration,
there remains the fact that the cortical area is associated with
various co-ordinating and other nervous mechanisms belonging
to the limbs by such close ties that these are thrown into dis-
order when it is injured. And, side by side with this, we may
put the remarkable fact, previously stated, that during an
abnormal condition of the cortical area — stimulation of the
area — instead of producing the appropriate movements confined
to the limb may give rise to movements of other parts cul-
minating in epileptiform convulsions."1*

If the word "associated" is given its full meaning, limbs
and co-ordinating mechanism constituting one class, and the
cortical surface the other, the hemispherical mantle of gray
matter being considered solely as a great sensory surface, the de-
mands of experimental evidence seem to us to be satisfied.
What are epileptic convulsions after all but manifestations of
excessive motor activity? . . . Can the latter be credited
to the cerebral cortex, as is now taught in text-books? Ob-
viously not, since experimental evidence proves that the cortex
has no motor properties per se. But irritation of this sensory
surface or an accumulation of physiological toxics, which peri-
odically becomes sufficiently great to so stimulate the supra-
renal system as to cause violent hypera3mia, not only of the sen-
sory cortex, but also of its executive mechanism, the middle
brain, are the clearly defined causes to which physiological and
chemical evidence points. Could the cortex without the middle
brain give rise to the same phenomena? That such is not the
case is shown by the preservation of all motor functions, in-
cluding co-ordination, after removal of the hemispheres. In-
deed, it is only when the middle brain is removed that the
experimental animal thus deprived of its sentient cortex and
of its dynamic center practically loses its identity as a living
thing. Hence it seems clear that the motor phenomena caused

14 All italics are our own.

PHYSIOLOGY OP THE POSTERIOR PITUITARY. 509

by stimulation of the motor areas of the cortex are manifestations
of activity of the lower or central brain, incited therein ly sensory
impulses from these cortical areas.

What constitutes this middle brain? The co-ordination,
so evidently preserved in animals deprived of their hemi-
spheres, points to the cerebellum as a possible member of the
group of organs to be considered in this connection. Includ-
ing this organ, therefore, and beginning with the anterior
structures, we would now have: the posterior pituitary body;
the infundibulum; the central gray matter, forming "a bed
for the development of the nuclei of the cranial nerves"; the
tegmental system, — i.e., the reticular formation in the medulla
continued to the subthalamic region, and to which belong the
red nucleus and other bulbar nuclei. All this forms what
Professor Foster characterizes as "a more or less continuous
column of gray matter" connected with the spinal cord by
various ties, besides being, as it were, "a continuation of the
spinal gray matter." It is as evident that the optic thalami and
corpora quadrigemina are also members of the group, since
these related organs appear to be necessary for the success of
the experiment in which both cerebral hemispheres are re-
moved. Thus, referring to the frog, Foster says: "In this
animal it is comparatively easy to remove the cerebral hemi-
spheres, including the parts corresponding to the corpora
striata, leaving behind, intact and uninjured, the optic thalami
with the optic lobes, the representatives of the corpora quad-
rigemina, the small cerebellum, and the bulb. If the animal
be carefully fed and attended to, it may be kept alive for a
very long time: for more than a year, for instance."

If, with this list before us, we now examine the annexed
illustration, originally from His's work, and, therefore, not
recently drawn, a rather suggestive coincidence appears, indi-
cating, perhaps, a total independence, in the embryo, of the
region containing all the structures enumerated from the
vesicle which subsequently develops into the hemisphere of
the same side. In mammals the latter is at first insignificant,
but it develops very rapidly, soon overlapping the middle
structures. The outline of the latter is colored bluish gray.
The name of each part is given on the cut: a feature that will

510 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

better convey the mutual relations of the various structures
included in this system than a verbal description.

Again, the location of the posterior pituitary at the very
head of the entire spinal system, as shown in the illustration,
adds further testimony to that already submitted to demon-
strate the functional relationship between the nervous struct-
ures lying in the posterior pituitary, including the floor of the
fourth ventricle, and the bulb.

To ascertain this was the main purpose of our inquiry
into the comparative functional attributes of the hemispheres
and the middle brain. But we must not lose sight of the
fact that, in doing this, we have also given nerve-impulses their
true identity as mechanical energy: i.e., energy similar to that
supplied to the suprarenal system by its center, the anterior
pituitary. That a center for the conversion of chemical energy
into mechanical energy should be necessary for a relatively
short nerve-path as is that of the suprarenal system indicates
the physiological need of such a center as a source of energy
for all nerves.

A summary of all these facts, i.e., (1) that the posterior
pituitary body has a phylogenetic history which distinctly
identifies it as a part of the entire neural tract; (2) that it
presents clearly defined histological characteristics of an active
neural organ; (3) that these characteristics extend to the in-
fundibulum, the tuber cinereum, the floor and sides of the
third ventricle; (4) that these structures are continuous with
the reticular substance of the tegmental region, the medulla,
and the cord; (5) that the posterior pituitary body has been
found to be in direct relation with the olfactory center and
the bulbo-spinal axis in all classes of vertebrates; (6) that a
current passed between the olfactory and bulbar centers may
cause heart-inhibition and death; (7) that all the nerve-centers
are included in the structures with which the pituitary is func-
tionally connected in all vertebrates; and finally (8) that death
is caused by a puncture in the region of the vagal bulbar center
through interruption of the efferent and afferent impulses
through which the cardio-pulmonary system is incited to ac-
tivity and governed, seems to us to warrant the conclusion
that:—

MEDIAN AND VERTICAL SECTION DF A TWO AND
DNE-HALF MONTHS' EMBRYO, [His.]

[Considerably Enlarged.]

1, Aqueduct of Sylvius. 2, Medulla Dblongata. 3, Cerebellum.
4, Pans Varolii. 5, Anterior Tubercula QuadrigEinina. B, Posterior
Tubercula Quadrigemina. 7, Infundibulum and Pituitary B o dies.
B, Tuber CiriEreum. 9, Dptic Thalamus. ID, Fourth Ventricle.
11, Hypoglossal Nerve [Twelfth Pair], 12, Third Ventricle. 13,
Hemisphere Vesicle,

PHYSIOLOGY OF THE POSTERIOR PITUITARY. 511

The posterior pituitary lody is the general center of the or-
ganism from which all the nervous energy transmitted by the ~bulbar
centers arises.

All the above evidence and the various facts that we have
not included in the summary which sustain the conclusion just
submitted being of a physiological kind, it seems evident that
we should, in view of the important functions ascribed to the
organ, also be able to adduce clinical evidence. It is perhaps
needless to say that the testimony available can only be in-
direct, the prevailing belief that the organ is not endowed with
physiological functions having kept it out, as it were, of the
clinical field. And yet if it holds the important relation to
the nervous system we believe it does, its influence in the
pathogenesis of general neuroses must be very great. No dis-
ease having so far been associated with this lobe, our only hope
lies in our being able to discern among the symptoms of typical
disease of the anterior lobe what signs might be assigned to
implication of the posterior, with which it is intimately blended.

It is interesting to note, in this connection, that quite a
number of exceptionally able clinicians — von Recklinghausen,
for instance — have considered acromegaly as a trophic neuro-
sis, the organic disease of the pituitary being considered by
them as secondary. Again, the neural canal of lower forms
led Collina15 to suggest that the hypophysis (as a whole) also
produced a fluid capable of nourishing nervous elements and
that deficiency of this fluid, by reducing the activity of the nu-
tritional processes, gave rise to acromegaly: further evidence
that the tie between the nervous system and these organs is
sufficiently marked clinically to have attracted considerable at-
tention. That the various theories adduced also bear upon
nutrition of the nervous elements is significant as testimony in
favor of our view. Indeed, the clinical signs that point to
impaired nervous action are numerous, and are present in
practically all cases of acromegaly when the anterior lobe has
become sufficiently enlarged or functionally disordered to in-
volve the posterior lobe, either directly by pressure, continuity
of tissue, etc., or indirectly by overstimulating the adrenals, or,

"Collina: Gazzetta degli Osped., Jan. 8, 1899.

512 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

in the later stages, by causing insufficiency of these organs.
In a previous chapter we have — and correctly we now see —
ascribed to overactivity of the adrenals the stage of "erethism,"
and to insufficiency of these glands that of "cachexia." But,
if we ask how these states are produced by the adrenals, the
answer which would not have been available before now seems
to be within our reach.

We have previously referred to the vicious circle that ob-
tains in acromegaly. Though primarily located in the anterior
pituitary, the lesion probably gives rise to no untoward symp-
tom until well advanced: i.e., until pressure occurs either upon
its own structure by the pathological elements or upon the
posterior pituitary. Even slight pressure upon the whole organ,
as shown by de Cyon,16 gives rise to typical suprarenal symptoms.
But if the posterior pituitary is also considered as a factor in
the production of the symptomatic phenomena, as a source of
nervous energy, we not only have the vascular erethism of
suprarenal overactivity, but distinct evidence of nervous ere-
thism besides. This is well illustrated by the following quoted
lines, i.e., Gauthier's definition of the erethic stage of acro-
megaly as given by Hinsdale17: "The phenomena of erethism
which characterizes the first stage embraces, first, a painful
hypercesthesia, which manifests itself in headaches and rheu-
matic pains; second, an hypertrophy of the muscular fibers
which may give to patients a muscular power greater than
usual; third, palpitation of the heart accompanying the hyper-
trophy of that organ; and, finally, the polyphagia and polyuria
which may be considered to be connected with an erethic state
of the respective organs." Everything here points to over-
activity. But these are only the milder manifestations. Tam-
burini, for instance, describes a case in which "the mental
symptoms, on account of which the patient was sent to the
asylum, began to show themselves only a year before her ad-
mission. They consisted chiefly in delusions of suspicion ac-
companied by threats and acts of violence. The patient pre-
sented, in a marked degree, the bodily changes characteristic
of acromegaly. While in the asylum she was confused, resistive,

16 De Cyon: Archives de Physiologic, July, 1898.
" Hinsdale: Loc. tit., p. 30.

PHYSIOLOGY OF THE POSTERIOR PITUITARY. 513

and suicidal, and refused her food. . . . Only the anterior
lobe was involved, the posterior presenting no change either
in volume or structure." This typifies the irritability or stimu-
lation induced by pressure without organic change.

The phenomena produced are of another kind when both
organs are involved in the morbid process, as appears to be
the case in the following instance reported by Johnston and
Monro18: The patient, a woman, "was taciturn and intellect-
ually obtuse, and her memory was bad. Her utterance was
thick and indistinct, as if her tongue were too big for her
mouth. Her gait was slow and shuffling; her expression partly
melancholic, partly demented. . . . The skin of the face
is of a dull-yellowish tint; the mucous surfaces are pale.
. . . Hearing is somewhat impaired. Eeflexes are dimin-
ished. The subject of these notes remained in hospital for
about four weeks. She scarcely ever spoke, took no interest
in anything, and slept about sixteen hours daily. . . . She
was readmitted in September — blind, more deaf, more drowsy,
very feeble in muscular power. She could no longer rise with-
out assistance. Control over the sphincters was lost. . . .
Paralyzed. For a couple of months before death there was a
discharge of clear fluid from the nose. . . . The pituitary
body is represented by a large, red mass, almost diffluent —
much softer than brain-substance." The entire organ being
destroyed, the posterior lobe had obviously followed the fate
of its mate.

In a case described by Pirie19 the history of the nervous
symptoms is very clearly defined, though the author was un-
fortunately unable to obtain an autopsy. "The disease first
manifested itself in 1886, when menstruation finally ceased.
Pains and parsesthesia of the arms and legs were felt, and
the patient noticed that her hands and feet were getting larger
and more awkward. . . . Along with the development of
physical symptoms a peculiar alteration of mental condition
took place. Attacks of narcolepsy overcame her, she became
sluggish and irritable, and she suffered much from the ennui
of life. . . . Breathlessness on the slightest exertion ap-

18 Johnston and Monro: Glasgow Medical Journal, August, 1898.
"Pirie: London Lancet, Oct. 5, 1901.

514 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

peared, and ultimately the muscle weariness so gained upon
her that she had to take entirely to bed. . . . Sensory
disturbances are marked. Shooting pains in combination with
paraesthesia, tingling, and numbness are complained of in the
arms and legs. Neuralgic pains are felt also in various parts
of the body, viz.: the face, chest, back, and loins. A remark-
able perversion of thermic sensibility is found in the lower
limbs and over the front of the abdomen and chest up to about
the level of the fourth rib, the patient having no sensation
of heat in these regions. . . . Sternberg remarks particu-
larly on the occurrence of pain and parsesthesia as valuable
signs for diagnosis in the early stages of the disease; they are
probably due, he considers, to changes in the cutaneous nerves."

In a previous chapter we said: "Whether the mental
symptoms are ascribable to the cerebral hyperaemia or to the
impairment of certain functions of the pituitary itself, or to
both, it is as yet impossible to say." It now seems evident
that loth organs are involved in the pathogenic process. If the
far-reaching meaning of this fact is freely grasped, it seems
clear that there lies hidden under the whole fabric — of which
we only now see the outline — a truth of overwhelming impor-
tance to we physicians: i.e., the fact that it is not only in
acromegaly that the typical signs of impaired function of the poste-
rior pituitary shows itself, but in all syndromes directly ascribaUe
to the suprarenal system: i.e., myxcedema, cretinism, exophthalmic
goiter, and Addison's disease, which include in their aggregate the
majority of organic changes of a morbid kind to which the system
is liable.

This may be briefly illustrated by further quotations from
Dr. Pirie's excellent paper, entirely devoted to the one case.
As regards the muscular system, the author states that "mus-
cular atrophy is a prominent feature, affecting the thenar,
hypothenar, and interossei muscles of the hands, the forearm-
and arm- muscles, the calf- and thigh- muscles, and also the
glutei," and refers to Duchesnau,20 "who has made a special
study of the atrophy of muscles in acromegaly. So marked is
it in some cases that it has been mistaken for syringomyelia,

80 Duchesnau: These de Lyon, 1891.

PHYSIOLOGY OF THE POSTERIOR PITUITARY. 515

progressive muscular atrophy, or amyotrophic lateral sclerosis;
it has also been mistaken for Charcot's cervical pachymenin-
gitis hypertrophica and for erythromelalgia." Referring to the
skin, Pirie says: "Its chromatogenous functions are disturbed,
much as in rheumatoid arthritis. Small freckles are frequent;
patches of a yellowish bronzing occur also on the face, the
chest, and the insides of the thighs. (Motais describes a bronz-
ing such as occurs in Addison's disease.) Numerous small
warts are present. (Mollusca fibrosa are described in many
cases and xanthoma-like tumors by Dallemagne.) The patient
suffers from a brownish seborrhcea, especially troublesome in
the scalp. The hair is thick and coarse and stands straight
upward. There is a scanty beard and moustache. Profuse
perspirations are constantly complained of. The heart is di-
lated. There is tachycardia, the heart beating about 98 to
the minute. A soft, systolic, basic murmur is heard at times.
Palpitations and fainting fits occur very often. Dyspnoea is
marked, and asthmatic-like attacks occur, during which the
patient has to sit up in bed and fight for her breath." . . .
"The soft parts are remarkably changed as well as the bones.
The scalp is much thickened, as is also the skin of the face.
. . . In addition to the kyphosis there is a compensatory
lumbar lordosis and also a certain degree of scoliosis. The
clavicles are enormously hypertrophied. The ribs are thick-
ened and expanded, the costal cartilages feel bony, and there
are nodular projections resembling the 'rachitic chaplet' at
the junctions of the ribs and their cartilages." . . . "With
regard to the organs of special senses, the skin of the eyelids
is thickened and puffy. The lacrymal glands are hypertro-
phied. Increased lacrymation occurs at times, and I have
noticed a colloid-like secretion between the eyelids." . . .
"There is amblyopia, nearly complete in the left eye, and color-
vision for blues and yellows is defective. Bitemporal hemi-
anopsia is present. The pupils contract in accommodation and
react to light, though very sluggishly in the case of the left
eye. With the ophthalmoscope optic atrophy is found."
. . . "She suffered much at this time from polydipsia and
glycosuria, and for over twelve months there was an almost
constant dribbling of saliva from the mouth. . . . The

516 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

thyroid was greatly enlarged, but under treatment with thy-
roid substance it diminished much in size." We have seen
how dependent the organism is upon the integrity of the
suprarenal system when infectious diseases develop.

We can fully agree with Harlow Brooks21 when he says:
"It is quite natural to expect pronounced abnormalities in the
various portions of the nervous system in a disease which ex-
hibits so many neurological symptoms"; and his statement that
"examinations of the nerve-tissues have shown quite extensive
and general changes" further sustains our deductions. Evi-
dence of this kind, garnered from all sides long before the
feature it serves to support is thought of, appears to us of the
strongest kind. We again prefer to use the author's own
words, therefore, rather than our own, when he reviews the
pathology of the disease, and which seems to us to portray
in parvo the main landmarks of neurological pathology. We
have only omitted those of the author's own estimates that
do not bear directly upon our subject and what text was not
purely descriptive: —

"Peripheral Nerves. — The trunks of the peripheral nerves
are, for the most part, enlarged; this is directly due to an
increase in the connective tissue of the endoneurium and peri-
neurium. Often the sheaths of the nerve-trunks also show
considerable thickening. This general connective-tissue hyper-
plasia frequently so encroaches on the nerve-fibers as to destroy
them, and degenerated nerve-fibers are quite commonly found
some of which may show complete axis-cylinder destruction
(Arnold, Comini). These conditions may persist throughout
the entire nerve-trunk, extending even into the nerve-roots.
(Arnold, Duchesneau.)

"Ganglia. — In the posterior-root ganglia, also, we find the
connective-tissue elements greatly increased, so that even
macroscopically the ganglia are often considerably enlarged.
Microscopically the ganglionic cells are sometimes pressed upon
and atrophied (Marie, Marinesco). Arnold reports that he
found vacuoles in the nerve-cells. In Cases I and II of the
author's, the alterations in the ganglion-cells were slight.

21 Harlow Brooks: Archives of Neurology and Psychopathology, vol. I, No. 4,
8, p. 592.

PHYSIOLOGY OP THE POSTERIOR PITUITARY. 517

"It is difficult to determine whether the nerve-cell lesions
are secondary, perhaps directly dependent on the connective-
tissue hyperplasia about the cells and fibers, or are primarily
due to defective nutrition of the ganglion-cell bodies. Per-
haps these ganglionic changes are wholly, or in greater part,
responsible for the degenerations and atrophies which take
place in the muscles of the voluntary system.

"Sympathetic Ganglia. — The changes in the sympathetic
ganglia and trunks have been made the subject of special study
by several very prominent investigators, among whom are
Marie, Marinesco, and Arnold, and have been looked upon by
many as factors of an etiological nature. Finding, as we do,
such pronounced change in the blood-vessels, it does not seem
at all strange that lesions in the sympathetic ganglia should
be present; but a view intimating a dependence or relation
of the vascular changes to the lesions in the sympathetic sys-
tem is not in accordance with our own ideas expressed at the
close of this paragraph. In general, the changes in the sym-
pathetic ganglia are very similar to those already described in
the ganglia and trunks of the cerebro-spinal system. In some
cases the size of the ganglia is considerably increased (Arnold,
Marie, Marinesco), and, microscopically, the connective-tissue
web is thickened and proliferating. The ganglion-cells are
often reported as exhibiting evidences of degeneration."
. . . "Arnold has found vacuolization; not infrequently
considerable deposits of pigment are seen within the cytoplasm.
But, as in Case II, the ganglion-cells may be normal; the Nissl
bodies are present in normal arrangement, volume, and shape,
and show no deviations in their staining reactions; and the
pigmentary deposit is not abnormally abundant. The sym-
pathetic ganglia in the case reported by Gauthier were also
normal. It is advisable, at this point, to call attention to the
fact that the interstitial hyperplasia is by no means a lesion
characteristic of the sympathetic system, but is simply an ex-
tension of the general process so often alluded to. The growth
of connective tissue in the sympathetic may depend in part
on lesions in the walls of the vessels; or both may be referable
to the common factor of deranged nutrition.

"Cord and Medulla. — The pathological findings in both

518 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

the cord and medulla differ greatly. Virchow, and also Fritsche
and Klebs, have reported hypertrophy of the medulla. The
spinal cord was enlarged in the case reported by Linsmayer.
Many observers have reported various degenerations in the
cord. Baruch's case was associated with symptoms of syringo-
myelia; Debierre gives a case with diseased posterior columns,
while Arnold, Dallemagne, and Tamburini have found at au-
topsy irregular degenerated areas in the cord, affecting, how-
ever, no special place with any degree of constancy. Usually,
as in the first two cases reported in this paper, no abnormalities
of either the medulla or cord are found.

"Brain. — No constant changes are found in the brain, but,
as is the case with every other organ of the body in acro-
megalia, the encephalon may be enlarged (Fritsche, Klebs,
Halsti), though the increase is rarely proportionately as great
as that of the body. Usually few microscopical changes of note
are found. Demonstrable cytological degenerations are absent,
though interstitial and vascular lesions are sometimes re-
ported." This paragraph appears to us to add further testi-
mony to the teachings of experimental physiology which tend
to isolate the hemispheres from the true neural tract.

The nature of the process through which the nervous
energy liberated by the posterior pituitary affects nervous
structures suggests itself as the next subject to receive atten-
tion.

THE HISTOLOGY AND PHYSIOLOGICAL CHEMISTRY
OF THE NEURON.

We are first brought to inquire into the relationship be-
tween the modern conception of the structural composition of
the cerebro-spinal axis and the views we have submitted.
Granted, therefore, that the posterior pituitary body is the
seat of a process through which chemical energy is converted
into nervous energy, and that this constitutes the nervous im-
pulses which the cerebro-spinal axis transmits to the various
organs, how do the nerve-elements utilize this energy when
functionally active?

We refer, of course, to Waldeyer's neuron as the morpho-
logical unit of the cerebro-spinal axis, and the processes of

THE PHYSIOLOGY OF THE NEURON. 519

which are not in contact, hut sufficiently close, one to the
other, as to make it possible, when required, for a nerve-impulse
to cross the interval between them. These facts have been
satisfactorily established by modern methods, especially
through the labors of Golgi and Ramon y Cajal. But the
manner in which the gap between the processes is closed — i.e.,
how the impulse passes from the terminal brush of the axon
of one nervous element to the dendrites of the next — is still
to be determined. It has been suggested, however, that the
processes behave, in a limited manner, as do the pseudopodia
of the amoeba, and that by a slight extension the interval
between the processes is closed. When the processes are not
in contact they are said to be in a state of "retraction/' Much
as such a function would facilitate and shorten our analytical
work could incontrovertible experimental facts be adduced to
sustain it, we are brought, by a review of the literature of the
subject, to recognize that such facts are not available. Indeed,
the majority of physiologists and neuro-histologists now con-
sider the question of "amoeboid .movements of the neuron" in
the light of a working hypothesis.

There is one feature of the investigations in this direction
which may serve to throw more light upon the whole ques-
tion if one of the more prominent deductions submitted by
us in the present work is taken into consideration: i.e., the
fact that all drugs cause overactivity or insufficiency of the
adrenals.

Much of the physiological work done in connection with
the neuron includes the administration of various toxics, —
strychnine, chloroform, morphine, etc., — and amoeboid move-
ments or other active manifestations of the protoplasmic proc-
esses are thus ascribed to the action of the drugs upon the
neurons per se, whereas, in the light of our views, the changes
of form witnessed should be ascribed to increased or reduced
blood-supply when toxic doses are given. To illustrate our
meaning we will give in outline an experiment which repre-
sents one of the key-stones of the entire theory, that of
Demoor. Before doing this, however, it may, perhaps, be well
to state that we will consider the terms "neuron" as applying
to the complete nerve-cell, including processes; "neuraxon"

520 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

to the (usually) single and long process which extends along
the center of the nerve-fiber, and is then called "axis-cylinder;
"dendrites" to the cell's many processes — some of which end in
many branches or tufts — other than the neuraxon. With
Foster and Sherrington we will consider that neuraxons carry
impulses away from the cell, while dendrites transmit impulses
into the cell. Two other prominent morphological features are
the "gemmules" — minute projections all along the dendrites —
and their terminal twigs, which recall those on the stems of
the moss-rose, and the varicose, or irregular, swellings that may
be observed in the course of the dendrites or their terminal
twigs.

The experiment of Demoor was briefly as follows: He
killed a dog by injections of morphine; a second dog was given
morphine for some time, then killed by cutting the medulla;
a third was trephined. The next day a piece of the left hemi-
sphere of the latter dog was removed; the animal being then
morphinized, another piece — but of the right hemisphere this
time — was removed. Portions of the hemispheres of the two
killed dogs having also been removed, all specimens were
treated in precisely the same manner. The cellular changes
were found to be similar in all specimens taken from the mor-
phinized animals: their gemmules had disappeared. Alone of
the series the piece removed before morphine had been given
was covered with regularly distributed gemmules. Now the
fact we wish to emphasize is this: while this experiment is
thought by its author to show that the retraction of the gem-
mules constitutes the inactive state, as induced by morphine
through the local action this drug is now thought to have upon
nerve-cells, the retraction of the gemmules, as we view the ex-
perimental result, is due to the suprarenal insufficiency (total
arrest of function in the dog killed with morphine) produced
by the toxic. And this is an important feature, since we thus
have, instead of a purely local effect, an example of the general
physiological process through which the neuron passes from
the active to the passive state — provided the histological pict-
ure is not a misleading one.

Again, the same structures treated by different methods
have been found to yield different results. Thus, H. H. Baw-

THE PHYSIOLOGY OF THE NEURON. 521

den22 found that "all material treated according to the slow
method of Golgi shows, as a rule, an almost absolute freedom
from varicosities; varicose cells occasionally occur/' The
mixed method and the rapid were found to yield practically
the same results when the dendrites had taken the stain: the
gemmules were almost invariably present and regular. In
some sections almost every dendrite was varicose; in others
hardly any. All these results were similar whether normal or
"toxic" material was used, and the author concludes that "it
is impossible for an unprejudiced observer to differentiate or
distinguish between the two kinds of material." Lugaro,23
who has upheld the retraction theory, also reached the con-
clusion that "imperfect fixation is very largely, though not
entirely, responsible for the formation of varicosities and the
disappearance of gemmules." Weil and Frank summarize what
a review of the literature of the subject shows, when they say:
"The findings have been in almost every case positive, although
there are occasionally records of negative results and even
contradictions, — as, for example, between the investigations
of Demoor and of Soukhanoff on the effects of chloroform.
. . . Eetraction of the gemmulse and coincident swelling of
the dendrites form the essential features of every description."

Judging from the foregoing estimates as to the effects
of stains upon dendrites, these phenomena are to be consid-
ered as artifacts: i.e., as artificially produced changes. Under
these conditions, it is clear that the latter should appear, irre-
spective of the condition of the animal at the time of its death:
i.e., whether under the influence of toxics as stated, fatigue,
etc.

That prevailing views in this connection are erroneous is
our firm belief after a critical analysis of available experimental
evidence. Particularly instructive and valuable in this con-
nection are the experiments of H. H. Goddard,24 which con-
sisted "in cutting through the entire head of the animal at a
single blow with a very thin sharp knife, the parts of the head
falling instantly into large dishes of Cox's solution warmed

22 H. H. Bawden: Journal of Comparative Neurology, May, 1900.

23 Lugaro: Rivista di patol. nerv. e ment., vol. iii, 1898.
14 H. H. Goddard: Jour, of Compar. Neurol., Nov., 1898.

522 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

to 39° C. In his first experiment, puppies about seven weeks
old, sisters from the same litter were used, the one while some-
what tired, the other after having slept. A careful count of
the pyramidal cells of the cortex of the somewhat fatigued
puppy gave a proportion of 31.1 per cent, of cells showing
varicosity, while cells from the same region of the puppy killed
after sleeping was 8.5 per cent. In the former animal 15.9 per
cent, of the cells showed much varicosity; in the latter only
0.8 per cent, showed a similar state. In the second experiment
the first of two sisters was killed on waking in the morning;
the second at night when tired and very sleepy. While it "was
difficult to find a single varicosity on the dendrites of the morn-
ing puppy, for long distances in the cortex of the evening
puppy" it was difficult to find a cell "whose processes" were
"not more or less varicose." It is evident that in these in-
stances at least the stain was not alone the source of vari-
cosities, since it was only in the tired puppies that the vari-
cosities were very marked, while in the thoroughly rested
animal practically none could be found.

Judging from these experiments, varicosity of the den-
drites coincides with a fatigued condition. This corresponds
exactly with the experiment of Demoor, previously described,
since retraction of the gemmules is accompanied by varicosity;
so that fatigue and a large dose of morphine must have pro-
duced similar results.

If the staining process alone caused the formation of vari-
cosities in Demoor's experiments, — the same method having
been used for all specimens, — how is it that one of the latter
showed gemmules (which means absence of varicosities), and
that this solitary specimen is precisely from the only animal
which had not received morphine? Berkley25 found that poi-
soning with alcohol "in considerable doses, continued over a
moderate time, will produce decided and ascertainable lesions
of the nutrient structures and nervous elements of the cere-
brum" very similar in character to the pathological lesions pro-
duced by other more virulent soluble poisons. The terminal
twigs of the dendrites were also found to have become varicose

28 Berkley: Brain, Winter, 1895; and Johns Hopkins Hospital Reports, vol.
vi, 1897.

THE PHYSIOLOGY OF THE NEURON. 523

or beaded, the gemmules being very scarce or absent. Here,
again, is a condition which, as does fatigue, morphine, and, we
may add, chloroform, chloral hydrate, and other toxics used
by Demoor and others with similar results, all tend in the one
direction: i.e., to morbidly reduce functional activity. This is
a well-known characteristic of the bromides. In a study of the
cortical cells under the influence of poisonous doses of potas-
sium bromide, H. K. Wright26 says: "If the primal ascending
dendron is followed to its visible termination, several ampullous
or varicose swellings of varying size are met with," . . .
"on the basal processes also varicosities are to be seen; but
they are small and, like those of the ascending protoplasmic
process, are sharp in outline, and shorn of the lateral projec-
tions which obtain on the unaltered part of the extensions.
One may be seen pn each secondary branch, and ranges in size
from a small and scarcely recognizable to a readily obvious swell-
ing. None of them, however, reach the dimensions of the
apical projection and its branches."

If the method of staining is the cause of all this, we are
brought to the conclusion that it must be selective as to the
parts of the dendrite it affects, and that only functionally-
impaired cells are so affected by the stain as to show varicosi-
ties. Even then staining methods would furnish precious in-
dications. But it seems clear to us that, while the newer
chrome-silver methods still furnish imperfect pictures of the
morbid alterations of the neuron, they cannot with justice be
said to either cause or prevent the formation or disappearance
of gemmules and varicosities; in other words, that they are
not artifacts of the Golgi method. The marked tendency of
the swellings to locate at the apices, and the gradual reduc-
tion of the varices as the cell-body is approached recall, on the
other hand, a well-known pathological principle: i.e., that the
morbid effects of impaired general nutrition are first felt by
terminal structures.

And the painstaking experiments of Weil and Frank do
not appear to us in the least to prove their conclusions that
"the varicosities must be regarded as artifacts" and that "they

28 H. K. Wright: Brain, Summer, 1898.

524 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

depend for their presence and their amount on the form and
method made use of." Demoor employed the same method in
each of his comparative experiments and his results were not
similar, the non-morphinized specimen alone differing from all
others. Hubbard used the identical method in both his com-
parative experiments, and likewise obtained results which dis-
tinctly showed a marked difference between the rested and
fatigued animals. In these and other experiments referred to,
the pathogenic agency, including fatigue, was allowed suffi-
cient time to produce alterations in the cortical cells, if nutri-
tion has anything to do with the process.

In Weil and Frank's experiments the animals were over-
whelmed by the quantity of toxic administered, and death
occurred — if our views are sound — by arrest of the adreno-
cardiac functions, long before any marked action upon the cells
could possibly have occurred. The doses of morphine admin-
istered were 0.38 and 0.41 gramme (6 and 7 grains), respect-
ively, with death in 15 minutes; of strychnine nitrate, 0.018
gramme (V3 grain), death in 20 minutes; of hypertoxic urine,
125 to 150 cubic centimeters (4 to 5 ounces), death in 15 to
25 minutes. That these are overwhelming doses in rabbits is
evident. One animal was killed with serum (30 cubic centi-
meters— 1 ounce) in 5 minutes; others with chloroform inhala-
tions in 10 minutes; one by tracheal clamping in 8 minutes.
The rest, six animals, were destroyed instantly by instrumental
procedures. In none of these animals was there any distinction
established as to whether they had been sleeping, eating, or
romping, etc. That some were old and others young in the
series of nineteen is probable; f as is well known, erethism, espe-
cially in such delicate structures, is greatly influenced by age,
and a few months in the rabbit represent as many decades in
man. The weight of each animal was not recorded in order
to establish the relative action of a given dose of the toxic
used per pound of animal, though, of course, in the experi-
ments, the large doses used precluded any usefulness on this
score.

Finally, the authors themselves will surely admit that "no
varicosities," "varicosities," "slightly varicose/' and "very
slightly varicose," the method of notation utilized by them,

THE PHYSIOLOGY OP THE NEURON. 525

conveys but little exact information. And still, even this sus-
tains a deduction opposite to theirs. Indeed, the short period
of time that elapsed between the injection of the toxics in the
animals killed in this manner — represented by 108 blocks of
slides — must have sufficed to initiate retraction of the gem-
mules and the formation of varicosities, since only 10.2 per
cent, of these blocks show no varicosities. When, on the other
hand, the proportion of animals killed instantly by instru-
mental procedures — 93 blocks of slides — is analyzed, over two
and a half times as many, i.e., 28 per cent., are found to show
no varicosities.

But a fair question suggests itself in this connection:
Why do the remaining 72 per cent, show any varicosities?
Only 14 per cent, of the blocks from the instantly killed ani-
mals are recorded as "varicose," the remaining 58 per cent,
being entered as "slightly" or "very slightly" varicose. In their
explanation of the scope given these terms, the first means "at
least some varicosities" and the second as "only very few vari-
cosities." Now, the authors state that "in the first nine cases
here recorded the brains were placed in fixing fluids within
three to five minutes." Nothing is said of the rest; so that
we may infer that the ten other brains were immersed after
longer intervals. We have previously seen, when the conver-
sion of myosinogen into myosin was studied, that oxidation
processes continued even after death: i.e., until all the oxygen
had been utilized. That this must be the case with the brain,
which contains one-fifth of the blood of the whole body, and
that products of metabolism, especially C02, should form in
the entire encephalon is evident. It normally follows that we
have in this factor a potent cause for the retraction of gem-
mules and the formation of varicosities.

Indeed, the contrast between the results reached speaks
for itself when compared to those of Goddard, who resorted
to procedures in which the exact condition at the instant of
death were preserved, "the parts of the head falling instantly
into large culture dishes warmed to 39° C." Even continua-
tion of the normal brain temperature was insured. And what
were Goddard's results? "It was difficult to find a single vari-
cosity on the dendrites of the morning puppy," — i.e., the thor-

526 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

oughly rested animal; while in the thoroughly tired one "for
long distances in the cortex . . . it is difficult to find a
cell whose processes are not more or less varicose." That
fatigue is the result of an accumulation of products of metabo-
lism and especially C02 is generally recognized.

Goddard's procedure appears to us to represent as nearly
perfect a one as available staining methods (Cox's and the rapid
method show considerable parallelism in Weil and Frank's
report, while the mixed and slow methods appear unreliable
and contradictory) will allow; and Ms results, in our opinion,
portray the actual changes that are produced in the neuron under
the influence of poisons of any kind and during sleep: i.e., when
the blood-supply of the brain is reduced.27

Weil and Frank state that they "are able fully to cor-
roborate the statement of Cajal that normal and toxic mate-
rial cannot be differentiated by the number of varicosities or
of gemmules." The care with which such experiments must
be conducted, apart from the method of staining adopted; the
need of immediate immersion, and other details to which we
have referred, invalidate any opinion that the distinguished
Spanish histologist may have expressed on this score, unless
he can show that his experimental physiological procedures
were as perfect as his staining work must have been. Indeed,
we must express the belief that the greater part of the physio-
histological work done so far in this connection is valueless
owing to the absence of the precautions to which we refer.

Again, Ramon y Cajal's conclusions that "the nerve-cells
do not move, but, on the other hand, that the neuroglia-cells
do move" (which underlies his view as to the gemmules and
varicosities showing no difference when normal or "toxic"),
has been shown by Dercum to embody its own refutation.
"Cajal," says the latter author, "points out the fact that the
processes of the neuroglia-cells have numerous short arbores-

27 We wish to particularly emphasize the fact that we are in no way criticis-
ing adversely the work of Drs. Weil and Frank. We have nothing but praise to
express for these investigators. Much of the searching inquiry to which we are
submitting their paper includes the use of features introduced for the first time
in the present work, and obviously unknown to them. Indeed, if our views
eventually prove to be sound, we will owe much to the counter-evidence Drs.
Weil and Frank— and, we may add, Dr. H. Heath Bawden— have published.— S.

THE PHYSIOLOGY OP THE NEURON. 527

cent and plumed collaterals, and he states that in these cells
two different phases can be observed: first, a stage of contrac-
tion,— that is, a stage in which the cell-processes become short-
ened; and, secondly, a stage in which the cell is relaxed, — that
is, a stage in which the processes of the neuroglia-cells are elon-
gated. He maintains that the processes of the neuroglia-cells
represent an insulating and non-conducting material, and that
during the stage of relaxation these processes penetrate between
the arborizations of the nerve-cells and their protoplasmic
processes, and so make difficult or impossible the passage of
the nerve-currents; on the other hand, in the stage of contrac-
tion the processes of the neuroglia-cells are retracted, and they
no longer separate the processes of the nerve-cells, and the
latter are thus permitted to come into contact.28 Evidently
Ramon y Cajal admits the very thing against which he con-
tends, for if the nerve-cell processes are at one time not in
contact and at another are in contact, they must certainly
move, and the question before us is self-admitted. It matters
not whether the processes of the nerve-cells move little or
much, but that they move at all is the question at issue, and
this Ramon y Cajal admits, though he makes the movement
a purely passive one."29 To us it appears clear that, since
Ramon y Cajal held the nerve-cell to be a passive structure,
requiring an independent connecting-link to close the circuit
with the adjoining cell, he must have denied both the gem-
mules and the varicosities any physiological importance. His
opinion, therefore, that normal material cannot be differen-
tiated from toxic material, when applied to the retraction of
gemmules and the formation of varicosities, cannot be said to
rest upon solid premises, and, for the time being at least, to
in no wise affect the question.

In a comprehensive review of the anatomy and physiology
of the nervous system, L. F. Barker30 makes the following re-
marks: "The physiologist of the present day sees in the func-

28 We will see farther on that Cajal's observation as to the relaxation and
contraction of neuroglia-cell processes is valuable in that it proves that the tips
of the gemmules do not transmit nervous energy.— S.

^Dercum: University Medical Magazine, April, 1897.

80 L. F. Barker: New York Medical Journal, May 15 et seq., 1897-98.

528 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

tions of the nervous system, even in those which are most
complicated, only certain manifestations of energy. Moreover,
he believes that in neurons, as in all other cells of the body
and as in the world generally, the law of the conservation of
energy during transformation holds, and consequently regards
the phenomena of irritability, as exhibited by a neuron or by
groups of neurons, as the kinetic representative of the poten-
tial forces of the cells and their foodstuffs. The metabolic
activities and the vital manifestations of the cell are concomi-
tant processes — another example of the inseparable connection
which exists between what we term matter and energy. There
has been in many quarters a certain amount of hesitancy in
accepting the view that the capacities of the nervous system,
particularly those of the brain, are dependent directly upon
the chemical and physical alterations which are continually
going on within its constituents: a hesitancy which, though
it has in the past proved a serious obstacle to progress, is
happily now fast disappearing. For the plant, all the evi-
dence goes to prove that under the influence of sunlight and
heat marked chemical and physical changes take place within
it which we recognize in its vital processes. In the animal —
be it granivorous, carnivorous, or, like man, omnivorous — it is
the chemical energy introduced as food which represents, in
the main, the source of the energy of the organism. . . .
The physiologists have been struggling for fifty years or more
to gain an insight into the nature of what they call nerve-
impulses, by which is to be understood the occurrences inside
axons: for example, at the time when we have good reason
to believe that they are functionally extraordinarily active.
Their efforts have supplied us with a multitude of data, phys-
ical and chemical, interesting enough, no doubt, but which can
serve as only the barest prolegomena to an explanation of the
essence of the occurrences. If we are so badly informed con-
cerning these elementary and fundamental phenomena we may
very well be content to be modest for some time to come in our
claims as regards a physiological psychology. It is by no means
impossible that in the nervous system forms of energy are
concerned which do not exist outside the animal body and
which yet remain to be recognized and studied.

THE PHYSIOLOGY OF THE NEURON.

Truly, to find out the properties of a single neuron would be
a task appalling enough; but, when we remember that of the
millions of neurons in one individual perhaps no two are just
alike, the quest would seem hopeless. But instead of burying
ourselves in pessimistic reflections, or being discouraged by
what is at present unattainable, by what may perhaps forever
remain to us unknowable, we may profitably turn to the con-
sideration of some of the points which lie more within our
ken. One point, self-evident enough when one's attention is
directed to it, but which often appears to have been overlooked
in connection with the neurons, is the unremitting character
of their activity. With a metabolism as complicated as that
occurring within the nerve-units it is inconceivable that there
can be any period in which alterations in chemical structure,
and consequently energy transformation, are not going on.
From moment to moment, throughout all the hours of the
day and night, analytical and synthetic processes are taking
place, associated with the alterations in physical forces which
necessarily accompany these changes. In common with every-
thing that lives, the neurons know no absolute repose. As I
have said, in speaking of their metabolism, periods of extrava-
gant activity may alternate with periods of more -economic
change, but total rest is inconsonant with continuance of ex-
istence. We are forced to believe that what we ordinarily
speak of as the passage of a nerve-impulse represents, as it
were, a stormy process in the nerve-fiber, and that just as absence
of a storm does not mean absence of weather, there are in all
probability minor alterations — currents, if you will — passing
to or fro or passing to and fro in a given nerve-fiber in the in-
tervals between the more violent excitations."

The words that we have italicized will doubtless recall
some of the more prominent features previously emphasized
in respect to the relative nervous processes involved in the
functions of the various organs reviewed. We have termed
"passive" that form of energy continuously transmitted to tis-
sues and vessel-walls. A quiet and steady flow of blood into
the cellular structures, sustained by the tonic contraction of
the arteries, and a stream of nervous impulses to the tissues
coinciding in rhythm, perhaps, with that sent to the vessels,

530 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

suffice to insure nutrition and to hold the structures thus sup-
plied ready for active work. What is the source of this energy?

If the posterior pituitary reinforces the flux of impulses
when functional activity is demanded, passive energy would
seem to require another source, and as the lower, or middle,
brain and the cord are included in the "sphere of influence"
of this organ, the hemispheres are the only parts of the en-
cephalon that can supply the need. But they do not. Removal
of the hemispheres, we have seen, does not impair muscular
activity; a frog can jump, a pigeon can fly, etc., and, after a
short period of shock-paralysis immediately after the opera-
tions, movements return: evidence that their nutritional
metabolism, incited and regulated by nervous impulses, con-
tinues. Evidently, therefore, the hemispheres have nothing
to do with the process; they are solely the seat of the "mind,"
and constitute an organ among the rest, itself supplied with
vasomotor nerves (Obersteiner, Gulland, Huber, Hiirthle,
Cavazzani, Frangois-Franck, et al), and probably with its own
nutritional nerve-system. We are, therefore, brought back to
the posterior pituitary as the only organ capable of satisfying
the needs of the situation: i.e., as the only source of passive
energy.

This suggests that metabolism may suffice, through the
agency of the blood's oxidizing substance, to sustain physio-
logical activity during the intervals between "stormy processes
of the nerve-fiber"; but this is promptly shown to be a wrong
interpretation when the effects of section below the medulla
are recalled. As all the arteries of the organism are imme-
diately relaxed, a continuous stream of impulses must have
served to hold the vessels in tonic contraction: evidence that
passive nervous energy is a factor to be reckoned with. Thus,
the fact that all co-ordinated muscular movements continue
after removal of the hemispheres relegates to the middle brain
the function of supplying active energy — and, obviously,
passive energy likewise, the need of the latter being shown by
division of the medulla. Indeed, passive energy may well be
described as passing to and fro in a given nerve-fiber in the
intervals between the more violent excitations, while active
energy can as fittingly be likened to "a stormy process in the

THE PHYSIOLOGY OF THE NEURON. 531

nerve-fiber": both ascribable, it now seems likely, to the one
organ, the posterior pituitary body.

To establish the functions of the posterior pituitary within
its proper physiological limits, however, it is necessary to as-
certain how nervous elements in general and neurons in par-
ticular are nourished, since it is upon the degree of perfection
with which the nutritive processes are carried on by the blood
that the functional integrity of these structures depends.

The fact that a general nutritional process prevails, of
which the suprarenal system is the primary motive agency, we
have shown; but it finds further support in the following
statements of Professor Barker's — which, of course, but em-
phasize a generally known fact — that, "in the absence of sub-
stances in the body derived from the thyroid gland, the nervous
system undergoes very important and serious metabolic modi-
fications, evidenced by the remarkable nervous and mental
phenomena with which all are now familiar. On restoring
these substances to the body by the administration of a thyroid
extract the symptoms may sometimes be made to disappear.
It is likely, however, that the neurons find their staple foods
in the main nutritive constituents of the blood as derived from
the food digested in the stomach and intestines and purified
by the lymph-glands and liver."

We have, we believe, satisfactorily shown that the thy-
roid secretion sustained the activity of the anterior pituitary
body, and therefore of the entire suprarenal system, by pour-
ing its secretion — thyro-iodine perhaps — into the blood. The
functions of the digestive organs we have also reviewed.
Among the latter, however, are two upon which we laid con-
siderable stress, — i.e., the spleen and pancreas, — and we called
attention to the great importance of trypsin — the spleno-
pancreatic ferment — in the conversion of albuminoid sub-
stances, and especially of their toxic derivatives, into benign
products. These albuminoid substances, we have seen, then
pass through the liver, and, after traversing the cardio-pulmo-
nary circuit, are distributed broadcast throughout the organism.
There is a feature which we kept in abeyance, however, —
though a well-known one, — since at the time its true weight
would not have asserted itself: i.e., the fact that albuminoids

34

532 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

include nucleins derived from the animal and vegetable cells in-
gested with food, which nucleins contain at least 8 per cent, of
phosphorus. We can now realize how great is the physiological
role of the pancreas and of the spleen in the organism.

Indeed, the functions of these two organs may be said
to constitute one of the pillars upon which the vital functions
rest. As a constituent of calcium phosphate, phosphorus is
found in the bones, teeth, cartilage, and other tissues; in the
blood, milk, etc., in quantities which bespeak of its functional
prominence, since calcium phosphate is represented by nearly
six pounds among the organism's constituents. Sodium phos-
phate— which gives the blood, lymph, and other body-fluids
their alkalinity and fluidity, and the potassium and magnesium
phosphates, which fulfill much the same role, obviously find
in phosphorus their main dynamic attributes. But it is when
we reach the nervous system that the functional worth of this
element reaches its highest mark.

How are nervous structures — neurons, axis-cylinders,
sheaths, etc. — adequately supplied with blood-plasma, their
oxidizing substance, their phosphorus, etc.?

THE PHYSIOLOGICAL CHEMISTRY OF NERVES. — The func-
tions of myelin, or white substance of Schwann — a jelly-
like homogeneous and transparent material which surrounds
the axis-cylinder of nerves, and is only separated from it by
a thin protoplasmic film — may be said to be unknown. It
is a fatty substance, blackened by osmic acid, and which,
after death, coagulates and becomes opaque, loses its homo-
geneity, etc. Myelin is now universally considered as a pro-
tective coat: a function which the overlying neurilemma al-
ready fulfills. Is myelin fatty in the true sense of the word?
Examined chemically in quantities, a very large proportion of
dried nerve-substance — about one-half, according to some ob-
servers— consists of a peculiar body: cholesterin. This body
is not a fat, but an alcohol; like glycerin, however, which is
also an alcohol, it forms compounds with fatty acids. "Though
we do not know definitely the chemical condition in which
cholesterin exists during life in the medulla," says Professor
Foster, "it is more than probable that it exists in some com-
bination with some of the really fatty bodies also present in

THE PHYSIOLOGICAL CHEMISTRY OF NERVES. 533

the medulla, and not in a free isolated state." . . . "Besides
cholesterin, 'white7 nervous matter contains a less, but still
considerable, quantity of complex fat whose nature is disputed.
According to some authorities rather less than half this com-
plex fat consists of a peculiar body, lecithin, which we have
already seen to be present also in blood-corpuscles and in mus-
cle. Lecithin contains the radical of stearic acid (or of oleic,
or of palmitic acid), associated, not — as in ordinary fats — with
simple glycerin, but with the more complex glycerin-phosphoric
acid, and further combined with a nitrogenous body, neurin,
an ammonia compound of some considerable complexity; it is
therefore of remarkable nature, since, though a fat, it con-
tains both nitrogen and phosphorus." Cholesterin (C26H440),
lecithin (C44H90NP09), and neurin (C5H15]ST02), as shown by
the formulae, are all oxygen-containing bodies. May this sup-
posed coating and insolating material, myelin, not be to the
nerve what myosinogen is to muscle?

Cholesterin, we have seen, is associated with hepatic func-
tions. "It is singular," says Professor Foster, "that, besides
being present in such large quantities in nervous tissue, and
to a small extent in other tissues and in blood, cholesterin is
a normal constituent of bile." We have previously referred to
the fact that this alcohol, the only one which occurs in the
body in a free state, combines with glycocholic acid in the
formation of bile, and is thus eliminated by the liver. This
view sustains that of Austin Flint, who looked upon cholesterin
as an excrementitious product derived from the nervous sys-
tem: i.e., the result of nerve-metabolism. Cholesterin is pres-
ent in abundance in the white substance of the cerebro-spinal
axis, as well as in the myelin, or white substance of Schwann,
in nerves. We have seen, however, that the elimination of
excrementitious products by the liver is carried out by the
combination of various agencies: mainly glycocholic and tauro-
cholic acids derived from cholic acid through an oxidation
process in which the oxidizing substance plays the predomi-
nating role. That an oxidation process also occurs in a nerve
during functional activity is suggested by the following lines
of Mathias Duval: "Direct experimentation has shown that the
functionating nerve is the seat of increased combustion; this

534 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

is accompanied by the liberation of heat, the presence of which
Schiff has demonstrated even up to the nerve-centers, under
the influence of fear, of excitation of the senses, of any cause
— in a word — which produces cerebral activity."

Lecithin — "a conspicuous component of the brain, nerves,
yelk of egg, semen, pus, white blood-corpuscles, and the elec-
trical organs of the ray" — suggests its identity as at least one
of the sources of energy we are seeking by the fact that if
merely allowed to stand at the ordinary temperature its solu-
tions acquire an acid reaction and are decomposed. In the
intestines it sometimes breaks up into its constituents: fatty
acids, glycerin, phosphoric acid, and cholin (Ho well). Neurin
is, in reality, cholin, and therefore a decomposition product of
lecithin. As previously stated, Tappeiner31 obtained fatty acids
as a result of cholic-aeid oxidation. These facts, of course, are
only cited as mere landmarks to indicate that we are dealing
with oxidizable bodies. As far as the nerves themselves are
concerned, therefore, it seems probable that we have in lecithin
an agency capable, by the character of its molecule, — i.e., car-
bohydrates, phosphorus, etc., — of acting as a potent source of
working energy when brought into contact with the oxidizing
substance; and in cholesterin the main waste-product of nerve-
catabolism.

Admitting, then, that we have in the lecithin of myelin
a body capable of acting as a source of energy in a way similar
to myosinogen in muscle, how does the oxidizing substance of
the blood-plasma reach it? The nodes of Ranvier and the
neurilemma that covers them allows silver stains to reach the
axis-cylinder, but the myelin itself does not permit of this.
This suggests that the nodes themselves — i.e., the rings form-
ing them — may allow the blood-plasma to filter through them,
thus bringing the oxidizing substance in immediate contact
with the axis-cylinder. The finer anatomy of nerves indicates
that such may be the case. Indeed, the nodes referred to occur
at regular intervals, and separate the nerve, as is well known,
into as many segments, which recall, in a measure, the muscle-
fiber and the liver-cell or, at least, features characteristic of
both these structures. If the blood-plasma can penetrate the

» Tappeiner: Zeitschrift fiir Biologic, Bd. xii, S. 60, 1876.

THE PHYSIOLOGICAL CHEMISTRY OP NERVES. 535

nodes of Eanvier as do stains, there only lies between it and
the axis-cylinder an extremely delicate layer of protoplasm, —
Mauthner's sheath, — which in no way would impede the en-
trance of the fluid into the axis-cylinder itself.

The term "cylinder" suggests the tubular shape of the
latter: in accordance with Remak's view that it consists of a
delicate, longitudinally striated tube, filled with an albuminous
liquid. The prevailing view, however, is that of M. Schultz,
who considers the axis-cylinder as made up of fibrils united
by an intervening unknown substance. This seems to us to
vividly recall the arrangement of muscular fibers as regards
their relation with the blood-plasma: i.e., minute fibers into
which the plasma may freely enter. Again, we must not lose
sight of the fact, in this connection, that the axis-cylinder is
nothing but the elongated axon of a neuron, and that the
fibrilla3 now referred to, therefore, represent the intimate
structure of a neuron's axon. Now, as Schaf er holds that these
fibrillae are extremely fine tubes filled with fluid, and as the
character of this fluid is not known, we have good reason to
believe that they are channels for the blood-plasma: i.e., for
the oxidizing substance.

But there is another feature which points to the axis-
cylinder as a channel for the oxidizing substance: i.e., the fact
that the so-called "medullary sheath" — i.e., the myelin itself —
contains a supposed "supporting frame-work." The strias rep-
resenting them were at first termed "clefts" or "incisures" by
Schmidt, Lautermann, and others, but Eanvier considered
them as protoplasmic septa which subdivide each internodular
segment of the nerve into several conico-cylindrical cham-
bers. W. H. Wynn,32 who gives an excellent review of this
subject and the results of personal researches, refers to those
of Rezzonico33 and Golgi,8* who "from the examination of fibers
treated by a mixture of bichromate of potash and osmic acid,
and afterward by nitrate of silver, find that each cleft is
occupied by what appears to be a thread of darkly-stained
substance passing spirally around the fiber. They consider," he

88 W. H. Wynn: Journal of Anat. and Physiol., April, 1900.
"Rezzonico: Archivio per le Sci. med., Torino, vol. iv, 1880; and Gazzetta
med. ital. lomb., Milano, vol. i, 1879.

8* Golgi: Arch, per le Sci. med., Torino, vol. iv, 1880.

536 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

adds, "that the supporting frame-work of the sheath consists
of a chain of funnels surrounding the axis-cylinder, each fun-
nel being formed by a spiral thread." Tizzoni35 "believes
that there is but one net-work closely investing the axis-
cylinder, and that it is in connection with the slits of Lauter-
mann." McCarthy is stated to have shown that, "after a
nerve has been hardened with picric acid and ammonium
chromate, the medullary sheath contains minute, rod-like
structures, which pass radially between the axis-cylinder and
the primitive sheath so as to give the cross-section of a fiber
the appearance of a wheel. The rods stain with carmine and
haematoxylin, which do not stain the myelin. It is not possible
to isolate the rods as separate elements, for they are not dis-
tinct from one another, but united." Finally he refers to the
fact that Lautermann, von Stilling, Roudanowski, and Mc-
Carthy all believe that there is "a system of hollow canals in the
sheath of the axis-cylinder," and himself reaches the conclu-
sion that the cones they form are protoplasmic, and not com-
posed of neuro-keratin, as is usually held. He divides "each
cone into six segments placed at regular distances apart and
converging from the primitive sheath to the axis-cylinder."
This is well shown in the annexed illustration, reproduced from
his paper. If we now consider the segments as canaliculi
leading from the axis-cylinder, we can readily see how the
blood-plasma can penetrate the myelin and its oxidizing sub-
stance, and these bodies carry on, when brought into contact,
a reaction similar to that which occurs in muscle-fiber. Indeed,
if the various features enumerated are collectively considered,
it will become apparent that the myelin, or white substance of
Schwann, when in contact with the oxidizing substance of the
Hood-plasma undergoes a reaction in which chemical energy is
liberated.

When we consider that the axis-cylinder is, as stated, the
continuation of a neuron's axon, it is not difficult to account
for the various phenomena, known under the general term of
"nerve-degeneration," — i.e., the disorganization of myelin, the
dissolution of the myelin, etc., — at the distal end of a nerve,

'Tizzoni: Archivio per le Sci. med., vol. iii, fasc. 1, 1878.

THE PHYSIOLOGICAL CHEMISTRY OF NERVES.

537

when the latter has been cut. Very suggestive, in this connec-
tion, are the following lines by Professor Barker36: "Waller
proved that if a motor nerve was severed there resulted com-
plete degeneration of the fibers in the peripheral end, even

DIAGRAM OF RELATION BETWEEN LONGITUDINAL AND TRANSVERSE
SECTIONS, SHOWING CONES CUT ACROSS AT DIFFERENT LEVELS.

1, at base of cone; 2, through middle of cone; 3, through apex of
cone; 4, through interval between two cones. In 1, 2, and 3 the cone
segments and protoplasmic sheaths are seen. In 4 only the thin pro-
toplasmic sheaths beneath primitive sheath and around axis-cylinder are
visible. (W. H. Wynn.)

to the muscles which they govern, the central end remaining
apparently intact. As a matter of fact, the changes charac-
teristic of the Wallerian degeneration could not, as a rule,
be traced farther in the central end than to the first node
of Kanvier." Stewart37 states that "in the degenerated nerve

»« Barker: Loc. cit., p. 740.

87 Stewart: "Manual of Physiology," p. 607.

538 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

the substances soluble in ether are relatively increased owing,
in part, to fatty degeneration of the axis-cylinder," and that
"the percentage of phosphorus is markedly diminished (Mott
and Barratt)."

Another process which seems to acquire a certain degree
of light is nerve-regeneration. It is obvious that if we grant
the axis-cylinder, as the extension of the axon, all functional
and nutritive attributes, we may easily explain peripheral
nerve-degeneration, but not regeneration, the peripheral seg-
ment being unprovided for by reason of the section. We know,
on the contrary, that a piece of the nerve must be removed in
order to prevent reunion, and that otherwise in two or three
weeks, and often earlier, its functions will be restored. New
cylinders and fibrils grow, acquire myelin, and, perhaps, guided
and assisted by (nucleated) neurilemma, soon meet those of
the peripheral segment and become connected with them.
Physiological functions of a normal kind must underlie this
process even in the peripheral end of the nerve; otherwise
union would not take place. Finally (we can only refer to a
few of the more prominent processes involved in the vast sub-
ject now claiming our attention) the functional phenomena
that follow after division of the cord distinctly indicate the
continuation of nutrition and the functional activity — though
impaired — in the distal fragment. Foster, for instance, says:
"In the mammal (dog) after division of the spinal cord in the
dorsal region regular and apparently spontaneous movements
may be observed in the parts governed by the lumbar cord.
When the animal has thoroughly recovered from the operation
the hind-limbs rarely remain quiet for a long period of time;
they move restlessly in various ways; and, when the animal
is suspended by the upper part of the body, the pendent hind-
limbs are continually being drawn up and let down again with
a monotonous rhythmic regularity suggestive of automatic
rhythmic discharges from the central mechanisms of the cord.
In the newly-born mammal, too, after removal of the brain
movements apparently spontaneous in nature are frequently
observed. But all these movements, even when most highly
developed, are very different from the movements, irregular
and variable in their occurrence, though orderly and purposeful

THE IDENTITY OF NEUROGLIA. 539

in their character, which we recognize as distinctly voluntary."
Indeed, the nervous energy that myelin and the oxidizing sub-
stance procure is that which allows a frog deprived of its
hemispheres and its middle brain "to sink in water as though
the animal were of lead."

The axis-cylinder composed of fibrils into which blood-
plasma penetrates being continuous with the axon of a neuron,
we are brought to realize the nature of the parallelism between
the functional phenomena of the latter and those of the supra-
renal glands to which we have already referred. But we must
not lose sight of the fact that each "medullated" nerve-fiber
is divided by the nodes of Ranvier into as many subdivisions,
and that each internodal segment receives its own supply of
plasma. Does the neuron receive its supply through this chain
of segments, or, rather, through the axis-cylinder that passes
through them? That the former mechanism alone prevails is
improbable, since so prominent a part of the entire structure
as its cell-body, the seat of its nucleus, would hardly be sup-
plied in so indirect a manner. The very importance of its
functions betokens the existence of direct supply. Does such
a vascular system exist? Fortunately, we have not far to seek.

THE CIRCULATION OF THE NEURON. — Barker, in a review
of the facts that have been adduced for or against the neuron
doctrine,38 concludes that "it may be said, with fairness, that
the control instituted by hundreds of histologists in various
parts of the world has practically in every instance in which
the method of Golgi or the method of Ehrlich has been em-
ployed gone to confirm the conception that the neuron is a
unit in the sense of Waldeyer." The latter investigator's
words, giving the gist of his doctrine, are also quoted: "If
we review the main advance, made certain by the anatomical
investigations discussed, it lies, in my opinion, in the sharper
limitation, now possible, of the anatomical as well as the func-
tional elements of the nervous system (for such we have to
consider the nerve-units-neurons), and also the discovery of
collaterals, with their end-arborizations, by Golgi and S.
Ramon y Cajal." The following lines of Waldeyer's are also

Barker: American Journal of Insanity, July, 1898.

540 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

quoted: "If we assume, with Golgi and B. Haller, the existence
of nerve net-works, the conception is somewhat modified, but
we can still retain the nerve-units . . ." — all of which
tends to show that, while the neuron doctrine stands on a solid
foundation, there is a stumbling-block in its way which has not
as yet been removed. Especially is this true since the investi-
gations of Apathy, of Naples, who, after several years' study,
has unquestionably demonstrated the existence of a net-work
of what he terms "neuro-fibrils."

That Apathy's "neuro-fibrils" as well as Golgi and Haller's
nerve net-works are not nerve-elements, but fine capillaries
which serve for the circulation of blood-plasma, seems to us
probable. In the following extracts the italicized words will
serve to call attention to the various links between these struct-
ures and others that we have analyzed. Professor Barker sum-
marizes Apathy's views as follows: "Apathy has been convinced
for some twelve years that the nervous system is composed of
two varieties of cellular elements entirely different from each
other: nerve-cells and ganglion-cells. The nerve-cells, the
architecture of which is quite in accord with that of muscle-
cells, give rise, he thinks, to neuro-fibrils. A neuro-fibril, in
turn, passes out of a process of a nerve-cell and then goes through
a number of ganglion-cells, and ultimately, after leaving the last
ganglion-cell with which it is connected, passes more or less
directly to a muscular fiber or to a sensory cell. The neuro-
fibrils are, as conducting substance for the nerve-cells, what the
muscle-fibrillce are as contractile substance for the muscle. The
pathways to be followed by the neuro-fibrils are predestined
from the earliest embryonic stages, for they correspond, ac-
cording to Apathy, to the intercellular protoplasmic bridges"
That we have all required elements in support of our belief ia
evident; we have seen that muscle-fibers are, in reality, deli-
cate tubes; that vascular channels for the transmission of
blood-plasma should be protoplasmic is as obvious as is the
need of their penetrating into and out of the cells.

What appears to us as conclusive evidence is indirectly
afforded by the deductions of Ehrlich, suggested by his study
of the methods of staining living nerve-cells and their processes
with methylene-blue. "Ehrlich found," says Barker, "that by

THE IDENTITY OF NEUROGLIA.

541

injection of a solution of methylene-blue dissolved in salt solu-
tion intra vitam into the blood-vessels of an animal, the axis-
cylinders of many of the nerve-fibers (see Fig. 1), as well as
numerous (particularly sensory) nerve-endings (see Fig. 2),

Pia. 1. — NERVE-FIBERS FROM A FROG INJECTED WITH METHYLENH-
BLUE (METHOD OF EHRLICH). (After Kolliker.)

The axis-cylinders are stained dark blue. In places the myelin
sheath is somewhat stained. The nodes of Ranvier and the divisions of
the fibers at some of the nodes are well shown.

were stained after a time, when exposed to the air, an intense-
blue color, the other tissue-elements remaining little or not at
all affected/' It seems clear that, if a solution introduced
through blood-vessels can stain the axis-cylinders, the liquid

542 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

within the latter must be more or less a continuation of that
in the hlood-vessels. Again, we have suggested that the blood-
plasma, including its oxidizing substance, was the liquid in the
axis-cylinders; that this is true is shown by Ehrlich's observa-
tion that "the conditions in the nerve-structures essential to
the methylene-blue reaction" were, he thought (1886): "(1)
oxygen saturation; (2) alkalinity." We have shown that these
are the essential attributes of blood-plasma.

Fio. 2. — SENSORY NERVE-ENDINQ STAINED WITH
(METHOD OP EHRLICH) IN THE EXOCARDIUM OF THE LEFT AURICLE
OF A GRAY RAT. (After Smirnow.)

This seems to us to afford an insight into the physiological
chemistry of the axis-cylinder of the neuraxon when a short
distance below the latter it has become a medullated nerve.
Indeed, the prevailing view that the myelin represents a pro-
tective and insulating coat may at least be said to be open to
doubt, especially when coupled with the facts that its chemical
composition is unknown, and that there is another external coat:
the neuro-keratin neurilemma, which suggests, by its composi-
tion, that it is an isolating covering and that it also fulfills this

THE IDENTITY OP NEUROGLIA. 543

role in non-medullated nerves. That the myelin is the seat of
a combustion process during which heat is liberated and a de-
composition product, cholin, is formed, we have seen. If we
now consider the composition of the active component of
myelin, lecithin, i.e., carbohydrates and phosphorus, and its
analogy, as regards carbohydrates, to myosinogen, the prob-
ability that it serves as a source of energy, as does the latter
when in contact with oxygen, suggests itself. That such is the
case, however, is shown by the fact that the contents of the
neuraxon or axis-cylinder fulfills the conditions necessary for
methylene-blue staining, as laid down by Ehrlich, i.e., oxygen
saturation and alkalinity, the characteristics of blood-plasma.
Indeed, it seems to us permissible to conclude that: —

1. Myelin, or the white substance of Schwann, is to nerve-
structure what myosinogen is to muscle-fiber: i.e., its immanent
source of energy.

2. The axis-cylinder and the canaliculi derived therefrom
are made up of fibrils that serve as channels for blood-plasma.

3. A part of this Nood-plasma penetrates into the axis-cylin-
der through Ranvier's nodes.

4- Lecithin, a body composed mainly of hydrocarbons and
phosphorus, the active constituent of myelin and a prominent com-
ponent of the electric organ of the ray, when exposed to the action
of the oxidizing substance liberates energy: i.e., nervous energy.

Continuing our quotations from Professor Barker's arti-
cle, we will introduce the various points of comparison which
appear to us to sustain our interpretation of Apathy's neuro-
fibrils. "Inside the ganglion-cells a reticulum of fine fibrils
derived from the neuro-fibrils in transit can be stained a beau-
tiful deep-violet color by Apathy's chloride-of-gold method."
That the latter method can be considered as similar in action
to the methylene-blue method and that the stain follows the
same channels and affects the same chemical constituents of
the plasma is shown by the following remark of Professor
Barker's: "With a little care and a good sample of methylene-
blue the nerve-endings and the axis-cylinders of medullated
fibers, with which they are continuous, can be stained in a
way far surpassing in constancy and completeness the best re-
sults of the uncertain gold-chloride procedure." As the methy-

544 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

lene-blue and a modified chloride-of-gold stains were those
mainly used by Apathy, no confusion can occur on this score.

Indeed, if we convert all of Apathy's neuro-fibrils into
minute capillaries, their identity as inherent parts of the gen-
eral circulation is placed on a solid foundation by the following
remark of Professor Barker's: "The doctrine of the fibrillary
nature of the axon and unstainable portion of the protoplasm
of the nerve-cell has recently received support from the studies
of Lugaro39 and Levi.40 The former, too, in his studies of the
nerve-cell under pathological conditions — for example, after
poisoning with lead and arsenic — finds that the fibrils may be-
come very distinct in the nerve-cells." That this directly points
to the one system through which the morbid changes can occur,
i.e., the adrenal system, and that it precisely coincides with the
foregoing remarks bearing upon this system, is evident.

The similarity of the neuro-fibril, on the one hand, to the
axis-cylinder and its cell-body extensions, on the other, now
becomes a normal consequence. "Each neuro-fibril is," Apathy
states, "made up of a large number — near its origin, at any rate
— of 'elementary fibrils/ and in the course which it follows ele-
mentary fibrillaB are being given off at short intervals until
finally the neuro-fibril itself may be reduced to a single ele-
mentary fibril." The fibrillary structure of an axis-cylinder is
as clearly reproduced here as it can well be; the giving off of
fibrils but typifies the irregular distribution of "non-medul-
lated" nerve-fibers, and particularly those of the "sympathetic"
system.

All this recalls a structure which appears to us to be inti-
mately connected with the general circulation, the neuraxon
and its cellular extensions, and Apathy's neuro-fibrils — all
being considered as component parts of the general vascular
system: i.e., Virchow's neuroglia.

The prevailing view concerning the role of this structure
is that it affords a supporting frame-work for the nervous ele-
ments. Both in the white matter and gray matter the medul-
lated nerve-fibers are separated one from the other by a net-
work of glia-fibers. In the gray substance, however, the neu-

89 Lugaro: Rivista di patol. nerv. e mentale, vol. i, 1896.
*° Levi: Rivista di patol. nerv. e ment., vol. 1, 1896.

THE IDENTITY OF NEUROGLIA. 545

roglia, though present in greater abundance, as a rule, than
in the white substance, varies considerably, the net-work of
fibers being especially thick in certain parts. "The neuroglia
is present in greatest abundance in the gray matter immedi-
ately surrounding the central canal of the cord and the ven-
tricles of the brain (the ependyma, as it is called)," says
Stewart41: a suggestive feature in connection with the views
submitted in the present chapter. The neuroglia-cells, as is
well known, are of two kinds: those provided with mossy proc-
esses and those that have smooth extensions. A large number
of investigators still consider that the latter represent true
processes, and that, by freely anastomosing, they make up the
mesh-work which surrounds the nerve-cells and their prolonga-
tions. Eanvier, however, after a searching study of the sub-
ject, was led to conclude that the smooth processes of these
(stellate) glia-cells, were in reality neuroglia-fibers which
merely passed through the latter in all directions, without
forming part of the cellular structure per se. We have seen
that Apathy's neuro-fibrils, when they left the "nerve-cell,"
also passed through the cells after forming a reticulum in the
latter: a feature which suggests that Apathy's neuro-fibril and
the neuroglia-fiber may be structurally similar.

It was formerly thought that neuroglia was a variety of
connective tissue, but this view no longer prevails. Indeed,
so distinct is the latter from neuroglia that the two structures
can be differentiated from each other by the simplest tests;
thus, Eanvier and Malassez found that connective tissue placed
in cold water was not modified after several days' maceration,
whereas neuroglia-fibers were completely destroyed after two
or three days. On the other hand, connective tissue was com-
pletely destroyed by prolonged boiling in water, while neu-
roglia was hardly altered under similar conditions. The sug-
gestive relationship between Apathy's neuro-fibrils and glia-
fibers offers some ground for the belief that glia-fibers are also
nervous elements. This appears to be sustained by the fact
that identical results ensue when nerve-fibers and connective
tissue are submitted to the last of the two tests mentioned, the

« Stewart: Physiology, p. 671, 1900.

546 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

nerve-fiber being merely rendered opaque, while the connective
tissue is destroyed. As the latter is gelatinous, its destruction
is easily accounted for, but why should the nerve-fiber be ren-
dered opaque? Evidently non-medullated fiber had been used
in the test, for medullated fiber is always opaque, while the
non-medullated is translucent. We are led to suspect, in view
of our belief that the axis-cylinder of a nerve contains blood-
plasma, that it is the latter which became opaque during the
boiling process. This is an important feature, for it would
mean that neuroglia-fibers also contain plasma.

The identity of neuroglia-fibers as plasma-channels be-
comes emphasized when the morbid effects of poisons upon
them and upon their cells are studied. Berkley42 found the
cell-bodies of the vascular neuroglia "larger, the protoplasmic
extensions" being "thick and knotty and the arms extending
toward neighboring vessels more prominent than in the normal."
This was noted in slides derived from animals submitted to
experimental acute alcoholic poisoning. When we consider
that alcohol primarily stimulates the adrenal system with great
violence and that the neuroglia closely invests the blood-ves-
sels, it seems permissible to surmise that the thickenings and
knots are dilations due to the centrifugal pressure of the plasma
derived from the capillaries. Especially does this seem prob-
able when the fact that "capillaries, like the intermediary ves-
sels, are tortuous and twisted" is added to the rest of the
evidence. And these alterations, besides an "exceeding abun-
dance of the polynuclear leucocytes in and around the cerebral
vessels," etc., are not peculiar to alcohol, for Berkley emphasizes
the fact — demonstrated for the first time — that the lesions
produced "are very similar to the pathological lesions produced
by other more virulent soluble poisons": additional proof that
the adrenal system underlies the morbid process. Serum-
poisoning was also found to cause great swelling of the bodies
of the vascular neuroglia, "thick groups of these swollen cells"
surrounding "nearly all the vessels of any size in the gray
layers." In ricin poisoning Berkley found the cell-bodies
"universally much larger than the control," and "apparently

43 Berkley: Johns Hopkins Hospital Reports, vol. vi, No. 1.

THE IDENTITY OF NEUROGLIA.

547

swollen, even globular in outline." The extensions were also
thicker and more nodular. "Are these elements, which belong
to the lymphatic apparatus," queries the author, "taking up
detritus from the degenerating protoplasm of the nerve-cells
and becoming engorged?" The conclusion that they belonged
to the lymphatic system was reached because they were found
to contain lymph, which, in the language of Johannes Miiller,
is "blood without its red corpuscles": i.e., Hood-plasma, and,
of course, its due proportion of oxidizing substance.

Evidently then, it is the plasma found in the capillaries
of cellular elements of all organs which, crowded by excessive
back-pressure (due to the marked contraction of the central
vascular trunks induced by the poisons), causes the endothelial
plates or cells constituting the walls of what Berkley terms the
"intermediary vessels" to look, using his words, "as if they
had been subjected to severe strain" as their even walls have
"many irregular bulges in their outlines." That the neuroglia-
fibers are the channels through which it is transmitted is also
suggested by a remark made in connection with the effects on
the gemmules, the retention of which, writes Berkley, "clearly
shows that the swelling comes from within the substance of the
stem and pushes the gemmulse, which are still adherent, out-
wardly and apart."

Does a direct connection between the neuroglia-fibers and
the protoplasmic processes of neurons exist, as suggested by
the fact that Apathy's neuro-fibrils are stated by him to pene-
trate the cell-bodies — provided his fibrils are glia-fibers? To
establish this upon a firm basis, the thickening, bulging, etc.,
found by Berkley upon the vascular neuroglia must also be
shown to extend to the processes of the neuron.

Golgi has expressed the opinion that the greater part of
the nerve-cell — i.e., the entire structure excepting the axis-
cylinder — was concerned with its nutrition: a view which met
with considerable dissension. Among the opponents of this
interpretation was Forel,43 who contended that the entire cell
was simultaneously endowed with nutritional and functional
attributes. This conception was defended by Ramon y Cajal,

*» Forel: Archiv fUr Psychiatrie und Nervenheilkunde, vol. 1887.

548 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

and seems likewise sustained by our analysis, so far. Indeed,
we have seen that the axis-cylinder, if our interpretation is
sound, is able, through the presence of its coat of myelin and
its plasma-containing fibrils, not only to supply chemical' —
probably nervous — energy, but also to undergo nutritional
metabolism. Can we say the same of the cell-body of the

neuron:

We have seen that the fibrils penetrate the nerve-cell, and
that various poisons, as shown by Lugaro and Levi, cause them
to become "very distinct." Referring to the intracellular
distribution of the fibrils, Barker says of Apathy: "He de-
scribes the finer peripheral neuro-fibrils as follows: They are
seen to enter the cell-body and passing out to the peripheral
part of its protoplasm, there to break up into a complicated
plexus composed of anastomosing elementary fibrils in the
outer chromatic zone. From this peripheral plexus there pass
through the 'inner alveolar' zone radial branches to the in-
ternal chromatic zone, in which is to be -seen another fine
plexus of elementary fibrils, which, anastomosing and converg-
ing, finally form the single strong motor neuro-fibril, which
passes out of the cell through the very center of its pyrifcrm
process. In other animals studied by Apathy there are cells
with definite dendrites entirely separate from the axon and in
these the cellulipetal neuro-fibrils enter ~by way of the dendrites,
ramify and anastomose freely inside the cell-body, and then,
reuniting, take their exit from the cell by way of the axon. Similar
relations exist in the ganglion-cells of the vertebrates which
he has studied thus far."

This strikingly coincides with the course of the plasma-
fibrils or capillaries as we interpret it. Indeed, if the fibrils
enter the cell, form a plexus therein, and pass out "by the way
of the axon": fibril, plexus, and axon represent a continuous
channel which must contain plasma, since we have ascertained
that the axon contains this fluid. Again we obtain a clear
indication as regards the path of the blood-stream: it enters
by the dendrites and passes out by way of the axon. It is with
the dendrites, therefore, that the vascular neuroglia-fibers
found thickened, globular, etc., by Berkley in his poisoned
animals must be connected. But this fact suggests that these

THE IDENTITY OF NEUROGLIA. 549

structures should likewise present irregular swellings under
the influence of the same agencies, and that the axis-cylinder
should show less, the intracellular formation of plexuses and
anastomoses interposing a harrier to the too free passage of
plasma. That such is actually the case is illustrated by the
annexed plates by Berkley, which represent the lesions found
in the neurons of the poisoned animals to which reference has
been made.

If the protoplasmic processes or dendrites are the first to
bear the brunt of the vascular engorgement, the plasma being
carried to them through fibrils connected with their tips, these
tips or extremities should first show evidence of the expansile
pressure. This is well illustrated in Fig. 1, a "psychical cell
from the second cellular layer of the cortex," which shows, using
Berkley's words, "a few pathological tumefactions on the upper-
most branches of the apices of the apical dendrite. Other-
wise the cell is normal/7 This cell was selected from a section
derived from the brain of an animal poisoned with ricin, death
having occurred in thirty-six hours. A feature of importance,
however, is that it is the main, or apical, dendrite — that giving
off the greatest number of subdivisions — which shows the evi-
dences of engorgement; the extremities of the other dendrites
are not thickened, but they show more or less marked evidences
of engorgement as the main trunk is approached. This ob-
viously suggests that the plasma penetrates the neuron by way
of the main dendrite and that it finds its way into its col-
laterals cellulipetally; in other words, that, instead of also
entering these collateral branches by way of their tips, it is
supplied to them by the main trunk — precisely as if it were
the main stalk of a plant. Of course, this does not mean that
the apices of the collaterals may not subsequently show thick-
enings; being terminals, they should naturally do so when the
pressure exceeds a given limit. This feature is illustrated by
Fig. 2, especially by the larger stem of the main trunk. This
cell, a projection-cell from the second layer of the cortex, shows
the effects of forty-eight hours' ricin poisoning: i.e., of some-
what more prolonged engorgement.

Worthy of special notice, also, is the fact emphasized by
Berkley (referring to Fig. 2), that: "there is now distinct

550 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

diminution of the gemmulae wherever the swellings are found"
— which suggests that these minute ball-tipped projections from
all collaterals are structurally similar to them, and that, when
the engorgement exceeds in centrifugal pressure the resistance
of a given area, the walls of the latter, including the gemmules,
are more or less flattened out. Suggestive, likewise, is the fact
that all the gemmules stand out boldly in both preparations.
As many as thirty-six or forty-eight hours having elapsed be-
fore death ensued, the animals were evidently submitted to a
primary period of intense stimulation, during which the gem-
mules were overdistended to such an extent as to cause them
to lose their retractile property. Indeed, the sudden cessation
of adrenal functions and consequent death must have left the
cerebral structures much as if the animals had been suddenly
killed.

Of marked interest in Fig. 3 is the presence at the ex-
tremity of the main, or apical, dendrite of a section of what
appears to us to represent a fiber or capillary from which the
neuron with which it is connected might have derived its blood-
supply. The fact that it crosses its path suggests that the den-
drite itself may be a branch of the vessel. Berkley describes
this neuron as follows: "Projection-cell of the long apical
process variety, showing numbers of large swellings of the pro-
toplasm of the apical dendrite, thinning of the protoplasm of
the stems in the interval between the nodules, and considerable
loss of the gemmulse along the margins. The lateral branches
have mainly disappeared. The basal processes are retained
intact."

The nodules seem to us to also illustrate the process
through which the collateral fibers become detached from the
main stem, as shown by the denuded cells represented by Figs.
4 and 5. The thinning of the plasma between the stems would
account for the manner in which the lateral branches are de-
tached, viz.: when the apical dendrite becomes sufficiently
engorged the plasma ceases to circulate in one or more of the
nodules, and the intervening protoplasm, failing to be nour-
ished, disintegrates. That the basal processes should be the
last to yield in this cell (corresponding in this with the condi-
tion of the same stems in Figs. 1 and 2) seems but normal

Fig 5

LESIONS IN THE NEURDNS DF ANIMALS AFTER
RICIN FDISDNING-, [Berk1

THE IDENTITY OF NEUROGLIA. 551

when we consider their proximity not only to the cell-body,
which contains a large supply of fibrils, but also to the axis-
cylinder (ax. in the drawings), which is the only centrifugal
channel through which the engorged plasma can escape.

A feature of the cells shown by Figs. 1, 2, and 3 which
strikingly links them to the adrenal phenomena brought on by
toxics in the general organism is the fact that, although they
are derived from animals in which the doses of ricin injected
were reduced with each animal, the morbid phenomena as ex-
emplified by each cell in turn are correspondingly intensified.
In other words, the adult rabbit represented by Fig. 1 was given
subcutaneously a dose of 0.5 milligramme, and death occurred
in thirty-six hours: the cell only shows apical lesions. The
second adult rabbit was given the half of the previous dose,
i.e., 0.250 milligramme, and death occurred in forty-eight hours:
the entire apical dendrite and two of the collaterals are dis-
tinctly involved. The third adult rabbit was given the half
of the last dose: i.e., 0.125 milligramme, and death occurred
in seventy-two hours: the apical dendrite is markedly studded
with thickenings, and all but two of its collaterals have dis-
appeared. It is, perhaps, unnecessary to lay stress upon the
fact that this is due to the prolongation of the stage of adrenal
stimulation: i.e., of the time during which central vascular con-
traction caused peripheral capillary engorgement. And this
need not be ascribed only to ricin. Berkley emphasizes this
assertion when he says: "The poison ricin, whose action is in
many ways similar to that of many toxalbumins of bacterial source,
is capable of exerting a deep and extensive degenerative in-
fluence on the protoplasm of the nerve-cells of the brain."
And this may further be extended to other toxics, for he also
says: "Poisoning with alcohol in considerable doses, continued
over a moderate time, will produce decided and "ascertainable
lesions of the nutrient structures and nervous elements of the
cerebrum, very similar in character to the pathological lesions
produced by other more virulent poisons/' We thus have in-
controvertible evidence that the unity of action displayed by
all poisons, owing to the fact that the dynamic source of the
phenomena witnessed is the one adrenal system, also extends
to the nervous system. That the alterations in the elements

552 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

of the neuron should be due to the same centrifugal pressure
that prevails in the capillaries of all peripheral structures dur-
ing the stage of adrenal stimulation seems undeniable. Finally
the fact that phenomena witnessed occur under the influence
of poisons in general affords the complemental evidence in
favor of our contention that a neuron is directly connected with
the circulation by one or more of its dendrites, which serve as chan-
nels for Hood-plasma.

Even the haemorrhages brought on by adrenal overactivity,
epistaxis, haematemesis, haematuria, etc., are exemplified in the
engorged neuron shown in Figs. 6 and 7, and also from Berk-
ley's series. The observation of Apathy's, -therefore, that his
"cellulipetal neuro-fibrils enter by way of the dendrite, ramify
and anastomose freely inside the cell-body, and, then reuniting,
take their exit from the cell by way of the axon" finds its appli-
cation if, as interpreted ~by us, his neuro-fibrils are considered as
Nood-plasma channels.

Still, the identity of the fibrils in the cell-body as blood-
capillaries has so far only been suggested by the fact that they
are continuous with the plasma-containing axis-cylinder and
fibrils. While this constitutes strong evidence, the fact that
they are blood-channels can only be determined by ascertaining
the nature of the process in which the plasma takes part. This
may probably be done by inquiring into the composition of a
neuron's ground-substance.

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON. — What
is the nature of the ground-substance: i.e., that between the
fibrils? After reviewing this subdivision of the general sub-
ject Barker says: "A neuron is made up, like all other cells,
of nucleus and protoplasm. In the latter a centrosome and
an attraction-sphere are present; at least it has been dem-
onstrated in a certain number of nerve-cells. The protoplas-
mic portion of the cell can be roughly divided into a periph-
eral exoplasmic portion and a central endoplasmic portion.
In neurons, as in muscle-cells, though less distinct in the
former than in the latter, there is a tendency to a fibrillary
structure, the fibrillaa tending to occur in the peripheral ex-
oplasmic portion of both nerve- and muscle- cells rather than
in the endoplasmic portion of the protoplasm. In both exo-

/'/</. (1

LESIONS IN THE NEURONS DF' ANIMALS AFTER
RICIN FDISDNING-, {Berkley,]

[Jo/lux Jfopkins 1 Instil,, I /.Vy,o/7.v.]

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON. 553

plasm and endoplasm there can be made out in tissues which
have been fixed a more or less homogeneous ground-substance
in which are deposited larger and smaller masses of a gran-
ular nature. The ground-substance corresponds in tissues
fixed with alcohol and stained by the methods of Nissl and Held
to the 'unstainable substance7 of Nissl, and the masses of gran-
ules to the 'stainable substance7 of Nissl and the pigment.

"The 'stainable substance' of Nissl in healthy animals of
the same age and species, with the same method of fixing and
staining, is tolerably constant in appearance and arrangement
in the cell-bodies and dendrites of the same group of nerve-
cells: a fact of extreme importance for nerve-anatomy and
pathology. The axons appear to be entirely devoid of the
'stainable substance' of Nissl. Whether the stainable sub-
stances represent bodies precipitated from solution through the
action of reagents or bodies pre-exist ent, though invisible, first
brought into view through the action of fixing or staining re-
agents in the hardened tissues, in either case they appear to
yield the chemical tests characteristic of the group of nucleo-
albumins. Whether the staining reaction characteristic of the
stainable substance depends upon chemical relations or upon
purely physical conditions must, for the present, remain un-
decided.

"The 'unstainable portion7 of the cell-body, — that is, the
ground-substance, — though probably functionally much more
important than the stainable, is not so well understood; its
nature and structure are still as obscure as those of protoplasm
in general." Still, the link with features previously brought
out by our analysis now seems within reach.

Held has maintained that the stainable Nissl bodies repre-
sent simply substances precipitated from solution by the action
of fixing mixtures; Fischer was led to the same conclusion.
Barker says, in this connection, that he repeatedly convinced
himself of the homogeneous appearance of the protoplasm of the
nerve-cell when it is examined immediately after the removal
from the living body. That the ground-substance is homo-
geneous, and that the unstainable portion is a product of dis-
sociation of some of its constituents, are therefore probable.
But the stainable portion we have seen has yielded the chemical

554 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

tests "characteristic of the group of nucleo-albumins." We are
not, therefore, dealing with the group of nitrogenous fats to
which lecithin, the main constituent of myelin, belongs, but
with what probably represents, not a mere artifact, but an in-
dividual constituent which is precipitated by the fixing mixt-
ures. It is important to determine, therefore, the exact na-
ture of the Nissl "bodies," and perhaps by a process of exclusion
ascertain that of the unstainable substance.

"Held," says Professor Barker, "undertook a most careful
and exact chemical study of the granules in alcohol tissues.
Thus, he found that the Nissl bodies are insoluble in dilute
and concentrated mineral acids, in acetic acid, boiling alcohol,
cold or boiling ether, and in chloroform. On the other hand,
they are easily soluble in dilute and concentrated alkalies.
With pepsin and hydrochloric-acid digestion he found that the
ground-mass of the protoplasm vanished and that the Nissl
bodies alone remained undigested: the reverse of what occurred
on treatment with an alkali. The Nissl bodies yielded no reac-
tion with Millon's or Adamkiewicz's reagent. Held obtained,
however, slightly positive results with Lilienfeld and Monti's
microchemical test for phosphorus, and a considerable quantity
of the gray matter of the spinal marrow after digestion with
pepsin and hydrochloric acid examined by Siegfried, of the
physiological laboratory of Leipzig, showed the presence of
phosphorus. Held concludes, however, from these various re-
actions, that the Nissl bodies belong to the group of the nucleo-
albumins: a view which agrees with the investigations of
Halliburton, who found in the gray matter a nucleo-albumin
which coagulated at from 55° to 60° C. and which contained
as much as 0.5 per cent, of phosphorus."

The large proportion of phosphorus further sustains the
preponderating role that the oxygen of the plasma must play
in the neuron, owing to the activity of the reaction between
these two elements. It also indicates a close relationship be-
tween the neuron and all other cellular structures of the or-
ganism. Thus, referring to Held, Barker says: "He asserts
that in numerous experiments with his method (formol freez-
ing) he has found in the most different organs constituents of
the cell-body which behave not only tinctorially, but also mor-

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON. 555

phologically, exactly as the stainabk substance in nerve-cells.
He described them in gland-cells, liver-cells, in cells of the
pancreas, in the cells of some sarcomatous tumors, in certain
connective-tissue cells, but especially in normal and pathological
lymph-glands. Cajal44 also asserts that the stainable substance
of Nissl is not specific for the nerve-cells, as he has demon-
strated its presence in certain of the leucocytes and of the con-
nective-tissue elements." Nissl's bodies appear to us, therefore,
as constituting an organized component of the ground-sub-
stance of the neuron, a nucleo-albumin rich in phosphorus,
which, judging from its similarity to a large number of cellular
structures elsewhere in the organism, represents the cell-struct-
ure itself, precisely as is the hepatic cell when free from glyco-
gen, bile, or the agencies from which these are derived. It is
to the neuron what the neurilemma, Mauthner's sheath, etc.,
are to the internodal segment of a nerve, and includes — as
does the protoplasmic membrane of Schwann — the nucleolated
nucleus.

The unstainable portion must be the equivalent of myelin:
the white substance of Schwann. We have seen that this is
also unstainable. Even picrocarmine does not stain it, and
Eanvier states that the axis-cylinder becomes stained at the
nodes because there is no myelin in this region of the nerve.
The similarity between myelin of the nerves and that of the
cerebro-spinal system is emphasized by Foster when he says:
"Obviously the fat of the white matter of the central nervous
system and of spinal nerves (of which fat by far the greater part
must exist in the medulla, and for nearly the whole of the
medulla) is a very complex body indeed, especially so if the
cholesterin exists in combination with the lecithin, or cerebrin
(or protagon). Being so complex, it is naturally very unstable,
and, indeed, in its stability resembles proteid matter." This
also suggests, however, that protagon, a nitrogenous body con-
taining phosphorus isolated by Liebreich from brain-substance,
may be the unstainable substance we are seeking. Hoppe-Sey-
ler and Diakonoff, having found it to be composed of lecithin
and cerebrin, the direct connection with the former is not re-

** Cajal: Revista trimest. micrografica, vol. i, No. 1, March, 1896.

556 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

moved. Protagon readily breaks up into its constituents.
Howell states that, "while protagon seems to be regarded as
the principal form in which lecithin occurs in the brain, simple
lecithin is believed to be present in the nerves and other or-
gans/' and he refers to Noll,45 who found "the quantity of
protagon in the spinal cord may amount to 25 per cent, of
the dry solids; in the brain, to 22 per cent.; and in the sciatic
nerve, to 7.5 per cent/' That it is difficult to analyze this
question is suggested by his closing remark: "Regarding the
synthesis of lecithin in the body, or the physiological im-
portance of the substance, nothing is known." We have seen
the important role that it probably plays as myelin; its pres-
ence in such large quantities, as a constituent of protagon, in
the cerebro-spinal system plainly points to it as of the unstain-
able ground-substance of the neuron.

What is the role of cerebrin, which, with lecithin, forms
protagon, and from which it is readily separated? In a study
of the chemistry of nerve-degeneration Halliburton and Mott46
refer to the fact that they had previously shown that in general
paralysis of the insane "the marked degeneration that occurs
in the brain is accompanied by the passing of products of de-
generation into the spinal fluid. Of these," say the authors,
"nucleo-proteid and cholin are those which can be most readily
detected. Cholin can also be found in the blood." Having
continued this work, they now find "that this is not peculiar
to the disease just mentioned, but that in various other de-
generative nervous diseases (combined sclerosis, disseminated
sclerosis, alcoholic neuritis, beriberi) cholin can be also de-
tected in the blood." The tests that they employed were
mainly two: (1) "the obtaining of the characteristic octahedral
crystals of the platinum double salt from the alcoholic extract
of the blood"; (2) a physiological test — and a very interesting
one, we may add, if the functions of the suprarenal system
are included in the process, namely: "the lowering of blood-
pressure," which the authors consider as "partly cardiac in
origin and partly due to dilation of peripheral vessels," and

"Noll: Zeitschrift fiir physiol. Chemie, Bd. xxvii, S. 370, 1899.
*• Halliburton and Mott: Journal of Physiology, Feb. 28, 1901.

THE PHYSIOLOGICAL CHEMISTRY OP THE NEURON. 557

"which a saline solution of the residue of the alcoholic extract
produces." This fall "is abolished," they further state, "if the
animal has been atropinized." We may incidentally remark
that these few lines embody the pathogenesis of most neuroses
attended with degeneration, — if our views are sound, — since
we have here the phenomena incident upon arrest of function,
auto-intoxication, and toxic suprarenal insufficiency. But di-
rectly bearing upon the subject in point is the evident iden-
tity of cholin as a product of degeneration. It "has its source
in lecithin decomposition and putrefaction," says Howell.
But it is likewise, as we have seen, a waste-product of normal
nervous-tissue metabolism, being eliminated with the bile in a
modified form. That cerebrin is also a product of putrefaction
and of physiological metabolism is suggested by two facts: it
is found in pus-corpuscles and its formula and that of cholin
present considerable analogy. Even taking as standard that
furnished by H. Miiller, which has given rise to considerable
controversy, cerebrin is C17H33N03 , while cholin is C5H15N02 .
Lecithin, therefore, becomes the functional ground-substance of
the cell-body of the neuron, just as it is in the nerve. Both in
the neuron and its continuation, the nerve, therefore, the vascular
fibrils carry blood-plasma, which, by passing through their walls,
maintains a continuous reaction, of which the phosphorus of
the lecithin and the oxygen of the blood-plasma are main re-
agents and chemical energy the end-result. The relationship
between the vascular fibrils and the ground-substance, nucleus,
etc., is well shown in the annexed familiar engraving.

But lecithin, though a useful product of metabolism, re-
quires in its formation the aid of protoplasmic function, as
does, in the muscle, the elaboration of myosinogen. In the
cell-body this is probably performed, we have seen, by structures
which the Nissl bodies, as nucleo-albumins, represent. Indeed,
in a study of the action of fixatives upon protoplasm Hardy
found47 that, "when a soluble colloid is fixed by the action of
a fixing reagent, it acquires a comparatively coarse structure
in the process, which differs wholly or in part from the struct-
ure of the soluble colloid." Again, that these protoplasmic

47 Hardy: Journal of Physiology, May 11,

558 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

FIG. 3.— SCHEMATIC REPRESENTATION OF THE LOWER MOTOR NEURON.
The motor cell from the ventral horn of the spinal cord, together
with all its protoplasmic processes and their divisions, its axis-cylinder
process with its divisions, side-fibrils or collaterals, and end-ramifica-
tions (telodendrions, or motor end-plates) in the muscle represent parts
of a single cell or neuron, n', Nucleolus. c, Cytoplasm showing the dark-
colored Nissl bodies and lighter ground-substance, d, Protoplasmic proc-
esses (dendrites) containing Nissl bodies. (Rarkcr.)

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON. 559

structures are supplied by a vascular net-work similar to that
of other cellular structures is shown by the observations of
Apathy, who took them for nerve-fibrils. Barker, referring
to this feature of his investigations, says: "As to the relations
of the neuro-fibrils to sensory surfaces, on the one hand, and
muscular tissue, on the other, Apathy makes very definite
statements, especially in the last chapter of his article. A
neuro-fibril entering the cytoplasm of an epithelial cell of a
sensory surface in the leech breaks up (very much as in a
ganglion-cell) into a finer reticulum composed of the elementary
fibrils. A large number of the constituent fibrils, however,
perhaps the majority, leave the cell in order to take part in
the formation of a complicated interepithelial fibril-plexus."
Neuron and nerve, therefore, appear to be similar to other
organs as functional entities and to be subject to the same
laws. Still, we can only state that analogy suggests that a neu-
ron, its dendrites and nerve, in elaborating lecithin, may depend
for their functional activity upon a nuclein rich in phosphorus
found in the protoplasm of which their frame-work is formed
and in the protoplasmic nuclei; . for, as we will see later on,
another source of lecithin exists.

The role of the blood-plasma is so clearly defined in the
foregoing analysis that we deem it permissible to conclude that
all the component parts of a neuron — cell-body, dendrites, axon,
and axis-cylinder — serve as channels for blood-plasma.

Are dendrites provided, as are the cell-body and the axis-
c}rlinder, with myelin? We have seen that, as stated by Barker,
"the stainable substance of Nissl in healthy animals of the
same age and species, with the same method of fixing and
staining, is tolerably constant in appearance and arrangement
in the cell-bodies and dendrites of the same group of nerve-cells."
He also states that "the axons appear to be entirely devoid of
the stainable substance of Nissl"; but Berkley,48 referring to
the nerve-fiber terminals which are extensions of the axon,
writes: "The researches of Flechsig, as well as my own, have
shown that these fine branches are furnished with a thin layer
of myelin nearly to their termination." As this refers to intra-

48 Berkley: Johns Hopkins Hospital Reports, vol. vi, p. 89, 1897.

560 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

cerebral nerve-fibers, we are brought to realize that the entire
nervous system is built upon the same plan: i.e., of fibrils con-
taining Hood-plasma, surrounded by a layer of my din. The main
constituents of these bodies, the oxygen of the plasma and the phos-
phorus of the myelin, are thus brought into contact, and nervous
energy is liberated.

All this seems to us confirmed by the manner in which
many, now paradoxical, phenomena are accounted for: —

The production of nervous energy, not only by the neuron,
but also by the neural myelin, confirms the "avalanche" theory
of Pfluger, which, though at first combated by Marey, was
sustained by the latter after a series of experiments. Pfluger
held that nervous excitation increased along the length of
motor nerves: a view which strongly sustains our own. Duval
emphasizes this fact, and states that, while the stream of im-
pulses— which he terms "molecular vibrations," in perfect
accord with modern physics — travels 28 to 30 meters per second,
it "presents the characteristic of increasing gradually as it is
transmitted, i.e., as it advances in its nervous conductor."
Richet has found that excitation of a sensory nerve was more
intense when transmitted from the periphery than when ex-
citation was applied to a part of the nerve nearer to its center
(Duval). It is evident, therefore, that an accumulation of
energy takes place in sensory as well as in motor nerves.

Our views are also sustained by the evidence afforded by
nerve-degeneration. Quoting Turck's conception, Professor
Barker refers to the Wallerian doctrine as follows: "Convert-
ing the Wallerian doctrine into terms of the neuron concept,
the following law may be laid down: When it has suffered
a solution of continuity, severing its connection with the cell-
body and dendrites of the neuron to which it belongs, the axon,
together with the myelin sheath covering it, undergoes in the
part distal to the lesion acute and complete degeneration. This
degeneration includes, not only the main axon, but also its
terminals, together with the collaterals and their terminals
connected with it." If the gradual increase of energy along the
nerve, just referred to, is considered as a factor of the function
and the sum-total of the energy utilized and is interpreted as
made up of neuron energy plus gradually increased nerve-energy,

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON. 561

the following main facts connected with nerve-degeneration
seem to us to find a ready explanation: —

Section of a motor nerve will cause degeneration of the pe-
ripheral fragment, and atrophy of the muscles supplied by it.
We have emphasized the functional importance of a continuous
supply of nervous energy, both upon the vascular and cellular
elements of any organ.

There is no degeneration of the upper, or proximal, frag-
ment, however, except as far as the first Ranvier node. This
has been ascribed to traumatism, but we can readily understand
now that section through an internodal segment destroys the
mechanism of that segment, the supply of oxidizing substance
failing to reach the myelin through the fibrils and their
canaliculi. Its nutritional or "passive" function is thus ar-
rested.

That the nerve and even its neuron require some of their
own energy to permanently sustain their own life, as empha-
sized by Marinesco,49 especially when long stretches of nerve are
involved, is shown by the fact that if the seat of its ultimate
distribution is destroyed, — a muscle, for instance, — or if it is
disconnected from the latter, the nerve may, as sometimes
occurs after amputations and peripheral neuritis, degenerate,
and the process extend up to and include the cornual cell.
That this does not always occur is doubtless due to the fact
that the subdivisions of a nerve all contribute to the main-
tenance of its life, and that the chances that degeneration of
a long nerve will occur are proportionate to the number of
branches it supplies in its course.

The sensory nerves show the same attributes, but, of
course, in a reversed direction. Section of the posterior root
above a ganglion is followed by degeneration of the dorsal
stump, which may include the extension into the cord. Am-
putation sometimes causes not only atrophy of the peripheral
fibers, but also of the ganglion-cells and their prolongations
in the columns. "The living muscle seems so organized that
without nervous stimulation it can no more live than can the
tropical animal without warmth or the rose without water,"

*» Marinesco: Neurol. Centralbl., Bd. xi, 1892.

562 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

says Morel. How true this is is emphasized by the precaution
Nature takes to nourish the nerve throughout its entire length
and thus to insure the conversion of the chemical energy con-
tained in its myelin and the plasma into nervous energy.

THE MINUTE CIRCULATION OF THE CEEEBRO-SPINAL SUB-
STANCE.— Such a circulation as that suggested by this title is
not thought to exist. Both in the central ganglionic and in
the cortical arterial systems the arteries are now believed to
be "terminal": i.e., to neither supply nor receive any anas-
tomotic branch. They penetrate the cerebral substance to
terminate there. The veins are similarly disposed. Deprived
of valves and muscular tissue, they are likewise considered as
"terminal" in the sense attributed to that word in respect to
the arteries: a normal outcome of the absence of connection
with the latter as supposedly indicated by the impediment
presented to the injection of fluids in them. And yet, how
does the blood, with its corpuscles, find its way from the ar-
teries to the veins? Does it filtrate through the arterial walls,
find its way through the lymph-spaces to the venous walls,
and reach the sinuses? Of course, we have elsewhere in the
organism both the effusion of plasma and the emigration
of corpuscles through vascular walls; but this is a process of
a different kind, and for which the blood-stream only plays
the part of purveyor; it represents the main factor of a repara-
tive and protective function, of which, indeed, the cerebro-
spinal system is a prominent beneficiary when need be. There
is a wide margin, however, between this process and the mech-
anism of circulation, which includes channels beginning at the
heart and ending in this organ, and having for its purpose, not
only to carry oxygen to all parts of the organism, but also to
rapidly remove blood as fast as its oxygen-ratio is being re-
duced. "Terminal" vessels do not satisfy this sine qua non
of perfect metabolism in the cerebro-spinal system, notwith-
standing the presence in the superficial structures of more or
less close capillary net-works. Indeed, the very presence of
these capillaries seems to us to point to these deeper "ter-
minals" as incongruities.

The marked evidences of engorgement so typically shown
by Berkley's illustrations, and to which we have referred, are

THE CIRCULATION OF CEREBRO-SPINAL, SUBSTANCE.

563

characterized by a suggestive feature: i.e., they occur, as far
as the neuroglia is concerned, in the elements adjoining the
blood-vessels or connected with them. Thus, Berkley writes:
"In the silver slides the support elements proper, so far as the
stain shows, present no variations from the control, but, on the
other hand, the vascular neuroglia gives indication that altera-
tions are taking place within its structures, and show consid-
erable variations from control preparations. The cell-bodies
are larger, the protoplasmic extensions are thick and knotty,
and the arms extending toward neighboring vessels are more
prominent than in the normal." As "the capillaries, like the
intermediary vessels, are tortuous and twisted," — evidences of
intense engorgement, further emphasized by the "closely
packed" white blood-corpuscles found in the vascular lumen,
— it seems but logical that the engorged capillary and the en-
gorged neuroglia-fibers should be continuous; otherwise the
latter neuroglia swelling would remain unaccounted for.

Keferring to the spinal cord, Berdal50 states that "the
moment the blood-vessels penetrate into the cord they become
covered, on a level with the perimedullary neuroglia layer, with
a coating of neuroglia, which follows them throughout all their
ramifications and accompanies them along their entire course."
Such a coating over cerebral capillaries would readily account
for the engorgement of both structures to which we have just
referred, since the channel, notwithstanding the alteration in
its external aspect owing to the assumption of an extra coat,
would, after all, be continuous. That such is the case is sus-
tained by the fact that in what has been termed "chronic
ependymitis" — doubtless a condition in which the layer of neu-
roglia becomes permanently engorged — a marked thickening of
the tissue occurs (0. Israel). The increase of blood in the
neuroglia-fibers which this morbid condition involves not only
coincides with the swellings observed by Berkley after various
forms of poisoning, but it is accounted for by the fact that
ependymal neuroglia-cells were found by Marchi to send "a
central extension which penetrates into the optic thalamus,
where it subdivides to become fixed upon the walls of the blood-

Berdal: Loc. tit., p. 193.

M

564 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

vessels" (Berdal). This recalls the interesting feature in Fig.
3 of the plate opposite page 550. In the projection-cell repre-
sented the extremity of the long and irregularly-swollen apical
process is also connected with the wall of what must be a
diminutive blood-channel, if plasma is at all the cause of the
cellular engorgement. Again, the neuroglia-cell, shown below,
copied from an article by Andriezen, to which we will presently
refer,61 may be seen to be directly attached to a vessel. Indeed,
we have Golgf s own testimony to the effect that some of the
protoplasmic extensions of the nerve-cell are attached to neu-
roglia-fibers and to blood-vessels.

Pio. 1.— "A PROTOPLASMIC GLIA-CEL.L FROM A HUMAN BRAIN
(FIRST LATER OF CORTEX)." (Andriezen.)

The manner in which the neuroglia-cells and their fibers
are connected with blood-vessels suggests that they are essen-
tially different structurally, the neuroglia-elements being, not
branches or subdivisions of the vascular system, but nervous
structures which, at a given time during embryological devel-
opment, became affixed to the vascular walls. This is sustained
by the fact that neuroglia is, like all nervous elements, of epi-
blastic origin. Again, there is considerable analogy between
nerve- and neuroglia- fibers. Foster emphasizes this fact when

"i Andriezen: Brain, Winter, 1894.

THE CIRCULATION OF CEREBRO-SPINAL SUBSTANCE. 565

he says: "Since the nerve-filaments, like the neuroglia-fibers,
are very fine, and take, like them, an irregular course, it often
hecomes very difficult in a section to determine exactly which
is neuroglia and which are nervous elements."

What is the role of the neuroglia and how is it functionally
related to the true nervous elements? Suggestive, in this con-
nection, are the following lines of Professor Foster's: "A
medullated nerve-fiber of the white matter of the spinal cord
resembles a medullated nerve-fiber of a nerve in being com-
posed of an axis-cylinder and a medulla; but it possesses no
primitive sheath or neurilemma. This is absent, and, indeed,
is not wanted; the tubular sheath of neuroglia affords, in the
spinal cord (and, as we shall see, in the central nervous system
generally), the support which in nerves is afforded by the
neurilemma."62 This conclusively shows that for a certain dis-
tance, at least, the neuroglia-sheath and the myelin act as coats
for the one axis-cylinder: i.e., for the fibrils containing blood-
plasma. But we have seen that myelin is not the passive in-
sulating substance that it is now thought to be; if our views
are sound, it represents one of the two most important factors
of nerve-composition, and, indeed, the main source of nervous
energy. In modifying the accepted view concerning its func-
tions, however, we have eliminated its role as insulating layer,
leaving nothing but the neurilemma, or external, tubular in-
vesting sheath, for the protection and insulation of the "battery
elements/' as it were, the myelin and its oxidizing plasma. It
is, therefore, this protective and insulating sheath that the neu-
roglia replaces in the white substance of the cord and in "the
central nervous system generally": i.e., wherever the myelin
and its inclosed blood-plasma are present in the cerebro-spinal
axis.

We have seen that, according to Barker, and as shown by
the researches of Flechsig and Berkley, the dendrites of neu-
rons are furnished with a thin layer of myelin nearly to their
termination; while we have shown, — conclusively, we now be-
lieve— that their central canal contains blood-plasma. We have
precisely, therefore, the structure of a nerve, minus its neu-

All italics are our own.

566 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

rilemma. Indeed, the similarity even extends to the subdivision
of the dendritic central canal into fibrils, for Berdal says, re-
ferring to the dendrites: "These prolongations seem striated
longitudinally as is the cell, and appear to be composed of
fascicles of fibrils which are continuous with those of the cellu-
lar body." A single structure is missing, however, that which,
we have just seen, is represented by the neuroglia in cerebro-
spinal nervous elements: i.e., the neurilemma. Obviously, the
absence of a protective insulating sheath around the cell-body
of the neuron and its extensions, considering their functional
importance as generators of nervous energy, becomes absolutely
incompatible with existing conditions, since the myelin would
thus be exposed externally. Indeed, that the cell-body and its
dendrites are supplied with an external sheath is shown by the
following lines of Berkley's63: "Around the body of the cell
we find an insulating mass of fluid contained in the pericellular
lymph-sac, and as a capsule to the sac there appears a slight
condensation of the tissue at this point that would take the
place of a retaining membrane. This membrane apparently
terminates where the first of the gemmulae are thrown off from
the ascending portion of the primordial process, and likewise
at the location where the first buds appear on the basal den-
drites. Does the insulating fluid and covering really end at
this point? In absolute-alcohol sections of the cortex of the
cerebellum taken parallel with the surface and stained with
the anilines, particularly the blue-black, it is quite readily
demonstrable that the thin membrane, which is now undoubt-
edly composed of fine glia- filaments, does not really cease at this
point, but becomes attenuated, and continues to ascend and
cover the protoplasmic prolongations of the cell." This speaks
for itself; the cell-body of the neuron and its dendrites are supplied
with a covering which is to them what the neurilemma is to nerve-
fibers; this covering is similar to that investing these nerve- fibers:
i.e., a sheath of neuroglia.

This only affords, however, information concerning the
neuroglia supplied to the neuron per se, and to the structures
which the axons become a short distance below the cell: i.e.,

"Berkley: Loc. cit., pages 90 and 91.

THE CIRCULATION OF CEREBRO-SPINAL SUBSTANCE. 567

nerves. But we have still to study an important question: i.e.,
the identity of the intermediary fibrils of neuroglia — important
in the sense that it has a certain bearing upon the concordance
between the older views of Gerlach and the modern observa-
tions and conclusions of Golgi. Indeed, if the entire cerebro-
spinal axis is made up (as far as true nervous elements go) of
these medullated glia-covered nerve-fibers and dendrites, we
may well conclude with Gerlach that nerve-cells are united by
an intricate net-work of extremely delicate nerve-fibrils. If,
on the other hand, the cell-body, its dendrites, and its axon
are alone medullated and glia- or neurilemma- covered, the
connection with the vascular system being established by non-
medullated fibrils, we are in accord with Golgi, who denies the
existence of any connection through nervous structures between
neurons.

That Golgi's view prevails is suggested — provided our own
view that fibrils are plasma-channels is accepted — by the fol-
lowing lines by Professor Foster: "The larger part of the gray
matter consists, besides a neuroglia supporting the nervous
elements, of nerve-filaments running in various directions and
forming, not a plexus properly so called, but an interlacement
of extreme complexity." If the italicized words "nerve-fila-
ments" are converted, in accordance with our view, into neu-
ro glia- fibrils, the rest of the quotation will lead us to the solu-
tion of the question: "These filaments are, on the one hand,
the fine medullated fibers spoken of above as being recognized
with difficulty, and, on the other hand, non-medullated filaments
ranging from fairly wide and conspicuous naked axis-cylinders
down to fibrils of extreme tenuity, the latter arising apparently
either from the division of axis-cylinders and nerve-fibers pass-
ing into or out of the gray matter or from the continued
branching of the nerve-cells."

The solution, it seems to us, lies in the fact that non-
medullated fibrils exist at all, and that these range from fairly
wide axis-cylinders down to fibrils of extreme tenuity, some of
which, at least, appear to originate from dendrites. Indeed,
this indicates that these non-medullated fibrils (of neuroglia,
as stated by Berkley) represent the continuation of the main,
or apical, dendrite (or dendrites, for there are often more than

568 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

one). Since these neuroglia-fibers are deprived of myelin, they
cannot serve as sources of nervous energy, and merely repre-
sent, therefore, delicate channels through which blood-plasma,
obtained by them directly or indirectly from a so-called "ter-
minal" capillary, finds its way to the apical, or main, dendrite.
The conclusion which this imposes seems to us self-evident:
A neuron is an autonomous organ as a source of nervous energy,
and is supplied with blood-plasma through non-medullated neu-
roglia-fibrils, which are continuous with the external covering of
its apical dendrites.

Are Apathy's fibrils, which, in the leech and earthworm,
were found by him to penetrate the cell-bodies of neurons, the
neuroglia-fibrils just studied? Gerlach, Haller, and others have
also referred to the existence of delicate nervous net-works
connected with the cells. The mere transformation of these
fibrils into plasma-channels has enabled us, we have just seen,
to link them with all the other elements of the function
studied. In other words, we simply converted the fibrils into
neuroglia blood-channels and found them to satisfy the require-
ments of the latter. Apathy found that a neuro-fibril passed
out of "a process of a nerve-cell": there is no fibril other than
the neuroglia-fiber that is continuous with the apical dendrite
that this neuro-fibril could represent. The neuro-fibril was
found by Apathy to be composed of "elementary fibrils": we
have seen that this is precisely the arrangement within the
neuroglia-fibers. He states that in their course "elementary
fibrillae are being given off at short intervals, until finally the
neuro-fibril itself may be reduced to a single elementary fibril":
we have quoted the statement of Professor Foster's that, as
regards the "fibrils of extreme tenuity," — those we found to
act as neuroglia neurilemma, — they arose "apparently from
the division of axis-cylinders." Finally, the neuro-fibrils, after
freely anastomosing in the cell-body (having entered by way
of the dendrite), are stated "to take their exit by way of the
axon." This seems to us to conclusively show, in addition to
the evidence adduced in the foregoing pages, that Apathy's
neuro-fibrils and the various net-works thought to be composed of
nerve-fibers by Gerlach, Golgi, B. Haller, and others represent the
one and same system of neuroglia-fibrils, some of which contain

THE CIRCULATION OP CEREBRO-SPINAL SUBSTANCE. 569

myelin and blood-plasma and may, therefore, be considered as
nerves, while others only contain plasma and are, therefore, blood-
channels.

Under these circumstances, are the above-mentioned in-
vestigators not justified in considering the net-works referred
to as nervous structures? They would be justified in doing so,
did all the neuroglia-fibrils contain myelin; but it is the ab-
sence of this compound in the fibrils that serve as channels for
plasma between blood-vessels and the apical dendrites of the
neuron which seems to us to neutralize their view. Were there
any evidence that a medullated fiber of any kind connects any
portion of the cell with another structure capable of converting
chemical energy into nervous energy, the question would re-
main an open one; but such is not the case; the absence of
myelin in the neuroglia-fibrils connecting the neuron with the
source of its blood-supply seems to distinctly point to the need
of its absolute isolation, not only to avoid the promiscuous dis-
persion of the nervous energy it is able to produce, but also
to enable it to store this energy and to direct it in the physio-
logical paths.

The presence of the non-medullated fibers among the
cerebro-spinal nervous elements becomes evident when the
structural difference between the gray matter and the white
matter is interpreted from the standpoint of our views. "Owing
to the relative abundance of white refractive medulla," says
Professor Foster, "the white matter possesses in fresh spec-
imens a characteristic opaque white color; hence the name."
. . . "In transverse sections of the cord nearly the whole of
the white matter appears, under the microscope, to be com-
posed of minute circles, the transverse sections of the longi-
tudinally-disposed fibers." . . . "The gray matter, from
the relative scantiness of medulla, has no such opaque-whiteness,
is much more translucent, and, in fresh specimens, has a gray
or rather pi?ikish-giay color, the reddish tint being due to the
presence partly of pigment and partly of blood, for the blood-
vessels are much more abundant in the gray matter than in
the white." That in the cerebral cortex, for instance, these
vessels should represent the starting-point of the neuroglia non-
medullary fibrils needs hardly to be emphasized. They are now

570 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

termed "terminal/' but their appearance as such is readily
accounted for by the fact that here, as in the cord, they are
said to be imbedded in neuroglia, whereas, in reality, the latter,
composed, as it is, of a mass of diminutive fibrils, is directly
affixed to the vessel, acting precisely as would a multitude of
minute subdivisions of the vessel itself. Each fibril (in which
the blood-stream is so slender that it only appears "pinkish"
through its translucent covering) is, in fact, a composite coun-
terpart of the ependymal fibril and other neuroglia structures
to which we have referred. In other words, each neuroglia-
fibril is affixed to the wall of the vessel either directly or through
the intermediary of a neuroglia-cell, and therefrom extends to the
main, or apical, dendrite, or dendrites, of some neuron. In ad-
dition, however, this enables us to conclude that a neuron
receives its nutrition and its oxidizing substance directly from the
general circulation, and that the blood which enters by way of the
apical dendrites is distributed to the free dendrites and to the cell-
body.

A question suggests itself in this connection, however, viz.:
How does the blood in the collaterals return to the main den-
drite to find its way with the latter' s blood into the cell-body?
This appears to us to find its explanation in the following
(already quoted) sentence, in which Berkley describes the cell-
body: "Around the body of the cell we find an insulating mass
of fluid contained in the pericellular lymph-sac, and as a capsule
to the sac there appears a slight condensation of the tissue at
this point, that would take the place of a retaining membrane."
The retaining membrane is doubtless the neuroglia covering
of the collateral, as it is of the entire cell; underneath, there-
fore, is the lymph-sac — which we consider as a plasma-sac. But
we have seen that Flechsig and Berkley's researches have shown
that these "fine branches are furnished with a thin layer of
myelin nearly to their termination." That this myelin must,
as elsewhere, be supported by the neuroglia covering and in
contact with it is evident: a feature which relegates the plasma
toward the center, though in contact with the myelin. If we
now recall the fact that fibrils have also been discerned even
in these delicate collaterals, it becomes a question whether they
serve to transmit plasma, centrifugally or centripetally. As

THE CIRCULATION OF CEREBRO-SPINAL SUBSTANCE. 571

Berkley's experiments have shown that they become the seat
of swellings under the influence of poisons, there must be no
escape for fluids through their walls; indeed, gemmulation
would become impossible were the centrifugal pressure neces-
sary counteracted by the escape of the plasma into lymph-
spaces. That the blood returns toward the cell-body and
through some of the central fibrils is therefore probable. Un-
der these circumstances we can say, as a working proposition,
that the plasma which enters the collaterals is returned to the apical
dendrite, and to the cell-body with the blood of the latter. The Uood
of the cell-body then passes out through the axon.

How does the blood leave the axon of the neuron in the
substance of the brain and cord? This question plainly re-
solves itself into the following: How does the blood reach the
veins from the axon? "The perivascular lymphatics . . .
are especially found in connection with the vessels of the brain"
says Gray54; "these vessels are inclosed in a sheath which acts
as a lymphatic channel, through which the lymph is carried to
the subarachnoid and subdural spaces, from which it is returned
to the general circulation." This familiar fact would be un-
explainable after the views we have advanced concerning the
circulation of arterial blood were the return of blood to the
veins not the purpose of the lymphatic sheaths, for the same
authority states that lymphatic vessels "have not at present
[1901] been demonstrated in the dura mater or the substance
of the brain/' Again, when we consider that perineural, as
well as perivascular, spaces exist, we are brought to realize that
by linking the axon of a neuron to a venule, with a lymphatic
space as intermediary, we have the elements of a mechanism
which not only utilizes structures that are known to be present
in the cerebro-spinal axis, but which also satisfy the needs of
the function. Finally, if an axon is itself buried (up to the
neck of its bulbous terminals) in a perineural sheath, which in
turn communicates with a vein through stomata, as is the case
in nerves, the blood of the axon is provided with a clear path
to the general blood-stream.

That the blood of the neuron is eliminated as it is in other

"Gray: Loc. cit.

572 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

nervous structures — via the axon — is evident; but do lymph-
spaces connected with veins actually receive this blood? Re-
ferring to the effects of acute alcoholic poisoning upon the
veins, Berkley says: "Changes in the coats of these vessels are
similar to those in the arterial system, but aggregations of
dying polynuclear corpuscles are more frequent, and are by far
the most striking feature both of their contents and surround-
ings. These aggregations, which may vary from three or four
to a dozen or more, are located both within and without the
lumen of the vessel (especially the smaller ones). Within the
lumen are collections of white corpuscles filling the interior,
and numbers are seen penetrating the walls. So vast are the
collections in the perivenous spaces that the whole cavity is
occasionally filled, and backward pressure from the plugs and
compression of the vessel from the outside have attained such
a height that in a number of instances the vessel's walls have
ruptured and red corpuscles are intermingled with the white
and fill the space completely." These features are well illus-
trated in the annexed photographs. The center of Fig. 8 shows
"polynuclear leucocytes in the perivascular space of a small
intermediary vessel compressing its walls," while Fig. 9 shows
"leucocytes in the blood in a cross-section of a large vein." The
fact that the leucocytes are found in the "perivenous spaces"
and "within the lumen of the vessel," coupled with the ob-
servation that they are "seen penetrating the walls," so clearly
point to the process involved that further evidence seems un-
necessary. The blood (we have seen that even red corpuscles are
present) of the axon evidently finds its way into a lymph-space
connected with a vein} thence to the general circulation.

Still, there is a feature of the whole process which requires
elucidation. Why should the veins, which, of course, com-
municate with channels through which the blood can be freely
evacuated, become engorged under the influence of the adrenal
stimulation induced by alcohol? Engorgement of the arteries,
their capillaries, the neuroglia channels, and the dendrites is
a normal consequence of adrenal stimulation; but, the veins
being outlets, such is not the case with the venous engorge-
ment. This anomaly is accounted for by the now generally
admitted fact that the vessels of the cerebral substance per se

. «•&*•

••;* ***, *•

»•> ./
** ^ ^

. * *

^•-,- -•:••.-.;•,..•*.
'-''M-;-: t;' >••-••
•S^ •• t!- ";•••-'

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«.«»

v^-v, J>^-,;:,«

LEUCOCYTES IN THE FERIimSCULAR SPACES AND
IN VESSELS, AS A RESULT DF ACUTE ALCO-
HOLIC FDISONINC, ' [Berkley,]

l,,!,!;!,,* J/Mf.if,,/ /;,'j,or/X.}

THE CIRCULATION OF CBREBRO-SPINAL SUBSTANCE. 573

are not supplied with vasomotor nerves. "Vascular nerves may
be found without trouble or difficulty in muscles, glands, etc.,
by the silver and other stains/7 writes Berkley, "but in the sub-
stance of the encephalon they are never to be seen with similar
staining methods; hence it is fairly reasonable to suppose that
they are not present in this location and that some other con-
trolling mechanism takes their place. I have most carefully
looked for them in many brains, both human and of the lower
animals, but have never seen the slightest trace of their pres-
ence within the nervous structures. . . . Tuke and An-
driezen, who made researches in the same field, have also failed
to find them." As we will have occasion to show, this is an
extremely important factor in the pathology of all toxemias,
mental and nervous diseases, for it indicates that stimulation
of the adrenal system by toxics of any kind causes vascular en-
gorgement of the vascular channels of the brain-substance simul-
taneously with the engorgement of the peripheral capillaries of the
other parts of the organism.

Under these conditions contraction of the central vascular
trunks through excessive adrenal activity causes not only con-
gestion of the surface, but also of the brain. Strikingly con-
firmatory of this fact are the following statements of Professor
Foster's: "It is argued that, in the absence of vasomotor nerves
of their own, the cerebral vessels are wholly, so to speak, in
the hands of the general motor system; so that when the blood-
pressure is high, owing to a large vasoconstriction in the ab-
dominal viscera, more blood must necessarily pass to the brain,
and when, again, the pressure falls, through the opening of the
splanchnic flood-gates, less blood necessarily flows along the
cerebral vessels." . . . "Again it has been observed that
certain drugs have an effect on the volume of the brain quite
incommensurate with their effect on the vasomotor system."

If our views are sound, — i.e., if our interpretation of the
data available is exact, — our conception of the neuron's inherent
functions coincides with some of the main conclusions reached
by Deiters, Gerlach, Golgi, Forel, and Cajal. In outlining the
conclusions to which these investigators were led, however, we
will only refer to those which are directly connected with our
own inquiry.

574 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

Deiters (1855) affirmed the prevailing theory — undemon-
strated at the time — that the nerve-cell was supplied with two
kinds of processes, the protoplasmic and the nervous, the latter
constituting the nerve-fiber. Gerlach confirmed the views of
Deiters, and showed that the protoplasmic processes subdivided
into a fine reticulum, which, he thought, anastomosed with that
of other cells. Golgi then demonstrated that, besides the two
kinds of processes described by Deiters, there were given off
collateral processes which, with the nerve-process, or axis-
cylinder, constituted the only truly nervous structures of the
cell, the other processes and the cell-body being purely nutri-
tional. The subdivisions of the protoplasmic processes or anas-
tomoses were not, in his opinion, continuations of those of
other nerve-cells, either by continuity or through nervous net-
works, though some of the protoplasmic extensions were con-
nected with neuroglia-fibers and blood-vessels. Forel con-
tended that the entire cell and its processes were simulta-
neously functional and nutritional. Ramon y Cajal concluded
that net-works of nervous fibrils did not unite the collateral
processes, and, these being absolutely free, there could be no
continuity of nervous substance between them, contiguity of
their extremities alone prevailing.

We need hardly emphasize the fact that Golgi's views are
strikingly confirmed by our own; indeed, had this great his-
tologist converted the neuroglia-fibrils connected with blood-
vessels into blood-channels, our interpretations would have
been similar, though reached from entirely different directions.
And we must admit that we consider this striking similarity,
apart from the single line of research to which we have devoted
all these pages, — i.e., the microscopical anatomy of the circu-
lation of the nervous system and the manner in which nervous
energy is produced, — as a strong indorsement of our own con-
ceptions. While Forel is fully sustained by our analysis when
he asserts that all the parts of the neuron are simultaneously
functional and nutritional, Golgi is likewise in accord with us
when he considers the collaterals and the axon as the truly
nervous structures, the others being nutritional. We have seen
that the dendrites connected with the neuroglia-fibrils are
really blood-channels. True, they are covered with gemmules

THE CIRCULATION OF CEREBRO-SPINAL SUBSTANCE. 575

and lined with myelin, a feature which shows that they serve
for the formation of nervous energy; yet this energy is not
utilized in these dendrites, but by the collaterals, in addition
to that elaborated by their own myelin. Nor is the greater part
of the blood which courses through the main dendrites used
by them; it passes into the cell-body: a great center for the
production, we have seen, of nervous energy, which energy is
mainly utilized, not by the cell-body per se, but by the dendrites
and the axon through which the whole neuron's blood is con-
tinuously passing.

Golgi's observation that some of the protoplasmic proc-
esses were connected with neuroglia-fibers and blood-vessels
furnishes histological proof that our interpretation of the
manner in which the neuron is connected with the circulation
is based on solid premises. The prevailing ideas, however, as
to the nature of neuroglia normally suggested that his views
included a nervous net-work as intermediary between cells,
neuroglia-cells being likewise considered as truly nervous
structures. Hence the affirmation of Cajal that collaterals
were totally independent of one another, especially if he gave
neuroglia-fibers and cells the credit of only being what they
are now generally thought to be: i.e., a "peculiar ground-
substance," in which the "blood-vessels, the nerve-cells, and
nerve-fibers" are "imbedded." The neuron is autonomous
functionally: i.e., as a nervous organ, each neuron is connected
with the circulation ~by its own neuroglia Uood-channels. An
illustration of the continuity of neuroglia-fibers with the cere-
bral circulation is afforded by Berkley's experiments with alco-
hol. "Besides the swellings in the course of the dendrons,"
says this author, "we must always be on the watch to exclude
certain processes of the support neuroglia-cells that traverse
long distances of the cortex and exhibit a pearl-string swelling
in the course of the fiber."

Are nerve-cells contiguous, as thought by Cajal? Berkley
states that the great Spanish investigator writes "that the
ascending fibers of the cortex, which have a vertical or oblique
course through the medu-llary layers, have their points of con-
tact with the protoplasm of the dendritic structures in the
intervals between the short transverse processes (gemmulae)

576 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

around which the ascending fibers twine." In other words,
the tips, or extremities, of the axon of one neuron, instead
of being in contact with the tip of the gemmule, touch the
intervals between gemmules. "Such a discharge of the nerve-
forces from cell to cell taking place at hundreds of indefinite
points," continues Berkley, "could not fail to produce stimuli
that would be more often aberrant than direct, and, in all
likelihood, such an arrangement would produce the utmost
confusion of thought and motion, a veritable inco-ordination
of the cerebral functions, which would reduce direct cerebra-
tion to a nullity." This point seems to us to be well taken,
and the identical argument prevails as regards contiguity, for
if, as we believe, myelin and the oxidizing substance are con-
stantly in contact in the neuron, — i.e., the cell-body, dendrites,
and axon, — nervous energy is continuously being formed, and
promiscuous contact with the dendrites of other cells would
give rise to the untoward effects enumerated. In the light of
our views, therefore, continuous contiguity between neurons
through their dendrites or axons does not appear possible.

How do neurons transfer their nervous energy to other
neurons? Berkley states that it is "more than probable that
it is only at the free bulbous terminations of the nerve-filaments
[axons] that we have naked protoplasm, and from this uncov-
ered nervous substance the dynamic forces, generated in the
corpora of the nerve-cells, are discharged, through contiguity,
on to the protoplasmic substance of other cells. Thus, in con-
tradistinction to the hypothesis of Cajal," continues the author,
"we have only comparatively few points at which the nervous
forces may discharge themselves from ajsons to the protoplasm
of other cells, and these are seated at definite points on the
terminal arborizations of the nerve-filaments, for otherwise
what would be the necessity of a terminal apparatus were the
nerve-conductors free to discharge their dynamic forces at any
point at which they came in contact with the substance of a
dendron?"

It seems to us that the feature to ascertain in this con-
nection is the character of the functions of the gemmules. Why
do these little projections of the dendritic walls become erect
during the cerebral congestion induced by poisons? Are they

THE CIRCULATION OP CEREBRO-SPINAL SUBSTANCE. 577

really intended to receive discharges of nervous energy from
the bulbous tips of axons? They outnumber the axonal end-
organs out of all proportion. Indeed, their multiplicity around
all the stems excepting the axon hardly points to them as ter-
minals endowed with such important functions as those at-
tributed to them. Again, Berkley states that "the twigs of
the dendrites and the fibers touch each other frequently and
in a manner that appears to be perfectly indifferent for the
different kinds of nervous substance, receptive and protective."
Such promiscuousness plainly testifies, it seems to us, against
the identity of the substances in contact being exposed sur-
faces capable of transmitting to each other a stream of nervous
impulses.

In the light of our views, however, a function perfectly in
keeping with the experiments of Goddard in puppies, of Demoor
with morphine, of Berkley with alcohol, ricin, serum, etc., sug-
gests itself. We have seen that during functional activity the
gemmules project, while during inactivity they recede. If we
now connect these facts with the presence in the gemmules of
a thin layer of myelin immediately under their external or
limiting covering, and concede that the latter and the myelin
take part in the formation of each gemmule, it will become
evident that during the erethic state the surface of myelin ex-
posed to the action of the oxidizing substance of the plasma
will be greatly increased and the proportion of nervous energy
produced correspondingly augmented. Eetraction of the gem-
mules, on the other hand, by emptying them of their plasma,
will normally cause diminution of energy-production, the mye-
lin of the main channel sufficing to sustain nutritional functions
during sleep, for instance, when the gemmules are retracted.
We have what seems to us a counterpart of these minute struct-
ures in the muscle-cell, the myosinogen of the latter being
replaced by the myelin. We have also, in the processes out-
lined, an active and a passive functional stage in keeping with
other organs. All this so thoroughly coincides with the various
attributes which the gemmules have been shown by various in-
vestigators to possess, that we feel warranted in concluding that
the gemmules are peripheral extensions of the dendritic walls hav-
ing for their purpose to increase, when erect, the area of myelin

578 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

exposed to the action of the oxidizing substance of the plasma, and
thus to render the dendrite functionally active : i.e., able to trans-
mit or receive nervous impulses. When the gemmules are retracted
or collapsed, therefore, functional activity is in abeyance, as during
sleep, anesthesia, etc.: i.e., they are unable to transmit or receive
impulses.

This tends to show that none of the gemmules serve per
se to transmit impulses, and that the dendritic tips must alone
be endowed with this function. That such is the case seems to
us suggested by Fig. 2 on the plate opposite page 550, which
exemplifies the condition of a dendron before the engorgement
induced by ricin has become far advanced: i.e., at a time when
the dendron's lumen has not as yet become completely blocked.
The two central dendrites may be seen to terminate with bulb-
ous tips, while the remaining gemmules immediately adjoining
the latter are not apparently enlarged. This would point to
the enlarged extremity as a dissimilar structure in respect to
the gemmules, a terminal organ as it were. Again, the gem-
mules and terminal organ would have presented a certain de-
gree of resemblance under the influence of the engorgement
under the action of poisons, had they been similar; their ap-
pearance, on the contrary, suggests dissimilarity. Berkley
states that, "so far as the end-apparatus of the collaterals from
the psychical cells is concerned, the terminations of the inter-
mediary cells, the fibers entering from the medullated masses,
all have the same end-apparatus, which consists solely of a
simple freely terminating bulbous ending, situated upon the
extremity of the finest branches of the nerve-fibers." As he
then refers to figures in one of his illustrations which represent
axons supplied with bulbar extremities, we infer that it is to
the dendritic terminals that he alludes, and not to those of
the gemmules, as a broad application of his preceding para-
graphs might suggest. If the bulbous terminals of the entire
dendrite as well as the axon are referred to, the quoted lines
afford additional evidence tending to show that the dendritic
extremities alone transmit or receive impulses. Indeed, in
the article in which chronic alcoholic poisoning is studied,
Berkley remarks: "The process of tumefaction always appears
to begin at or near the fine extremity of the dendron, be it the

THE CIRCULATION OF CEREBRO-SPINAL SUBSTANCE. 579

extremity of the main apical process or one of its collateral
branches, and not infrequently the extreme termination of the
dendron, is seen to be somewhat swollen when no other portion
of the cell is involved"** He also states that "in his description
of the mode of ending of the collaterals of the great pyramidal
cells" Cajal "describes their finest branches as terminating
freely by a nodosity" All these facts seem to us to warrant
the conclusion that each of the collateral dendrites of a neuron
and each axon, or subdivision of the latter, is supplied with a
bulbous end-organ.

How is an axonal end-organ of one neuron functionally
related to that of a dendrite of another neuron? Berkley,
alluding to the subdivisions of the axon, each of which is sup-
plied with its bulbous end-organ, says: "These spherical ap-
paratuses are closely adjusted against the bulbous tips of the
gemmules, at times the approximation being so close that the
impression is given of actual contact, though it should be re-
membered that the slightest overlapping will produce the same
effect; and, on the whole, it is more probable that there is no
actual contact, but that the axonal discharges of the stimuli
overleap the infinitesimal distance between bulb and gem-
mule." For the reasons adduced, we do not think that the
gemmules serve for the reception of impulses. These reasons
also suggest that each axonal end-organ can only discharge its
stream of impulses into the bulbous terminal of a neighboring
dendrite, which bulbous terminal would, under these circum-
stances, present some analogy with the end-bulb of Krause,
and, indeed, with several peripheral sensory organs. We have
also submitted reasons that seem to us to offset the assertion
that the end-organs actually touch. Indeed, that an "infin-
itesimal distance" between the efferent axonal end-organ and
the afferent dendritic end-organ exists seems to be the only con-
clusion warranted by the histological picture, as described by
Berkley. It seems to us, in other words, that each of the bulbous
end-organs of an axon, though apparently in contact with the end-
organ of one of the dendrites of a neighboring neuron, may be
separated from it by an infinitesimal distance.

w All italics are our own.

37

580 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

The bearing of this arrangement, as an element of func-
tion, asserts itself when the stress we have laid upon the vibra-
tory character of a nervous impulse is recalled. When study-
ing the nature of the functional activity of muscles, we had
occasion to say, referring to the governing action of motor
nerves: "As the vibratory rhythm of the impulse and that of
the muscle always correspond, any variation of rhythm by the
brain-center correspondingly modifies the muscular contrac-
tion." If we now analyze what this vibratory rhythm means
when the dendritic end-bulb and the axonal end-bulb are sepa-
rated by an infinitesimal distance, but one answer appears to
suggest itself: i.e., that there can be no flow of impulses from
one to the other. But we must not lose sight of the fact that
the contradictory histological pictures described by Cajal and
Berkley are those of non-living cellular elements, and that
death may leave the two end-bulbs juxtaposed, as seen by Cajal,
or separated by an "infinitesimal distance," as seen by Berkley.
Thus, each histologist is right in his way as regards dead tissue.
But what of living structures? Cajal and Berkley will again
assist us in reaching a deduction in this connection, for each
investigator furnishes one-half of the main physical function
involved: i.e., vibration, which, means rapidly alternating jux-
taposition and separation of the 'bulbous end-organs.

The rapidity with which the gap between the two terminals
is opened and closed — i.e., the rhythm — regulates, we have seen,
functional activity. But can we conclude from this that non-
activity of an organ means cessation of vibration of the bulbous
end-organs involved in the function? We have seen that the
nutritional processes of all tissues are continuous, nervous
energy being supplied to the cellular elements as long as life
lasts. Forel, as stated, was led by his admirable investigations
to the conclusion that "living muscle appears to be so organized
that without nervous stimulation it can live as little as the
tropical animal can without warmth or the rose without water."
This applies to all living tissues: a feature of the problem
which necessarily implicates the continuous development of
nervous energy and, as a consequence, an unceasing vibration
of the end-organs. It seems to us, therefore, that, inasmuch
as the nutritional processes of the organism require a continuous

THE CIRCULATION OF CEREBRO-SPINAL. SUBSTANCE. 581

supply of nervous energy, all the systemic axonal and dendritic
end-organs are in a state of constant vibration.

In our analysis of muscular contractility we made the fol-
lowing statements: "The impulse-wave simply sets the muscle-
elements to a given vibratory rhythm, and they retain this
whatever be the intensity of the exertion required. . . .
This may aptly be compared to the manner in which a note
on a violin is made loud or soft. The power with which the
string is pressed upon with the moving bow modifies the in-
tensity of the sound; but the note remains the same. This
means that its pitch does not vary, and if, for example, the
lower C is given, we will know that the sound-wave of that
note represents two hundred and sixty-one vibrations per sec-
ond. So may the impulse-wave transmitted by the brain
through a 'motor' nerve be represented by a fixed number of
vibrations. Eetraction, the muscle being then most tense, is
therefore characterized by the greatest number of vibrations/'
If this interpretation is sound, it is likewise applicable to the
"to-and-fro" motions of the bulbous terminals which constitute
vibration, the number of these motions within a given time
representing a given intensity. Any modification of the num-
ber of these to-and-fro motions within a given time, therefore,
correspondingly modifies the intensity of the resulting vibra-
tory impulse-wave, the PASSIVE state of function (that during
which cell-nutrition alone occurs) l)eing represented ~by the lowest
number of vibrations, the ACTIVE stage (during which the function
is in full sway) by the highest number of vibrations compatible
with normal health.

Still, in accordance with our views, this applies to the im-
pulses transmitted by the posterior pituitary body, since this
organ, directly and through its extension in the cord, governs
the passive stage of function and incites the cellular elements,
both through the terminal vasomotors and the net-works dis-
tributed to the cells themselves, to higher activity when the
active stage becomes necessary. Can we say the same of the
independent hemispheres? This carries us back to the circu-
lation of the brain, for the question involves another: i.e.,
whether the cerebro-spinal functions, active and passive, are
carried out in a manner similar to that of all other organs.

582 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

We are now able to say that they are, for the neuroglia- fibrils
of the substance of the brain and cord represent their blood-supply,
just as the cellular capillary net-work of any other organ represents
its blood-supply.

Indeed, we must not overlook the fact that, while the
neuroglia-fibrils representing the capillary supply of the cere-
bro-spinal substance are not supplied with vasomotor nerves,
the peripheral vessels connected with the organ are, thus fur-
nishing it with what we have termed elsewhere an extrinsic
supply. This extrinsic system would thus be represented by
the pial vessels, which, as shown by Andriezen,66 are supplied
with vasomotor nerves. "We find," writes this investigator,
"that it is possible to stain the vasomotor nerves with Golgi's
method. Starting from the carotid and vertebral plexuses we
can trace them no farther than the circle of Willis by anatom-
ical dissection (using a lens). Do nerves accompany the cere-
bral arteries as they go off from the circle of Willis; and, if
so, how far; and what is their ultimate distribution? Our
observations on the kitten's brain show that bundles of nerve-
fibers accompany the middle cerebral artery (the one specially
chosen for our study) and its branches in the pia. These fibers
run in tortuous and zigzag fashion, and in the finer pial
branches they can be seen to form a very fine (non-anastomotic)
plexus of fibrils lying between the outer and the muscular coats.
From this perimuscular plexus terminal fibrils issue which, run-
ning a short distance along the muscular layer either longi-
tudinally, transversely, or obliquely, end in small spherules:
little ovoid bulb-like arrangements abutting against the mus-
cular elements (cells). We have succeeded in tracing these
terminals and their distribution to the finest pial cells, but no
farther. The intracortical continuations of the pial vessels
have constantly failed to give us the least evidence of this
perimuscular plexus, which therefore — so far as our investiga-
tions go — we are compelled at present to imagine as stopping
with the pial branches, and not continued along the intracortical
vascular branches."57 This evidence, added to the facts already
outlined concerning the pericerebral vascular supply, seems to

"Andriezen: Brain, Winter, 1894.

57 The word "not" is alone italicized by Dr. Andriezen.

THE CIRCULATION OF CEREBRO-SPINAL SUBSTANCE. 583

us to plainly indicate that the cerebral circulation is governed,
as is that of any other organ, ly the posterior pituitary body, the
vasomotor nerves of the pial vessels ~being terminals of the general
motor system.

This only furnishes us, however, the functional mechanism
of the passive stage. In other words, the nervous energy de-
veloped owing to the presence of a given proportion of oxidizing
substance (brought into contact with the myelin through the
tonic vascular contraction insured by the general motor sys-
tem) only causes the entire brain to create the nervous energy
which, as we have seen, is essential to its own life. But how
is the active stage incited in any one part of the cerebrum?

As is well known, groups of individual muscles may be
caused to contract simultaneously, while some of the muscles
which enter into the formation of these groups may be re-
placed by others. This is well exemplified by the mechanism
of piano-playing: the index, thumb, and little finger, to form
one chord; the annular and thumb to form the next, etc. Trac-
ing this mechanism back to the structure which incites and
governs the muscular adduction and abduction through which
the keys are struck and released, we are brought back to a
neuron. But how is the neuron incited to activity? In other
words, how is the increased speed of blood through its myelin-
lined dendrites, cell-body, and axon incited and governed? Can
we ascribe this all-important function to the posterior pitui-
tary body? We have seen that removal of the hemispheres did
not prevent muscular action; a frog can swim, a pigeon fly,
etc., and, indeed, continue to live a considerable time — months
— if carefully fed, notwithstanding the absence of its hemi-
spheres. This suggests that, while the posterior pituitary
body either directly or indirectly incites and governs the
functional activity of all organs, exception should be made of
the brain, though it governs the circulation of this organ.

Still, the cellular elements of all organs are supplied with
a net-work of terminal nerves, and it is through the inter-
mediary in this net-work that its functional metabolism is
governed by the posterior pituitary. How is the same func-
tion fulfilled in the hemispheres: i.e., how are its cells, the
neurons, "incited and governed"? Are they also supplied with

584 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

a net-work of fibrils which receives impulses from the poste-
rior pituitary body? There is no evidence available to suggest
that such is the case, and the functional relationship with the
latter through the vasomotor supply of the pial vessels is the
only link between the two organs that existing data permit us
to accept. If, therefore, a regulative mechanism exists, it must
be one connected with the vascular system, and so disposed as
to enable it to govern the circulation through one or more
neurons simultaneously. It must supply its own nervous en-
ergy, for we have seen that Andriezen found the vasomotor
nerves to distinctly terminate upon the muscular coats of the

"A PROTOPLASMIC NEUROGLIA-CELL FROM THE HUMAN BRAIN
(FOURTH LAYER OF CORTEX) SHOWING Two EXPANDED CONICAL
DISK-LIKE ATTACHMENTS TO A VESSEL." (Andriezen.)

pial vessels; indeed, it must be as autonomous an organ as is
the neuron itself.

Such an organ we have, it seems to us, in the neuroglia-
cell shown in the above illustration, which Andriezen has named
the "protoplasmic neuroglia-cell," and describes as follows58:
"The protoplasmic glia-cell has a distinct cell-body, which is
irregularly oval, frequently pyriform. Its various protoplasmic
processes are of moderate length, they exhibit great variations
of caliber, some being stout and coarse and others exceedingly
fine. These processes are also dendritic: a thing never seen
in the stellate cells. A most striking feature is the shaggy

"Andriezen: British Medical Journal, July, 1893.

THE CIRCULATION OP CEREBRO-SPINAL SUBSTANCE. 585

granular contour, as if a fine moss constituted the protoplasmic
processes. . . . Further, by one or more of their coarser
processes the protoplasmic cells are attached to the perivascular
sheaths. The figure [on the opposite page] shows the cell with
two such vascular processes, each attacked to the vessel by a conical
disk-like expansion ('foot')."

We could hardly produce stronger evidence than this in
favor of our view that neuroglia-cells and fibrils are channels
for blood. Bearing directly upon the question in point, how-
ever, is the fact that this cell, as indicated by its gemmules and
its dendritic appearance, must be supplied with myelin. The
association of this myelin with the blood-plasma in transit at
this point — i.e., so close to the blood-vessel — seems suggestive,
for, if the illustration is closely examined, dendrites are not
alone found around the cell, but also fibrils, which start from
various parts of these dendrites. That these protoplasmic neu-
roglia-cells are directly connected with the blood-vessels so
as to admit plasma is demonstrated by the fact that they also
take part in the engorgement of neuroglia structures that fol-
low poisoning. "The bodies of the mossy neuroglia-cells,"
writes Berkley, alluding to the effects of ricin poisoning, "are
larger than normal, rounded, sometimes globular in outline,
and the tentacles are thickened and knotty. There are general
evidences that these structures of the lymphatic system are
undergoing modifications of a pathological nature." We have
already stated that this "lymph" was, according to our view,
its next o' kin: i.e., blood-plasma.

Eeferring to the paper from which we have just quoted,
Andriezen remarks59: "We also stated at the time that the
evidence of staining with Golgi's method shows us a system
of lymph-spaces surrounding the cell-body and its branches.
Careful and fresh observation confirm us in this opinion, viz.:
that there is an exceedingly fine system of canaliculi and lymph-
spaces surrounding the body, and dendritic processes of the
protoplasmic glia-cell, and directly continuous with the peri-
vascular lymph-spaces." If the annexed sketches by Andriezen
are now examined and interpreted from our standpoint, addi-

69 Andriezen: Brain, Winter,

586

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

tional testimony in favor of our conception of the whole mech-
anism of brain-function will appear. Indeed, the canaliculi
are evidently the openings into the neuroglia-fibrils. But these
microscopical channels, which are often one-sixth the size of a
blood-corpuscle, would soon be blocked were the latter allowed
to reach them. There is interposed between them, therefore,
a lymphatic membrane, similar to the one which, as we have
seen, forms the lymph-space from which veins start. Here,
however, a double purpose is served, as shown in the sketch.
It forms two cavities: the one surrounds the blood-vessel, and

h

d f

RELATIONSHIP OF THE VASCULAR AND LYMPH CHANNELS IN
THE BRAIN. (Andriezen.)

a, Pia-arachnoid. 6, Brain-substance, c, Epicerebral space, d, Ad-
ventitial sheath. «, Intra-adventitial space, f, Extra-adventitial space.

(According to our view, these are all blood-channels: The blood arrives
in pial artery (g), and escapes through the walls of the latter into the
"intra-adventitial" space (e). Part of the plasma of this blood passes
through sheath d into the "extra-adventitial" space (f) and enters neu-
roglia- fibers and cells (h, h, h), and then passes into the apical dendrites
of neurons; the rest of the plasma and all corpuscles return to the veins
by way of the "intra-adventitial" space at c.—S.)

represents the channel connected with the venous system, to
which all corpuscles return; the other, or external, space re-
ceives only the blood-plasma which has passed through the
membrane. The latter, being mainly composed of endothelial
plates, is therefore phagocytic and bactericidal, and thus admits
into the neuroglia canaliculi not only plasma relieved of all its

THE CIRCULATION OP CEREBRO-SPINAL SUBSTANCE. 587

cellular elements, but also asepticized plasma. The outside of
a vessel covered with a neuroglia-ridden sheath is shown in
Fig. 3.

The two kinds of neuroglia-cells may be seen to take part
in the formation of the external net-work of fibrils in the illus-
tration on page 586. It is here, it seems to us, that the gov-
erning attribute of the "protoplasmic neuroglia-cell" shows
itself, as suggested by the dendritic appearance of its exten-

f/g.3

BLOOD-VESSEL OF THE HUMAN BRAIN, SHOWINO SEVERAL NEU-
ROGLIA FIBER-CELLS SURROUNDING IT AND FORMING A FELT-WORK
(PERIVASCULAR SYSTEM). (Andriezen.)

a, An encircling cell. 6, Perpendicular neuroglia-flber entering the
sheath at right angles from a distant (extrinsic) cell.

sions. Indeed, Eanvier has been lead to conclude that the
other variety of neuroglia (stellate) cell is not much more
than a mass of aggregated fibrils in transit, the latter passing
through them without forming part of the cellular structure.
Still, as it contains a nucleus, it may possess a regulative ac-
tion. The larger cell, however, imposes itself as an organ of
a very active kind — capable probably of playing in the brain
the part that the vagus plays in various organs: *.«., to incite

588 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

active function and govern it in the neurons with which it is
connected, either directly or through the intermediary of other
neurons. The connection with the latter would be not estab-
lished by continuous fibers, but through their end-bulbs, the
axonal of the one to the dendritic of the other, etc., in order
to allow of the transmission of vibratory impulses. Eeferring
to these larger "protoplasmic" ganglia cells, Andriezen writes:
"They occur abundantly throughout the gray matter, in all
the layers of the cortex, but are rare in the white substance."
Indeed, if our views are sound, the latter is a mass of axis-
cylinders coming from the upper strata, and surrounded by
their myelin, wherein energy increases with distance: a true
"avalanche" — using Pfiuger's expression — of nervous force
toward the lower cerebral structures.

The predominating function of both varieties of neuroglia-
cell asserts itself, however, when the characteristics of the
cortical layers are reviewed. The first, or molecular, layer
contains but few nerve-cells, according to Andriezen. Its
proximity to the pial vessels normally suggests that, if glia-
cells are intermediaries between these vessels and the brain-
substance's circulation, they should occur in large quantities
in this region. "Its outermost, or superficial, region is formed
of a system of neuroglia fiber-cells," says Andriezen, and by
means of the annexed illustration, among others, he emphasizes
the varied directions and the length their extensions may as-
sume. But if the illustration on page 586 is examined, the
manner in which these cells (according to our interpretation)
are supplied with plasma may be easily understood. As shown
therein, the pial vessel dips into the brain-substance, sur-
rounded by its lymphatic membrane in such a manner, we
have seen, as to form two spaces, the internal of which is for
the blood and corpuscles to be returned by the veins to the
general circulation; the other, or external space, being that
in which the plasma for the neuroglia-cells passes after pene-
trating the lymphatic membrane, in order to reach the neu-
roglia-fibrils. This affords a supply to both kinds of cells,
which are seen to line the plasma-containing space. That both
are intimately connected with the circulation appears to us
beyond doubt; that the mossy, or protoplasmic, cell is endowed

THE CIRCULATION OP CEREBRO-SPINAL SUBSTANCE.

589

with some function other than as a mere distributing center
is as likely; that this function should be to regulate the cir-
culation in the neurons, or groups of neurons with which it
is connected (as shown by the effects of poisons upon all struct-
ures thus connected), is strongly suggested by the fact that,
while the need of such a regulative system is evident, there
is no discernible or known organ or system of organs, directly
connected with the pial blood-vessels, other than these cells
to which this important function could be ascribed. The fol-
lowing conclusions, therefore, seem to us warranted: —

SEVEN CAUDATE NEUROGLIA FIBER-CELLS FROM THE HUMAN BRAIN-
CORTEX (FIRST LAYER). (Andriezen.)

a, Tangential fiber-system. 6, Cell-bodies, c, Descending fiber-sys-
tem. The dotted line shows the limit between the first and second and the
second and third layers.

The neuroglia-cells are the intermediaries between the general
circulation and the capillary system (neuroglia- fibrils) of the
brain-substance. The smooth stellate cell seems only to serve for
the equable distribution of the blood-plasma to the neurons, while
the mossy, or protoplasmic, cell presents the attributes of an organ
to which the function of inciting a group of neurons to action by
activating its blood-supply and of governing the quantity of nerv-
ous energy produced in these neurons can be ascribed.

Judging from the admirable histological work of Andriezen

590 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

and Berkley, the engorgement caused by poisons affects the
three upper layers of the cortex most markedly. The bead-
like swellings of the first-layer dendrites are well shown in the
annexed illustration, the lesions being those found in alcoholic
insanity. The second layer and third layer are represented
by the plate opposite page 550, reproduced from Berkley's
article, ricin poisoning, as previously stated, having been the
cause of the cerebral engorgement. The cells of the last, or
fourth (polymorphous), layer are not represented in the series

TERMINAL TUFTS AND ENDINGS OF THE PROTOPLASMIC APICAL PROC-
ESSES IN THE FIRST LAYER (HUMAN BRAIN-CORTEX).
(Andriesen. )

Showing bead-like and moniliform swellings, coalescence of fine
miliary granules in place, and loss of fine granulation in the most af-
fected parts. The dotted line marks the limit between the first and second
layers. Alcoholic insanity.

of illustrations, but the fact that Marchi found that the epen-
dymal neuroglia-cells sent a central extension to the optic
thalamus, where it divided and became attached to the blood-
vessels, represents but one of many examples which could be
adduced to show that the circulatory system as we view it is
that of the entire cerebro-spinal system, including the organ
which governs the supply of blood to all tissues: i.e., the poste-
rior pituitary body.

THE CHIEF CENTER OF THE NERVOUS SYSTEM. 591

THE POSTERIOR PITUITARY BODY AS THE CHIEF CENTER
OF THE NERVOUS SYSTEM.

Howell,60 in the course of experiments which led him to
conclude that "the infundibular lobe of the hypophysis (the pos-
terior pituitary) is, in all probability, not a rudimentary organ,
but a structure that has some important physiological activity,"
found, as we have already stated, that "the extracts of the
glandular lobe (the anterior pituitary) have little or no per-
ceptible effect when injected alone. Extracts of the small in-
fundibular lobe, on the contrary, have a distinct and remark-
able effect upon the heart-rate and blood-pressure, an effect
which resembles, in some respects, and differs, in others, from
that shown by suprarenal extracts."

We have seen in our previous analysis of these observations
that the symptoms produced were those of suprarenal over-
activity. In other words, the extract acted like a toxic; the
heart-beat was "not only slowed, but considerably augmented
in force," says Howell, "as shown by tracings taken with a
Hiirthle manometer," etc. When both vagi were cut or a
little atropine was given, the slowing of the heart was less
marked. The result of vagal section is evident. As to the
atropine, it prevented the slowing because it served to increase,
when added to the pituitary extract, the dose of toxics in the
blood, thus causing suprarenal insufficiency, instead of over-
activity. But an interesting query imposes itself in this con-
nection: The extract having, by its action upon the anterior
pituitary, stimulated the activity of the adrenals, how did the
former, through the increased oxidizing substance, bring about
increased vagal action? The answer is easily reached: the pos-
terior pituitary being also copiously supplied with blood, its
activity is likewise increased. This emphasizes an important
feature: i.e., the fact that the posterior pituitary is functionally
stimulated, as is any other organ, by the oxidizing substance in
the blood passing through it. Indeed, the nerve-fibers which
Berkley found to accompany the arteries suggest the presence
of a functional arrangement similar to that of any organ, while

60 Howell: "Transactions of Congress of American Physicians and Surgeons,"
vol. iv, p. 83, 1897.

592 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

the presence of so many neuroglia-cells at the apex — i.e., where
the posterior pituitary meets the infundibulum — indicates that
the neurons which they supply are the seat of marked func-
tional activity.

The salient feature brought to light by Howell's experi-
ments, however, is the identity of the posterior lobe as only one
containing an active agency. This obviously harmonizes with
our views, since, as we have seen, the anterior lobe is, to a
certain degree, passive in that it is stimulated to an inordinate
degree only when toxics are present in the blood, while its nor-
mal activity is sustained by the secretion of the thyroid gland.
Though the purpose of both organs is similar, therefore, —
the conversion of chemical energy into nervous energy, — the
manner in which this is done is not similar. Indeed, in the
posterior lobe, the exciting agency is, as just stated, precisely
as it is in any organ: i.e., oxygen. The posterior pituitary
must, therefore, become physiologically active through the same
chemico-physical process that prevails elsewhere in the or-
ganism.

Indeed, we have seen that the posterior lobe is, in reality,
but an aggregate of neurons — and a precious aggregate it must
be, ensconced, as it is, in a bony cradle and resting on a pillow
of blood, to preserve it against shocks or traumatisms! That,
like all neurons, this aggregate depends mainly upon a phos-
phorus-containing ground-substance has been shown. We will
recall, in this connection, the labors of de Cyon,61 who, in the
course of a large number of experiments, observed that: "1.
Any, even slight, pressure upon the hypophysis (i.e., both or-
gans) immediately gives rise to a sudden variation of blood-
pressure and to a notable reduction in the beats of the heart,
the strength of which is at the same time considerably in-
creased. 2. Electrical stimulation of the hypophysis, even with
extremely weak currents, produces exactly the same phenom-
ena as does mechanical pressure, but in a much more intense
manner. 3. Extract of hypophysis, injected into the veins
of an animal, produces upon the heart and upon blood-pressure
effects that are analogous to those caused by electrical and

81 De Cyon: Archives de Physiologie, July, 1898.

THE CHIEF CENTER OF THE NERVOUS SYSTEM. 593

mechanical stimulation of this organ." To ascertain the iden-
tity of the agent which gave rise to these results de Cyon had
the extract analyzed by as competent a chemist, M. Rossbach,
as he is himself a physiologist, and ascertained that the active
principle was phosphorus, evidently that of the only organ of
the two which Howell found to be active: i.e., the posterior
pituitary body. It seems clear, therefore, that the posterior
pituitary body and the anterior pituitary ~body are loth centers for
the conversion of chemical energy into nervous energy, and that
the posterior pituitary, being mainly composed of neurons and
their protoplasmic extensions, is the seat of reactions similar to
those that prevail in other neurons.

The intrinsic processes upon which the physiological
functions of neurons and nerves depend seem to us to be rep-
resented in the foregoing pages, but we have still to account
for the "stormy processes in the nerve-fiber" to which Barker
refers: i.e., the exacerbations through which passive functions
become active. Can we attribute these to the cells in the sev-
eral centers? "Notwithstanding almost infinite minor varia-
tions in form," says Professor Barker, "the neurons in the most
different parts of the nervous system present surprisingly
similar general external morphological characteristics." We
have seen, by the details furnished by the histological studies
of Berkley, that such is not the case with the neurons in the
posterior pituitary. Indeed, there are in this organ ten cells,
exclusive of four of the neuroglia type that differ in morpho-
logical characteristics, each of which receives from Berkley a
separate description. We have seen with what significant reg-
ularity all the axons of the cells in this lobe point upward:
i.e., toward the infundibulum. That a similar diversity of cel-
lular shapes occurs in the latter is beautifully illustrated in the
plate of Berkley's shown opposite page 594, and representing a
diagrammatic drawing of a transverse vertical section of the in-
fundibular region.

We have seen that above the infundibulum — i.e., in the
structures of the third ventricle — he found "varieties of epen-
dymal neuroglia-cells, previously supposed to have entirely
disappeared from the central nervous system," etc., and which
were thought to be confined to "reptiles, amphibia, and fishes."

594 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

The physiological role we have ascribed to neuroglia-cells and
fibers further emphasizes the importance of these structures
and of the marked nutritional activity of which they are the
seat. As a complement of this we showed that Andriezen traced
a direct nervous connection in all classes of vertebrates between
the "posterior lobe of the pituitary," on the one hand, and
"the olfactory center" and the "bulbo-spinal centers," on the
other.

When these facts and others reviewed are placed side by
side with the adduced evidence (1) that the middle brain is the
seat of a nervous mechanism through which highly differen-

TRANSVERSB VERTICAL, SECTION OF THE INFUNDIBULAR REGION.
a, Lumen of ventricle, a', Lumen of infundibulum. 1, Primary forms of
ependymal neuroglia, the processes extending from a cell-like body at the edge
of the ventricular cavity to the subpial limit. 2, Coarser and less ramified
variety of ependymal cell. 3, Coarser ependymal cells, branching within the
inner half of the infundibular wall. 4, Portions of ependymal cells with tufted
subpial branchings. 5, Unstained nerve-cells. 6, Pyramidal cells with long, fine
processes. 8, Transversely lying cells of small size with knobbed extremities.
9, Pyramidal cells with large numbers of apical processes. 10, Probable axis-
cylinder extension of pyramidal cells with thickenings, and rectangular exten-
sions to the subpial limit. 11, Nerve-fibers passing from the infundibular wall
into the tissues along the border of the ventricle. 12, Burr-like cells of the
infundibular wall. 13, Line of the floor of the brain. 14, Long-rayed ependymal
cells of the juncture of the ventricular and infundibular cavities. 15, 15, Fir-tree
ependymal cells of various sizes and forms lining the border of the ventricle. A
few of them are seen to have rounded knobs adjusted against the pial limit of
the basis cerebri. 16, Neuroglia cell approximating the short-rayed type of Golgi.
17, 17, Sustentacular glia-cells of the inferior border of the tuber cinereum. 18,
19, Glia-cells with numerous long and stout hairy processes from the bodies, and
thicker projections, probably transition forms between the sustentacular cells and
cells of later development. 20, Probable nerve-cell resembling some of the glia-
cells. 21, 21, Large mossy cells situated at some distance from the ventricular
border. 22, 22, Nerve-cells of different forms. (Berkley.)

tiated afferent impulses meet with response, and (2) that the
structures to which Berkley and Andriezen refer are contained
precisely in the central gray matter which Foster considers as
"perhaps in point of origin the oldest part of the brain" and
which "seems to serve chiefly as a bed for the development of
the nuclei of the cranial nerves," it seems clear to us that the
posterior pituitary body is a general center in which active func-
tions are incited and governed in response to afferent impulses.
A neuron, we have seen, presents all the attributes of other
organs; that the analogy includes the functional limits of these
organs is very probable. Under these circumstances and taking

21

SEMIEIAG-RAMMATIC TRANSVERSE VERTICAL

SECTION DF THE INFUNDIBULAR REG-ION

DF THE BRAIN, [Berkley,]

[Brain,]

THE CHIEF CENTER OF THE NERVOUS SYSTEM. 595

the digestive system as example, a group of neurons consti-
tuting the origin of a nerve would be able to automatically
continue its passive functions between meals. But just as the
onset of digestion, the active functional state of the stomach,
involves a reflex modification of the vibratory rhythm in all its
nervous supply, through the vagus, so would a nerve-center on
passing from the passive to the active state reflexly receive from
the posterior pituitary ~body the particular vibratory rhythm re-
quired by the organ to which its terminals are distributed.

Professor Foster's reference to the central gray matter
as a bed "for the development of the nuclei of the cranial
nerves" suggests that the posterior pituitary might possibly
supply energy for all cranial nerves. The complex origins and
connections of the optic nerve would, under these conditions,
convert the posterior pituitary into a source of energy, pure
and simple, for general distribution.

But the variety of cells which the posterior lobe contains,
as compared to the single type of ball-tipped fibers of the ante-
rior, suggests that such is not the case. Berkley says, referring
to the latter organ: "No nerve-ce/Zs are to be found in the sub-
stance of the organ, and all nerves belonging to it appear to
be derived from branches of the carotid plexus." This indi-
cates that nervous energy supplied by this organ to the supra-
renal system, while produced through the action of oxygen
upon the phosphorus-containing epithelial protoplasm and
therefore similar in kind to that produced elsewhere in the
organism, is due to a stimulating influence other than that
which prevails in the posterior lobe. In other words, while
the iodine in organic combination in the thyroid secretion is
the normal stimulus of the whole anterior lobe, — and one of
the many stimuli to which it responds, — the posterior lobe is
made up of many types of neurons which depend upon the leci-
thin formed between their protoplasmic partitions for their
functional activity.

The organs differ markedly and significantly in one re-
spect, therefore: i.e., in the fact that, while the whole of the
anterior lobe is devoted to the one purpose of energizing the
suprarenal nerves, the posterior is an aggregate of many cen-
ters. This indicates, it seems to us, that, if the organ were a

596 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

general source of energy for the whole bed of cranial nerves,
irrespective of the individuality and purpose of each nerve, it
would have been similar in general construction to its mate,
the anterior lobe. That it is not distinctly suggests that each
group of neurons in the posterior pituitary lody is a highly
specialized center for a single class of nerves. Indeed, this is
experimentally, though indirectly, sustained by Andriezen's
researches. He could not have traced a direct nervous con-
nection with the olfactory bulb and with the cerebro-spinal
axis had the organ been a center for the production of energy
intended to be diffused promiscuously in the central gray
matter.

Again, the connection between the posterior lobe and the
nervous system cannot be limited to the cranial nerves, since
we have seen how intimate is the functional relationship in
which afferent impulses obtain, between the middle brain and
the entire motor system. Were the cranial nerves alone in-
volved, the skeletal muscles would have to be omitted from
the list of structures under the organ's control. As we have
seen, removal of the middle brain abolishes all "bodily move-
ments," as Foster puts it, "carried out by means of co-ordinate
motor impulses, influenced, arranged, and governed by coin-
cident sensory or afferent impulses."

Yet, how can the posterior lobe influence organs with
which it has no anatomical connection? Thus, the most prom-
inent motor paths, the pyramidal tracts, arise, in the cortex,
from the upper two-thirds of the central convolutions, pass
down behind the knee of the internal capsule, and then pene-
trate the middle third of the pes cerebri, then the pons and
the medulla, and finally pass down the cord. Where is the con-
nection with the posterior pituitary? When the tracts "emerge
from the pons," says Edinger,62 "their fibers form two large bun-
dles in the ventral portion of the medulla," — i.e., in the regions
of the middle brain, — where, as we have seen, not only all nerves
endowed entirely or in part with motor properties — the second,
third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, elev-
enth, and twelfth pairs — are represented either by their nuclei

e2 Edinger: Loc. cit.

THE CHIEF CENTER OP THE NERVOUS SYSTEM. 597

or by communicating roots, but also where all nerves acquire
tlieir vasomotor properties.

But what is the difference — as regards the role of the nerv-
ous energy involved — between a motor and a vasomotor nerve?
None, evidently, and perfect equipoise between the energy
transmitted to the cellular structures of an organ, and that
necessary for its vasomotor functions, being a sine qua non to
proper function, a single organ was intrusted by Nature with
the inciting and governing role: i.e., the posterior pituitary
body. Of course., this relegates all motor impulses "influenced,
arranged, and governed by coincident sensory or afferent im-
pulses" to this organ, and makes it the general center of the
motor system. We have previously referred to the fact that the
medulla is only a transmitting center: a general station to
which impulses from various directions arrive by the cord from
below, by the commissures from the encephalic structures,
and establish junctions with the several paths with which they
are related. "The encephalon is a very complicated system of
large and small continents of gray or central nervous sub-
stance," says Professor Duval, "communicating one with an-
other and with the medulla by numerous commissures."

We have seen how absolutely independent of motor func-
tions the hemispheres are, though volitional attributes enable
them to utilize the motor system. Indeed, the experimental
evidence adduced on this score is incontrovertible. But the
same distinguished physiologist says: "The nerve-cells of the
cord form in this organ a continuous central gray mass, extend-
ing from one extremity of the organ to the other. But, if the
anatomist locates the superior limit of the cord on a level with
the occipito-atloidian articulation, for the physiologist the cord
extends into the interior of the cranium; it reaches to the
aqueduct of Sylvius (the true origin of the motor oculi com-
munis and patheticus) and even on a level with the third ven-
tricle— the gray substance of the walls of this ventricle." We
have seen that he also referred to its reaching up to the sella
turcica. That it is within this bony structure that the main
center of this vast mechanism — with its extensions and ter-
minals, including the vasomotor fibers — lies we have suffi-
ciently emphasized. We feel, therefore, that we have good

598 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

ground for the conclusion that the posterior pituitary body is
the center from which the impulses that incite and govern the func-
tional activities of the general motor system originate.

The relationship that exists between the cranial nerves and
the posterior pituitary body now becomes apparent. Not only
do the ten nerves endowed with motor properties either in toto
or in part owe their functional impulses to this body, but those
which regulate their functional blood-supply also. Again, as
all organs require functional impulses and blood, and inasmuch
as these impulses and the blood must be incited and governed,
all organs must be functionally dominated by the posterior
pituitary body. Indeed, all the data that we have presented in
this work tend to show that the posterior pituitary body is the
chief motor center of the organism; it incites and governs the
functional activity of all organs, including the vascular system
and, through the latter, the brain.

The anatomical relations of the posterior pituitary are
shown in the annexed colored plate prepared by us to portray
the relationship between this organ, the floor of the third ven-
tricle, the medulla, the pons, and the cord — all of which struct-
ures are continuous.

THE POSTERIOR PITUITARY AS THE CENTRAL SENSORIUM.

From all the data submitted and the normal functional
association embodied in reflex phenomena manifested through
various nerves — the vagus, for example — motor-efferent phe-
nomena are the normal sequences of sensory-afferent impres-
sions, and the two are necessarily linked. The pons Varolii, or
at least its gray ganglionic substance, is now thought to originate
motor impulses that are independent of mental processes and
to be the seat of instinctive acts. "It is, indeed, to the pons,"
says Professor Duval, "that, in a general way, we appear au-
thorized to ascribe the most important role in great emotional
expressions: laughing, weeping, the cry of pain; in a word, in-
voluntary manifestations. It is in this sense that the term
sensorium commune applied to the pons should be understood.
Indeed, if, as was done by Vulpian, the corpora striata, the optic
thalami, the tubercula quadrigemina, and the cerebellum™ are

M The hemispheres had doubtless been previously removed.

• . , i v i

THE POSTERIOR PITUITARY BDUY AS G-ENERAL
CENTER DF THE NERVOUS SYSTEM, [Sajaus],

Showing Continuation fram the Posterior Pituitary Body, of
the Infundibulum, the Floor of the Third Ventricle, the Medulla
Dblongata, and the Cord.

1, Corpora EjluadrigEmina. 2, Motor Dculi. 3, Patheticus.
4, PostErior Pituitary Body. 5, Supposed ITasomator Jlrea.
B, Cerebellum. 1, Hbducens. B, Trigeminus. 3, Fourth Ven-
tricle. ID, G-losso-pharyngeus. 11, Facial. 12, Pneumogastric
[Vagus], 13, Auditory. 14, Hypoglassal. 15, Spinal AooEssory.
IB, Spinal Cord. 17, Superior Cervical Ganglion. IB, Left Hemi-
sphere. 13, Third Ventricle. 2D, Infundibulum. 21, Anterior
Pituitary Body. 22, Optic Nerve. 23, Carotid Plexus. 24,Cas-
s Brian G-anglion. 25, Spheno-palatine G-anglion. 2B, Pans Varolii.

THE CENTRAL SENSORIUM. 599

successively removed, the animal still shows, by characteristic
agitations and plaintive cries, the pain it experiences when sub-
mitted to strong external excitations: i.e., when its leg is
squeezed with pincers or a bare nerve is excited. If the pons
itself and the upper part of the medulla are now destroyed, the
animal at once ceases to respond by similar cries and agita-
tions/' . . . "An animal that has lost its pons has there-
fore lost a center for the perception of sensitive impressions."
The gray ganglionic substance of the pons is, we have seen, a
part of the central gray matter which begins in the posterior
pituitary body: a fact which suggests that the latter is the
seat of functions now ascribed to this part of the pons.

Indeed, these instinctive involuntary acts are dominant in
the entire phylogenetic scale even in vertebrates devoid of skull
or brain: the amphioxus, for example, down to which Andriezen
traced the structures which ultimately become the pituitary
bodies. It is difficult to conceive of an inciting and governing
efferent impulse from the posterior pituitary without an af-
ferent impulse conveying to it the needs of the organ to be
incited to activity and governed. Duval refers to weeping, for
instance; tears, we have seen, are brought on by increased cir-
culation and stimulation of the cellular elements of the lacry-
mal glands; what is this but functional activity enhanced by
impulses to the posterior pituitary — if our previous conclusions
are at all warranted?

True, we are dealing primarily with a mental phenomenon,
but this only proves that afferent impulses may reach the poste-
rior pituitary from the cortex of the hemispheres as they can
from any organ. Nor is the act an instinctive one; but this
fact also affords supporting testimony, since it demonstrates
that the organ is not only influenced by impressions of a purely
reflex kind, or connected merely with organic life, but also by
the highest form of nervous action: i.e., mentality. What
better evidence can we have of this than the violent cardiac
action; the trembling; the involuntary excretion of urine, of
fasces, of sweat; or even the sudden arrest of the heart, all of
which phenomena may attend intense fear, and all due to loss
of control ~by the posterior pituitary, under the violence of the
mental impulses over . . . muscular tissue: cardiac, skele-

600 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

tal, cystic, intestinal, and sudorific? To this list me may add
loss of control over all vasoconstrictors, since we have relaxa-
tion of the larger internal vascular trunks, central engorge-
ment, in virtue of the principle — "vessels supplied with a mus-
cular coat and capillaries are mutually antagonistic in contrac-
tion and dilation" — submitted in the earlier chapters and the
mechanism of which we can now understand. Both antag-
onistic conditions are expressed in another symptom of fear:
i.e., intense pallor, the lividity of Asiatic cholera and, indeed,
of the moribund. Truly instinctive, however, is the sudden cry
or scream brought on by unexpected pain: evidently the result
of an impulse to the posterior pituitary, since we again have a
series of muscular actions of the chest, glottis, etc., which are
necessary for the cry. Laughing, sneezing, coughing, and other
kindred acts are all manifestations of motor activity; and so is
vomiting the result of afferent and efferent vagal impulses,
again with muscular structures as the mechanical factors and
the posterior pituitary as inciting and governing organ.

And a striking proof of this is furnished by the fact that
these manifestations of activity not only prevail in a frog de-
prived of its hemispheres, but that, if the animal is kept alive
and in good health, signs suggestive of intelligence appear.
"For days or even weeks after the operation," says Professor
Foster, "there may be no signs whatever of the working of any
volition; but, after the lapse of months, movements, previously
absent, of such a character as to suggest that they ought to be
called voluntary, may make their appearance. . . . Even
in their most complete development such movements do not
negate the view that the frog, in the absence of the cerebral
hemispheres, is wanting in what we ordinarily call a 'will/" Nor
need they, for these so-called involuntary, instinctive acts are
dominant even in vertebrates devoid of skull or brain: the
amphioxus, for example, down to which Andriezen traced the
structures which ultimately become the pituitary bodies.

That the posterior pituitary is a discerning organ, and one,
at that, capable of simultaneously subserving many functions,
is sustained on all sides. Totally independent of the brain,
though its servant when need be, it appears to us as the undoubted
seat of the many centers — i.e., for cardiac action, respiration,

THE CENTRAL SENSORIUM. 601

vasomotor action, sneezing, coughing, etc. — that have been
located in the medulla oblongata. True, local disease or trau-
matism point to the "bulbar" areas concerned as "centers."
But if the bulb is given the role which we believe it to fulfill, —
one which, perhaps, may allow us to call it a consociating organ,
— it will become apparent that any lesion capable of blocking
the multitude of afferent and efferent impulses that traverse
it at all times and which represent the aggregate of the organ-
isms inciting and governing energy must necessarily compro-
mise life or the functions of an organ to which the blocked
nerves are distributed.

We have expressed the belief that there are but two gen-
eral subdivisions of the nervous system, and that both of these
have the posterior pituitary body as their general center. This
view has not only been sustained by our analysis of the func-
tions of the various organs, but it seems to us to fully coincide
with established facts.

As Regards Efferent (Motor) Impulses.— It has been experi-
mentally determined that all fibers that originate from roots in
the anterior portion of the cord are efferent: i.e., transmit motor
impulses from the cord to the periphery. Section of these
fibers causes: in muscles, paralysis; in glands, cessation of
secretion; in vessels, dilation.

Interpreted from our standpoint, these morbid phenomena
are accounted for as follows: As the active functional state of
any organ is brought on by constriction of its arterioles beyond
the limits of tonic constriction (that attending the passive
functional state), section of the nerve transmitting the con-
strictive impulses brings on the opposite of active function, —
i.e., paralysis, — or, if distributed to a gland, arrest of secretion.
Although the same impulses serve to incite and govern the
cellular activity of the organ, paralysis, muscular or glandular,
is not due to the loss of these two functional attributes, since
section of vagal efferent nerves, which only incite and govern
the active functional state beyond tonic contraction, does not
cause paralysis. The immediate cause of the latter is slowing
of the blood-stream: i.e., reduction of the supply of oxidizing
substance. The cellular elements lose their mechanical energy
and can no longer be incited to action and governed. The

602 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

mechanical energy being due to the oxidizing substance, it is
traceable through the adrenal system to the anterior pituitary
body, while the inciting and governing influence, being of
cerebro-spinal origin through the anterior root severed, is
traceable to the posterior pituitary body. That it is of central
origin is proven by the fact that section of the medulla is fol-
lowed by general vasodilation.

Control experiments are represented by the well-known
facts that stimulation of an anterior root causes vasoconstric-
tion and increased functional activity, and, if sufficiently
strong, convulsive movements of muscles. The latter, as we
have repeatedly seen, are due to excessive oxidation of the
muscular elements — complemental testimony to the effect that
inadequate oxidation is the primary source of paralysis and
that our conception of the functional process is not erroneous.

We have previously shown that the so-called vasomoter
center and the cranial nerves that possessed motor properties
occupied the same medullary region: the upper. As general
motor nerves possess vasomotor properties, the reason for this
is obvious. Again, we ascertained that the cranial nerves which
acquire motor properties by anastomosis were grouped in the
lower portion of the medulla. The entire organ thus becomes
a conductor for general motor impulses, whether transmitted
by the cord (as indicated by the general vasodilation incident
upon medullary section) or by cranial nerves.

Although this aggregate of motor areas in the medulla
represents but radiating paths from a common center, the
posterior pituitary lobe, present conceptions as to their dis-
tribution— whether to the extremities, the thorax, the cranial
nerves, etc. — or their anatomical relations with the hemispheres
— the cerebellum, etc. — are in no way modified. All we need
to recall is that — if our views are sound — the sympathetic
system is not an autonomous system of nerves, and that it is
a subdivision of the general motor system originating, like all
motor nerves, from the cord, while its impulses emanate from
the common general center. Indeed, the lull is a consociating
organ, but not a primary center, nor the seat of a multitude of
specific centers. It is purely an extension of the spinal cord; and
its nuclei, roots, etc., correspond to the spinal roots, though more

THE CENTRAL SENSORIUM. 603

developed than the latter, and, like them, transmit impulses of
which the primary functional source is the posterior pituitary
lody.

As Regards Afferent (Sensory) Impulses. — It has likewise
been experimentally ascertained that all fibers that originate
from roots in the posterior portion of the cord are afferent: i.e.,
transmit sensory impulses from the periphery toward the cord.
Section of these roots is followed by loss of sensation.

Interpreted from our standpoint, sensory impressions are
similarly transmitted from all parts of the organism, and the
one general sensory system supplies the needs of all. The
nature of the impulse being governed by the specific cellular
characteristics of the peripheral structures which receives the
impressions, whether related to a special sense, general sensi-
bility, variations of functional activity, etc., they all reach
the posterior pituitary. That such is the case is demonstrated
by the fact that, while frogs deprived of the hemispheres ex-
hibit typical signs of continued co-ordination and sensation,
removal of the bulb then causes them to no longer show these
signs. This does not exclude the functions of subsidiary cen-
ters,— i.e., reflex centers, ganglia, etc., — which probably serve
as accumulators of energy, and act in lieu of the posterior
pituitary body unless the peripheral stimulation exceed their
potential as to the efferent energy actively used. The law of
generalization of Pfliiger, — i.e., propagation of (reflex) impulses
to the medulla under excessive excitation, — which, according
to our view, applies to the posterior pituitary, typifies the
maximum effect produced under such conditions, and further
demonstrates the connection between the periphery and the
latter organ.

Control experiments are represented by the familiar re-
sults of stimulation of the dorsal roots, which causes augmenta-
tion of reflex activities and of conscious sensations. The reflex
inhibition of functional activity of certain organs we have
ascribed to excessive stimulation: in accord, therefore, with
foregoing facts. This affords the complementary concordance
required to place our conception of the functions involved on
a solid foundation.

There is a feature of practical value in this connection

604 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

which must be emphasized: i.e., the identity of the posterior
pituitary body as the center upon which all emotions, shock,
etc., react, and as the organ which initiates the phenomena
that attend the impressions thus produced.

That this organ is directly or indirectly connected with
the cerebrum in all phenomena pertaining to intelligence,
reason, and will, precisely as its motor functions — other than
the purely automatic ones — may be dominated by these higher
manifestations of nervous activity, need hardly be emphasized.
"Sensory" interpreted by us — i.e., in its broad sense — refers
to impressions received by all end-organs endowed with sensa-
tion, as previously stated. Whether these first reach the eye,
the ear, the cutaneous surface, the gustatory papillae, the olfac-
tory area, etc., or be due to traumatism, surgical procedures,
an abnormal mental state, such as attends fear, grief, or other
emotions, etc., we are always dealing with molecular jarring
of the posterior pituitary body: harmless when slight, patho-
genic when sufficiently intense, but fatal when a certain limit
is reached. Precisely as the current passed through the region
by the Weber brothers inhibited the heart, so can fright, in-
tense pleasure, or shock prove fatal by inhibiting the heart,
but primarily by jarring the posterior pituitary body — or,
speaking more correctly, by inducing excessive molecular vibra-
tion of its elements.

The maximum effect of shock thus becomes an arrest of
nervous impulses through which function is sustained via the
cerebro-spinal axis. This may well be illustrated by the de-
scription given by Professor Stewart of the "various phenomena
which are grouped together under the name of shock" as ex-
emplified by section of the cord. "When the spinal cord of a
dog is divided, — e.g., in the dorsal region, — all power — all
vitality, one might almost say — seems to be forever gone from
the portion of the body below the level of the section. The
legs hang limp and useless. Pinching or tickling them calls
forth no reflex movements. The vasomotor tone is destroyed,
and the vessels gorged with blood. The urine accumulates,
overfills the paralyzed bladder, and continually dribbles away
from it. The sphincter of the anus has lost its tone, and the
faaces escape involuntarily." We hardly need to emphasize the

THE CENTRAL SENSORIUM. 605

fact that we have here a summary of all the phenomena which
attend loss of functional activity: that over which the poste-
rior pituitary body presides.

But this experimental section of the cord was also chosen
as an example of the wonderful resources of Nature when
life's functions are to be preserved. "If we were to continue
our observations only for a short time, a few hours or days/7
continues the author, "we should be apt to appraise at a very
low value the functions of that part of the cord which still
remains in connection with the paralyzed extremities. But
these symptoms are essentially temporary. They are the re-
sults of shock; they are not true 'deficiency' phenomena. And
if we wait for a time, we shall find that this torpor of the lower
dorsal and lumbar cord is far from giving a true picture of
its normal state; that, cut off, as it is, from the influence of
the brain, it is still endowed with marveleus powers. If we
wait long enough, we shall see that, although voluntary motion
never returns, reflex movements of the hind-limbs, complex
and co-ordinated to a high degree, are readily induced. Vaso-
motor tone comes back. The functions of defecation and mic-
turition are normally performed. Erection of the penis and
ejaculation of the semen take place in a dog. A man with
complete paralysis below the loins and destitute of all sensa-
tion in the paralyzed region has been known to become a
father (Brachet). Pregnancy carried on to labor at full term
has been observed in a bitch whose cord was completely divided
above the lumbar enlargement."

How is this to be accounted for? Simply by the fact that
the "sympathetic" chain of ganglia does not constitute an
autonomous system, but a part of the general motor system,
which is able to compensate, in a measure, even for spinal
functions. It serves as conductor for impulses, through its
communicating branches, and thus supplies a bridge, as it
were, between the two segments of the cord: i.e., between the
isolated lower segment and its source of impulses, the poste-
rior pituitary body. The same ganglia and the splanchnics also
using this chain as intermediary to the adrenals, the continua-
tion of the quasinormal functions in the mutilated animal are
accounted for and the unity of the whole mechanism shown.

606 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

In view of all these facts, the following conclusion seems to us
warranted: The posterior pituitary ~body is the center upon which
all emotions, shock — psychical or traumatic — and kindred sources
of nervous functional excitement or depression react, and impair-
ment of its functions accounts for the pathological phenomena now
ascribed to such causes.

THE PITUITARY BODIES AS THE GOVERNING CENTERS
OF THE VITAL PROCESSES.

The foregoing facts sufficiently emphasize the physiological
importance of the posterior pituitary body, for, in transferring
to this organ the functional attributes so long thought to belong
to the medulla and the pons in addition to others herein out-
lined, we have concentrated within its precincts the entire con-
trol of all chemico-physical agencies that enter into and serve to
sustain life's processes. This, of course, indicates that even the
anterior pituitary body is governed by its mate. That such is
the case is evident: the terminal fibers that have been very
properly termed "vasomotor" hold all vessels in their grasp,
while it is through their intermediary that cellular metabolism
and the oxygen-supply to all tissues are incited and governed.
Indeed, this diminutive organ appears — to us at least— as one
of Nature's most wonderful achievements. And yet, does the
anterior pituitary not govern its mate? We have sufficiently
emphasized the increased oxidation that occurs in all organs
when this lobe is unduly active; that the posterior lobe is no
exception to the rule is obvious. It thus becomes evident that
both pituitaries are interdependent: a proof, indeed, of their
supremacy over all other organic functions.

With due reserve, however, and fully realizing that all the
deductions recorded in this volume may be faulty in the light
of data with which we may not have been familiar, we venture
to submit the following conclusion: —

The pituitary bodies are the general centers which actively
sustain cellular metabolism: the anterior pituitary insures oxy-
genation of the Nood and all oxidation processes; the posterior
pituitary adjusts the vibratory rhythm of all nervous impulses
which incite and govern functional activity.

This is not intended to imply that the pituitary bodies are

THE GOVERNING CENTERS OF VITAL PROCESSES. 607

the source of life, for this is a property of every cell in the
organism. During the earlier years of our existence, while the
adrenal and nervous systems (including their chief centers) are
undergoing development, their functions are relatively circum-
scribed, the thymus supplying deficiencies. As will be shown
in the next chapter, we have evidence of this in the liability
of children to certain infectious diseases which do not affect
the adult. While the latter is able to counteract the patho-
genic organisms and their toxins by means of adequate immu-
nizing agencies, the child is not, because it is only supplied,
through the intermediary of its thymus, with relatively ineffi-
cient quantities of these agencies; in other words, the total
immunizing energy developed by its organs is inadequate.
Indeed, the first year of a life is the period of greatest exposure:
Nature supplies, in the mother's milk, not only nutriment, but,
as previously stated, oxidizing substance — besides other anti-
toxic elements.

Even the anterior pituitary, the governing center of the
oxidation processes, can in no way be deemed a life-center.
During the earlier portion of its existence the organism is, in
a measure, independent of its pituitaries, and able to sustain
life with the centers of the lower brain and cord as governing
ganglia. Even in the adult the adrenals are not solely de-
pendent upon their own center. As we have seen, they are
connected with the cord by communicating filaments: those
which probably supplied them with their first impulses and
sustained their functional activity until their chief center had
reached a state of development able to satisfy the needs of the
perfected organism. That these spinal communicating nerves
may be able to resume or continue their role as channels for
impulses to the adrenals, in case of injury to, or destruction
of, the pituitaries, is probable. The very importance of these
organs in the economy suggests the presence of a mechanism
capable of insuring the continuation of life — even though in-
competent to afford protection against disease.

The two pituitaries, intrusted, as they are, with functions
which include high powers of differentiation, are complement-
ary, and, so to say, terminal structures. They develop with
the body, and are only functionally perfect when the latter has

608 THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

reached its maturity; but the fact that they are at all subject
to development proves their identity as parts of the whole, and
though endowed with sovereignty over all functions, they stand
no higher than any other organ as a life-center, though perhaps
the seat of inordinate metabolism.

Oxygen, we have seen, is the active agency through which
the anterior lobe carries on its functions; phosphorus is that
upon which the posterior lobe depends — with the oxidizing
substance of the plasma — for the elaboration of its intrinsic
energy. These two elements underlie the functional activity
of all cells, and their mutual affinity accounts for the display
of vital energy of which all cellular structures are the seat.
Oxygen-laden blood brought into contact with phosphorus-
laden cells of which all tissues are built represents, therefore,
the foundation of functional activity. Indeed, Pfliiger,64 re-
ferring to the photogenic organs of lightning-bugs, says: "Here,
in the wonderful spectacle of animal phosphorescence, Nature
has given us an example that shows where the taper burns that
we call life. . . . It is certainly no rare exception, but only
the special expression of the general law, that all cells are
burning continually, although with our corporeal eyes we do
not see the light."

64 Pfliiger: "General Physiology," by M. Verworn; translated by F. S. Lee,
1899.

CHAPTER XI.

THE INTERNAL SECRETIONS IN THEIR RELATION
TO IMMUNITY.

THE UNITY OF CELLULAR LIFE.

IN the present state of our knowledge the inaccuracy
of the view that bacteria per se cause disease independently
of the toxins they generate hardly needs to be emphasized.
Apart from the mechanical effects which the accumulation
of micro-organisms in the blood may cause, every disease
distinctly traceable to them is attended with intoxication.
Whether there occur after infection a rapid multiplication and
a wide-spread distribution of germs, as in anthrax and septi-
caemia; or a more localized though prodigious multiplication
of bacteria, as in cholera and pneumonia; or, again, an abso-
lutely circumscribed multiplication at the site of infection,
as in diphtheria: phenomena such as toxins alone can cause
invariably appear. In the entire sphere of bacterial activity
is encompassed that which is manifest in all Nature: a dis-
play of energy through change. Micro-organisms, by their
growth and multiplication, not only generate products of
metabolism, bu£ these, by their physico-chemical effects upon
surrounding liquids, engender the fermentative processes which
underlie all infectious diseases, — "infectious" only in the sense
of the.ir being transmissible.

Again, we can legitimately assume that the reactions
caused by micro-organisms in the body-fluids are similar to
those brought on by the venom of snakes, insects, and toxic
plants. Unity of cellular life applies to and includes all path-
ogenic cells, whether these be of animal or vegetable origin; it
applies likewise to their metabolism, the toxic elements gen-
erated by them, and to the reactive effects on their surround-
ings. While Weir Mitchell, Reichert, and others have dem-
onstrated the albuminoid nature of the toxic principles of
snake-venom, Roux has emphasized the analogy between these
principles and the toxalbumin of diphtheria. The urticaria

(609)

610 THE INTERNAL SECRETIONS AND IMMUNITY.

caused by the thistle is precisely that caused by the medusa, and
is traceable to the same agency, formic acid: the irritating prin-
ciple of the caterpillar, the ant, and other insects. Calmette1
found that cobra-venom caused, in the conjunctiva, an inflam-
matory process precisely similar to that brought on by abrin
and jequirity. ' We are also familiar with the beautiful experi-
ments of Ehrlich with abrin and ricin: two albuminoid vege-
table poisons which correspond with bacterial poisons even to
their being able to confer immunity. Just as there are harm-
less cells in the animal structure, so are there harmless cells
in vegetable structure. In the ascending steps of morbidity,
in which these benign organisms may take part under the
influence of various reactions, we witness, howev.er, not only
a biochemical parallelism in all phenomena engendered, but
also, as rightly contended by Charrin,2 a common symptoma-
tology. Thus, in their physical interchanges, morbid effects,
and semeiology, all cellular structures, can be united in a com-
mon class.

THE ADRENAL SYSTEM IN ITS RELATIONS TO PHAGOCYTOSIS
AND LEUCOCYTOSIS.

Metchnikoff terms "phagocyte" any cell deprived of a
cellular membrane and capable of incorporating bacteria and
other substances, and of disintegrating them. In the blood,
certain leucocytes, particularly the mobile or wandering neutro-
philic or polymorphonuclear forms (the "microphages"), the
fixed endothelial and connective-tissue cells, those of the
splenic pulp, and the large lymphocytes of the blood ("macro-
phages"), are endowed with this property. Precisely as do the
familiar amoeba, so do these phagocytes ingest bacteria and
assimilate them. An animal is immune, according to Metch-
nikoff, as long as its phagocytes freely take up and destroy
pathogenic organisms. In proportion, on the other hand, as
the functions of the phagocytes are impeded, so is the animal
susceptible to disease. That living and dead bacteria are thus
disposed of seems to have been satisfactorily shown, while
chemotaxis fairly accounts for the affinity which phagocytes

1 Calmette: Annales de 1'Institut Pasteur, vol., 1892.

2 Charrin: "Poison des Tissus," quoted by No6, loc. cit.

THE ADRENAL SYSTEM AND PHAGOCYTOSIS. 611

show for certain germs in preference to others. Metchnikoff's
doctrine as regards the power of certain leucocytes, migrating
and fixed, to act as phagocytes is sustained by experimental
evidence; the process can easily be followed visually and the
leucocytes be seen to ingest micro-organisms, to which they
are drawn by chemotactic influence. In 1862 Haeckel wit-
nessed the ingestion of indigo by leucocytes; in 1863 lleckling-
hausen observed that pus-cells were endowed with amoeboid
motion, and, having injected cinnabar grains in the dorsal
lymph-sac of frogs, saw that they were ingulfed by cells float-
ing in the lymph. Cohnheim in 1867 noted that the smaller
vessels of the mesentery became dilated and saw leucocytes
range themselves along the vascular walls, plunge their pseudo-
podia through the mural stomata, and penetrate beyond them,
thus migrating and becoming "pus-cells." These pus-cells, in
the light of MetchnikofFs theory, are the remains of protective
microphages which have succumbed after migrating through
vascular walls to meet offensively the pathogenic organism.
Dead material, pigment-granules, fragments of tissue, dust-
particles, indigo, ivory (in the osseous medullary canal, ac-
cording to Kolliker), in fact, almost any foreign substance
capable of invading the living organic structure, seems to
become their prey. An aseptic catgut ligature, a fragment of
bacilli-laden tis'sue, etc., soon becomes coated with an exudate
filled with leucocytes which first ingulf the bacilli and then
the disintegrated tissue. Let any inhibiting cause appear,
however, — an excessively virulent germ, an abnormally high
temperature, for instance, — their powers cease, and at once
the bacilli multiply, causing death of the animal used for the
experiment. The rapidity of the multiplication of pathogenic
organisms is an additional factor operating against successful
phagocytic action. When such is the case the phagocytes are
themselves destroyed.

Successful phagocytes may be traced from their working
field by staining the latter, as was done by Eosenberger; long
lines of colored cells may then be seen to radiate in various
directions from the stained area. The pathogenic germs, once
ingulfed, usually cease to multiply, and, either through a toxic
action or starvation, soon die and disappear. That organisms

39

612 THE INTERNAL SECRETIONS AND IMMUNITY.

are ingested alive Metchnikoff has shown. Spermatozoa, for
instance, ingested by macrophages were seen to continue their
motile activity until the tail had also been taken up. Begun
in 1865 with the digestive epithelium of Gedesmus bilineatus,
the cellular elements of which were shown to digest various
extrinsic substances, MetchnikofFs labors developed in 1883
into his present doctrine of phagocytosis, which, notwithstand-
ing much adverse criticism, is steadily gaining ground.

The rapidity with which the protective process is carried
on in cases of general infection is well illustrated by Cantacu-
zene3: "Immediately after injecting anthrax bacteria in a vein
of a rabbit's ear," says this author, "the organisms are taken
up by phagocytes. At the end of seven minutes in the liver,
eight minutes in the lungs, and one hour in the spleen none
of the germs are free. Their destruction in the phagocytes
is at first very rapid, but soon some of the latter are overcome,
and the bacteria, by multiplying within them, cause them to
become centers of pullulation. Still, the bacteria that escape
from the dead phagocyte are seized by others; but, the number
of the former becoming greater as the battle progresses, their
protective powers are correspondingly reduced, and the bac-
teria finally invade the entire blood-stream. In the liver
. . . practically all the bacteria are destroyed and digested
within a few minutes after the injection. This superiority of
the hepatic phagocytes in the fray lasts almost throughout the
disease; but the activity of the phagocytes finally decreases;
the bacteria multiply within them and become generalized.
In the lungs there is rapid destruction of bacteria by poly-
nuclear cells, then intracellular development of bacteria and
generalization."

The phagocytes just referred to, the microphages, are
wandering or migrating cells — free to respond and travel more
or less promptly toward pathogenic bacteria, in virtue of the
chemotactic attraction possessed by the latter.

Immediately connected with the role of these migrating
cells is the process of leucocytosis, — a more or less transient or
marked increase, in a given area or organ, of leucocytes, — the

3 Cantacuzene: Quoted by Marcel Monnier, Gazette Medicale Beige, July 13,
1899.

THE ADRENALS, LEUCOCYTOSIS AND PHAGOCYTOSIS. 613

polymorphonuclear variety, included among those which Metch-
nikoff termed microphages, usually predominating. Leucocy-
tosis has been the source of considerable controversy. Some
investigators have connected it directly with phagocytosis;
others have ascribed to leucocytes the production of substances
destined to endow the blood-plasma with antitoxic properties.
That leucocytosis especially attends, besides leukemia, infec-
tious and inflammatory disorders, pneumonia, suppurative
processes, rheumatism, etc., is well known. Inflammatory dis-
eases of serous membranes, — peritonitis, pericarditis, menin-
gitis, etc., — malignant tumors, wasting diseases, haemorrhages,
etc., also show it at times. Various drugs produce leucocyto-
sis, and it often follows cold baths, massage, and other stimu-
lating measures. It is normally present in the newborn and
often occurs during pregnancy, digestion, after violent exer-
cise, etc.: the "physiological" form observed in normal subjects.

In contradistinction to leucocytosis is hypoleucocytosis:
a condition in which the leucocytes are decreased. This is
met with in typhoid fever, acute tuberculosis, lobar pneumonia,
influenza, tubercular pleurisy, measles, inanition, etc. The
causes of this condition may be said to be at least obscure,
judging from the .variety of doctrines vouchsafed by as many
investigators and based upon contradictory experiments. In-
deed, while some have observed leucocytosis in a given disease,
other experimenters fully as reliable have witnessed hypoleu-
cocytosis. While some have observed a primary decrease of
leucocytes after the injection of toxic substances into the
blood, others have noted that the capillaries of various organs,
including the liver and the lungs, were crowded with leucocytes
during this stage. That considerable uncertainty reigns as to
the nature and purposes of leucocytosis is evident.

Leucocytosis, however, seems to present many bonds of
association with phagocytosis, while the functions of the ad-
renal system as described in this work seem related to both.
A rapid increase of leucocytes, — say, from 3000 to 10,000, — in
typhoid fever, for instance, is thought to indicate that perfo-
ration is about to occur. And yet, Harvey Gushing4 refers to

4 Harvey Gushing: Archives Generates de M6decine, Jan., 1901.

614 THE INTERNAL SECRETIONS AND IMMUNITY.

four cases in which laparotomy was resorted to in this connec-
tion with the view of closing ulcers, in which none were found.
While the operation led to no complications, it is obvious that
leucocytosis, in this connection at least, proved misleading.
This assertion- is further strengthened by the fact that Cabot
states that an increase to 15,000 leucocytes may be witnessed in
the absence of complications. Colin K. KusseP analyzed the
question in thirty-six uncomplicated cases and obtained a varia-
tion ranging between 2000 and 12,000. In one of the cases a
leucocytosis of 28,000 led to operation; a perforation was found
and the patient recovered. In another case the leucocytosis
only reached 4800. Yet, operation led to the discovery of a
ruptured bowel and six other ulcers which had nearly pene-
trated the whole thickness of the intestine. The patient died.
A third case showed 14,500 leucocytes and was operated, but
no perforation was found. While this in no way detracts from
the great value of operative procedures in perforation, it seems
evident that as a sign of this complication leucocytosis is un-
reliable.

Analysis of the cases in which laparotomy disclosed no
perforation notwithstanding leucocytosis, however, may furnish
a clue to the cause of these discrepancies and elucidate the
physiological function involved. In one of the cases referred
to by Kussel (Dr. -Hamilton's) the leucocytosis reached 16,000,
but was 14,500 when the operation was begun. There was pain
in the lower left quadrant and marked rigidity of the abdom-
inal muscles. Nothing unusual was found beyond the condi-
tion of the bowel "to be expected at that stage of the disease.''
The next day the blood-counts revealed 10,000 leucocytes. The
usual intestinal ulcers could alone, therefore, have been the
source of the temporary exacerbation. In another case of the
same kind, with a pre-operative leucocytosis of 17,000, the only
feature found was unusual tension and swelling of the ileo-
caecal glands. As there was no perforation, we are relegated
to the ulcerative process alone as the source of the symptoms
witnessed. It is not with the perforation that this increase
of leucocyte-count could be associated, therefore, but with the
ulcerative inflammatory process.

Colin K. Russel: Boston Med. and Surg. Jour., April 18, 190L

THE ADRENALS, LEUCOCYTOSIS AND PHAGOCYTOSIS. 615

Harvey Gushing refers to abdominal pain, rigidity and
tenderness of the abdominal walls as having been observed by
him in all cases some time before the perforation occurred.
Are these symptoms due to the direct effect of the intestinal
lesion upon neighboring structures, or are they localized ex-
pressions of a general perturbation? Lennander, of Upsala,6
has recently shown that, while the parietal peritoneum — that
immediately underlying the abdominal walls — was sensitive
and painful even when only touched, rubbed, or stretched, the
visceral peritoneum, on the contrary, could be rubbed, incised,
cauterized, or chilled without causing the least discomfort.
Neither here nor in the greater part of the small intestine,
its mesentery, the great omentum, the caecum and appendix,
and the colon was there the least evidence of the presence of
nerves capable of transmitting tactile, thermal, or painful
impulses. If intestinal pain does appear, therefore, before
perforation, the parietal peritoneum must be included in what-
ever protective process the threatened complication may
awaken. The occurrence of this symptom elsewhere than in
the neighborhood of the lesion further sustains this fact. E.
Palier,7 for example, describes a case in which abdominal symp-
toms were so marked that the diagnosis of appendicitis was
made by a consultant and an operation performed. The au-
topsy showed pneumonia with empyema, the abdomen being
normal. J. L. Morse8 also refers to the danger of mistaking
a case of so-called "abdominal pneumonia" in children for one
involving the abdominal organs, and states that he has seen
two cases in which the abdomen had been opened by experi-
enced surgeons, because appendicitis was supposed to be pres-
ent. Mirande9 even goes so far as to suggest, in this connec-
tion, that a special form of pneumonia be distinguished: i.e.,
that to which the name "appendicular pneumonia" has been
given, owing to the predominance of the symptoms simulating
appendicitis. These symptoms only occur, he found, in the
early stages of the disease, and rarely persist longer than the

6 Lennander: Centralb. fiir Chirurgie, Feb. 23, 1901.

7 E. Palier: New York Medical Journal, Sept. 16, 1899.

8 J. L. Morse: Annals of Gynaec. and Pediatry, Nov., 1
•Mirande: Medical Press and Circular, June 5, 1901.

616 THE INTERNAL, SECRETIONS AND IMMUNITY.

fourth day. The pain, rigidity, and sensitiveness of the abdom-
inal wall cannot, therefore, be the result of a local, direct action
of the intestinal lesion upon overlying tissues through pressure,
contiguity of tissue, etc., but, instead, the incidental expression
of a general physiological function of which leucocytosis is an
important attribute.

That this is true is also sustained by the facts that the
anatomical subdivisions of the peritoneum are purely arbitrary
and that, as far as continuity of tissue goes, we are dealing
with a single membrane. Unless the entire peritoneum be in-
volved in the inflammatory process, therefore, the plea that
the symptoms referred to are due to extension of the latter to
its parietal or sensitive portion cannot hold. The cases in
which eoeliotomy reveals no signs of peritoneal inflammation
notwithstanding the presence of these symptoms; the sudden-
ness with which the latter .may develop; the facts that they
often appear before perforation has occurred and that the pain
sometimes appears here, as in appendicitis, in spots quite re-
mote from the area in which the lesion occurs, need only be
mentioned to show that such cannot be the case.

Further evidence that we are dealing with a general proc-
ess is afforded by the long list of diseases in which leucocytosis
occurs and which includes, as already stated, all inflammatory
disorders. Among the tissues which show a special predilection
for diseases attended with leucocytosis are the serous mem-
branes. Pleurisy, peritonitis, pericarditis, meningitis, etc., are
familiar diseases in this connection. All are also accompanied
by a more or less copious exudation of serum in which leuco-
cytes, fibrin, and products of tissue-proliferation of the endo-
thelial and connective-tissue cells prevail.

When, in the course of typhoid fever, perforation is about
to occur, the fact that localized inflammation of the sensitive
parietal peritoneum is not always found to account for the
presence of leucocytes does not preclude the possibility of sud-
denly developed cellular overactivity manifested by enhanced
cellular metabolism. Under these circumstances the sensitive
parietal layer would be as markedly involved as the visceral.
The pain and superficial tenderness would thus appear not-
withstanding the total absence of sensation possessed by deeper

THE ADRENALS, LEUCOCYTOSIS AND PHAGOCYTOSIS. 617

structures and merely because the parietal layer is supplied
with nerves capable of transmitting pain-impulses. This would
tend to suggest that the adrenal system might underlie the
whole process, since increased activity of this system, brought
on by a generalized infection originating in the intestinal ulcer-
ation (a toxin acting like any other poison), would correspond-
ingly increase the oxyhaemoglobin ratio, and therefore enhance
tissue-change and leucocytogenesis in proportion.

The effects of quinine upon the adrenal system will enable
us to test this question. That this alkaloid produces upon this
system effects similar to those caused by other sufficiently
active drugs may readily be ascertained. In the stage of ad-
renal overactivity we have cerebral and peripheral congestion,
manifested by headache, tinnitus, muscular agitation, convul-
sions, etc.; increased peripheral vascular pressure, shown by
the flushed face, haematuria, spontaneous epistaxis, etc.; in-
creased heart-action, shown by strengthened pulse-beat, with
lowered frequency — sometimes down to 40, and other signs.
When the stage of insufficiency is reached, great muscular
weakness appears, followed by paralysis, — sometimes perma-
nent in frogs, — lowered and depressed vascular pressure, with
superficial anaesthesia; rapid and greatly weakened heart-beat;
lowered temperature; dyspnoea, with lessened C02 elimination;
methgemoglobinuria, etc. Five grains have been known to cause
symptoms bordering on the latter stage. This is well illus-
trated by a case reported by Ciaglinski,10 credited to "idiosyn-
crasy": a term which may become obsolete, since the special
vulnerability which it serves to represent appears to be due
to functional impairment of the adrenal system. The untoward
symptoms occurred in a girl of 22 years, after a dose of only
5 grains. One hour after this was taken there suddenly devel-
oped agonizing pra?cordial and periumbilical pain, obstinate
nausea, repeated vomiting and diarrhoea, with profuse, offen-
sive stools of a black color. At the same time her body and
extremities became covered with patches of urticaria. The
rash disappeared spontaneously. The pulse was rapid, the
pupils contracted, and there was marked tenderness of the

10 Ciaglinski: Gazeta Lekarska, No. 13, 1892.

618 THE INTERNAL SECRETIONS AND IMMUNITY.

abdomen. A small dose taken some time before produced the
same effect; morphine had likewise given rise to unusual
symptoms. Adrenal insufficiency is also well exemplified in
a case witnessed by A. E. Roberts.11 The patient, a woman of
36 years, after .taking about 300 grains, became totally uncon-
scious and inert. The surface was cold and livid; the axillary
temperature, 95° F. (35° C.); the respiration almost imper-
ceptible, shallow, and slow; and the pulse thin and small. The
pupils were considerably dilated, and did not respond to light.
She vomited what the author terms "coffee-ground substance"
several times. She recovered, but with impaired vision.

Taken collectively, all the symptoms of poisoning enu-
merated distinctly show that quinine is no exception in respect
to the effects of drugs recorded in the second chapter, and yet
we meet with ample testimony to the effect that this alkaloid
checks the migration of leucocytes. At first sight, therefore,
it would seem that the stimulation of the adrenals which qui-
nine undoubtedly induces cannot be considered as the under-
lying factor of leucocytosis, and that the increment of tissue
metabolism attributed to the adrenal overactivity supposed to
account for the symptoms referred to has no part in their
production. The experiments of Binz, Kerner, Cutter, Hare,
and Martin12 not only distinctly show the inhibiting effect of
quinine upon leucocytes, but also that in sufficiently strong
solution it may arrest their amoeboid movement: the sine qua
non of phagocytic action. Analyzed more closely, however, the
question assumes another aspect.

Although these investigators were necessarily working in
the dark as regards the governing influence of exact do
and the results reported thus lose much of their value for the
present analysis, they nevertheless furnish many elucidative
data. Binz, for instance, using the method of Colmheim.
curarized the frogs used for the experiment, so that the ani-
mals' adrenals were not only submitted to the influence of one
toxic, but of two: curare and quinine. That the animals were
already suffering from the effects of adrenal insufficiency when
their mesentery was exposed upon the stage of the micro-

u A. E. Roberts: Lancet, March 9, 1895.
«H. C. Wood: Lor. cit., p. 534.

THE ADRENALS, LEUCOCYTOSIS AND PHAGOCYTOSIS. 619

scope is therefore probable. No accumulation of leucocytes
occurred under irritation and, when after a time they began
to accumulate, Binz at once checked them by a small hypoder-
mic injection of the alkaloid: a normal consequence, if the ad-
renal insufficiency had anything to do with the production of
leucocytosis. Again, Binz took two young cats, and, "after
poisoning one of them with quinine," says Wood, "examined
their blood. In the blood of the unpoisoned animal the white
cells were far more abundant than in that of the poisoned cat/'
It is from these experiments that Binz deduced that quinine
acted destructively upon leucocytes "in the same way as when
they are out of the body." If the role of the adrenal system
is what we deem it to be, the opposite is true: The poisoned
animal did not show leucocytosis because its adrenal system had
been rendered insufficient by the poison, while the unpoisoned
animal showed marked leucocytosis because its adrenal system
acted normally. As to the extra corpore effects of quinine upon
the blood, the reader has doubtless already thought of their
valuelessness if the, adrenal system is the source of toxic symp-
toms.

It is probable that all the animals used for the experiments
referred to were given sufficiently large doses to produce ad-
renal insufficiency. Only small animals were used, and, if we
consider that 30 grains are sufficient to bring the adrenals of
some normal adults unaccustomed to quinine to the brink of
insufficiency, it is more than probable that the doses employed
in the experiments far exceeded those capable of only bringing
on the stage of excitement or overactivity. Wild, of all the
investigators referred to by Wood, is alone stated to have used
very weak solutions (1 part to 5000). In contradistinction to
the contraction of blood-vessels noted by others, he observed
"an enormous dilation of the vessels, with consequent increased
rapidity of passage through them of liquid under pressure."
The inference is obvious.

Hare's remarks, supplemented by Wood's deductions, are
very interesting in this connection when the proposition sub-
mitted in the first chapter — "muscular vessels and capillaries
are antagonistic in contraction and dilation" — is recalled.
Hare, who had also been led to conclude that quinine prevented

620 THE INTERNAL SECRETIONS AND IMMUNITY.

"the extrusion of white blood-cells from the frog's mesentery,"
found "that the vessels in the cinchonized frog were much
more contracted and had their walls much thicker than in a
corresponding frog without quinine." Wood, on the other
hand, says that "it is certain that the alkaloid reduces very
markedly the force of the heart" and adds "it is therefore
possible that the quinine prevents the outwandering by lessen-
ing the force which is driving the corpuscles and at the same
time increasing the resistance of the capillary walls." It is
evident that the contractions of these vessels witnessed by
Hare would, if the foregoing proposition represents the actual
mechanism involved, be the normal effect of toxic doses, while
the "outwandering" of the leucocytes and the "resistance of
the capillary walls" would occur as normal sequences of the
process. Underlying it all appears the weak heart, suggesting
that its normal stimulant had been reduced quantitatively
through the inhibitory action of the alkaloid upon the ad-
renal system.

When all these features of the problem are collectively
considered, it seems permissible to conclude that leucocytosis,
or at least the more or less prolonged exacerbations of this condition
witnessed in various diseases, is the result of overactivity of the
adrenal system, induced by the toxins of pathogenic germs, poisons,
venoms, products of metabolism, foreign substances, etc., when any
of these penetrate the blood-stream in sufficient quantities.

This not only accounts for the leucocytosis observed in
disease and for that witnessed after active exercise, massage,
etc., — the so-called physiological leucocytosis, — but also for
that due to the introduction of various drugs into the system:
the so-called "medicinal" leucocytosis. The very existence of
such a subdivision of the subject as the latter points to a com-
mon source for protective functions: one in which the adrenals
play a commanding part, if the effects of drugs upon the ad-
renal system as depicted in this work at all obtain.

Further evidence is available in the literature upon the
antitoxic effects of various serums. Besredka,13 for instance,
found that leucocytic serum produced effects that varied very

"Besredka: Annales de 1'Institut Pasteur, vol. xiv, 1900.

THE ADRENALS, LEUCOCYTOSIS AND PHAGOCYTOSIS. 621

greatly. While 3 or 4 cubic centimeters of a normal rabbit's
serum killed guinea-pigs in a few hours, after these animals
had shown extreme hypothermia, diarrhoea, and collapse, the
necropsy revealing the presence of an abundant limpid and
sterile exudate in the peritoneum with but few cells, smaller
doses gave rise to very abundant leucocytosis. According to
Schiitze,14 the steps of the process in guinea-pigs are as follows:
At first a limpid fluid containing a few leucocytes is exuded;
after about twenty-four hours an increase becomes manifest,
while on the third and fourth days it becomes extreme (Bes-
redka); after a second dose on the fourth day the count, from
17,500, gradually increased until 166,500 per millimeter was
reached. This investigator attributes the stimulating effects
observed to an action upon the leucocyte-producing organs:
a correct interpretation, provided the adrenal system is in-
cluded in the process. Indeed, we have submitted ample testi-
mony to make it evident that the adrenal system, under the in-
fluence of toxics, at first increases, by its secretion, the oxyhsemo-
globin in the blood, and correspondingly enhances all the func-
tions of the organism. We can, therefore, legitimately conclude
that the activity of all physiological protective processes, including
the elimination of toxics by the liver, and the production of leuco-
cytes, i.e., of bactericidal cells, by the lymphatic system, the bone-
marrow, and the spleen, is likewise enhanced when the adrenal
system is over stimulated by poisons.

Another feature of phagocytosis as a physiological func-
tion is embodied in the postulate — "muscular vessels and capil-
laries are antagonistic in contraction and dilation" — when all
structures made up of endothelial cells, capillaries, serous mem-
branes, etc., are included in the process. Phagocytosis, as con-
ceived by Metchnikoff, is not limited to the polymorphonuclear
neutrophilic, and other wandering leucocytes, but it also in-
cludes stationary endothelial and connective-tissue cells, which
take up pathogenic organisms and foreign substances and dis-
integrate them, precisely as do the free cells. It also includes
Kupffer's stellate cells, the pulp-cells of the spleen and of the
bone-marrow. The quantity of living elements thus brought

14 Schiitze: Deutsche med. Wochenschrift, No. 27, 1900; quoted by W. Bulloch,
Practitioner, May, 1901.

622 THE INTERNAL SECRETIONS AND IMMUNITY.

into protective activity is, indeed, suggestive when their ex-
tensive distribution is recalled. As is well known, endothelial
cells line all spaces, channels, or cavities, large or small, that
permeate the great connective-tissue system. The peritoneal,
pleural, pericafdial, and arachnoid cavities, the lymph-vessels,
and the inner surface of blood-vessels are thus protected
throughout with a complete layer of these elements.

Especially important is it to recall, in this connection, a
few classic features, namely: that the capillary system is prac-
tically made up of endothelial cells joined edge to edge; that
the circulation of the blood in these minute vessels is relatively
slow; that the peripheral portion of the blood coursing through
them, that part in contact with their endothelial walls, adheres, so
to say, to the latter and is further delayed; and, finally, that
serous membranes are, like the capillaries, endothelial struct-
ures. The peritoneum, the pleura, the pericardium, the me-
ninges, etc., thus become an extension of the capillary endothelial
system, and when, in the light of the doctrines advanced in this
work, these serous structures and the capillaries are consid-
ered as one, we have constituted an extensive system -of epura-
tion, the physiological mechanism of which seems to us to be
represented in the following summary: —

The "blood-vessels, supplied with a muscular coat, when un-
duly contracted through the excessive functional activity of the
adrenal system induced by toxics, force the blood into the peripheral
capillaries, and, in some disorders, into those of serous membranes;
all these capillaries, owing to their phagocytic endothelial walls
and the wandering phagocytic leucocytes of the blood-plasma, thus
become collectively transformed into a vast immunizing field.

It may prove interesting, in this connection, to refer to
the importance of the capillary system as viewed by Claude
Bernard15 when compared to the balance of the vascular sys-
tem: "The larger vessels, the arteries, the veins," writes this
great physiologist, "are but streets which enable us to meander
through a city; but with the capillaries we can enter the houses,
in which we can directly study the modes of life, occupations,
and customs of the inhabitants. Thus, when a toxic or medic-

18 Claude Bernard: "Physiologic Operatoire," 1879; quoted by M. Duval,
loc. cit.

THE ADRENALS, LEUCOCYTOSIS AND PHAGOCYTOSIS. 623

inal substance is introduced into the circulatory tree, this sub-
stance will remain without effect as long as it will only circulate
in the arteries and veins. It will only begin to manifest its
activity on reaching the capillaries, and in them bathe the
anatomical elements upon which it especially acts." As we
view the process, of course, it is the toxic that is acted upon
by the anatomical elements: the reverse, therefore, of Claude
Bernard's view.

The application of our interpretation to Eussel's typhoid-
fever cases — the six in which details are furnished — may fur-
ther serve to elucidate the whole question. Why did Mrs. V.,
Case III, die notwithstanding surgical intervention? On the
sixteenth day of the disease her leucocyte-count showed 6100.
Evidently the ulcerative process was already far advanced; the
blood was markedly filled with pathogenic elements, and the
adrenals were nearing the stage of insufficiency; hence the low
leucocyte ratio. The prevailing view as regards the diag-
nostic value of leucocytosis in respect to perforation suggesting
safety in this direction, it was only when the classic signs of
perforation suddenly developed that cceliotomy was resorted
to. The leucocyte ratio was then 4800: evidence that the
adrenal system had lost ground. The patient died because the
functions of this system had become so compromised by the
toxaemia that her entire vital mechanism, through the imperfect
Hood oxidation involved, had become correspondingly inadequate.
The toxaemia having overcome her adrenal system, the pro-
tective processes in the capillary, serous, hepatic, etc., cellular
elements not only failed, but all her functions, including that
of leucocytogenesis in the bone-marrow, spleen, etc., likewise.
Briefly, her adrenal system stood as the foundation of her life's
mechanism, i.e., the underlying factor of her oxygen-talcing powers
and of her autoprotective functions, and dissolution followed when
it failed her.

Four of the cases submitted to operative procedures that
showed a high leucocyte-count — namely: 28,000, 12,000, 14,500,
and 17,000 — recovered. The sixth case, however, showed a
blood-count ranging from 12,000 to 14,000; but, operation
being delayed, it reached 32,000. Why did this patient die?
The very fact of the presence of so high a percentage points

624 THE INTERNAL SECRETIONS AND IMMUNITY.

to extensive toxaemia with adequate adrenals, but we have here
an example of excessive toxin-dosage. The organs suddenly
failed precisely as they did in the case of poisoning with 300
grains of quinine, and the symptoms of collapse of the one are
those of the other. Since all poisons act similarly upon the
adrenal system, toxins must ~be similar to drugs in their effects
upon the adrenal system.

As to its diagnostic value in typhoid fever, leucocytosis
being a protective process varying in degree (all things being
equal) with that of the toxaemia, it fluctuates proportionally
with the efficiency of the adrenals. We therefore have in leu-
cocytosis, not a direct sign of impending perforation, but a
means of gauging the likelihood of perforation through the in-
tensity of the ulcerative process as reflected by the toxaemia. An
excess of from 3000 to 10,000, therefore, points to a correspond-
ingly active ulceration, which may at any moment bring on
this complication, though the pulse show no unusual rise. Yet
the leucocyte-count may reach 14,500, as stated by Cabot, and
even far beyond, and perforation fail to occur. When, however,
a high ratio is reached, another source of danger appears upon
the scene: a more or less sudden inhibition of adrenal func-
tions through excessive dosage of toxins. Finally, hypoleuco-
cytosis may point, especially with a weak pulse, hypothermia,
etc., to gradually increasing reduction of adrenal efficiency —
all signs of a vicious circle that will soon end in death unless
the focus of intoxication can be eradicated. These clinical
features show that the views herein submitted are capable of
standing the crucial test of practical application, and that
overactivity of the adrenal system is the inciting factor of leu-
cocytosis and therefore of phagocytosis.

Analyzed in the light of the foregoing statements, phago-
cytosis might possibly be made to subserve all the requirements
of a function capable of protecting the organism against bac-
teria and other disease-breeding bodies. The endothelial lining
of the pulmonary alveoli alone, for example, constitutes a
potent barrier against the intrusion of pathogenic germs. The
vast surface of phagocytes arranged in perfect battle-array, so
disposed as to at once capture, ingest, and destroy any in-
truder as soon as he comes near enough to excite, by his own

THE ADRENALS AND BUCHNER'S ALEXINS. 625

chemotactic influence, a reaction in each soldier cell; the sec-
ond line of free, mobile, phagocytic leucocytes in the plasma
bathing the first line of defense, ever ready to pounce upon any
single enemy who may have escaped the attacks of the first
line; the vascular endothelial walls, built of phagocytic cells;
the slowly moving, searching leucocytes in the plasma itself,
able to send one or more pseudopodia through their stationary
fixed kindred of the capillary walls, then pass into the neigh-
boring lymph-spaces themselves, to reinforce, if need be, the
connective-tissue phagocytic cells and surround the threaten-
ing germ; and finally the great cremator and eliminator, i.e.,
the liver, constantly supplied with a quantity of oxidizing sub-
stance which no other organ, except the lungs, can approach
— all constitute a system of defense wonderful in the extreme.

BUCHNER'S BACTERICIDAL ALEXINS.

What phagocytosis really means is but meagerly depicted
in this brief summary of its role, and yet it is undoubtedly
supplemented with functions calculated not only to afford even
greater protection against disease to the cellular structures of
which the various organs are built, but also to facilitate and
insure the proper execution of all functions, organo-vital and
protective. Indeed, the higher in the evolutive scale a living
structure has reached, the greater seem the precautions taken
by Nature to preserve its integrity.

A seemingly strong argument against phagocytosis as the
only source of physiological immunity soon appeared after
Metchnikoff's earlier labors became known: i.e., the fact that
various body-fluids — the plasma, exudates, etc. — were quite
able to destroy bacteria without the presence of leucocytes.
Thus, Pfeiffer,16 having injected contaminated bouillon into
the peritoneal cavity of guinea-pigs, found, — after withdrawing
some at intervals of ten, twenty, and thirty minutes after the
injection, — in the peritoneal fluids of these animals, motionless
granules representing as many degenerated and dead bacteria.
The peritoneal cavity containing but a minimum proportion
of leucocytes, he failed to admit that this evident destruction

"Pfeiffer: Zeitschrift fur Hygiene und Infectionsk., vol. xvi, p. 287, 1895.

626 THE INTERNAL SECRETIONS AND IMMUNITY.

of micro-organisms could be attributed to phagocytosis, and
expressed the view, therefore, that the bactericidal power could
only reside in the serum.

In the light of the functions herein attributed to the
adrenal system, this conclusion might appear fallacious; but
it is not so when reduced to appropriate limits. An important
feature of suprarenal functions, in this connection, must be
emphasized: i.e., that their normal activity seems only to l)e
heightened to a subjectively and objectively appreciable level
when a certain degree of toxcemia has been reached. In other
words, the symptoms of which the adrenal system is the cause
seem always to be due to the presence in the blood of poisons,
venoms, toxins, etc., in sufficient quantities to defy the normal
local cellular and humoral systems of defense. Hence the total
absence of adrenal symptoms noted after the use of remedies
when the dose administered is sufficiently small. And yet, if
our views are sound, we are no longer dealing with the entire
body as the basis of our estimates concerning the physiological
action of drugs, but with a single organ: the anterior pituitary
body. To this organ, no larger than a small pea, and its func-
tional fluctuations, must now be ascribed a long list of general
phenomena which we have all been taught to ascribe to the
direct action of our remedies upon the blood and the tissues
at large. It is this diminutive organ that all toxics of various
kinds attack, but only provided they are allowed to reach it by
the defensive cells and chemical bodies, with which, as we will
see, the blood-plasma is amply supplied. But its protective
offices are not called into use merely when toxics are ingested
or introduced into the blood-stream by contamination; it is
exercised at all times. We have in physiological leucocytosis
evidence of this fact, for this phenomenon merely shows that
after active physical exercise, a sufficient or copious meal, a-
cold bath, etc., waste-products of metabolism have accumulated
in the tissues to an abnormal extent, and that the greater oxi-
dation which unusual adrenal activity can procure has become
necessary. This lasts as long as required, and the adrenals
resume their relatively passive state. It thus becomes evident
that the blood-serum is an important factor of the protective
process.

THE ADRENALS AND BUCHNER'S ALEXINS. 627

Pfeiffer's conclusion that the bactericidal power resides in
the serum, therefore, was not unwarranted, although the local
leucocytosis — that available from the immediate surroundings
through the chemotactic influence of the pathogenic germs in-
troduced— might have sufficed to account for the destruction of
the latter. Yet, how was the field so rapidly cleared of leuco-
cytes as it was, and what was the origin of the granular detritus ?
Granting that the fluid did possess microbicidal properties, how
could Pfeiffer explain the presence of bacteria within phago-
cytes, which presence he had himself witnessed? The fact that
these organisms were, dead led him to conclude that phagocytes
were really only scavengers, and that they ingested dead bac-
teria after the serum had killed them. Hence, to the serum
belonged, in his opinion, all the bactericidal power.

Metchnikoff,17 while recognizing the strength of Pfeiffer's
observations in respect to the ability of the peritoneal effusion
to kill germs, showed that leucocytes capable of acting as
phagocytes in the peritoneal cavity were accumulated in masses
on the surrounding free surfaces, and that those damaged dur-
ing the fray could easily be detected in the serous fluid if the
latter were withdrawn in from two to six minutes after the
injection. The colored plate opposite page 628 is interesting in
this connection. Metchnikoff further showed that these dam-
aged leucocytes were nevertheless able to destroy them by their
secretions: a feature which explained the bactericidal property
of the liquid. All these facts have since been demonstrated
by a large number of experiments. The doctrine of phago-
cytosis has remained unassailed, . . . but so has Pfeiffer's
view.

Denys showed that the bactericidal property of the serum
increased or decreased according to the number of leucocytes
present. Anthrax bacilli placed in small bags permeable only
to the fluids of the blood and introduced into various bodily
fluids were found to be dead when withdrawn. Metchnikoff
and Bordet were led to conclude that this was due to the pres-
ence, in the blood-serum, of a substance, "microcytase," which
was always found in plasma rich in phagocytes, and was in-
variably absent, however, when these cells were also absent.

17 Metchnikoff: Annales de 1'Institut Pasteur, June 25, 1895.

628 THE INTERNAL SECRETIONS AND IMMUNITY.

This feature was thought to point directly to the latter as the
"bactericidal agents.

EXPLANATION OF PLATE.— Fig. 1.— Pfeiffer's phenomenon occurring in the
exudation taken from an untouched guinea-pig, the exudation having been with-
drawn ten minutes after the injection of 1 cubic centimeter of bouillon containing
one loopful of a culture of Constantinople cholera and 0.04 cubic centimeter of
preventive serum (of the strength of Vs milligramme). Staining with methylene-
blue. I, Lymphocytes. Ocular 3. Vis Zeiss.

Fig. 2. — Mass of granules placed around a collection of leucocytes. Exuda-
tion of a guinea-pig withdrawn nine minutes after the injection of 1 cubic centi-
meter of bouillon to which had been added a third of a culture of Oriental-
Prussia cholera and 0.04 cubic centimeter of preventive cholera serum of goat
(strength, 0.0002). Ocular 2. D. Zeiss.

Fig. 3. — Granular leucocyte surrounded by a zone of vibrionic granules.
The exudation was withdrawn twenty-five minutes after the peritoneal injection
of one-tenth of an agar-agar culture of Massowah vibrio. Ocular 2. Vis Zeiss.

Fig. 4. — Two mononuclear leucocytes surrounded by granules; a lym-
phocyte (I) and a red blood-corpuscle (h) from the same exudation. Same power.

Fig. 5. — The same cells after remaining for three and one-half hours at 26°.

Fig. 6. — Five polynuclear leucocytes from the exudation withdrawn four
minutes after the injection into the peritoneum of a guinea-pig (highly vacci-
nated and prepared with 3 cubic centimeters of bouillon) of 1 cubic centimeter of
bouillon with one-third of an agar-agar culture of Oriental-Prussia cholera, n,
Nucleus of a crushed macrophage. Staining with methylene-blue. Ocular 3.
Vis Zeiss.

Fig. 7. — Mononuclear leucocyte filled with Courbevoie cholera vibrios.
Peritoneal exudation of a guinea-pig. Ocular 3. Vis Zeiss.

Figs. 8 and 9. — Two polynuclear leucocytes from the same exudation. The
vibrios stained gray in the plate are vibrios in the eosinophile stage. Ocular 3.
Vu Zeiss.

Figs. 10 to 14.— Various phases in the formation of cultures of cholera
vibrio (Oriental Prussia) within leucocytes. Hanging drop, stained with methy-
lene-blue, of the exudation of a guinea-pig hypervaccinated for almost six months
and prepared with 3 cubic centimeters of bouillon. The exudation was with-
drawn four minutes after the peritoneal injection of one-third of an agar-agar
cholera culture placed in 1 cubic centimeter of bouillon and kept at 38°. Ocular
3. Vis Zeiss.

Figs. 15 to 18. — Various phases in the formation of cultures of the Kiel red
bacillus within leucocytes. The hanging drop was kept for twenty hours at 17°
and was made with the exudation from an hypervaccinated guinea-pig prepared
with an injection of 3 cubic centimeters of bouillon. The exudation was with-
drawn four minutes after the introduction into the peritoneum of the Kiel
bacilli. Ocular 3. Vis Zeiss.

Figs. 19 and 20. — Two consecutive phases of a culture of Kiel red bacilli
grown from within a polynuclear leucocyte in a hanging drop of peritoneal ex-
udation. The drop was prepared from the exudation of an hypervaccinated
guinea-pig, withdrawn three hours and fifty minutes after the injection of Kiel
bacilli into the peritoneum, n, Nucleus. Ocular 2. Vis Zeiss.

Then came a series of investigations upon the antitoxic
power of the blood and other liquids of the organism which
appear to us to harmonize with the views of Metchnikoff and
Pfeiffer. The most noteworthy were those of Hankin, von
Fodor, and Nuttall, whose labors led to a doctrine of which

INTRAFHAGDCYTIC DESTRUCTION DF
BACTERIA, [Metchniknff,]

</<• /' In.tfifi/t

THE ADRENALS AND BUCHNER'S ALEXINS. 629

Bucliner is the main exponent. According to this investigator,
the blood-serum and body-fluids kill bacteria because they con-
tain substances termed "alexins," which are thought to repre-
sent the secretory products of leucocytes. The effects of these
alexins were found to vary greatly: under certain conditions
they can overcome myriads of bacteria in a short time; under
others their influence becomes practically nil. The loss of cer-
tain salts, for example, deprives them of their bactericidal prop-
erty. This also occurs when they are diluted in ten times their
volume of water, or when exposed at least thirty minutes to a
temperature of 55° C. The addition of certain alkalies, how-
ever, enables them to preserve their properties up to 70° C.
On the other hand, a brief exposure to the normal body-tem-
perature, 37° C., causes them to become somewhat attenuated.
More recently Laschtscenko,18 working in Buchner's laboratory,
found it possible to extract the bactericidal alexins from the
leucocytes of rabbits without destroying these cells. It is evi-
dent, therefore, that, while leucocytes may act as phagocytes,
they may also, while living, secrete a bactericidal substance.
Metchnikoff's doctrine in respect to phagocytosis proper, and
Pfeiffer's doctrine as regards the bactericidal powers of body-
fluids, are thereby sustained, but with limitations, since it is
clear that phagocytes are not mere scavengers and that they
need not die to become poisonous to pathogenic germs. In
fact, everything goes to prove that the phagocytic action and
the alexinic destructive processes are carried on simultaneously:
i.e., that the alexins given out by the leucocytes first weaken the
bacteria, and that the latter are then ingulfed, alive or dead, ~by
the phagocytes.

As to the nature of the bactericidal substance, Buchner
believes it to be a ferment capable of splitting proteids, and
that it submits the bacteria to a process of digestion resembling,
to a degree, the effect of blood-serum upon the albuminous
constituents of blood-corpuscles.

If to the protective role of phagocytes in the system we
now add alexins or substances secreted by each leucocyte and
capable of weakening or killing bacteria, the protective role as

18 Laschtscenko: "Transactions of the Thirteenth International Congress,"
1900.

630 THE INTERNAL SECRETIONS AND IMMUNITY.

depicted a few pages back becomes enhanced. The epithelial
cells of the pulmonary alveoli not only seize the pathogenic
germ, but they are capable of further insuring their destructive
work by first weakening their enemy with their secretion. If
bacteria penetrate the first line of defense, they meet not only
the free leucocytes beyond, but their alexins. It is when, if
still active, they become engaged in the capillary net-work,
however, that bacteria undergo their greatest exposure. In-
deed, both the fixed and wandering leucocytes and their secre-
tions are all crowded together in these vessels, — or bactericidal
channels, — and the pathogenic organisms, dragged along by the
blood-stream, must indeed be numerous to overcome the de-
fensive hosts placed across their path.

If the toxic products of the bacteria in the blood exceed
a given limit, adrenal overactivity is awakened. An influx
of blood in the entire capillary system ensues, bringing along
with it a steadily increasing array of phagocytes, each endowed
with its poisonous atmosphere and capable of ingulfing a large
number of bacteria. Veins and venules, arteries and arterioles,
by responding through the muscular fibers in their walls to the
suprarenal impetus, lock up, as it were, the offensive and de-
fensive host together on the field of action, — i.e., the capillaries,
the fluids in the connective tissue, lymph-spaces, etc., — and,
"muscular vessels and capillaries being antagonistic in con-
traction and dilation," the latter are dilated through the
greater quantity of blood forced into them, and the efficiency
of the defensive processes is rendered all the more efficacious.
The heart-beats are slower, but firmer and stronger; the sur-
face of the body, replete with capillaries, is flushed and hot,
the temperature rises, etc. Briefly, all the signs of adrenal
overactivity, i.e., fever, appear, and continue until the patho-
genic organisms present are overcome.

All diseases would end favorably in a previously healthy
subject were bacteria alone to be contended with. But the time
has long passed since micro-organisms were considered as the
pathogenic factors per se in the diseases in which they are
found. Precisely as leucocytes secrete or produce alexins, so
do bacteria produce toxins. In fact, as is well known, bacteria
need not enter the general circulation at all and still produce

THE ADRENALS AND BUCHNER'S ALEXINS. 631

disease. Diphtheria and tetanus, for example, typify a class
of affections in which toxins alone enter the blood, in contra-
distinction to cholera, typhoid fever, and other maladies in
which the bacteria penetrate into the circulation and there
develop their toxins. Snake-venom, mineral and vegetable
poisons, etc., represent other classes of agents in which no
bacilli enter the blood and which must meet therein counter-
acting influences. On the whole, it appears evident that there
must also exist some means or property in the body through
which the effects of the specific toxins produced by pathogenic
organisms, snake-venoms, and poisons of all kinds are antag-
onized.

Buchner expresses the belief that the proteid-splitting
ferment secreted by leucocytes and that secreted by pathogenic
bacteria may be similar, and refers to Hahn's experiments,19
which showed the presence of these ferments not only in yeast-
cells, but also in the typhoid and tubercle bacillus. It seems
evident to us that such cannot be the case. The alexins se-
creted by leucocytes and bacteria being similar and mutually de-
structive, these cellular structures would become atifodestruct-
ive. In other words, a leucocyte under such circumstances
would be creating a substance for its own destruction and so
would the pathogenic germ. No protective process would,
therefore, prevail. When germs and leucocytes would meet in
a given region, — the interior of a capillary, for instance, — all
structures vulnerable to the alexins or proteolytic ferment —
leucocytes, bacteria, red corpuscles, the capillary walls, etc. —
would be sacrificed. Indeed, Buchner accounts for the break-
ing down of abscesses in this manner. But it seems clear that,
if applicable to a limited area, the destructive process should
also prevail when in general affections the entire capillary sys-
tem is replete with leucocytes and bacteria, and that, as a result
also prevail when in general affections the entire capillary sys-
tem would also be sacrificed. Briefly, the similarity between the
bacterial and leucocytic alexins might stand analysis were it
applicable only to strictly localized morbid processes involving
but a very limited area, but it is inadequate when applied to

18Hahn: Miinchener med. Wochenschrift, Sept. 26, 1899.

632 THE INTERNAL SECRETIONS AND IMMUNITY.

general affections. Again, the blood in severe cases of septi-
ca3mia and cholera literally teems with bacilli: living evidences
that the phagocytes, notwithstanding their destructive powers,
physical and chemical, over bacteria, have failed in their pro-
tective functions. This vast accumulation of pathogenic germs
in the blood-stream necessarily involves the production of
quantities of toxin. Even admitting the possibility of auto-
exhaustion, how could, under such circumstances, any bacilli-
ridden and toxin-saturated patients ever survive? We might
invoke the potent assistance of the adrenal system and through
this a steady outpour of leucocytes, an inordinate degree of
hepatic and general cellular activity, etc. But we must not
overlook the destructive effect which suprarenal overactivity
would thus involve, since the adrenals would then be urging
the production of so-called protective cells, which, as soon
as they would reach the field of action, would not turn their
whole offensive energy against the pathogenic organisms, but
contribute to the latter's efforts in seeking general destruction!
Quite another position is assumed by Buchner's alexins,
however, when they are considered only as leucocytic products
functionally associated with Metchnikoff's phagocytes and
Pfeiffer's bactericidal serum. In fact, it is probable that the
latter owes its properties to Buchner^s alexins; it appears to
us that as far as the destruction of bacteria is concerned, phago-
cytes and alexins satisfy all the needs of the organism. Not
so, however, with the bacterial toxins; nothing, so far, seems
to have furnished a clue to the manner in which their virulence
is antagonized in the blood-stream. This question will be taken
up later on.

THE ADRENAL SYSTEM AND THE VULNERABILITY OF
CHILDREN TO INFECTIOUS DISEASES.

We can reasonably surmise that the tissue-cells are not
provided with a special line of defense for each kind of poison,
and that all are, in a general way, submitted to the same phys-
ico-chemical antagonism when introduced into the body. The
effects, we now know, vary with the dose, whether it be a toxin
or any other poison; but we also know that the same dose may
prove much more active in one individual than in another.

THE ADRENALS IN CHILDREN'S DISEASES. 633

Drug and dose being identical, we can only incriminate the
protective process, and we are thus led to inquire into the
causes that may militate against phagocytosis and against the
formation of sufficient alexins to maintain the serum up to its
highest degree of efficiency.

The relationship between the production of leucocytes and
adrenal overactivity has already been shown. In disease the
symptomatic concordance is such as to eliminate all doubt
that the increased blood-oxidation incident upon adrenal over-
activity is the underlying factor of leucocytosis, and therefore of
phagocytosis. The difference between the effects of similar
doses in different individuals has also been referred to; we have
seen that "idiosyncrasy," or abnormal sensitiveness to the
effects of drugs, is easily explained by the reduced resistance
that disease or functional impairment of the adrenal system in-
volves. The frequency with which the adrenals are the seat of
fatty degeneration has been emphasized by Arnaud and Kol-
leston. We have also seen to what extent they react to the
effects of drugs, and that any local disorder brings them nearer
the stage of insufficiency in proportion as the lesion is pro-
found. We may thus not only have varying degrees of sensitive-
ness to the effects of drugs, but, for the same reasons, we can
also account for the variation in our resistance to disease. Im-
pairment of the functions of the adrenal system involves a corre-
sponding loss of resistance to the effects of toxics of all kinds, —
toxins, poisons, venoms, etc., — because this system governs the in-
tensity of the oxidation processes and, therefore, nutrition. Such
being the case, phagocytosis and the production of alexins, when
inadequate, but reflect a corresponding impairment of the adrenal
system.

The far-reaching meaning of this relationship between
the adrenals and the physiological protective processes soon
becomes apparent when the results of the varying degrees of
adrenal insufficiency are considered. Most prominent among
these is the predilection of children to infectious diseases. If
experimental evidence is to be taken as standard, Ehrlich's
experiments with ricin, abrin, and robin upon mice, supple-
mented by those of Wernicke, Hiinener, and Vaillard, clearly
indicate that his conclusion that immunity is not conferred by

634 THE INTERNAL SECRETIONS AND IMMUNITY.

parent to offspring must prevail. Ehrlich has also shown that
the offspring can acquire immunity from its mother through
the placental circulation — i.e., from the mother's blood — and
through her milk.-

Immunity is not conferred, therefore, through the ger-
minal cell by the spermatozoa or by the ovum, but through a
medium, the blood or milk, which contains the antitoxic ele-
ment, whatever that may be. Yet these two sources of immu-
nity, if the adrenal system is at all concerned in the process,
must be considered as differing totally one from the other etio-
logically. Indeed, in respect to the influence of the maternal
blood, i.e., the placental circulation, the human fcetus is merely
a part of its mother precisely as is one of her organs. The
foetal adrenal system undergoing development, its usefulness
as a protective agent is therefore inhibited. In fact, the fcetus
may reach maturity notwithstanding the total absence of these
organs.20 As to the influence of maternal milk, which is given
the child when it has to depend upon its own protective re-
sources,— i.e., after birth, — we are simply in the presence of
a process through which a physiological antitoxic serum is admin-
istered and the immunizing attributes of which are communicated
to the child.

In our analysis of the physiology of the mammary gland
(page 289) we referred to the fact that the liquid portion of
milk was, in the main, blood-plasma, containing, therefore,
oxidizing substance. We may now, it seems to us, add Buch-
ner's alexins to the list of its constituents.

Analysis of the pathology of the adrenal system during
early life also points to deficient protection from the adrenal
system. From the observations of Leconte, Rolleston, Mattei,
and his own, Arnaud was led to conclude that 46 per cent, of
cadavers showed lesions in the adrenals ranging from slight hy-
peraemia to disruptive hemorrhage. A comparative study of the
100 cases of suprarenal haemorrhage collected by this author,
however, shows that the newborn alone make up 45 of the 46
per cent, referred to, so that childhood, adult age, and old
age are only represented by the remaining 1 per cent. The

80 Winckel: "Transactions of the Thirteenth International Congress," 1900.

THE ADRENALS AND THE TUBERCULIN TEST. 635

inference is obvious: This remarkable predilection of the new-
born exactly coincides with the moment at which the adrenals
assume their protective functions, which functions had been pre-
viously carried on by the mother's adrenals during the foetus's
uterine life.

If we now consider the fact, emphasized by Arnaud, that
"suprarenal haemorrhages are far more common in childhood
than in adult or old age," we are led to another important
deduction: This predilection to suprarenal hemorrhage in chil-
dren coincides with that during which they show vulnerability to
specific infectious diseases: the so-called diseases of childhood
especially.

Turning to the rarity of haemorrhage in adult and old age,
we are brought to realize that complete development of the
adrenals brings with it almost complete immunity to certain
toxins, especially those- generated in the course of certain dis-
eases of childhood. That this is true was demonstrated by a
personal analysis of 42 cases of fatal suprarenal haemorrhage
in adults and old age found in literature. Not one of these
could be traced to an infectious disease to which children are
particularly liable. Local or remote chronic processes, tuber-
culosis, cancer, Bright's disease, etc., or processes attended with
sudden and severe toxaemia, burns, traumatisms, uraemia, pneu-
monia, hepatic abscess, leg-ulcer, and cardiac affections were
the only disorders found.

On the whole, the conclusions which seem to be warranted
in this connection are the following: —

1. Children are vulnerable to certain infectious diseases, be-
cause their adrenal system is insufficiently developed, and thus
fails to adequately stimulate the organs upon which the immuniz-
ing process depends when toxins penetrate the blood-stream.

2. Normal adult and old subjects are not vulnerable to the
diseases of childhood, because their adrenals are developed suffi-
ciently to enable them to correspondingly stimulate the organs upon
which immunity to these diseases depends.

THE ADRENAL SYSTEM AND THE TUBERCULIN TEST.

Another question which the functional relationship be-
tween the adrenals and the physiological protective processes

636 THE INTERNAL SECRETIONS AND IMMUNITY.

seems to elucidate is the modus operandi of tuberculin in Koch's
tuberculin test. Why does fever appear when this substance
is injected only (it might be more proper to say "mainly") in
individuals who -are suffering from tubercular disease? Why
is it also harmless for healthy animals, but violently toxic for
tuberculous animals, going so far in these sometimes as to
produce death? A rise of 2° F. or more above the normal
temperature is brought about in tuberculous subjects, but if
another injection be made within a period covering sometimes
as much as two months, a reaction is not to be obtained. In
the light of what has previously been said as to the predilection
of the adrenals per se for tuberculosis, as observed in con-
nection with Addison's disease, it seems probable that these
organs must always be more or less organically diseased in any
but the earliest stage of practically all cases: a complication
which would explain the failure of Koch's tuberculin. Even
leaving out of all consideration this important element of the
tubercular process and considering the pulmonary, glandular,
osseous, etc., lesion that may be present as the only pathological
existing condition, the symptoms caused by the injections of
tuberculin seem easy of explanation.

In the healthy subject the glands are in their normal
functional state and the dose of tuberculin introduced into
the circulation is insufficient to cause them to assume unusual
activity. In the -tuberculous subject, on the other hand, the
diseased area is the source of toxins of various kinds which are
constantly stimulating the adrenals to unusual activity. The
dose of tuberculin does not alone under these conditions enhance
suprarenal activity, but it represents an addition to the kindred
toxin present; united, tuberculin and poison thus give rise to
an exacerbation of the glandular functions which becomes
manifest by the febrile state induced and other symptoms of
adrenal overactivity.

Spurred to unusual energy by the tuberculin, the adrenal
system excites correspondingly active metabolism in all cellu-
lar structures, including those endowed with leucocytogenesis.
Phagocytes and alexins are produced in profusion, the fixed
endothelial and the connective-tissue cells contributing their
share to the production of the latter, and there is thus con-

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 637

stituted a serum which confers upon the treated individual a
degree of immunity commensurate with the degree of the reac-
tion produced in the adrenals — provided these organs are not
seriously involved in the tuberculous process. It is, therefore,
probable that Koch's tuberculin gives rise to a febrile reaction
when a tuberculous process is present, because it adds to the toxic
elements incident upon the disease a new source of adrenal over-
activity.

THE ADRENAL SYSTEM AND ANTITOXIC SERUM.

We have considered so far but two of the means afforded
by Nature to protect the body against infection. If, however,
the foregoing illustrations of the relationship between adre-
nal functions and immunizing processes are closely analyzed,
it soon becomes apparent that phagocytosis and Buchner's
alexins — including those generated through the death of leu-
cocytes and other globulins, endothelial cells, etc. — do not, as
already stated, fully satisfy the needs of the situation. That
these agencies are capable of destroying bacteria is undoubted.
Behring found that the sterilizing effects of sheep's serum, for
instance, were far greater than those of the stronger solutions
of bichloride of mercury and carbolic acid employed in surgery;
we have also seen that the strength of the serum, as shown by
Denys, increased with the proportion of leucocytes contained
therein. But how are bacterial toxins antagonized?

Whether there exists in the body a physiological antitoxin
or antitoxic bodies capable of destroying bacterial toxins still
belongs to the domain of conjecture. The very need of
Ehrlich's ingenious side-chain theory points to this. In this
hypothetical conception each body-cell is even more complex
than we now deem it to be, and is supposed to be surrounded
by various groups or chains of atoms which Ehrlich terms
"toxophoric atoms"; these would possess a specific affinity for,
and would unite with, toxins. The reaction involved would
necessarily cause the production of bodies that would be use-
less to the cell and therefore be cast off. While the "toxophoric
atoms" would be replaced in the cell, the bodies cast off from
the latter would remain in the blood, and being still possessed
of considerable affinity for toxins, they would constitute in the

638 THE INTERNAL SECRETIONS AND IMMUNITY.

blood what we term "antitoxin." The evidence mainly con-
sists of the results of experiments in vitro, in which the affinity
of various tissues for toxins are shown. Thus, if to an emul-
sion of brain or -spinal cord in a salt solution there is added a
dose of tetanus toxin sufficient to kill ten rabbits, the toxin
will lose its power and prove harmless when injected into a
single animal. Evidently there must have existed in the tissues
thus used some substance capable of converting the toxin into
an inert body.

Analysis of Ehrlich's theory, however, seems to us to show
several vulnerable points. In the first place, we are called upon
to conclude that the protoplasmic cells are so constituted as to
be prepared to meet each individual toxin in a special manner.
In other words, there must be as many side-chains or groups
of "toxophoric atoms" as there are toxins. If we survey the
field of pathology, the number of toxins so far isolated will
already appear quite large; if we add to these what toxins may
yet be discovered, we cannot but conclude that the cells of
which our tissues are built must indeed be complex bodies if
the hypothesis proves to represent facts. Again, a precon-
ceived antenatal arrangement of the molecular elements of the
cells with adjustment to the needs of existence in disease-ridden
communities becomes necessary. Hertwig's view that acquired
characters are transferable to the germ may serve to establish
a connection between the development of the lateral atom
groups and the numerous diseases to which the innumerable
generations have been exposed in the past. But, as previously
shown, experimental evidence, to which Ehrlich himself has
contributed the most convincing data, tends to prove the con-
trary: i.e., that immunity is not transferred to progeny through
the germinal cell.

Again, Metchnikoff, Eoux, and other bacteriologists have
studied Ehrlich's hypothesis experimentally. Perhaps the most
striking of these is the repetition of Ehrlich's own and Wasser-
man's experiments, but followed by controlling experiments in
which carmine was used instead of brain and spinal-cord sub-
stance. Notwithstanding the substitution of this inert sub-
stance, however, the results were similar, the toxin being like-
wise rendered harmless by the carmine solution. It seems

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 639

evident, therefore, that the side-chain theory does not account,
in its present form, for the protective phenomena witnessed
and that the solution of the problem must be sought elsewhere.

The properties of the pathogenic agents may furnish a
clue. Beginning with organic poisons, it is desirable to fully
realize their identity as albuminoid bodies. This is demon-
strated by their common tendency to lose their toxic powers
when heated to 100° C.21 — likewise a characteristic of snake-
venom, as shown by Weir Mitchell and Reichert many years
ago. Venom not only responds to all the tests that denote its
albuminoid character, but so do toxins and the toxic bodies of
plants: ricinus, jequirity, etc. Again, the relationship between
these toxalbumins and vaccine substances is very close. Pro-
tective inoculation against small-pox may, as shown by Ber-
trand and Phisalix,2* be imitated for snake-venoms. These facts
not only reaffirm that all organic poisons, whatever be their
source, must be treated collectively as regards effects, but they
also show that they are all vulnerable in the same manner, through
the similarity of their molecular structure, to the physical agencies
present in the organism that tend to convert them into harmless
bodies.

How are poisons converted into harmless substances?

A striking feature of the introduction of venom into the
circulation is the loss of its identity as such. The poisoned
blood may be removed from an animal in the throes of toxic
manifestations of poisoning and injected into another, but nor-
mal, animal and produce no effect whatever. This was ob-
served by Laborde in 1875 and confirmed by Calmette, who
found that even an emulsion of the organs of the poisoned ani-
mal produced no effect upon a normal animal of the same kind.
Similar results were obtained from hypodermic injections of
cobra-poisoned blood taken from the heart, spleen, brain, and
bulb, into the pigeon, rat, guinea-pig, and rabbit. Bufalini23
injected 30 cubic centimeters of blood, taken from the vena
cava of a man who had died as a result of a viper-bite, into
the peritoneal cavity of a guinea-pig, but no untoward effects

21 A. Gautier: "La Chimie de la Cellule vivante."

**IUd.

28 Bufalini: Quoted by Romiti, Archives ital. de Biologie, 1884.

640 THE INTERNAL SECRETIONS AND IMMUNITY.

were noted. Even the transfusion of all the blood of a dying
scorpion-poisoned dog into the vessels of a bled dog caused no
serious symptoms, according to Paul Bert.24

What is the "nature of the process through which this is
accomplished? -It cannot be due to the smallness of the doses
employed, since it was the aim of the investigators named to
test the question: a fact, in itself, suggesting the use of large
quantities of poisonous blood. Again, the toxicity of viper- and
cobra- venoms, as previously shown in connection with blood-
changes, is exceedingly high. The benign effects were doubt-
less due to the attenuation to which the venom had been sub-
mitted. It is evident that, since the latter had, in each in-
stance, already passed through one animal, it had lost much of
its virulence. The dose injected or transfused was, therefore,
in no way comparable to the dose received in each case by the
first subjects so that, quantitatively as well as qualitatively, it
proved insufficient to create an adrenal reaction capable of giv-
ing rise to symptoms of poisoning. This confirms the need of a
sufficiently great dose of a sufficiently virulent poison to bring
about such active phenomena.

An important point is emphasized by the last of the ex-
periments mentioned, Paul Bert's: The transfusion of all the
blood of a dying scorpion-poisoned dog into the vessels of a
bled dog means that the latter animal must have been bled to
a sufficient degree to admit all the blood of the dying dog; in
fact, that the greater part of the blood of the former dog —
even if a larger animal than the scorpion-stung one — must have
been removed. We therefore have practically an exchange of
blood. The animal that received the poisoned blood having
suffered no serious symptoms, it follows (1) that the scorpion-
venom could not have disorganized this blood: i.e., caused direct
"hamiolysis" ; (2) that, on the contrary, it was the blood which
had disorganized the venom. It is obvious that, had the blood
of the first dog been injured chemically or morphologically to
any marked extent, the second dog would not have fared as it
did.

We are thus again made to fully realize the important fact,

2* Paul Bert: Societ6 de Biologie, August 8, 1885.

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 641

and in opposition to classic teachings, that poisons do not exert
their destructive action directly upon the blood, and that in
our analysis we must consider all the acute symptoms of poi-
soning which appear to helong to the domain of the adrenal
system alone as a separate entity: i.e., a symptom-complex with
which "blood-destruction," or "haBmolysis," is not concerned as
a causative factor.

The question has now become simplified. We have not
only eliminated the haemolytic property from all poisons, —
venoms, toxins, alkaloids, etc., — but, recognizing the unity
which all these destructive agencies undoubtedly show, we have
reduced the working elements of the inquiry to two approxi-
mately known quantities, Nood and toxic, — which we can now
transform into blood versus toxic, and study as independent,
though mutually related, propositions.

A general function 'betokens a broad principle of action.
Not only must such an attribute exist, but, as the function in
question is one directly connected with the preservation of life,
it must be a predominating one.

Is there such a predominating attribute in the physical
make-up of serum proper? That blood-serum is a mere men-
struum has been repeatedly shown. Even the normal serum
of animals that are naturally refractory to certain toxins was
found by Calmette,25 for example, to have no influence what-
ever upon those toxins in vitro. Of course, this only refers, as
regards physical effects, to an animal's own serum or to that
of animals in which it possesses kindred chemical properties.
The serum of a particular species possesses physical properties
peculiar to that species, and when used in others in which the
constituents vary quantitatively it may produce more or less
marked cytolysis, which may culminate in death. Thus, the
venous transfusion of a small quantity of a normal dog's serum
into a rabbit will soon prove fatal: the dog's serum is simply
not adapted structurally to the globulins and other bodies in
the rabbit's serum. This fact in itself furnishes evidence that
blood-serum is a mere vehicle, and that what antitoxic bodies
are contained in it are foreign to its own composition as serum.

26 Calmette: Annales de 1'Institut Pasteur, vol. x, 1897.

642 THE INTERNAL SECRETIONS AND IMMUNITY.

What is the nature of these antitoxic bodies? Or, in other
words, what is "antitoxin"?

The source of "antitoxin" has not been traced to any par-
ticular organ or" set of organs. All that is positively known is
that in immunized animals — i.e., animals into which toxins
have been injected in gradually increased doses — it appears in
the blood in constantly increasing quantities. In other words,
its relative quantity is constantly changing, and it fluctuates
with the quantity of toxins introduced into the circulation of
a given animal.

That the toxins injected into animals to obtain anti-
toxic serum for purposes of immunization act on the adrenal
system precisely as do other poisons needs hardly to be em-
phasized. When diphtheria toxins are injected, for instance, a
feature of the earlier period of the treatment is the tendency
to paralysis, which is often followed by rapid death. This
association between paralysis and sudden death is very sug-
gestive when we recall the influence of powerful toxics on the
adrenals, and the induction of paralysis as an advanced symp-
tom of 'the stage of insufficiency. Again, each injection causes
a marked reaction, attended with a rise of temperature which
sometimes reaches several degrees. As the doses of toxin are
very gradually increased, it takes months to bring the animal's
serum to the immunizing standard: i.e., to that state when it
contains, in a given quantity, a sufficient amount of antitoxin
to confer immunity when that given quantity is injected into
unprotected animals or human beings.

At the end of these months, however, an important change
in the resistance of the animal to the poisonous effects of the
toxins occurs: it is able to stand several hundred times the
dose of toxin that would have proven fatal at the start.
Ehrlich's experiments with abrin, the toxalbumin of the jequir-
ity-bean, and ricin, that of the castor-bean, have shown that im-
munity to their poisonous effects could be conferred precisely
in the same way. These purely vegetable poisons, in other
words, not only behave as do toxins, but treatment of animals
in the manner depicted above produces similar results, even
to the extent of conferring immunity. Snake-venom again
affirms its kinship to toxins and vegetable toxalbumins by

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 643

conferring equal protection. Calmette, Phisalix, and Bertrand,
by treating animals as above, have obtained an antivenm which,
injected into vulnerable subjects, protects them, as do anti-
toxin, antiabiin, and an^ricin, against its own deleterious
effects.

A feature common to all animals so treated, however, is
their tendency to "oversensitiveness" to the effects of the in-
jections, active — and usually fatal — symptoms of acute poison-
ing appearing suddenly in the midst of apparent health. If
this phenomenon is added to the adrenal signs already noted,
we are strikingly reminded of the critical stage of adrenal
overactivity and the sudden lapse of the glands into total in-
activity. The gradual habituation to the toxin, the vegetable
toxalbumin and the, venom, furnishes complementary evidence
as to the implication of the adrenal system in the process, typi-
fying as it does that observed in arsenic eaters and in such
conditions as morphinism, cocainism, etc. Indeed, it seems ob-
vious that the gradually increased injections do what all other
poisonous agencies do: i.e., they gradually increase and simul-
taneously develop the functional activity of the adrenal system.

This peculiar oversensitiveness to the effects of toxins and
other interesting features of the problem that will assist in
elucidating the question in point are referred to by Joseph
McFarland,26 as follows: "The occurrence of antitoxin in the
blood-serum is to be considered as a phenomenon of forced
immunization. During the immunization process it does not
seem to develop in proportion to the toxic endurance of the
animal, but, as Eoux has pointed out, is rather suddenly devel-
oped after the immunization has attained a high degree. Dur-
ing the continuance of the immunization it is a variable, not a
fixed quantity, and .while the toxin endurance of the animal
is kept up without variation, the antitoxin may gradually di-
minish. This I have seen many times illustrated in horses
producing diphtheria antitoxin, an excellent illustration being
afforded by one particular horse that furnished at one time a
serum containing 1400 units to each cubic centimeter of serum.
The immunity was maintained by cautious toxin injections for

28 Joseph McFarland: "Text-book upon the Pathogenic Bacteria"; edition,
1900.

41

644 THE INTERNAL SECRETIONS AND IMMUNITY.

a long period subsequently, and the endurance of the horse
remained unchanged for months, but the antitoxicity of its
blood gradually declined, until from 1400 units it fell to 100
units.

"This rather sudden appearance of the antitoxin and its
decline during the immunity of the animal prepare us for the
information that the animal's immunity does not depend upon
the antitoxin, but upon some other condition. The probable
proof of this is seen in the peculiar condition of hypersensitivity
to which Behring and Wladimiroff called attention, and of
which mention has been made. In these cases it makes no
matter how much antitoxic strength is contained in the blood,
the animal is just as sensitive to the toxin as if it had none,
and as if it had not been immunized. Moreover, the hyper-
sensitivity is not a cumulative action of the toxin that out-
weighs the antitoxin, as will be readily shown by a simple
calculation. A horse weighing 1300 pounds, possessing about
100 pounds of blood, of which about one-third, or 30 pounds,
is serum, has been immunized to diphtheria toxin according
to the method described in the chapter upon 'Diphtheria';
and while the serum contains 500 immunizing units of anti-
toxin in each cubic centimeter of blood-serum, the horse falls
into the hypersensitive condition and dies. What relation
exists between the antitoxin in its blood and the toxin that
produced death?

"It is certain that there is none, and that the antitoxin
that exerts a most remarkable protective influence upon other
animals does not protect the animal by which it is formed.

"If the horse's blood furnishes a total of 30 pounds of
serum, each pound being about equal to 500 cubic centimeters
of liquid, there is a total of 15,000 cubic centimeters of anti-
toxic serum in the horse.

"Suppose the minimum fatal dose of diphtheria toxin for
a 250-gramme guinea-pig to be 0.0045. If the serum under
consideration contain 500 units in each cubic centimeter, then
Vsoooo cubic centimeter will protect a guinea-pig against 0.0045
cubic centimeter of the toxin; VBOOO cubic centimeter against
0.045 cubic centimeter; 1/BOO cubic centimeter against 0.45
cubic centimeter; Y50 cubic centimeter against 4.5 cubic

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 645

centimeters; V6 cubic centimeter against 45 cubic centimeters;
and 1 cubic centimeter against 9 cubic centimeters of the toxin.
If each cubic centimeter of the serum of this horse is capable
of destroying the toxic effect of 9 cubic centimeters of toxin,
the total toxin-annulling capacity is 9 X 15,000 cubic centime-
ters of serum in the horse's blood = 135,000 cubic centimeters
of toxin.

"We must next see how much toxin has been received by
the horse during his immunization. The following doses, the
figures referring to cubic centimeters of toxin, probably repre-
sent an average careful manipulation extending over a period
of about three months: Y10, V4, V2, 1, 1, 2, 3, 5, 8; 10, 15, 20,
25, 50, 50, 100, 150, 200, 250, 300, 500, 500, 500, 500, making
a total of about 42 QO cubic centimeters of diphtheria toxin.
Now observe that the total quantity of toxin consumed by the
horse is 4200 cubic centimeters, but his protective energy is
135,000 cubic centimeters of toxin, so that the blood of this
horse, if drawn from his body, would furnish enough protection
to save 32 VT horses from doses of toxin as large as the total
amount administered to him during the entire course of his
treatment.

"This illustration is not only extremely instructive in
showing the paradoxic nature of the condition of hypersensi-
tivity, but certainly proves that the antitoxicity of the blood
is not the cause of immunity, but a phenomenon of that state.
It is also of great importance in considering the origin of the
antitoxin.

"Concerning the origin of the antitoxins, we must at once
dismiss from our minds the thought that bacteria have any-
thing to do with their formation other than through the toxins
they generate. The immunization of animals to feebly toxic
cultures, or to bacteria washed of their toxins, produces im-
munity; but immunity without antitoxic activity produces the
antimicrobic power of the blood presenting itself in these cases.
It is, therefore, the poison alone that is responsible for the
phenomenon, and a moment's reflection upon the anti-bodies
produced by immunization to ricin, abrin, venom, eel's blood,
etc., will clearly establish this fact. How does the poison
produce the antitoxin?"

646 THE INTERNAL SECRETIONS AND IMMUNITY.

After reviewing the various hypotheses that have been
proposed — that the antitoxin is the toxin itself, but in a modi-
fied form; that it is an enzyme produced in the culture; that
it is a product of cellular activity — McFarland concludes, in
accord with the prevailing opinion, that "probably the best
explanation of the histogenesis of the antitoxin" is Ehrlich's
lateral-chain theory. Indeed, some of the points made may
be adduced as evidence in favor of the latter. The phenomena
observed in the horse that furnished serum containing 1400
units, then 100 units, may be explained, for instance, by the
exhaustion of cataphoric atoms: a feature of the process which
simultaneously suggests its dependence upon the body-cells for
the formation of the antitoxin. Yet, while the same reasons
are applicable when the adrenal system is brought into the
process, — suggesting at the same time that normal adrenals
can produce a large amount of secretion, then become weakened
without lapsing into sudden insufficiency, — it is difficult, with
Ehrlich's theory, to account for the sudden sensitiveness ob-
served, without indulging in pure conjectures based upon hypo-
thetical deductions. The overwhelming evidence adduced as
to the tendency of the adrenals to suddenly cease their func-
tions and give rise to symptoms similar to those observed in
the injected animals, on the other hand, the sudden deaths in
Addison's disease, those that occur as the result of haemor-
rhage into the adrenals, etc., emphatically point to adrenal
insufficiency as its source. Adrenal insufficiency here obviously
means that the oxidizing substance is a main factor of the
entire process.

Indeed, that the presence of the oxidizing substance in
the blood-serum accounts for a large number of reactions the
nature of which has not, so far, been satisfactorily explained,
seems undeniable. The long list of chemical agents which
have been shown by Schmiedeberg, Salkowski, Jaquet, Lan-
glois and Biarnes, among others, to be oxidizable through
contact with various tissues and blood-serum represents but a
diminutive proportion of the bodies that can be converted
through a similar process into dissimilar compounds. Uric
acid, we have seen, is the end-product of a series of reactions
of this kind: a benign agent developed by oxidation from toxic

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 647

bodies of the purin group. Phosphoric acid must be a product
of a similar kind, since, like uric acid, its excretion fluctuates
under the influence of certain drugs, quinine, for instance
(Kerner). Thyroid extract, as is well known, increases meta-
bolic activity through the adrenal system, as we have seen, and
simultaneously augments phosphoric-acid elimination. Arsenic
does likewise and increases, as does thyroid, excretion of urea:
evidence of overactivity of the adrenals induced by the toxic.
The vast field covered by oxidation processes in the or-
ganism, apart from those connected with cellular function, is
well illustrated in the following quotation from an article by
J. W. Wainwright27: "In the body itself organic drugs, like
other chemical bodies, are either fully oxidized and burned to
carbonic acid and wat^r or urea or else a slight chemical change
results in the molecule, in which the annular grouping of the
nuclei is preserved. Besides, the organism possesses the ability
to bring about syntheses, and in this way hamper or abolish
the action of drugs to a certain degree. Our knowledge of
these processes had led to many valuable additions to our drug
treasury. Substances which comprise the three great groups
of nutritive material, such as albumin, fat, and carbohydrates,
are reduced almost completely to their lower metabolic com-
ponents in the body: C02, water, and urea. Generally speak-
ing, substances of the fatty series are readily accessible to oxi-
dation. The behavior of those bodies in which the nuclei have
an annular grouping is more resistant; in these only the fatty
lateral chains are oxidized, although under certain circum-
stances the benzol nucleus may also undergo combustion. The
fatty acids are oxidized in the body without exception, as are
likewise the oxy-fatty acids. It is otherwise with these bodies
when the H atoms are replaced by halogen radicals. Oxidation
then becomes more difficult, although trichloracetic and tri-
chlorbutyric acids are partly oxidized with separation of HC1.
The alcohols of the fatty series are oxidized to acids, as methyl-
alcohol to formic acid. The esters of methyl-alcohol, like that
substance itself, — methylamin, oxymethansulpho acid, formal-
dehyde,— also go over into formic acid. Ethyl-alcohol, acetone,
and other derivatives of the fatty series do not yield formic

27 J. W. Wainwright: Therapeutic Monthly, March, 1902.

648 THE INTERNAL, SECRETIONS AND IMMUNITY.

acid. Aldehydes, however, are never produced within the body
by oxidation from alcohol; but aldehydes may be reduced to
alcohol, as chloral hydrate to trichlorethyl alcohol, butyl-chlo-
ral to trichlorbutyl-alcohol. The higher alcohols of the fatty
series are not, -however, always completely oxidized. Isopropyl-
alcohol is changed in part to acetone, while the rest is excreted
unchanged. The primary and secondary alcohols are readily
oxidized in the body. More difficult is the sexivalent alcohol
mannit, which appears in the urine of dogs almost unchanged.
The tertiary and all halogen substituted alcohols are oxidized
with great difficulty. Thus, tertiary amyl-alcohol,

CH,^^
Amyl-alcohol : >C (OH). CH, CH,

and

^

Butyl-alcohol : CH3 - ^- 0^. as we^ as trichlorethyl-

alcohol, CC13.CH2.OH and

trichlorbutyl-alcohol: CH3. CH.C1. CC12. CH3. OH., appear for
the most part combined with glycorunic acid in the urine. The
dibasic acids behave in the following manner: Oxalic acid is
partly eliminated by the urine, and shows a certain resistance
to oxidation. Some claim that it undergoes no oxidation in the
body whatever. Glycolic acid, CH2 (OH). COOH, is oxidized in
the body without the formation of oxalic acid, as is likewise
glycoxylic acid, CHO. COOH. Malonic acid is transformed into
oxalic acid only in minute amounts, while a small portion is
eliminated unchanged in the urine. Tartronic acid and pyro-
racemic acid show themselves as combustible grain by grain.
Tartaric acid goes in part unchanged through the organism.
It is but slightly attacked by animal bodies."

Atropine decidedly increases the elimination of uric acid
(Wood), but in toxic doses reduces the percentage of urea
(Thompson). Drugs that tend to rapidly cause adrenal insuf-
ficiency, on the contrary, arrest the elimination of these prod-
ucts: evidence that they prevent the oxidation of toxics. Anti-
pyrin thus inhibits the elimination of urea, and acetanilid does
likewise in subjects sensitive to its effects.

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 649

All this evidence, in addition to the many kindred facts
already adduced, seems to us to conclusively show that the ox-
idizing substance is a prophylactic agency which converts certain
toxics, especially products of metabolism, into ~benign and elimi-
nable substances, by submitting them to an oxidation process.

This constitutes a continuous and physiological immuniz-
ing function. Its inhibition explains various pathological proc-
esses— gout, for instance, — and accounts for the action of cer-
tain remedies — iodide of potassium — upon this and other dis-
eases. The suprarenal overactivity induced by the physiological
stimulant of the anterior pituitary: i.e., thyro-io&ine, stands
here as the curative agency by correspondingly enhancing oxi-
dation. Still, the role of the oxidizing substance as a protective
agency is far more marked when its position as a stimulant for
all functions of the organism is borne in mind! Indeed, as such,
the oxidizing substance becomes a most important constituent
of antitoxin.

Interpreted in this manner it is clear that the antitoxic
action of the oxidizing substance should be greatest when in-
troduced into the system before the inroads of the disease have
become too great: i.e., while the several organs are still pos-
sessed of their recuperative powers. This characterizes the
use of antitoxin, as is well known, in diphtheria and tetanus.
Levy and Klemperer28 refer to the researches of Donitz, which
show, "in a conclusive manner," according to these authors,
"that the amount of serum necessary for curative purposes
is the greater the longer the period of time that has elapsed
between the intoxication and the institution of serum-therapy.
Eight minutes after tetanus intoxication six times as much
serum is required in order to save the animal as when the
serum is injected immediately after the poison. After an hour
the curative dose is twenty-four times the original dose; and
so on, until finally a period is reached at which it is entirely
impossible to save the animal, even with the largest amount
of the most active serum." It is hardly necessary now to more
than refer to the underlying cause of the gradual decline: the
rapidly increasing insufficiency of the adrenal system, and a

28 Levy and Klemperer: "Clinical Bacteriology," second edition, translated
by A. A. Eshner.

650 THE INTERNAL SECRETIONS AND IMMUNITY.

corresponding deficiency of oxidizing substance in the blood.
Among the organs stimulated by the oxidizing substance, or
rather awakened to physiological activity by the injections,
are those of the adrenal system itself; so that the adrenals
per se, by resuming their functions, continue the beneficial
effects of that injected into the blood. That this stimulation
actually occurs may easily be shown.

Lobar pneumonia, a disease in which the adrenals seem
to be stimulated to a much higher degree than in diphtheria,
is attended, as is well known, by marked leucocytosis. If, as
previously suggested, this phenomenon is the result of adre-
nal overactivity, it seems reasonable to conclude that when
it is present the adrenal secretion must simultaneously be
increased. The following lines quoted from Osier's "Practice of
Medicine"29 are significant: "There is in most cases a leuco-
cytosis which appears early, persists, and disappears with the
crisis. The leucocytes may number from 12,000 to 40,000 or
50,000 or even more, per cubic millimeter. The fall of the
leucocytes is often slower than the drop in the fever, particu-
larly when resolution is delayed. The annexed chart from J. S.
Billings's paper30 shows well the coincident drop in the fever
and in the number of leucocytes. A point of considerable
prognostic importance is that in malignant pneumonia the leu-
cocytosis may be absent, and in any case the continuous ab-
sence may be regarded as an unfavorable sign. Of 50 cases
shown in my clinic during the sessions of 1896-97 and 1897-98,
the lowest was 10,200." Von Limbeck noted this coincidence
in 1889.

It is plain that if a high degree of leucocytosis indicates
a correspondingly high rate of adrenal overactivity and the
fever follows the same fluctuations, the glands must also un-
derlie the production of the latter phenomenon.

That this is the case may be shown in another way. We
know that lobar pneumonia is sometimes afebrile in children
and drunkards. The weakness of the adrenals of the former
has been already referred to; one of the most marked results

'Osier: Third edition; article, "Lobar Pneumonia."
J. S. Billings: Johns Hopkins Hospital Bulletin, No. 43.

THE ADRENAL SYSTEM AND ANTITOXIC SERUM. 651

Feb., 1893

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652 THE INTERNAL SECRETIONS AND IMMUNITY.

of chronic alcoholism, as will be shown later on, is adrenal
insufficiency: a fact which at once accounts for the high mor-
tality in such subjects. The violence of adrenal protective
action in lobar pneumonia is illustrated by confirmatory signs,
the blood-tinged expectoration, the full and bounding pulse,
etc. — all of which suddenly cease in a few days in favorable
cases when the protective process has gained the mastery
through adequate suprarenal activity which the toxins could
bring on, but not overcome.

IDENTITY OF THE PROPHYLACTIC AGENCY THROUGH WHICH
TOXINS ARE ANTAGONIZED IN THE BLOOD.

After all the evidence adduced in this volume so far, we
deem it unnecessary to further emphasize the fact that over-
activity of the adrenals brings on corresponding overactivity of
all organs — including the posterior pituitary, the general center
of the nervous system, by enhancing the intensity of all oxida-
tion processes. We still have the dominant feature of the
immunizing process to ascertain, however: i.e., the manner in
which toxins, the direct pathogenic agencies of bacterial origin,
are antagonized in the organism.

Are we dealing with a special physiological agency in-
tended to destroy such substances? The multiplicity of patho-
genic organisms suggests the existence of a correspondingly
great number of varieties of toxins and the need of equally
numerous kinds of counteracting agents. In other words, the
question of specificity at once recurs. We have seen, however,
that this feature of immunity is not generally thought to be
subject to close limitations. While Levy and Klemperer31 refer
only to exceptions to the rule, Hueppe32 says: "Antitoxins that
are formed specifically in serum act in vitro upon poisons of a
specifically different character in the same manner as upon
poisons specifically similar, while the converse does not always
obtain; antivenin annuls the poisonous effect of abrin, but
not of diphtheria toxin, tetanus toxin, or ricin; antiabrin neu-
tralizes the toxic effect of snake-venom, diphtheria toxin, and
ricin, but not that of tetanus toxin; tetanus antitoxin is antag-

81 Levy and Klemperer: Loc. cit.

82 Hueppe: Quoted by McFarland, loc. cit.

THE IDENTITY OF ANTITOXIN. 653

onistic to snake-venom, but powerless against ricin and abrin;
rabies serum is potent against snake-venom, but impotent
against the diphtheria and tetanus toxins, and against ricin and
abrin; streptococcus serum is potent against snake-venom,
powerless against the others; cholera serum is moderately
effective against snake-venom, but without effect against the
others; diphtheria antitoxin is powerless against snake-venom,
tetanus toxin, ricin, and abrin; the antitoxic sera of swine,
erysipelas and typhoid are powerless against all these poisons."
Of course, these experiments are only referred to in this
connection to show that it is only in the light of prevailing
views that there is good ground for the assertion that specificity
is not subject to close limitations: a statement which, given its
true meaning, amounts to saying that the question of specificity
cannot be elucidated with the aid of prevailing doctrines. In-
deed, there is no connection between the action of one toxin
upon another, on the one hand, and the action of the organism
upon a given toxin introduced into the circulation, on the
other, even irrespective of any of the views we have submitted.
If, in addition, the fact that the experiments were performed
in vitro, i.e., apart from chemical influence which the constit-
uents of living blood and cells may exert upon the toxins, is
taken into consideration, it becomes clear that the evidence
they afford is misleading. Indeed, the clinical side of the ques-
tion affirms the contrary; as we interpret its teachings, they
clearly indicate that each germ, i.e., each toxin, as is the case
with any poison, possesses its own characteristic properties as
a molecular structure. True, there is considerable resemblance
between the effects of various toxics, and groups of these agen-
cies, such as those represented by "sedatives," "cerebral stimu-
lants," "narcotics," etc., in pharmacodynamics, may be formed.
But this only further emphasizes the truth of clinical teach-
ings, since the need of dividing the many remedies represented
into groups affirms the dissimilarity of effects shown by these
groups. That each group is itself composed of specific agen-
cies, each of which is endowed with its own mode of action, is
as well known; ether and chloroform, for instance, are both
anaesthetics, but they differ materially in their effects upon the
organism if absolute specificity is accepted as standard. These

654 THE INTERNAL SECRETIONS AND IMMUNITY.

commonplace facts appear so because they are so firmly estab-
lished that no one even thinks of disputing them. But this
in itself embodies the deduction we wish to reach: i.e., that
specificity is a factor of general toxicology (including toxins and
venoms) established on so firm a foundation that we would
regard all the work submitted in this volume as fallacious did
our views conflict with it. And, indeed, the fact that the one
organ, the anterior pituitary, is the organism's guardian would
tend to suggest an opposite deduction; but even a cursory
review of the functions of the adrenal system, as we understand
them, confirms the teachings of practical experience.

Indeed, since the adrenal system, to which we ascribe the
primary role in the prophylactic processes involved, is subject
to fluctuations of functional activity, and these, in turn, de-
pend upon the virulence of the toxic and the dose of the
latter, "specificity" must represent, as regards major symptoms,
variations of suprarenal activity: a feature which harmonizes
perfectly with the effects of the various poisons, venoms, etc.,
already reviewed. A given toxin under these conditions could
only stimulate the adrenal system up to a certain degree, but not
beyond. That this conception is not erroneous is suggested by
the fact that it accounts for the antitoxin record of the horse
referred to by McFarland, which reached 1400 units to the
cubic centimeter, then gradually declined to 100 units. While
this particular horse's adrenal system could stand stimulation
perhaps above this stage, it was the only stage to which diph-
theria toxins could bring it.

The specificity of toxics in general is further shown by the
constancy of the effects of a given drug in a normal subject and
the dissimilarity of these effects from those of another drug.
Quinine, for instance, will give rise to cerebral phenomena,
doubtless caused by hyperaemia and engorgement of the capil-
laries and — if our views are sound — of the glia-cells and fibers.
This hyperanria the bromides will never produce: simply be-
cause they are hardly able to stimulate the adrenal system
beyond its normal functional activity before they lower it; and,
simultaneously, the oxidation processes of the entire organism.
Indeed, when the entire list of drugs is arranged in the order
of their inherent potential as regards the reaction they initiate

THE IDENTITY OF ANTITOXIN. 655

in the adrenal system, each one is found to occupy a distinct
place, as a specific agency. And toxins do not differ from them.
This brings us back to the identity of the process through
which the pathogenic toxins are antagonized. Stimulation of
the adrenal system and its normal consequence, leucocytogene-
sis, — which involves an increase of phagocytes and alexins in
the blood to destroy bacteria, — adequately fulfilling the re-
quired bactericidal functions, to what organ can we ascribe the
formation of the principle which destroys bacterial toxins?

TRYPSIN AS THE TOXIN-DESTROYING AGENT.

We have previously referred to the identity of toxins,
venoms, vegetable poisons, etc., as albuminoid bodies: a fact
which at once suggests that we have in trypsin a potent toxin-
destroying agent. To indicate the overwhelming importance
in the organism which trypsin must fulfill, if our views are
sound, and to further affirm the identity of these toxins as
albuminoids, the following selections from the pen of a master
in physiological chemistry, Professor Armand Gautier,33 are
submitted: —

"CLASSIFICATION OF THE IMMEDIATE DERIVATIVES OF
ALBUMINOID SUBSTANCES. — We will divide into four classes
the nitrogenous derivatives between protoplasmic proteids and
urea, the simplest term of the nitrogenous-body series. The
following four classes represent, in their actual order, the vari-
ous steps of cellular disassimilation: —

"First class: Proteid derivatives of tissue albuminoids.
Peptones — toxalbumins or toxins.
Diastases and soluble ferments.
Venoms and vaccines.
Pigments.

"Second class: Amid bodies.
Complex amids.
Fatty-acid amids.
Tyrosin.
Amids containing sulphur.

88 Armaiid Gautier: "Chimie de la Cellule vivante," pp. 102 et seq.

656 THE INTERNAL SECRETIONS AND IMMUNITY.

"Third class: Leucomaines of animal bases.

(a) Neurin leucomaines.

(b) Creatin leucomaines.

(c) Xanthic leucomaines.

(d) Unclassified leucomaines.
Appendix: Ptomaines.

"Fourth class: Ureides.
Mono-ureides.
Di-ureides, etc.

"We do not intend to describe these substances, but sim-
ply indicate the origin of each, the principal ways in which they
are split, and their role in the economy.

"First Class: Albuminoid Derivatives. — (a) Peptones. —
We have seen that proteid substances when split by hydration,
are converted into peptones in the intestine, and that, though
much lower in molecular weight than their antecedent albu-
minoids, these peptones nevertheless preserve the general char-
acters of the latter. They represent their immediate deriva-
tives.

"As is the case with proteid substances, peptones contain
five elements: carbon, hydrogen, oxygen, nitrogen, and sulphur
in analogous proportions; they also tend, as do the former, to
become transformed into complex amids that accompany urea
and oxamids, which can undergo autoconversion, if hydration
continues, into carbonate and oxalate of ammonia. By means
of further hydration peptones may be split up into acid amids
— leucin, glycocoll, tyrosin, etc. — and ammoniacal salts. They
give the Millon and biuret reactions. They are, therefore,
essentially albuminoid.

"These very distinct basic properties of peptones, that are
hardly perceptible in the albuminoids from which they are
derived, make them the first term of the series of animal bases
or leucomaines. Before I had discovered the latter substances,
the basic properties of peptones were practically unperceived,
or, at least, they failed to attract interest; but to-day we are
aware that, besides these alkaloidal characteristics, peptones
are likewise toxic in rather large doses. Toxins, venoms, dias-
tases, secreted by microbes, white corpuscles, and certain glands,

THE IDENTITY OP ANTITOXIN. 657

also possess this characteristic of peptones, of being both albu-
minoid and basic, and, as such, belong to the family of com-
plex leucomaines produced by animals. Peptones and toxalbu-
mins constitute the subclass of proteid leucomaines.

"It is not only in the products of gastric and intestinal
digestion that peptones are met with. Many are to be found
in animal and vegetable cells, particularly in white corpuscles,
the lymphatic corpuscles that migrate from vessels, in em-
bryonic cells; in glands and in some instances (purulent foci,
nervous diseases) in the blood and urine; finally, in venoms.
Many microbes owe their toxicity to the peptones they secrete.

"It is very probable that the peptonization of albuminoids
produced in many cells of the economy, is due to the presence
in these of a certain quantity of pepsin or analogous ferments
(papain, pancreatin, etc.): -substances that have been observed,
outside of the gastric and intestinal glands, in the lymphatics
and in normal urine, for example.

"(1) Toxalbumins: Toxins. — Many normal tissues, treated
with cold water, or, better, with an aqueous salt (7 or 8 per
1000) solution, furnish extracts which, deprived of their crys-
tallizable bodies by dialysis, are extremely toxic: such, for in-
stance, are the extracts of spleen and especially of liver. A
dose of such an extract corresponding to 15 or 20 grammes of
hepatic tissue produces, in animals, extreme lassitude with con-
traction of the pupil; after one to two hours they are taken
with diarrhoea and die in prostration (Eoger). Aqueous extract
of kidney, prepared cold, causes pyrexia (Lepine). This tox-
icity seems to be especially due to certain soluble specific albu-
minoid substances, comparable to that of venoms, since, when
heated to 100° C., the extracts lose the greater part of their
toxicity.

"The production of albuminoid venoms by animals and
plants is now an established fact. It was in 1883 that Weir
Mitchell and T. Reichert observed that the venom of snakes —
particularly that of the rattlesnake and of the moccasin — con-
tained three specific albuminoid substances: a venopeptone, a
venoglobulin, and a venoalbumin. The two former are alone
venomous. They also observed (a feature which I had noted
a year before in connection with cobra-venom) that a tempera-

658 THE INTERNAL SECRETIONS AND IMMUNITY.

ture of 100° C. perceptibly altered the action of these sub-
stances, without causing it to disappear. Wall had observed
prior to my researches that, when daboia venom is heated, it
loses its convulsing power, but not its toxicity, as if only one
of the active substances were altered by heat.

"Soon after these researches, N. Wolfenden obtained from
the cobra capello venom an inert peptone, and also very toxic
globulin, serin, and casein. The serin kills by inducing ascend-
ing paralysis of the cord; the globulin, the most powerful of
the three former, assails the respiratory centers; the casein
acts similarly, but less actively.

"It is now well known that the blood of some animals
deemed inoffensive contains toxic albuminoids; such is the
blood of the eel and of the mura3nida3 (Mosso), the blood of the
water-snake (Phisalix and Bertrand), and that of the viper.
Finally, certain spiders have also been found to contain tox-
albumins.

"This property of the economy of thus producing toxic
albuminoids is evidently pretty general as well among the
larger animals as among inferior species; toxic mushrooms
and microbes often manufacture toxalbumins. Christmas has
shown that the poison secreted by the staphylococcus aureus
is albuminoid in nature; it possesses the attributes of these
bodies — it is digested by pepsin, leaving a nuclein residue,
which can be precipitated with alcohol. Injected under the
skin, it produces, in animals, a chronic cachexia (Gamaleia).

"Venomous albumins have also been found in ricin-seeds,
in those of the yellow lupine, in the fruits of the papaw and
of the jequirity; in the bark of the robinia pseudo-acacia.

"All these toxins lose a great part of their activity when
heated, even though their extracts do not become coagulated.

"(c) Diastasic Ferments. — From the toxalbumins to the
diastases there is but a step, although these substances essen-
tially differ. The origin of the latter, however, is especially
vegetable.

"Tuberculin, the active substance of the Koch bacillus
cultures, is obtained by methodically precipitating these cult-
ures by means of alcohol. It possesses all the properties of
albuminoids (Millon, Adamkiewicz, and biuret reactions); phos-

THE IDENTITY OF ANTITOXIN.

659

photungstic acid, tannin, and sulphate of ammonium precipi-
tate it completely.

"The active ferment of glanders, mallein, is also albu-
minoid in nature. Such is also the case with the diastase of
epizootic pneumonia of cattle (Arloing).

"Between toxic peptones, the albumotoxins of venoms, of
toxic bloods and the diastasic ferments, it is difficult to estab-
lish a limit other than their origin or their more or less marked
activity: 0.00008 gramme of cobra-venom suffice to kill a kilo-
gramme of rabbit; 0.0021 gramme of viper-venom, 0.01 gramme
of jequirity globulin, or 0.30 gramme of ordinary peptone are
necessary to produce the same effects.

"The gradation is imperceptible from inoffensive albumins
to toxalbumins, or peptones; and from peptones to leuco-
maines. From toxalbumins to vaccines there is but one step.
It is known to-day that viper-venom, and perhaps that of
the cobra capello, when heated and injected into the tissues,
become true vaccines which preserve animals against the
action of these same venoms (Phisalix and Bertrand). But
what is remarkable with the action of these soluble poisons, is
that, as is the case with vaccines, the toxins appear to act
rather as ferments by modifying slowly and deeply the general
nutrition of cells, than as chemical poisons. Indeed, their action
is not immediate; it is only after a certain period of incubation
that the fermentation occurs which gives rise either to immunity
or to disease** This, at least, is what occurs with the toxins of
heated venoms and with those of tetanus.

"The slowness of the action of these soluble poisons is
nevertheless not contradictory to the theory that their action
is purely chemical. Molecules possessed of mixed functions
react all the more slowly the one upon the other as they are
heavier and less active as conductors. This is the case with
albuminoid substances."

We thus have as main sources of intoxication, which it is
the function of trypsin to counteract, the following agencies: —

1. Toxins and diastases secreted ~by bacteria.

»* The italics are our own.

42

660 THE INTERNAL SECRETIONS AND IMMUNITY.

2. Diastases derived from leucocytes and glandular elements.

8. Tissue toxalbumins.

4- Snake- and other venoms.

5. Vegetable toxalbumins.

6. Diastasic ferments.

At the end of the eighth chapter we offered the following
deductions: 1. The cleavage processes to which trypsin sub-
mits albumins in the intestinal canal include the preliminary
steps of a protective function. 2. The spleno-pancreatic in-
ternal secretion is represented by the trypsin which reaches
the portal vein by way of the splenic vein, and which continues
in the blood-stream the cleavage processes begun in the intes-
tinal canal. 3. The main function of the spleno-pancreatic
secretion, trypsin, in the blood-stream is to protect the organ-
ism from the effects of the toxic derivatives of albuminoid
bodies.

That albuminoid poisons, including bacterial toxins, are
destroyed by the spleno-pancreatic ferment — trypsin — may also
•be sustained by experimental data. Charrin and Levaditi35
not only ascertained that toxins introduced into the digestive
tract were modified, but that the pancreatic secretion played
the preponderating role in this connection. Diphtheria bacilli,
injected into the pancreas of animals, lost their activity, while
the same quantity injected in the muscles proved toxic. Pan-
creatic extract itself was found to destroy micro-organisms.
In the light of the views herein recorded the active pancreatic
substance was the trypsin contained in the veins and ampullae
of the organ. Zaremba,36 in a series of experiments, ascertained
that toxins were greatly altered in the digestive tract, espe-
cially those of tetanus and diphtheria. To ascertain whether
pancreatic ferments exercised any influence in this direction, he
prepared extracts of this organ and mixed them with diph-
theria toxins. The pancreas extract of young animals — pups,
rabbits, etc. — was found to markedly reduce the virulence of
the toxin. Human pancreas was found inactive, but suspecting
that this was due to post-mortem changes in the organ, a num-
ber of hours having elapsed before the pancreases first obtained

"Charrin and Levaditi: Semaine M6dicale, March 22, 1899.

»• Zaremba: Archiv fiir Verdauungs-Krankheiten, Bd. vi, H. 4, 1900.

THE IDENTITY OF ANTITOXIN.

661

had been removed from the body, he succeeded in getting that
of a boy four and a half years old two hours after death. This
organ proved to be distinctly active against toxins, and in sev-
eral instances the pancreases of very young children removed
immediately after death were very active in the same way. In
some, however, and in older subjects and animals, no results
were obtained. We have seen that the period of splenic ac-
tivity or spleno-pancreatic digestion was the only one during
which trypsin was formed, as shown by the experiments of
Schiff and Herzen; that Zaremba's exceptions were made up of
pancreases in the passive state — i.e., when only the inactive
zymogens of all three ferments were present — is probable.

The results of removal of the spleen, in this connection,
are also suggestive. But here it is necessary to avoid being
misled by the action of injected toxics upon the adrenal sys-
tem, since a sufficient dose will kill an animal irrespective
of the presence or absence of its spleen. This is well illus-
trated in the following experiment: "Martinotto and Barbacci37
studied the function of the spleen in infectious diseases by
injecting anthrax bacilli into guinea-pigs and rabbits, in some
of which the spleen had previously been extirpated. The re-
sult was the same under both conditions. There were no
marked elevations of temperature, but a progressive fall, pre-
ceding death." Again, the protection afforded through adrenal
overactivity by exciting general leucocytosis and the production
of alexins, — both bactericidal agencies, — must not be over-
looked, since removal of the spleen does not reduce the pro-
tective powers. Indeed, the accumulation of toxic elements in
the blood that follows splenectomy tends to increase the latter
and thus compensate for the missing organ's beneficial influ-
ence. Both these features are well shown in the experiments
of Courmont and Duffau,38 who found that, in rabbits splenec-
tomized from two to twenty-five days beforehand, the staphy-
lococcus pyogenes and the bacillus pyocyaneus caused death in
a few hours, whereas normal rabbits survived longer or alto-
gether. Yet, when attenuated cultures of the very virulent
streptococcus were used, animals splenectomized a few hours

17 Martinotto and Barbacci: II Morgagni, Milan, Sept., Oct., 1891.
••Courmont and Duffau: Soci6t6 de Biologic, Lancet, June 27, 1896.

662 THE INTERNAL SECRETIONS AND IMMUNITY.

or days before always resisted better than normal rabbits, and
sometimes survived when the cultures used were further weak-
ened. The splenectomized rabbits simply had their adrenals
stimulated by two active toxic agencies, the normal rabbits
only by one, and the bacteria in the former were introduced
when the blood was filled with defensive bactericidal agents.
The fact, however, that the weaker organisms caused death
in splenectomized animals in a few hours, whereas normal
rabbits survived longer or altogether, is none the less cor-
roborative testimony, since it suggests that in the latter ani-
mals the only poisonous agents present, the toxins, had been
destroyed when formed. Indeed, Courmont and Duffau found
that the staphylococcus killed a splenectomized animal in ten
hours, while the same dose used in normal rabbits only caused
death a week later.

A predominating feature of all experiments of this kind
is the evident compensative influence of adrenal origin —
so marked at times as to entirely offset the loss and even to
temporarily and perhaps permanently, in some instances, pro-
vide unusual immunity to bacteria, the source of toxins. Thus,
Blumreich and Jacoby39 observed that when bacteria of vari-
ous diseases — diphtheria, cholera, etc. — were injected into
splenectomized animals, these lived longer or died less often
than the normal ones. They conducted experiments with
toxins, but these experiments all indicate that adrenal over-
activity equalized conditions whether the spleen has been re-
moved or not. Briefly, while in some experiments there is dis-
tinct evidence of temporary vulnerability to the effects of tox-
albumins, — i.e., toxins, — the majority of them as strikingly
illustrate an immediate compensative influence: i.e., a more or
less marked increase of the activity of the adrenal system, which
floods the circulation with phagocytes, alexocytes, and oxidiz-
ing substance. The enlargement of the spleen in fevers is
familiar to all clinicians. This may be, besides the result of
mechanical engorgement of adrenal origin, an additional source
of protection whereby albuminoid bodies are destroyed through
the excess of trypsin produced.

» Blumreich and Jacoby: Berliner klin. Wochenschrift, No. 21, 1897.

THE IDENTITY OP ANTITOXIN.

663

All these facts not only further emphasize the importance
of the adrenal system in the organism, but they also indicate
that the spleen is not the useless organ that it is thought to be
by many. True, its removal is not always followed with un-
toward effects, but this is merely due to the fact, illustrated
above, that the adrenal overactivity caused ~by the accumulation
in the blood of substances that would be destroyed in the liver if
the spleen were present correspondingly activates all the remaining
protective functions.

Interesting in this connection is the fact that the thyroid
gland is considered by many observers, including Bardeleben,
as the compensative organ of the spleen. That the adrenal
symptoms have invariably been ascribed to the thyroid we have
seen. General enlargement of the lymphatic glands and in-
tense congestion of the . bone-marrow have also been noted:
evidence that the production of leucocytes is very actively
stimulated. We have curious testimony as regards the con-
tinuousness of adrenal overactivity in a series of experiments
conducted by H. Martyn Jordan,40 which showed that partial
excision of the spleen in pups caused these to grow "somewhat
faster than their untouched brother." We have studied the
morbid influence of excessive adrenal activity in exophthalmic
goiter, acromegaly, etc., and noted the increased functional
metabolism of the erethic stages in both diseases. It seems
clear that in Jordan's experiments the unusually rapid growth
of the animals can be ascribed to adrenal overactivity — a fact
simultaneously proving its actual existence.

That the spleen is a protective organ is also suggested by
the great amount of lymphoid tissue it contains and the large
number of leucocytes it contributes to the portal circulation.
In this particular, however, we only regard this organ as one
of several sources of supply, and merely refer to it to show
that in addition to its main function, the secretion of a ferment,
it is occupied by leucocyte-forming structures such as there
are in other parts of the digestive system, of which the spleen
is an essential member. Indeed, the description of an intes-
tinal solitary follicle or of one of those that take part in the

40 H. Martyn Jordan: Lancet, Jan. 22,

664 THE INTERNAL SECRETIONS AND IMMUNITY.

formation of a Peyer patch, including the central "secondary
nodule" of Flemming,41 could as well be applied to splenic
lymphoid structures. These probably also subserve a dual
process, such as" that observed by Macallum in the intestine,
judging from .the fact that the splenic lymphocytes often con-
tain iron-pigment. This suggests that in the spleen the leu-
cocytes formed pass out into the pulp-channels and chemotac-
tically take up the iron-pigment then carry it to the liver via
the portal vein, just as in the intestine they are also formed
in the follicle, pass out into the intestinal tract, take a similar
supply, re-enter through the villi, and also proceed to the liver
via the portal vein. Again, the power of the intestinal leuco-
cytes to chemotactically take up iron-pigment demonstrates
their capability of acting similarly with bacteria; the same may
be said of splenic leucocytes, thus justifying MetchnikofFs view
that phagocytosis is one of the spleen's weapons in defense of
the economy.

All these features emphasize the identity of the spleno-
pancreatic ferment as a prophylactic agency, and we now feel
that we can, with confidence, submit the following conclu-
sions:—

1. The spleno-pancreatic system, through the agency of its
proteid-digesting ferment, trypsin, protects the system against dis-
eases caused by toxic albuminoid bodies.

2. The main toxic albuminoid bodies to the effects of which
the system is exposed are: —

(a) Toxins and diastases secreted by bacteria.

(b) Vegetable toxalbumins. ^

(c) Proteid toxalbumins. > Toxic foods.

(d) Peptone toxalbumins. J

(e) Vegetable poisons.

(f) Venoms.

8. Trypsin is the constituent of antitoxin which splits the
toxins of the diphtheria bacillus into inert bodies.

4' Trypsin is the constituent of blood-plasma which splits all
toxic albuminoids into inert bodies and thereby protects the system
against diseases due to their effects.

41 We purposely omit the term "germ-center," employed by Flemming, to
avoid the confusion that its use would obviously entail.

THE COMPOSITION OP ANTITOXIN.

665

THE COMPOSITION OF ANTITOXIN.

A review of the data submitted shows that phagocytosis has
fully merited the recognition it has received. This is due
mainly to the labors of Metchnikoff, who propounded the doc-
trine and whose views have been sustained by the investigations
of other observers. It has also proven itself unassailable by,
and eminently in keeping with, the views submitted in the
present volume. The mobile phagocytes in the blood-plasma
and the fixed phagocytes — i.e., the endothelial, hepatic-stellate,
connective-tissue, bone-marrow, lymphatic, and splenic-pulp
cells, etc. — unitedly constitute a protective system through
which all the living structures of the organism are primarily
protected. Phagocytes incorporate not only dead, but living,
bacteria, and are able to destroy them. They thus prevent
their pullulation and the production of toxins. The analysis
has also shown: —

That alexins, the presence of which in the body-fluids has
been shown through the labors of Hankin, Buchner, and other
observers, are likewise bactericidal and constitute active proph-
lactic agencies has also been sustained herein. Alexins are
secreted by leucocytes, and the bactericidal activity of the
blood-serum corresponds with the number of leucocytes present
in it. Their destructive power varies according to the micro-
organism present, though all are more or less weakened by
them. They also act, according to Buchner, as histolytic en-
zymes, capable of softening or even causing dissolution of mor-
bid histogenetic elements, abscesses, tubercles, etc.

That trypsin, to which we attribute the main prophylactic
function, — {.«., that of a proteolytic ferment capable of reduc-
ing bacterial toxins, toxalbumins, vegetable poisons, and ven-
oms to benign products, — is, in reality, endowed with these
functions, seems to us as fully sustained by the analysis to which
we have submitted this question. Its specific action upon albu-
minoids has been experimentally demonstrated, while the
identity of the above pathogenic bodies as albuminoids is as
conclusively established.

That the oxidizing substance, to which we attribute the
prophylactic function of destroying by oxidation all toxic agen-

666 THE INTERNAL SECRETIONS AND IMMUNITY.

cies susceptible to such a reaction that may either be physio-
logically formed in the organism or enter the blood-stream
from without, is the reagent to which all such processes are due
has likewise been demonstrated by its role in general functions:
the combustion of sugars and other hydrocarbons, the elabora-
tion of uric acid, phosphoric acid, etc.

That the thyroid secretion, which contains iodine in organic
combination, as demonstrated by various investigators, sustains
the functional activity of the anterior pituitary body and,
therefore, of the entire adrenal system. Being endowed with an-
tiseptic and stimulating attributes, owing to the presence of io-
dine, it may also act as such in the blood while in transit, but, as
no experimental proof to this effect is available, its action upon
the anterior pituitary body can alone be taken into account.

In view of all these facts it seems evident that phagocytes,
alexins, trypsin, and the oxidizing substance are the four main
defensive agencies with which the organism is provided to
antagonize pathogenic germs, their toxins, and other organic
poisons; and that they represent the active constituents of
antitoxin. We can therefore conclude, for the time being, that:

Antitoxin, the antitoxic serum obtained from animals by
means of injections of diphtheria toxins, is composed of the fol-
lowing main bodies: (1) Blood-serum, which acts as vehicle. (2)
Alexins, which act as bactericidal agents. (3) Trypsin, which acts
as toxin-, toxalbumin- (including vegetable poisons), and venom-
reducing agent. (4) Oxidizing substance, which submits to oxida-
tion all toxics possessed of sufficient affinity for oxygen.

A number of questions are awakened by this list, however.
How do the alexins originate, and to what agency do they owe
their bactericidal properties? Again, considerable evidence,
clinical and experimental, has shown that the protective func-
tions of the organism fluctuate under certain conditions. The
introduction of salt solution into the blood-stream, for instance,
often causes a seemingly moribund case to at once enter the
stage of convalescence. This suggests that we have only studied
the grosser phases of the immunizing process so far, and that
our inquiry must include, if it is to be of some practical value,
an analysis of the physiology of immunity, and of the intrinsic
conditions that tend to antagonize the immunizing process.

CHAPTER XII.

THE INTERNAL SECRETIONS AND THE
PRESERVATION OF LIFE.

WiLLOUGHBY1 refers to a case of opium poisoning in which
the narcosis was so profound that the application of the strong-
est possible interrupted current to the soles of both feet did
not excite the slightest movement even of the toes. When
about a quart of salt solution had been infused by gravitation
into the subcutaneous tissue of the flank, the effect was almost
immediate and striking. Within twenty minutes the duskiness
and coldness of the skin had given place to a natural color and
warmth, and the patient had so far recovered sensibility and
consciousness as to struggle violently against the mechanical
and electrical stimulation employed to keep her awake.

What is the intimate nature of the process through which
saline solutions are enabled to so wonderfully restore func-
tional activity? In the course of investigations concerning the
distribution of intravenously injected solutions of chloride of
sodium and chlorate of sodium, Sollmann2 found that, when
they were introduced directly into the blood-stream in large
quantities, the greater portion of them had disappeared in
three minutes, while in one-half hour the composition of the
blood was about as it was originally. A curious fact noted was
that the total quantity of blood was diminished notwithstand-
ing the injection of a large quantity of fluid. The latter left
the blood-stream to enter the "tissues," then passed out in the
urine. The itinerary of the fluid and salts up to their final
excretion was completed in about half an hour, and the molec-
ular concentration of the plasma showed no marked change.

In the light of our views, the "tissues," i.e., the proto-
plasmic cellular elements of which they are composed, are evi-
dently not the structures primarily influenced by the presence

* Willoughby: Lancet, May 10, 1902.

2 Sollmann: Archiv fiir experimentelle Pathologic und Pharmakologie, Bd.
xlvi, H. 1 und 2, 1901.

(G67)

668 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

of the solution in the blood, but, instead, the functional con-
stituents of the tissues, i.e., myosinogen, myelin, etc. Again,
the rapid disappearance of the alkaline solution from the blood-
stream does not point to tissue absorption, but to escape into
the lymphatic spaces and circulation, the aggregate area of
which is over twice that of the blood-system.

The introduction of the lymphatic system as a factor of
the problem before us, at once recalls the all-important pro-
tective role that leucocytes, — as phagocytes, alexocytes, etc., —
reviewed in the last chapter, play in the economy; it also re-
calls the evident connection between leucocytosis, or rather
leucocytogenesis, with all morbid processes. May we not have
in these white blood-corpuscles — so little concerning which, as
regards their intrinsic biochemical function, is known — the
main factor in the striking resuscitations which the use of sa-
line solution procures? These amoeboid cells must doubtless
be hampered in their movements (for they are not merely
dragged along as are the red corpuscles) as soon as the specific
gravity of the serum is raised; their pseudopodia cannot but
lose the freedom which adequate alkalinity of the fluid in which
they live had previously insured.

Indeed, the closer is the intimate nature of the leucocyte
examined, the more does one become impressed with the thought
that this cell must be endowed with functions greatly exceed-
ing in importance any as yet ascribed to it.

THE LEUCOCYTE IN ITS RELATIONS TO LIFE AND
ORGANIC FUNCTIONS.

Before inquiring into the physiological functions of each
of the various varieties of white corpuscles or leucocytes, we
have thought it advisable to study the cell as a unit, and par-
ticularly the functional attributes of its main component struct-
ures: (1) the nuclear and cellular reticulum or mitoma; (2)
the granules.

THE MITOMA. — Alluding to basophile leucocytes, Howell3
states that the nucleus "is divided into lobes that are either en-
tirely separated or are connected by fine protoplasmic threads."

'Howell: Loc. cit.

LEUCOCYTES! THEIR MITDMA AND
MICRDSDMES, [Gulland,]

[Jiiiirniil of Physiology.]

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 669

This is well illustrated in the annexed plate from a valuable
study of the subject by G. L. Gulland,4 by Fig. 1, a hyaline
leucocyte from a newt's blood. These cells are undeveloped
and their protoplasm does not as yet show "threads!" But
their nucleus is clearly supplied with them even at this early
stage — a feature which suggests that the nucleus is an au-
tonomous structure. This is further sustained by the pres-
ence, in the perinuclear portion of the cell, of a small body, the
astrophere, shown in Fig. 7, another undeveloped, or "hyaline,"
cell. This astrophere is likewise present in fully developed
leucocytes, as may be seen in Figs. 10, 12, and 16. Each cell
may, therefore, be said to contain two functional centers, each
supplied with its net-work of fibers or threads.

Heidenhain is stated by Gulland to have found that "the
granules are arranged radially to the astrophere, with the
smallest granules next the sphere, the largest at the periphery."
This is exemplified with especial clearness in Figs. 10 and 16,
and if the threads, or fibers, are traced from the center of the
astrophere, the gradual increase in size of granules as the
periphery of the cell is approached is clearly indicated. Hei-
denhain also concluded, a feature fully confirmed by Gulland,
that "there are never any granules within the astrophere it-
self." It thus becomes evident that while the nucleus is an
autonomous structure, the same may be said of the astrophere.
In other words, a leucocyte seems to be supplied with two in-
dividual, though doubtless correlated, functional systems: (1)
the nucleus per se, which contains a net-work of fibrils and
granules; (2) the astrophere, which represents the center of
the cellular net-work of granule-laden fibrils.

As may be seen in the numerous cells represented in
Gulland's plate, which cells have been drawn by him with the
utmost care and fidelity to microscopical appearances, the fibers
in the nucleus divide the latter into several irregular areas,
while the radiating net-work of which the astrophere is the
center forms relatively regular spaces. The fibers in both
structures run to their external boundaries, however, precisely
as if they were attached to the external limiting membranes of

* G. L. Gulland: Journal of Physiology, vol. xix, 1896.

670 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

each. And yet the nucleus alone seems to be supplied with
such a membrane, while the surface of the cell is not. Indeed,
a prominent feature of these cells is the fact that their proto-
plasmic exterior is absolutely bare.

After a .study of the characteristics of the granules, Gul-
land writes: "The granules of leucocytes are therefore not
products of the metabolic activity of the cell imbedded in a
structureless protoplasm, as Was hitherto supposed, but represent
an altered condition of the microsomes [the granules]. They
always form part of the cytomitoma [the net-work of fibers]
and are therefore plasmatic, and not paraplastic. They are
probably concerned with amoeboid movement, and they and the
rest of the mitoma are more visible the more active the cell."
Granules, as the plate distinctly shows, are plentiful within the
nucleus, and in the cellular substance likewise; indeed, in the
latter they are crowded around the centrosphere, the deepest
portion of the cell.

If the granules are plasmatic, i.e., formed by substances
derived from the plasma, how does the latter reach the minute
areas in which the granules are formed? Channels seem to us
absolutely necessary for the passage of the blood-plasma, its
alkaline phosphates, and other plasmatic salts from which the
granules are formed.

The prevailing view that the threads (mitoma) are con-
cerned with the amoeboid movements of leucocytes, as also in-
ferred by Gulland, is by no means, it seems to us, incompatible
with the possibility of their being plasma-channels, or efferent
canaliculi. Indeed, their elasticity does not eliminate the pos-
sibility of their being tubular, while their extension and re-
traction may, as in the sweat-glands, afford the mechanical
elements of an expulsive process. "It is certainly interesting
to note that, the more active the cells of this series become,"
writes Gulland, referring to the acidophile (phagocytic) leuco-
cytes, "the more visible become their mitoma and the micro-
somes which form part of it. The lymphocytes in which no
mitoma can be seen are practically non-amoeboid. The hyaline
cells in which it is not very evident move but sluggishly. The
oxyphile cells, with a well-marked mitoma and microsomes,
move more rapidly, and the eosinophile cells, whose mitoma

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 671

and microsomes are the most visible of all, move most rapidly."
Again, he says: "It is certain that the length of thread lying
between the microsomes varies immensely in different parts of
the cell, and the short threads are usually the more deeply
stained; so that it looks as though they were contracted and
therefore thickened. On the other hand, the microsomes at the
periphery are, generally speaking, the largest, and there can be
no doubt that it is the circumference of the cell which moves
most and moves farthest." As regards the basophile leucocytes,
he states that, "as far as one can judge from fixed specimens,
the larger basophile cells seem to have more power of move-
ment than the smaller ones" — a feature easily accounted for,
since they are not bactericidal, as are the acidophile leucocytes.
It seems evident, however, that in both acidophile and baso-
phile cells the fibers take part in the mechanism through which
they travel in the plasma, while contraction, thickening, etc.,
i.e., the elements of a suction or expulsion process, are present
to suggest the identity of the mechanism to which they owe
their powers of locomotion.

Basophile leucocytes are not phagocytic; they do not,
therefore, ingest foreign substances as do the latter, i.e., by in-
globing them. They must, therefore, be provided with a dif-
ferent mechanism for this purpose. If, in accord with our view
the mitoma represents a system of centrifugal canaliculi, it
cannot serve for this purpose. Indeed, the external agencies
penetrate the cell to the nucleus itself. Thus "W. R. Stokes and
A. Wegefarth,8 alluding to the researches of Bail,6 say: "After
injecting virulent staphylococci into the pleural cavity of rab-
bits he found that the leucocytes underwent, a characteristic
change. They formed round, empty bodies, containing several
vacuoles in the nucleus."

How did the virulent staphylococci reach the nucleus's
vacuoles? MetchnikofFs plate (opposite page 628 in this vol-
ume) will assist us in elucidating this question. It not only
forcibly illustrates what this distinguished zoologist sought to
show, but likewise, it seems to us, a mechanism of ingestion,

5 W. R. Stokes and A. Wegefarth: Bulletin of Johns Hopkins Hospital, Dec.,
1897.

8 Bail: Berliner klin. Wochenschrift, Oct. 11, 1897.

672 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

differing somewhat from the recognized "ingulfing" or "inglob-
ing" process through which phagocytes take up germs, small
particles, etc. An example of this mode of appropriating vari-
ous plasmatic or foreign substances is illustrated in Fig. 5,
which shows bacteria penetrating, from various directions, into
the cell-wall, while Fig. 16 shows the bncteria within the peri-
nuclear vacuole. As all the cells in Metclmikoff's plate are
phagocytes, the mechanism of ingestion to which we refer is
not only that of basophiles, but is obviously a feature of all
leucocytes.

We must emphasize the fact that we say "perinuclear"
vacuole, and not "nuclear" vacuole, for, if this and the other
germ-laden cells just referred to are carefully examined, it will
become evident that the bacteria lie in a pocket contiguous to,
but not forming part of, the nucleus itself. We would not say,
therefore, with Bail, "vacuoles in the nucleus," but vacuoles
around the nucleus. Indeed, Gulland refers to Heidenhain as
considering that "the nucleus lies free in the interfilar spaces,
and is not organically connected with the cell-substance." This
is quite in accord with our view, and it seems to us that it
represents the cavity into which bodies ingested by leucocytes
normally arrive, though smaller vacuoles are likewise present
in the cytoplasm.

The actual presence of this perineuclear vacuole from
which canaliculi would start appears to us indicated in several
of the figures in the annexed Gulland's plate. Fig. 8, for in-
stance, stained with iron-ha3matoxylin, shows that the nucleus
is surrounded by an irregular limiting material of some kind;
but if we compare the outline of this limiting substance with
that of all the succeeding cells, an interesting feature asserts
itself, viz.: its thickness is extremely variable. Although 12
may be said to be moderately regular, the others, in the fol-
lowing sequence: 11, 10, 13, 8, 9, and 14, are increasingly irreg-
ular. If now this irregularity itself is scrutinized, a significant
fact is revealed: i.e., the bulges, or projections, in the limiting
structure are all at the expense of the nucleus. In Fig. 9, for
instance, just above a clover-like figure near the center of the
cell (probably the astrophere), the marked bulging shows every
evidence of having been formed by a substance which had com-

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 673

pressed the nuclear substance inwardly. The stages of this
compression are exemplified in Metchnikoff's plate, by Figs. 16
and 15, successively. In the former a single mass of liquid and
germs is seen to have indented the center of the nucleus on
one side, while in the second figure three cavities are shown
which have distorted it. (The nucleus is indicated by an n.)
In loth, however, the compression has exceeded the normal
boundaries of the limiting structure, and centrifugal bulging
has occurred at the expense of the pericellular protoplasm or
cytoplasm. So marked has this become in Fig. 14 that the
nucleus is not discernible.

The identity of the mitoma as a system of canaliculi seems
to us shown in another way. We have found that the axis-
cylinders of nerves, 'neuroglia fibrils, etc., contained blood-
plasma. Such being the- case, if the fibers or "threads" in leuco-
cytes are likewise plasma channels, they must stain, as do the
former, when treated to various dyes. We have seen (pages
541 to 543) that methylene-blue, dissolved in salt solution and
injected into the vessels of a living animal, colored the axis-
cylinders blue, according to Ehrlich, and that this investigator
defined the conditions of nerve-structure essential to the
methylene-blue reaction as "oxygen saturation and alkalinity"
— the very attributes of blood-plasma. Eeferring to the vari-
ous stains used by him, Gulland says: "In examining the baso-
phile cells I used almost entirely various methylene-blue solu-
tions," and, later on: "The basophile cells of the dog's intes-
tinal villi, when fixed with absolute alcohol and stained with
alcoholic methylene-blue, give exactly the same results, as to
mitoma and granules, as other basophiles." Evidently, as re-
gards the methylene-blue stain, nerve-fibrils and mitoma (our
canaliculi) are similar. Again, in addition to the plate we re-
produce, Gulland presents two colored plates in which the char-
acteristic affinity of each cell for stains appears; the six baso-
phile leucocytes stained with methylene-blue (normal) dis-
tinctly show that structures which stain most deeply is the
chromatic, i.e., the nuclear mitoma; then, more faintly, the
cellular mitoma. It seems clear that, as regards methylene-blue
stain at least, the conditions are similar to those of nerves as
far as the mitoma — or canaliculi — are concerned.

674 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

The same correspondence exists between nerve-fibrils and
the mitoma when hasmatoxylin is used. We have seen (page
536) that, according to McCarthy, the rods that project radially
from the axis-cylinder "stain with carmine and haematoxylin,
which do not stain the myelin." The fact that the axis-cylinder
takes haematoxylin hardly needs to be emphasized, its use in
histological laboratories when nervous structures are studied
being second only to picrocarmine for general staining. A
beautiful example of haBmatoxylin-stained human cerebro-
spinal and sciatic nerves is to be found in Clarkson's "Histol-
ogy," page 204, for instance. All the eosinophile leucocytes
shown in the annexed plate, in which the nuclear and the peri-
nuclear granules and mitoma are so clearly defined, were stained
with Heidenhain's iron-haematoxylin, which only differs from
the usual solution in that it colors the cellular elements that
take it a dark gray or black. This also shows that it is not only
with the mitoma of basophile leucocytes that the staining char-
acteristics of nerve-fibrils — i.e., plasma-containing channels —
coincide, but also with that of eosinophile cells. Even Apathy's
fibrils are recalled by the effects of corresponding stains, for
Senn writes,7 referring to the minute anatomy of the leuco-
cyte: "The reticulated structure is well shown by staining with
chloride of gold, which stains the protoplasmic strings, but not
the interstitial substance." It seems to us quite evident, there-
fore, that the mitoma, i.e., the intracellular and intranuclear net-
works of fibers in mature leucocytes, are canaliculi for Hood-plasma
and for the substances contained in this fluid.

FUNCTIONAL MECHANISM OF THE LEUCOCYTE. — We have
expressed the view that the nuclear canaliculi open into a
vacuole which surrounds the nucleus (see Fig. 14 in Gulland's
plate) and that the outer wall of this vacuole acts as terminal
for some of the canaliculi of the cell-substance. Although, as
suggested by Fig. 11, the canalicular orifices that open into
the vacuole from both directions may correspond (the nuclear
orifices being in that case opposite the cellular openings), such
is by no means always the case. Indeed, in Fig. 16, for exam-
ple, but two or three of the external canaliculi seem to be con-

7 Senn: "Principles of Surgery," third edition, 1901.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 675

nected with the vacuole, while this cavity serves as terminal for
all the mfoznuclear channels — if such they are.

Is the connection between this vacuole and the exterior of
the cell direct or indirect: i.e., through separate channels lead-
ing directly to the exterior or to those connected with the astro-
phere's system? That the communication is independent of
the latter is emphasized by the presence of granules in the
path of all canaliculi, as shown in Gulland's plate. A contin-
uous function depending upon an inflow of plasma would ob-
viously be in constant danger of arrest were the granular chan-
nels centripetal pathways. Again, in all leucocytes, acidophiles
as well as basophiles, the nucleus stains in the same manner,
the granules alone, as we have seen, showing variations in this
particular. The sanie may be said of the reticulum, for we
have seen, by the staining reactions, that the compounds com-
posing the granules are bathed in oxidizing substance. This
uniformity of nuclear and cellular fluids in the canaliculi sug-
gests the presence of a common mechanism — one, indeed, which
must serve to eliminate its contents, judging from the fact al-
ready mentioned, that the size of the intracellular granules in-
creases in size outwardly, the largest granules being at or near
the surface. A common centrifugal canalicular system again
suggests the presence of a system common to all leucocytes,
whether phagocytic or not, for the introduction (not necessarily
of particles or other discernible agencies) of more or less liquid
or viscid bodies required by the cell for its own nutrition, or
connected with its own physiological functions: i.e., the elab-
oration of granules. The canaliculi serving only for the cen-
trifugal elimination of the latter, the centripetal paths must
penetrate to the vacuoles between the canaliculi, or "threads,"
as already explained, and as shown in MetchnikofPs plate,
Fig. 5. We are evidently not dealing here with mere inclusion
or pseudopodial flowing around the germs, for the latter may
be seen to penetrate the cell between the granules, and, judg-
ing from Figs. 13, 14, 15, and 16, directly into the perinuclear
vacuole itself.

Is the cell supplied with centripetal canaliculi in addition
to the centrifugal system which we believe to be represented
by the reticulum? The fact that micro-organisms can pene-

43

676 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

trate directly into the vacuole between the external layer of
granules is not alone to suggest that such is the case, but the
manner in which the leucocyte takes up stains likewise does
so. As can readily "be seen, the absorption of the dye by the
cell occurs without involving any alteration of its shape which
can at all be associated with the process. That the absorption
cannot occur through the visible canaliculi, i.e., those that take
stain because they constantly contain fluid, is rendered very
probable by the presence of the granules, which must entirely
close their external orifices. It must occur, therefore, through
paths presenting some analogy to the pores of certain sponges,
which allow the surrounding water to pass into the interior of
the sponge, so long as it does not carry any harmful products
along with it (Metchnikoff). And yet the fact that such a sys-
tem of channels does not exist is shown by the promiscuous
directions taken by bacteria in penetrating into the cell. In-
deed, their bodies are not directed axially toward the peri-
nuclear vacuole; they seem, once within the external layer of
granules, to point in almost any direction. We are brought
back, therefore, to the soft, yielding, protoplasmic cell-sub-
stance of the amoeba, which will allow liquids to easily transude
through it, and the more dense materials to cleave their path
into it and down to the vacuole, without leaving a wound
behind them. "On introducing pigeon leucocytes filled with
anthrax bacilli (to which the pigeon is very refractory) into
bouillon," says Metchnikoff, "bacilli grow, pierce the proto-
plasm of the cells, and form well-developed filaments, showing
definitely that the bacilli were inglobed in a living condition."
We might say "ingest," however, for the perinuclear vacuole
asserts its identity as a digestive organ — the familiar digestive
vacuole — in several ways: i.e., as a cavity in which all the
materials that supply the cell with functional energy, — i.e.,
with life, — are drawn.

Metchnikoff,8 referring to the intracellular digestion to
which amoebae submit the materials they ingulf, writes as fol-
lows: "A closer observation of the group of protozoa compels
us to the conviction that this digestive function must play an

8 Metchnikoff: "Lectures on the Comparative Pathology of Inflammation,"
translated by P. A. and E. H. Starling, pp. 18 et seq., 1891.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 677

important role in the mutual relations of these lowly organ-
isms. Many rhizopoda and infusoria live in media swarming
with other unicellular organisms, including bacteria. The
latter, which multiply very rapidly, serve as food to many of
the protozoa. Thus, various amoeba? devour bacilli, which un-
dergo certain definite changes in the interior of the protoplasm.
Without altering their shape, the bacilli acquire the power of
taking up solutions of vesuvine, which does not stain these
microbes when living in their material conditions. Since pre-
cisely similar changes are also observed in the interior of vorti-
cellse and infusoria, which live on bacteria, it is evident that
they are due to a digestive influence exerted by the contents
of the protozoa." This conclusion is in harmony with the ob-
servation of B. Hofer9 on digestion in amoebae. This investi-
gator has shown that "the more the food is altered in the in-
terior of these rhizopods, the more easily does it stain with
aniline dyes." When we consider that aniline dyes include
methylene-blue, we have evidence, in view of Ehrlich's observa-
tion that the "conditions essential to the methylene-blue reac-
tion" are "oxygen saturation and alkalinity" that the proto-
type of amoeba, the leucocyte, must owe its nuclear functional
activity to the plasma as exogenous reagent.

Metchnikoff further says: "We may often see flagellated
monads taking up filaments of leptothrix several times as
long as themselves, and finally inclose them in their digestive
vacuoles." The process of ingestion is beautifully shown in
the plate opposite page 628, in Figs. 19 and 20, the organisms
here being spirilla of Asiatic cholera. "It is sometimes possible
to follow all the changes undergone by the bacteria within an
infusorium," continues the same investigator, "as is the case
of the digestion by stentor of the sulpho-bacterium thiocystis,
observed by le Dantec."10 . . . "It is evident that the di-
gestive function of the protoplasm of the protozoa must hinder
the invasion of these animals by the lower organisms, and it is
only in certain special cases that the latter can live as parasites
within the rhizopoda and infusoria."

The true identity of the perinuclear vacuole seems fur-

9 B. Hofer: Jenaische Zeitschrift, vol. xxiv, 1889.
10 Le Dantec: "Recherches sur la digestion intracellulaire," Lille, 189L

678 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

ther emphasized by the following lines, also quoted from Metch-
nikofFs text, that is to say, as interpreted by his translators:
"The sponges are ..of such undifferentiated organization that
they were long considered to be colonies of protozoa, consist-
ing like the protospongia, of separate flagellated and amoeboid
individuals. Later on, it was however ascertained that they
bore a certain relationship to the polyps and their allies (coelen-
terata)." . . . "There are a few species, such as the
siphonochalina coriacea, whose mesodermic cells alon3 inclose
all foreign bodies; so that the cylindrical cells of the endo-
derm merely serve to keep up the continuous passage of
the fluid through the sponge. The phagocytes of both layers
have the power of rejecting insoluble matters, which collect in
the larger efferent canals/' . . . "We are, however, chiefly
concerned here with the fact that the mesodermic phagocytes
are able to digest the substances as well as to inglobe them, and
to reject the insoluble residue."

The nature of the digestive process has, however, remained
obscure. "The bacilli which have been inglobed by leucocytes,"
continues Metchnikoff, "are much more rapidly digested in the
case of mammals that are either naturally refractory, as the
dog and fowl, or have been rendered artificially immune against
anthrax by vaccination, as the rabbit. This fact is shown by
the researches of Hess, as well as my own. It is easy to follow
the digestion of many other microbes within the leucocytes.
Vacuoles are often seen to form around the bacteria that have
been swallowed, just as we have noticed in the digestion of
nutrient material by the protoplasm of the protozoa and the
myxomycetes. I have been able to observe the changes under-
gone by the spirilla of recurrent fever in the leucocytes of
monkeys, as well as those undergone by the vibrio septica3miae
in the leucocytes of immunized guinea-pigs, and those by ery-
sipelas streptococci in the leucocytes of man, etc. We are at
present ignorant of the precise manner in which this digestive
and destructive action is accomplished, and do not even know
whether the substance which kills the microbes is a ferment
or not."

Before submitting this question to analysis the manner
in which the products of digestion, both the nutritional ele-

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 679

ments and the excrementitious products, are disposed of must
be ascertained.

In the sponge the materials rejected by the phagocytes
"and which collect in the larger efferent canals," says Metchni-
koff, are eliminated "through large apertures of crater-like
shape, the walls of which, according to some authors, are fur-
nished with muscular fibers." What have we in the leucocytes
to fulfill this function: i.e., to represent what in the higher
forms constitutes the intestinal canal? It seems to us that this
is particularly well shown in several of the figures in Gul-
land's illustration. In Fig. 10, for instance, a few "fibers"
— our canaliculi — may be seen to project from the inner aspect
of the line which to us represents the practically empty side of
the vacuole. The same arrangement is clearly to be seen in
Figs. 11, 12, 13, and 16.-

If all the foregoing features are considered collectively,
they seem to us to suggest that: —

1. Leucocytes can ingest solid, semisolid, and liquid bodies
through their cell-substance in two ways: (1) by projecting pseudo-
podia which infold or inglobe them; (2) by absorbing them without
projecting pseudopodia.

2. Solids and semisolids are mainly ingested by infolding,
and semisolids and liquids by absorption; but all substances, with
what plasma accompanies them, are collected in a vacuole that sur-
rounds the nucleus and in which the latter lies free; and, at times,
in the smaller vacuoles in the cytoplasm.

3. What physiologically useful bodies are formed in the cell
are mainly elaborated in the nuclear canaliculi and the perinuclear
vacuole, and are collected in the form of granules in the canaliculi.

4. All the functions of the cell are probably governed by the
astrophere.

THE GKANULES AS SECKETOKY PKODUCTS. — Gulland refers
to granules or microsomes in the following words: "Ehrlich
regarded the seven varieties of granules which he described as
being all formed by the cells, and as being either reserve mate-
rial or products for excretion. Hankin [1892-93] took the view
that the acidophile granules were secretory products, contain-
ing 'alexins/ and destined to be secreted into the blood or
lymph. Kanthack, Hardy, and Keng have taken much the

680 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

same view of these special granules. Sherrington has thrown
doubt upon it, and Metchnikoff disputes it and regards the
eosinophile granules as reserve material/' As viewed from our
standpoint, the granules simultaneously represent reserve mate-
rial and products of excretion. These processes are not the
only ones, however, with which leucocytes are concerned.

Bail, to whose investigations we have already referred, is
also stated by Stokes and Wegefarth11 to have observed that,
after the vacuole "in the nucleus" had formed, "the granules
generally disappeared." Furthermore, he noted that upon de-
stroying the staphylococci by adding ether, and diluting the
centrifugalized sediment, the granules showed a dancing mo-
tion, and were seen to leave the periphery of the cell and enter
the surrounding medium. Evidently at least some of the gran-
ules must have been dropped or ejected by the leucocytes, and
their canaliculi thus freed of the impediment their presence
constituted.

This is sustained by a closer examination of the question,
— the purpose of Stokes and Wegefarth's paper, who used in
their researches blood taken from about five hundred persons.
The granules, when observed by them with the aid of artificial
light, "resembled those of the eosinophilic or neutrophilic leu-
cocyte." Kept at the temperature of the room, the latter
showed no activity, but exposure for an hour to a temperature
of 35° C. caused them to become active. The following lines
are quoted from their article: "At times the granular leuco-
cytes become actively amoeboid, and the granules within the
neutrophile exhibit a characteristic activity which might be
compared to the swarming of bees around a hive. The number
of fine granules free in the plasma is perceptibly increased.
The eosinophilic granulations also show a less vigorous trem-
ulous motion, and both" varieties follow the changes in the
direction of the pseudopodia, the protoplasm being thrown out
first, and the granules following. The characteristic dancing
motion of the granules in the neutrophilic leucocyte can be
brought out very plainly by simply mixing the drop of blood
with an equal amount of distilled water containing 1 per cent.

u Stokes and Wegefarth: Loc. cit.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 681

of alcohol. The granules become very active and present a
characteristic picture." . . .

"Can these granules be actually seen to leave the leuco-
cyte? It is certainly not easy to be sure, even after continuous
observation for an hour or more, that one has actually seen one
of these granules leave an amoeboid leucocyte. We think, how-
ever, that we have observed this phenomenon upon several
occasions, both in fresh specimens of blood exposed to 35° C.
and in blood to which 1 per cent, of alcohol has been added."
Farther on in their text they say: "Many fine granules can
be seen in the clear plasma and around the neutrophile, and
it would seem that occasionally a granule leaves the active
leucocyte and becomes free in the surrounding fluid."

Bail's observation, however, that the granules actually
leave the periphery of- the cell has been sustained by other
observers. Gulland refers to this feature of the problem in
the following words: "It has often been remarked that the
large cells show a great tendency to leave their granules behind
them; thus, one might come on a group of granules while the
nearest cell was far away. Ballowitz was, I think, the first to
declare that all or most of these groups of granules were at-
tached to the cell by fine protoplasmic bridges. It is not al-
ways easy to show this." Gulland then says, referring to a fig-
ure in one of his plates (not shown in that reproduced herein),
in which the granules are evidently disunited from the cell:
"In the cell shown in Fig. 31, which was so isolated that there
could be no doubt that all the granules represented belonged
to it, no trace could be made out of threads extending from
granule to granule. They were probably stretched too much
to allow them to be visible."

The absolute separation of the granules from the cell wit-
nessed by Bail finds its complementary confirmation in the
observation of E. B. Sangree,12 who, after patient watching, —
sometimes several hours at a time, — states that he saw "three
granules escape from an eosinophile cell, and wander away until
lost under rouleaux of red corpuscles, after having reached a
distance of some six diameters from the parent-cell." . . .

"E. B. Sangree: Philadelphia Medical Journal, March 12, 1898.

682 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

"While inside the cell," says this pathologist, "these granules
had participated in the constant, though rather sedate, move-
ments of the granule mass, — but owing, doubtless, to the differ-
ence in specific gravity of the containing medium, — instantly
upon emerging from the parent-cell they underwent the wildest
possible gyrations. The first to come out were two attached
pole to pole, and these rolled frantically over each other,
pushed this way and pulled that, all the time oscillating widely
and rapidly, yet constantly and definitely traveling farther and
farther from the cell, until finally lost to view. The single
granule behaved in an exactly similar way. I noticed, too, that
before becoming lost to view the motion of these granules had
become considerably less marked and approximated more that
ordinarily seen in these bodies." If these facts are considered
as a normal sequence to the evidence adduced that the cellular
net-work of fibers represents the secretory system of the leu-
cocyte, it seems permissible to conclude that: —

The granules in leucocytes are the products of an intracellular
metabolic process and represent a true secretion.

THE PHYSIOLOGICAL CHEMISTRY OF LEUCOCYTES. — A
feature which clearly points to the autonomy of the nucleus and
of the net-work of canaliculi in all leucocytes is the uniformity
with which they all stain with similar dyes. The nuclear can-
aliculi and granules and the canaliculi of the cell-substance all
take the aniline dyes, methylene-blue and methyl-green, for ex-
ample: evidence that in all leucocytes the structures mentioned
must find in the oxidizing substance a source of energy as do
other organs. Beginning with the nucleus, with what chemical
body contained in this part of the cell could the oxidizing sub-
stance initiate and sustain a reaction? It is, of course, not
the composition of the nuclear granules that this question in-
volves, but that of what might be termed the nuclear ground-
substance. Foster refers to this substance in the following
words: "There is present, in somewhat considerable quantity,
a substance of a peculiar nature, which, since it is confined to
the nuclei of the corpuscles, and further seems to be present in
all nuclei, has been called nuclein. This nuclein, which though
a complex nitrogenous body is very different in composition and
nature from proteids, is remarkable, on the one hand, for being

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 683

a very stable, inert body, and, on the other, for containing a
large quantity (according to some observers, nearly 10 per cent.)
of phosphorus, which appears to enter more closely into the
structure of the molecule than it does in the case of proteids."
We evidently have, in the nuclein of the nuclear ground-sub-
stance, a body which, as does lecithin in the myelin of nerves,
myosinogen in muscles, etc., enters into active combination
with the oxidizing substance, and the resulting reaction must
necessarily yield functional energy, as elsewhere in the or-
ganism.

The character of the reaction which the simultaneous
presence of nuclein and the oxidizing substance within the
precincts of the nucleus sustain is clearly suggested by the kind
of dyes taken by the canaliculi (both of the nucleus and of the
cell-substance) and the p'erinuclear vacuole. E. T. Williams,13
in a study of the chemical properties of leucocytes, refers to
this feature of the problem in the following words: "The nu-
clei of all three classes stain best with alkaline dyes, as methy-
lene-blue, methyl-green, or dahlia. They are, therefore, acid."
Farther on, he says: "We have seen that all nuclei are acid.
They owe this property, without doubt, to the nuclein which
they contain. Nuclein is acid. When boiled with alkalies it
yields phosphoric acid. Phosphoric acid, it may be remarked,
is the only mineral acid which does not coagulate albumin. It
is the presence of this acid undoubtedly which makes nuclein
acid. According to the experiments of Kossel, quoted by
Vaughan and Novy,14 nuclein, when boiled with acids, yields
certain organic, albuminoid bases, as adenin, sarcin, xanthin,
spermin, and others." . . . "We must conceive, therefore,
of nuclein as some sort of a phospho-albumin whose composi-
tion has not been precisely determined." The source of the
various chemical bodies involved in these processes is shown in
the following lines of Professor Foster's: "The ash of the white
corpuscles is characterized by containing a relatively large
quantity of potassium and of phosphates, and by being rela-
tively poor in chlorides and in sodium. But, in this respect,

" E. T. Williams: Boston Medical and Surgical Journal, Sept. 5, 1901.
14 Vaughan and Novy: "Ptomaines and Leucomaines," 1891.

684 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

the corpuscle is merely an example of what seems to be a general
rule (to which, however, there may be exceptions) that, while
the elements of the tissues themselves are rich in potassium
and phosphates, th'e blood-plasma on which they live abounds
in chlorides and -sodium salts."

The chemical process involved may easily be traced with
the foregoing factors as main elements: The blood-plasma (if
the views already submitted are sound) evidently reaches the
nucleus through the intracanalicular substance of the cell-body;
this is shown by the fact that this substance likewise — though
to a less-marked degree — stains with methylene-blue. Under
ordinary circumstances, according to microscopical evidence,
the perinuclear vacuole is practically collapsed: i.e., its nuclear
wall is more or less close to that of the cell-body. This is well
shown in Gulland's plate, by Figs. 10 and 12. The nucleus
thus bathes in blood-plasma, and its canaliculi become filled
with the latter along with the vacuole. The nuclein of the
nucleus under these circumstances itself bathes in the plasma,
being thus exposed to the action of the latter's oxidizing sub-
stance.

Still, this suggests the presence of a stream of plasma
flowing through the nucleus itself, with the canaliculi as emunc-
tories. The contraction and retraction of the canaliculi — or
reticulum — to which Gulland and others refer represent the
only mechanical device in the cell by means of which the
vacuole can be drained.

These minute vessels probably serve as continuous chan-
nels for the stream of plasma, which contains, besides the
oxidizing substance, the alkaline salts necessary to the intra-
cellular processes. The plasma's oxidizing substance and the
nuclein's phosphorus, thus brought into contact, liberate con-
siderable heat, and the alkaline salts in the plasma then take
part in the reaction to which Williams refers, and which in-
volves, we have seen, the formation of phosphoric acid and
other agencies to which we will presently allude.

We must not lose sight of the fact, however, that nuclein
is derived from nucleo-proteids, and that during the oxidation
process waste-products are formed: we have in the "adenin,
sarcin, xanthin, spermin, etc.," to which Williams refers, a

THE LEUCOCYTES IN ORGANIC FUNCTIONS. . 685

series of catabolic products. This awakens an important patho-
logical feature. We have seen that, when nucleo-proteids un-
dergo cleavage in the organism, the process involved must be
brought to a finish: i.e., to the stage of phosphoric-acid forma-
tion. The penalty, if completion does not attend the series of
reactions, is the presence, in the blood-stream, of the above-
mentioned purin bases, which are now considered, we have seen,
as the source of the so-called "gouty diathesis." Slight insuf-
ficiency of the adrenal system, therefore, by reducing the pro-
portion of oxidizing substance in the blood, must inhibit the
intracellular reactions that we have just outlined, thus giving
rise to this disorder. Or the injudicious use of rich foods, by
surcharging the proportion of nucleo-proteids taken up by the
cells, may lead to the same result though the normal proportion
of oxidizing substance be 'present in the plasma.

Another phenomenon which appears to us elucidated by
the presence of the oxidizing substance of the plasma is the
manner in which worn-out leucocytes are destroyed. As fre-
quently observed by histologists, each of the varieties may be
seen at a given time to become "oxyphile," or oxygen-loving,
and to undergo disintegration. Even the eosinophile leuco-
cytes, which, according to Metchnikoff,15 are unable "to inglobe
foreign bodies, and therefore cannot act as phagocytes," are
destroyed by oxidation. The affinity of these cells for acid dyes
might account for their oxidation, however, and suggest a limit;
but such a limit does not exist, for basophile cells also yield
to the same agency. Indeed, Gulland, referring to a figure in
his colored plate which gives a vivid illustration of a cell un-
dergoing disintegration, describes it as follows: "Degenerated
basophile cell from the mesentery of newt. Methylene-blue."
In other words, an eosinophile is always acidophile, while a
basophile is only acidophile when it is dead or about to die.
We have seen that .methylene-blue stains oxygen-laden media;
hence, the oxidizing substance is evidently the active factor in
the destructive process.

It seems to us that we can conclude from the above data
regarding the physiological chemistry of leucocytes, or white
blood-corpuscles, that: —

» Metchnikoff: Loc. cit., p. 115.

686 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

1. The granules which constitute the secretion of all varieties
of leucocytes are the products of a continuous reaction in the
nucleus, in which the nuclein of its nucleus, the materials ingested
by the cell, and the plasmatic oxidizing substance and alkaline
salts take part. •

2. When a leucocyte becomes functionally incompetent it is
destroyed by oxidation in the blood-plasma.

CLASSIFICATION OF LEUCOCYTES. — We have proceeded as
far as we could with our analysis of the leucocytes as a unit, and
it now becomes necessary to ascertain, if possible, the functions
of the various types which histologists, headed by Ehrlich, have
established with the aid of staining methods.

Kanthack and Hardy16 not only give a clear, though suc-
cinct, outline of the various varieties of cells, but they empha-
size features of the problem which are of special interest to
us. After briefly reviewing the more prominent contributions
to our knowledge of the subject since Wharton Jones's me-
moirs, published in 1846, including the investigations of Kind-
fleisch (1863) and Max Schultze (1865), appeared, they write
as follows: —

"After Max Schultze, no further advance was made or,
indeed, was possible in the histological analysis of the sporadic
mesoblast, until Ehrlich, in 1878, furnished a rational basis
for the use of staining reagents by his far-reaching discovery
that the elective affinity of certain constituents of tissues for
particular stains could be referred to two factors: the chemical
nature of the staining substance employed and — a point too
often neglected by workers who have followed his methods —
the nature of the medium in which the stain is dissolved.17
Ehrlich drew particular attention to the granules, the pos-
session of which characterizes various forms of wandering cells.
These, he divided into five classes, differing either in their
special affinity for bases, acid, or neutral dyes, or in size. The
a or eosinophile granulation colors only with acid dyes; the /3
granulation colors with both acid and basic dyes (amphophile);
the y granulation colors only with basic dyes, and the individual
granules are large; the $ granulation colors only with basic

18 Kanthack and Hardy: Loc. tit., p. 82.
17 All the italics are our own.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 687

dyes, but the individual granules are small; and the e granu-
lation colors only in neutral dyes.

"The nomenclature of the granules was extended to the
cells bearing them. Thus, the various forms of white cells
found by Ehrlich in blood were: I. A small cell free from
granules, to which the name lymphocyte was given, from the
fact that it appears to be developed in lymphoid tissue. This
is the small, non-amoeboid form of Max Schultze. II. A cell
characterized by possessing fine granules and one or several
nuclei. This is by far the most numerous form of white blood-
corpuscles in mammalia, and was found by Ehrlich to be neu-
trophile in man, and amphophile in rabbits and guinea-pigs.
III. The eosinophile cell, or coarsely-granular cell of Wharton
Jones and Max Schultze. It occurs only in small numbers in
the blood of mammalia, but is abundant in the blood of lower
vertebrates. IV. A basophile cell with fine basophile granules
(<$ granulation).

"The mononuclear amoeboid cells of Max Schultze are
apparently grouped with the neutrophile cells by Ehrlich. In
addition to these forms Ehrlich describes a basophile cell with
coarse granules (y granulation), occurring mainly in connective
tissues and also in the blood of frogs, but not in the blood
of mammals. These he calls 'Mastzellen. . . .'

"From what we have said so far it will be seen that the
group of finely-granular blood-corpuscles described by Max
Schultze includes the amphophile and neutrophile and the
finely-granular basophile cells of Ehrlich. Since Ehrlich's work
no contribution to our knowledge of the morphology of the
wandering cells has been made except on points of detail.
Mention must, however, be made of the group of cells recog-
nized by Metchnikoff18 in his treatise on inflammation. The
term 'leucocyte,' originally applied by the French school of
physiologists, is used to designate wandering cells, and the fol-
lowing varieties are recognized: (I) lymphocytes; (II) mono-
nuclear leucocytes with abundant protoplasm and a round
nucleus; (III) polynuclear leucocytes, or 'leucocytes neutro-
philes'; (IV) eosinophile leucocytes."

"Metchnikoff: Loc. cit.

688 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

Our purpose being to ascertain the physiological functions
of the various types, Ehrlich's four classes, by affording def-
inite microchemical limits, will probably prove more useful
than the simplified groupings that other histologists have in-
troduced, and which, by reducing the number of divisions, have
tended to efface landmarks that can serve as clues for research.
We will preserve, therefore, Ehrlich's classification, and try to
ascertain whether the various types of cell do not differ phys-
iologically from one another as they do histologically.

LYMPHOCYTES AND HYALINE CELLS. — The first cell of
the Ehrlich series, the lymphocyte, seems fully entitled to the
position accorded it- by histologists in general: that of a leu-
cocyte in process of development. The cellular substance is
devoid of canaliculi (or net-work of mitoma) and of granules,
although the nucleus itself is supplied with both, and is evi-
dently functionally active. Lymphocytes are considerably
smaller (6 to 6.5 fi ) than leucocytes, and represent less than
one-fourth of the total number of these cells. They are devoid
of amoeboid motion. Hyaline cells have been classed in the
same category, the cell-body being likewise free from granules,
as shown in Gulland's plate, Fig. 1. Both may become active,
however, before complete maturity is reached.

NEUTEOPHILE LEUCOCYTES. — These are extremely impor-
tant members of the leucocyte family, for they represent fully
three-fourths of the white cells of the blood, and constitute
MetchnikofFs main group of phagocytes. They are termed
"neutrophile" by Ebrlich because their granulations stain with
both acid and basic dyes. Their reaction to acid dyes is very
much less intense, however, than is the case with purely acido-
phile cells, according to Kanthack and Hardy. Their gran-
ules are small as compared to those of other acidophile cells.
Though termed "polynuclear" leucocytes by Metchnikoff, the
masses thought to represent as many nuclei, are united by
thin bridges, thus constituting a single nucleus. Especially
is this likely since the only other type of cell deemed phago-
cytic by Metchnikoff is a mononuclear cell. Gulland contends
that no shape of nucleus is invariably associated with granules
of a special kind. It seems evident, therefore, that the phago-
cytic cells are only distinguishable by their affinity for alkaline

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 689

dyes and a slight affinity for acid dyes, and by the concurrence
of these histological properties with small granules.

Kanthack and Hardy, who refer to this leucocyte as a
"finely-granular oxyphile cell," speak of it as follows: "It has
a very limited and precise distribution, for, under normal con-
ditions, it is entirely absent from extravascular spaces, and
occurs only in the blood,19 where it is by far the most numerous
corpuscle, forming 20 to 70 per cent, of the total number of
white corpuscles. The fluctuation in this percentage is prob-
ably due, in the main, to the great periodic variations in the
number of lymphocytes present in the blood. Thus, the effect
of a meal is to cause a considerable increase in the number of
lymphocytes in the blood, and, therefore, a fall in the share
of the total white corpuscles due to finely-granular cells. If
this disturbing factor be* eliminated," continue these investi-
gators, "and the percentage of the finely-granular oxyphile cells
be taken of the adult white corpuscle only, then this is found
to be always very high: in man, 75 to 90 per cent."

Metchnikoff, referring to the phagocytic properties of
these cells, writes as follows20: "Even outside the organism
these amoeboid cells readily inglobe a large number of foreign
particles with which they may come in contact, and they may
often be seen literally crammed with all sorts of granules. Like
the amoeba?, they swallow not only inert bodies, such as gran-
ules of carmine or other substances that are insoluble in the
fluid surrounding the leucocytes, but also a large number of
living organisms." This is merely quoted to emphasize the fact
that the leucocytes differentiated by Ehrlich from all others by
the term "neutrophile" are, irrespective of the form of their
nucleus, the wandering cells which Metchnikoff has shown to
fulfill the physiological function he has termed "phagocytosis."

But the property which these cells so strikingly show, i.e.,
their ability to ingulf or rather ingest substances of all kinds,
seems to us to suggest that they are intrusted with another role
in the body: i.e., its nutrition. In the second chapter we re-
ferred to the fact that Macallum had observed, in sections of
intestines taken from animals first starved, then fed upon

19 All italics are our own.

20 Metchnikoff: Loc. cit., p. 115.

690 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

a substance containing albuminate of iron, free leucocytes
crowded with granules of iron-pigments, in the intestine.
Some of these cells appeared to pass out through the epithelial
cells, while others advanced into the subepithelial elements.
Macallum had also found them in the venules of the villi, the
spleen, etc.

We have just seen the reference of Kanthack and Hardy
to the "considerable increase in the number of lymphocytes
in the blood, and, therefore, a fall in the share of the total
white corpuscles" caused by a meal. Both these two phenom-
ena become normal events instead of a "disturbing factor" if
the process of digestion includes the use of a large proportion
of adult or fully-developed leucocytes to transport various
materials from the intestinal canal to various parts of the or-
ganism. It is evident that under these circumstances the im-
mediate neoformation of lymphocytes, and their rapid growth,
as is probably their wont, to the state of mature cells, becomes
a sine qua non of continued existence.

Overlooking the possibility of such a function, and led by
his own hypothesis to ascribe to intracellular processes the
presence of food-products in the leucocyte, Metchnikoff writes21:
"The digestion of proteid substances by the leucocytes is well
shown by the gradual changes that take place in the muscular
fibers which have been inglobed by leucocytes in cases of acute
muscular atrophy. The presence of peptone in leucocytes, which
has been so often proved by Hofmeister, is sufficiently ac-
counted for by this fact of intracellular digestion, and need
not, therefore, be referred, as done by this author, to an ab-
sorption by these cells of the peptone formed in the alimentary
canal" We need hardly observe, however, that, added to the
foregoing testimony, Hofmeister's view seems sustained.

Indeed, the process to which the peptones owe their pres-
ence within the cell is not difficult to trace, if the latter's me-
chanical functions, as we have construed them, are taken into
account. The presence of peptones within the perinuclear
vacuole being an accepted fact (since it is recognized by both
investigators), the presence therein of substances from which

21 Metchnikoff : Loc. cit., p. 124.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 691

the peptones are elaborated must be accounted for. Metchni-
koff traces these to products of degeneration, as suggested by
his comparison, and perhaps to waste-products of digestion.
Hofmeister's conception differs only from this in implying a
closer or more direct relationship between the leucocytes and
the intestinal contents of their host. In other words, while
Hofmeister associates leucocytes with the process of digestion,
Metchnikoff looks upon them only in the light of scavengers.
That phagocytes may fulfill both roles is obviously suggested,
not only by their own chemico-physiological characteristics,
but also by their itinerary in the system. Both Hofmeister
and Metchnikoff are right, therefore, each in his own way.

In his review of the absorption of proteids Stewart22
writes: "Although a certain amount of egg-albumin and other
native or slightly altered proteid substances can be absorbed
as such by the small and even by the large, intestine, there
can be no doubt that the greater part of the proteids of the
food is first changed into proteoses and peptones. But proteose
and peptones are absent from the blood, and, indeed, when in-
jected into the blood they are excreted in the urine. When
injected in larger amount they pass also into the lymph, from
which they gradually reach the blood again, and are eventually,
as before, eliminated by the kidneys. The clear inference is
that when absorbed from the alimentary canal they must be
changed into one or both of the chief proteids of blood and
lymph (serum-albumin and serum-globulin) in their passage
through its walls. And it has actually been shown that during
digestion of a proteid meal the mucosa of the stomach and
intestine contains proteose and peptone, while none is present
in the muscular coat or in any other organ. They rapidly dis-
appear from a portion of the mucous membrane kept at a tem-
perature of about 40° C. outside the body; but not if it has
been thrown into boiling water immediately after excision, nor
even if it has been heated at 60° C. for a few minutes and then
kept at 40° C. Now, a temperature of 60° C. does not destroy
an unorganized ferment, but kills a living cell. The regenera-
tion of the proteose and peptone must, therefore, presumably

22 Stewart: "Manual of Physiology," fourth edition, 1900.

M

692 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

take place in cells, and the only available cells in this locality
are those which line the intestine, or the leucocytes which
wander hetween them. Accordingly, both have been credited
with the power of absorbing and transforming these sub-
stances."23

If our views concerning the functions of the epithelial
cells of the intestines, as submitted in the seventh chapter, are
sound, they subserve an entirely different function from that
now generally ascribed to them: i.e., that of supplying the
intestinal tract with a secretion calculated mainly to asepticize
the intestinal contents. On the other hand, we showed that
the lymph-follicles, including Peyer's patches, supply leuco-
cytes, formed in the cytogenic area of the follicles (Flemming's
central nodule) to the intestinal cavity through the fenestrated
membrane overlying each follicle. As our inquiry did not
afford evidence to the effect that all these leucocytes served
to insure destruction of pathogenic bacteria, we stated that
some of them carried out this function. Indeed, we had good
ground for this limitation, for we had already referred to the
iron-laden leucocytes observed by Macallum and we were led
later on to allude to those charged with the return of bilirubin
to the circulation. That the leucocytes supplied to the intes-
tinal canal by the cytogenic follicular areas, include some — and
probably a large proportion — whose functions it is to ingest
proteids with the iron and bilirubin, then re-enter the intes-
tinal wall by way of the villi, is very likely. To the various
agencies thus incorporated in the organism can now be added
that referred to by Metchnikoff in the sentence: "The presence
of peptones in leucocytes which has been so often proved by
Hofmeister." While this contributes further evidence to show
that our conception of the whole process must be poised upon
solid premises, it also suggests that leucocytes ingest proteids,
and not peptones, from the intestinal canal, because peptones
are the terminal products of the digestion of proteids.

If leucocytes ingest proteids, these must accumulate in
their perinuclear vacuole and find their way into the nuclear
canaliculi. These cells being freshly supplied to the intestinal

All italics are our own.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 693

canal from the follicles, the proportion of blood-plasma in them
must be limited when, laden with proteids, they enter the ven-
ules of the villi to find their way to the portal vein. Even in
this vessel they must again find a dearth of oxidizing substance,
for we have seen that this channel is essentially venous. We
must not lose sight of the fact, however, that potent additions
to its contents are obtainable here: the spleno-pancreatic in-
ternal secretion, i.e., trypsin, to which the plasma of arterial
blood and dextrose may be superadded when the precincts of
the hepatic artery, i.e., the hepatic lobules, are reached.

If these cells do take up proteids and other bodies utilized
in nutrition or in the building up of various organic structures,
their own canaliculi, i.e., those of the cell-substance, must serve
as the eliminatory channels. In other words, proteids ingulfed
by the leucocyte must be submitted to a process of digestion
in the nucleus and its vacuole, and the products be passed out
as granules. This elevates leucocytes to the rank of glandular
organs, but we must not overlook the fact that glands in gen-
eral supply their secretion in the form of granules. Eeferring
to the parotid, for instance, Professor Foster speaks of the
secretion as "generally in the form of granules" and of the
"granules" which in the submaxillary gland "may obscure the
nuclei/' The granules of the pancreas, of the intestinal epi-
thelial cells, etc., are also familiar examples. Indeed, all these
granules only differ from those of leucocytes in being less com-
plicated molecularly and smaller.- They seem to us fully to
represent a true, cellular secretion.

What is the nature of the neutrophile's secretion, i.e., the
composition of its granules? Milroy and Malcolm24 state that
the finely-granular amphophile (or neutrophiles) granules "are
usually taken to be proteid in nature," and refer to the fact
that Sherrington had suggested that they might be "of nucleo-
proteid nature": a view which their own researches confirm.
Under the action of alcohol kept at boiling-point, neither fine
nor coarse oxyphile granules were dissolved; ether also at boil-
ing-point gave similar results. These agents being then used
successively, the granules remained practically unaltered: a

24 Milroy and Malcolm: Journal of Physiology, vol. xxv, 1899.

694 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

fact which leads the authors to conclude that the granules
cannot consist of fat or lecithin. Weak alkaline solution at 115°
to 120° C. almost' entirely removed the granules from the
finely-granular cells, "but the most striking feature was the
persistence of two structures, the nuclei and the coarse oxy-
phile granules." Solutions o"f sodium carbonate (1/2 to 1 per
cent.), followed by careful washing, almost entirely removed
the fine oxyphile granules in from one to sixteen hours, while
the coarse ones were left. Oxalic acid (0.4 per cent, in alcohol,
then 1 V4-per-cent. watery solution) entirely removed the small
granules, a few of the coarsely-granular oxyphile cells contain-
ing pink-stained granules, while others were vacuolated. As
a result of these tests (which should be read in extenso in the
original paper) Milroy and Malcolm write as follows: "The pos-
sibility of both types of granules consisting of the same kind
of organic matter either differently bound or with organic salts
attached in such a way as to alter the solubilities is certainly a
strong one. That it is not simply albumin or globulin appears
evident from the comparatively insoluble character of both
types of granules, but especially the coarse oxyphile ones.
Again, the fact that the fine granules are not only oxyphile,
but also basophile, supports the view that they are composed
of a complex proteid substance.25 . . ." The concordance of
these facts with those previously recorded appears to us con-
clusive.

Milroy and Malcolm's researches not only seem to us to
give neutrophile granules their own identity (though showing
a distinct kinship to the larger acidophile granules), but also
to emphasize the fact that these minute masses of proteid sub-
stance represent the end-result of the intracellular process that
occurs during the journey of the leucocytes from the intestinal
villus to the general circulation via the portal and hepatic
vessels.

Is it only in the cells that the reactions which serve to
convert proteids into assimilable products occur? The investi-
gations of Milroy and Malcolm will greatly assist us in eluci-
dating this question.

28 The italics are our own.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 695

In their first article on the "Metabolism of Nucleins"26
these investigators say, in the course of a review of the metabo-
lism of the nucleins under physiological conditions: "When
nucleins are taken by the mouth, the first change that they
undergo in the alimentary tract is a simple solvent one in the
stomach, and that only to a very slight degree. They are never
split up into their constituents. They are easily broken up,
however, by the pancreatic secretion2"1 into an organic phos-
phorus-holding acid (not nucleic acid) and albumose or pep-
tone. The important points to notice are that the phosphorus
is still in organic combination, and that neither ortho- nor
meta- phosphoric acid is so formed. It is probable that the
organic phosphorus-holding acid so formed is similar to thymic
acid. It forms soluble compounds with albumose and peptone,
and is, in all probability, so absorbed. After absorption the
bodies derived from the nucleins cause a well-marked leuco-
cytosis, and the excretion of phosphoric acid in the urine is
increased. Whether a hypoleucocytosis always precedes the
hyperleucocytosis is difficult to say. Almost all the writers on
this subject have emphasized the fact that, on giving nucleins
by the mouth, the phosphoric-acid excretion in the urine is
increased; but they have omitted to show that this excretion
cannot ~be accounted for by the phosphorus taken in the form
of nucleins, there being really more phosphorus excreted by
the kidneys than was present in the original nucleins."

Again, as a result of a series of experiments, Milroy and
Malcolm are led to the following conclusions among others:
"1. The digestion products of nuclein-holding tissues, nuclein
and nucleic acid, cause, on being absorbed, a temporary leuco-
cytosis, which is accompanied by a rise in the P205 excretion
above that derivable from the absorbed phosphorus. These
alterations are especially well marked after giving nucleic acid.
2. The alloxuric bodies are excreted in excess, after nucleic acid
has been given, and in all probability also after large doses of
nuclear-holding tissues or nucleins, although in our experi-
ments, owing to the small amount of thymus taken, there was
no distinct increase. 3. The uric-acid excretion after nucleic

26 Milroy and Malcolm: Journal of Physiology, vol. xxiii, No. 3, July 26, 1898.

27 All italics are our own.

696 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

acid was only slightly, if at all, increased. We were exceedingly
anxious to give larger doses of nucleic acid, but were unable to
do so because of certain rather disagreeable symptoms (severe
muscular tremors) which arose after the larger quantity had
been given."

The augmented phosphoric-acid excretion to which the
authors refer, and which they state cannot be accounted for
by the phosphorus taken in the form of nucleins, has doubtless
suggested to the reader as primary cause the increased func-
tional activity of the adrenal system induced by the phosphorus
ingested: an interpretation sustained by the presence of severe
muscular tremors, "which arose after the larger quantity had
been given." Of course, phosphorus here acts like any other
toxic as a stimulant, the anterior pituitary body responding
to the effects of organic poisons as well as those foreign to the
system as a chemical entity.

Still, this involves the necessity of showing that leucocytes
are themselves the seat of the enhanced metabolism and the
source of the excess of phosphoric acid to which the muscular
tremors are due, in accord with our previous statements, to
that effect. Again, if, as we have suggested, the granules rep-
resent the leucocytic secretion, an excess of granules must
occur under the influence of the stimulation of the adrenal
system induced. That such is the case is shown by the follow-
ing casual remark of Stokes and "Wegefarth,28 who, as stated,
based their studies of the free granules derived from leucocytes
upon examinations of blood taken from about five hundred
persons: "In perfectly fresh specimens the granules were not
numerous, but they seemed somewhat increased in patients who
had been taking tonics or various alcoholic drinks."

This, in turn, involves a query as to the manner in which
the anterior pituitary body becomes primarily stimulated when
nucleins are taken in excess, for it would seem that, locked up
in the perinuclear vacuole of the leucocytes, their phosphorus
could not influence the adrenal system through the blood-
stream. This would doubtless hold were the intracellular
process to cease at any time, but, as this must begin as soon

28 Stokes and Wegefarth: Loc. cit.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 697

as the cells enter the hepatic capillaries, after acquiring therein
their adequate supply of oxidizing substance, their normal pro-
duction of granules must start at once. An inordinate propor-
tion of nucleins in the food soon supplies the blood-stream,
through the agency of the cells, with an abnormal quantity of
these minute phosphorus-laden bodies. These at first give rise
to excessive functional activity, including among other signs
the "severe muscular tremors" to which Milroy and Malcolm
refer, coupled with an excess of P205 production. Persisted
in, however, the excessive (relative) ingestion of nucleins brings
on, as do other toxics, adrenal insufficiency, which, by entailing
a reduced production of oxidizing substance and trypsin upon
which the physiologically perfect intracellular reactions mainly
depend, correspondingly lowers the efficiency of the cleavage-
processes. This means, instead of the physiologically perfect
granules which, we have seen, Milroy and Malcolm found to be
proteid in nature, an accumulation in the blood of proteid
toxalbumins.

In their first paper, the above-mentioned investigators
draw attention to the two decomposition products considered
"as more or less characteristic signs of the decomposition of the
nucleins, viz.: the alloxur bases and phosphoric acid/' If our
conception as outlined in the preceding paragraph is justified,
these alloxuric bases are products of inadequate metabolism,
while phosphoric acid is the product of perfect metabolism.
Uric acid having likewise been considered by us as a product
of the complete process, a rise of alloxuric excretion cannot
occur along with excessive phosphoric-acid production. That
our conclusion, based mainly on Horbaczewski's work, was war-
ranted, is shown by what Milroy and Malcolm term "points
of special importance" as results of a series of experiments,
namely: "1. There is no doubt that the P205 excretion is
increased even when very small doses of thymus are given. 2.
^Relatively, also, the P205 is increased in proportion to the
nitrogen. 3. With the small amount of thymus taken there
was practically no appreciable alteration in the excretion of
the alloxuric bodies, either absolutely or relatively to the total
nitrogen or total P205." All this serves to emphasize another
feature of the problem: i.e., that phosphoric acid is the proto-

698 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

type of uric acid as a product of perfect or physiological intra-
cellular metabolism, and that the phagocytic leucocytes which take
up nucleo-proteids from the intestinal food-products are the seat
of the reactions through which these bodies are converted into as-
similable products, i.e., peptones.

Although we have only dealt so far, as regards the intra-
cellular processes with which nucleo-proteids are concerned,
with neutrophile leucocytes, these are not alone the seat of
reactions which, normally performed, end in the production of
uric and phosphoric acids. Indeed, we have seen that all leu-
cocytes contain nuclein in their "nucleus" — a fitting name
under the circumstances, and the physio-chemical process re-
viewed only typifies that which occurs in all varieties of leuco-
cytes. Wherein the neutrophile cells are distinguishable, how-
ever, is in their ability as phagocytes to take up nucleo-proteids
from the intestine, and to break them up, by means of the
trypsin and oxidizing substance subsequently absorbed by them,
into peptone and an organic compound containing phosphorus.

How are the various bodies, the presence of which this
suggests, utilized? The presence of pancreatic secretion in the
intestine, and of the spleno-pancreatic secretion in the portal
vein, would suggest that the leucocytes must be carriers of
carbohydrates: an important question when we consider the
leading functional role which myosinogen plays in muscular
contraction. Dextrose, formed from glycogen, itself in turn
a product derived from starches, forms part of a chain of events
which would, in a measure, have to occur within the cell itself.
That such is the case is suggested by the investigations of
Zabolotny,29 who found that phagocytes devoured particles of
starch-paste and digested them: features which led this in-
vestigator to conclude that "the presence of an amylolytic fer-
ment in the phagocytes cannot be doubted." But Zabolotny
likewise states that when leucocytes ingest starch they become
iodophile. This, as is well known, has been termed by Eanvier
and other physiologists the "glycogen reaction."

Foster, referring to this question, says: "In the case of
many corpuscles at all events, we have evidence of the presence

29 Zabolotny: Russian Archives of Pathology, April, 1900.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 699

of a member of the large group of carbohydrates, comprising
starches and sugars, viz.: the starch-like body glycogen. . . .
This glycogen may exist in the living corpuscle as glycogen, but
it is very apt, after the death of the corpuscles, to become
changed by hydration into some form of sugar, such as maltose
or dextrose." Indeed, he furnishes us complementary evidence,
alluding to the cellular proteids in the following sentence:
"One of these proteids is a body either identical with or closely
allied to the proteid called myosin, which we shall have to study
more fully in connection with muscular tissue." We have
shown that myosin is the post-mortem product of the action of
what remains of oxygen in the plasma upon myosinogen, and
that this is the cause, of rigor mortis. Professor Foster says,
in this connection: "And we have reasons for thinking that
in the living white corpuscle there does exist a body identical
with or allied to myosinogen, which we may speak of as being
in a fluid condition, and which, on the death of the corpuscle,
is converted, by a kind of clotting, into myosin, or into an allied
body which, being solid, gives the body of the corpuscle a
stiffness and rigidity which it did not possess during life." All
this seems to us to clearly suggest that these leucocytes, in the
light of our views, supply the muscle-cells of the entire organ-
ism with myosinogen.

Still, our analysis alone so far points to the neutrophiles
— by far the most numerous leucocytes in the blood-stream —
as the ones upon which this great function would devolve. We
deemed it necessary, therefore, to control this conclusion by
showing that excessive muscular exercise, by creating a demand
for myosinogen in the cells of all muscles, — skeletal, cardiac,
vascular, etc., — engenders a leucocytosis in which the neutro-
philes prevail. We were fortunate enough to find a study of
this subject by E. C. Larrabee,30 who writes as follows: "The
paper is based on a study of the blood of four of the contestants
in the Boston Athletic Association's Marathon race of 1901.
This is a road-race of about twenty-five miles (40 kilometers),
held each spring. The severity of the contest will be apparent
when it is said that the winner — not included in my four — •

R. C. Larrabee: Journal of Medical Research, Jan., 1902.

700 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

covered the distance in less than two and one-half hours. This
is about ten miles an hour, about as fast as an ordinary man
rides his bicycle for pleasure. . . . The blood of these four
cases [counted by the author, assisted by Dr. W. H. McBain]
before the race 'showed no abnormalities. The percentage of
polymorphonuclear neutrophiles may perhaps run a little high,
but this is to be expected in active young men in the best pos-
sible physical condition. After the race the blood was taken
immediately, within five minutes from the actual finish. In
every case a leucocytosis was found, varying from 14,400 to
22,200. The differential count showed that the increase was
mainly in the polymorphonuclear neutrophiles"

That the exciting cause of the leucocytosis was the increase
of waste-products, which in turn stimulated the adrenal system,
hardly needs to be dwelt upon. Vagal influence incited to in-
ordinate activity and controlled the organs charged with the
genesis of these particular cells, while the inordinate oxidation
processes started by the overactive adrenals in all tissues ac-
counts for the general leucocytosis which the word "mainly"
implies.

Myosinogen being a member of the globulin group of pro-
teids, the other members of this group should be represented
among the cell's products, particularly fibrinogen found in the
blood-plasma in association with serum-globulin and serum-
albumin. That such is the case seems evident. Stewart31
alludes to the sources of nucleo-proteid in the following words:
"In shed and clotting blood, the only possible sources of nucleo-
proteid, so far as we know, are the corpuscles and the blood-
plates. The red corpuscles we may at once dismiss, for, al-
though they contain a small amount of nucleo-proteid, not only
do they remain intact under ordinary circumstances during
coagulation, but there is the strongest evidence, as has already
been pointed out, that they do not make any essential contri-
bution to the process. We have left over the leucocytes and
the platelets. The latter are said and the former are known
to yield nucleo-proteids when they are broken up in the labora-
tory; and it is highly probable that from both, but especially

81 Stewart: Loc. cit.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 701

from the white corpuscles, nucleo-proteid is liberated in the
first moments after blood is' shed, and that this nucleo-proteid
is then changed into fibrin-ferment."

The relationship between the cellular nucleo-proteids and
fibrin which this quotation suggests finds itself sustained by
Eanvier,32 who, alluding to the role of granules in the forma-
tion of fibrin, says: "Free granulations, which we found in the
blood besides the red and white corpuscles, are very numerous;
they were termed 'elementary vesicles' by Zimmermann. In
a preparation of human blood examined after rouleaux of red
corpuscles have formed these granulations may easily be ob-
served, two varieties being distinguishable. The first are spher-
ical, small droplets of fat; the others are angular or variable
in shape, and appear at first as if they were fragments of white
corpuscles, but differ from the latter in not being altered by
water. They are stained by iodine, but remain colorless in car-
mine solutions. We will see that these are also the character-
istics of fibrin." After reviewing the phenomena that attend
coagulation, and exposure by washing of the fibrinous net-work,
he says: "When this preparation is examined and magnified
four hundred to five hundred diameters, the fibrinous retic-
ulum can be seen distinctly, and is disposed in a very interesting
manner: From an angular granulation, from 1 to 10 ft in di-
ameter, very tenuous fibrils start divergingly, then subdivide,
to unite with other fibrils, in order to form a delicate net-work.
The preparation is covered with these small net-works, each
of which has its central granulation. . . . The granula-
tions which serve as centers for each diminutive fibrinous retic-
ulum have the same microchemical properties as the fibrils."

A normal deduction which seems to us to impose itself
in this connection is that fibrin is to the blood what myosin
is to the muscle-cells, i.e., a post-mortem product due to arrest
of the oxidation process which during life is insured by the
oxidizing substance — the supposed "fibrin-ferment." In other
words, it not only becomes evident that peptones, myosinogen,
and fibrinogen are products of the same variety of leucocyte, the
neutrophile, and therefore chemically similar when liberated from

»2Ranvier: Loc. cit., 213.

702 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

the latter, but also that fibrinogen subserves the same purpose in
the blood that myosinogen does in muscle: i.e., it supplies it with
its primary source of functional energy.

True, the solubility of fibrin differs somewhat from that
of myosin, but 'this is probably due not to a difference in the
molecular structure of fibrinogen as against that of myosinogen,
but to the influence of the medium in which the granules are
dropped by the leucocyte. Indeed, the ashes of fibrin contain
a larger proportion of calcium and magnesium phosphate than
does myosinogen.

Another conclusion which now seems to us warranted is that
the neutrophile leucocytes are the agencies which take up proteids
in the intestinal canal, and, after submitting them to a process in
which various physio-chemical bodies taken up by them in the portal
and hepatic systems take part, distribute the products to every part
of the organism^ including the blood itself.

Such being the case, the proteids, inclosed in their diminu-
tive carriers, should not be found in the blood of the portal
system. Professor Foster writes, in this connection, after re-
ferring to the difficulties attending the experimental determina-
tion of the path taken by proteids: "Bearing this in mind, we
may state that all observers are agreed that peptone is absent
from chyle, or at least that its presence cannot be satisfactorily
proved. On the other hand, while some observers have suc-
ceeded in finding peptone in the portal blood after food, but
not 'during fasting, many have failed to demonstrate the pres-
ence of peptone in the blood either of the portal vein or of the
vessels at large, even after a meal containing large quantities of
proteids." Again: "If an artificial circulation of blood be kept
up in the mesenteric arteries supplying a loop of intestine
removed from the body, the loop may be kept alive for some
considerable time. During this survival a considerable quan-
tity of peptone placed in the cavity of the loop will disappear:
i.e., will be absorbed, but cannot be recovered from the blood
which is being used for the artificial circulation, and which
escapes from the veins after traversing the intestinal capil-
laries. The disappearance is not due to any action of the blood
itself , for peptone introduced into the blood before it is driven
through the mesenteric arteries in the experiment may be re-

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 703

covered from the blood as it escapes from the mesenteric veins.
It would seem as if the peptone were changed before it actually
gets from the interior of the intestine into the interior of the
capillaries/733 If our views are sound, the peptones are hidden
in the neutrophile leucocytes which the follicles of the segment
continue to produce. These cells, after migrating over the serum-
lathed (and thus constantly asepticized) epithelial surface, and
ingesting their burden, find their way into the villi's venules and
thence into the mesenteric channels.

If the foregoing analysis and the various deductions sub-
mitted are sound, the neutrophile leucocytes must fulfill a role
in the organism commensurate with their relative proportion
in the blood-stream. Indeed, the following conclusion seems
to us to have been sustained: —

The neutrophile leucocytes, through the intermediary of their
granules, the ft granulations of Ehrlich, supply (1) the blood and
all tissues (excepting the nervous system) their nutritive elements:
i.e., peptones; and (2) the muscles and the blood, the compounds
from which they obtain their mechanical energy when exposed
to the action of the oxidizing substance: i.e., myosinogen and
fibrinogen.

EHRLICH'S EOSINOPHILE LEUCOCYTES. — Metchnikoff does
not grant Ehrlich's eosinophiles phagocytic properties, these
cells being unable to inglobe foreign bodies. Again, as empha-
sized by Ehrlich, the granules of these cells are only stainable
with acid dyes, the other varieties either taking only alkaline
dyes or simultaneously, as does the neutrophile just reviewed,
both acid and alkaline dyes, etc. This marked affinity for acids
obviously gives the eosinophile an identity of its own, while
its non-phagocytic functions as clearly separate it from the
finely granular cell just reviewed, which is essentially phago-
cytic. Ehrlich's eosinophile is usually considered under the
heading of "coarsely-granular oxyphile cell."

These cells only represent from 2 to 4 per cent, of all the
leucocytes in the blood-stream, but this proportion is rapidly
increased during disease. Kanthack and Hardy, in the article
previously quoted, describe them as follows: "The coarsely-

83 All italics are our own.

704 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

granular oxyphile cell, or eosinophile cell, varies in size in dif-
ferent animals, not only absolutely, but relatively to the dimen-
sions of the other classes of cells. In man it is larger than
either the hyaline cell, the finely-granular oxyphile cell, or the
finely-granular basophile cell. In the rat, rabbit, and guinea-
pig, on the other hand, it is smaller than the largest hyaline
cells, but larger than the finely-granular oxyphile and basophile
cells.

"The nucleus is typically an elongated body bent to form
a horseshoe. In the rat the arms of the horseshoe are carried
so far round that in film preparations the ends often overlap,
giving to the nucleus the appearance of a circle with a large
hole in the center. Sometimes the nucleus is lobed; but we
are inclined to regard this appearance as being largely due to
the stresses to which the nucleus is subjected when the cell is
dying. In the living cell at rest, when it is spherical, the shape
of the nucleus, so far as it can be determined by the disposition
of the cell-granules, is a simple horseshoe or crescent. A dis-
tinct nuclear net-work is present.

"Cell-granules. — The cell-granules are relatively large,
spherical, or slightly ovoid bodies, and are sharply marked off
from the cell-substance by their very high refractive index, which
is so great that in fluid preparations the granules have a 'brill-
iant, greenish luster.54 The cell-substance in which they are im-
bedded has the appearance of a clear, transparent, structureless
jelly. The intensity of the oxyphile reaction of these granules
differs in different animals, but is always high. Thus, it is very
high in the case of the granules of man, these staining with
eosin dissolved in 95-per-cent. alcohol. . . . The granules
also stain with weak acid dyes, such as Orange G, haBmatoxylin,
and sodium sulphindigotate. Ehrlich-Biondi's mixture (washed
out with 95-per-cent. spirit) colors these bodies brown-purple,
and the 'neutral' mixture (washed out with water) stains them
a very intense purple. Corrosive sublimate increases the oxy-
phile reaction, as does also heat when applied to the dried
film."

Gulland found Heidenhain's iron-h&matoxylin extremely

34 All italics other than those of the side headings are our own.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 705

valuable to counteract "the bright refraction of the granules"
which "blinds the eye to the presence of the threads" (our
canaliculi). The granules are stained opaquely in shades of
black and gray. He was thus able to ascertain that the gran-
ules varied greatly as to size, the smallest granules lying close
to the astrophere and the larger at the periphery, the arrange-
ment pointed out by Heidenhain and shown in Figs. 10, 12, and
16 of Gulland's plate. In the newt's blood, as already stated,
"these cells are markedly amoeboid, and have the habit of
throwing out circular pseudopodia, which are often connected
to the main part of the cell only by a very delicate thread."
Gulland illustrates this feature in Figs. 3 and 6 of his plate,
and states that "it is evident that the threads are often broken
through and the spherical portion of the cell-body set free, as
the blood contains a large number of them." He also refers
to the fact that, "when the eosinophile cells are found degen-
erated in blood or pus examined in the fresh state, the granules
are always in the Brownian movement."

In our study of the granules of neutrophile cells we re-
ferred to the chemical analysis of Milroy and Malcolm and to
various points of dissimilarity between these cells and the
coarse oxyphiles now in question. Considered from the stand-
point of the latter, these investigations showed that, while
neither alcohol nor ether, nor both of these agents used suc-
cessively, produced alterations in either variety, the failure of
the latter process excluded the possibility of their consisting of
fat or lecithin. Weak alkaline solutions at about 120° C. caused
(a feature referred to by the authors as striking) the removal
of practically all the granules of the finely-granular cells (the
neutrophiles), and "persistence of two structures, the nuclei
and the coarse oxyphile granules." Acetic acid in alcoholic
solution and oxalic acid caused partial removal of both gran-
ules, but "sodium ethylate in alcoholic solution removed the
fine oxyphile granules almost completely and only affected the
coarse ones to a slight extent."

The authors, while concluding that the granules might also
be nucleo-proteid in nature, i.e., similar to those of the neutro-
phile cells, account for the discrepancies in the results of their
analyses by the following argument: "The fact that weak acid

706 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

solutions dissolve both types of granules at least partially is
not against the view that they are nucleo-proteid in nature,
because these bodies are more easily soluble in weak acid solu-
tions than almost any other complex proteid. The fact that
some granules 'are undissolved, while others are removed, is
probably due to the fact that the former have undergone coagu-
lation, while the latter have been rapidly fixed, although it may
be also due to the nature of the salts which are combined with
the proteid."

Still, the very high refractive index to which Kanthack
and Hardy and Gulland refer is not characteristic of the neu-
trophile granules, and this seems to us to testify against an
absolute functional similarity between them and the granules
of the eosinophiles. Indeed, with the plasma as excipient for
the oxidizing substance, we can as readily account for the
presence of the "brilliant, greenish luster" witnessed by the
above authors as we can for the phosphorescence of the pho-
togenic organs of lightning-bugs: i.e., by the simultaneous
presence of phosphorus and oxygen. This seems to us to indi-
cate that we are dealing with a nucleo-proteid body, as Milroy
and Malcolm contend, but with one richer in phosphorus than
that forming the neutrophile granules.

What are the functions of the eosinophile leucocytes in the
organism? The high percentage of phosphorus in their gran-
ules suggests the possibility of their being lecithin-carriers;
but we have seen that the investigations of Milroy and Mal-
colm clearly show that this organic body is absent. L. F.
Barker,35 of Baltimore, noted the presence of iron in the gran-
ules of the eosinophile leucocytes, — a point which he thinks
may be of some value in determining the significance of the
leucocytic granulations, — but we cannot consider them as the
cells intrusted with transportation of iron from the intestine,
for they are not phagocytic. Indeed, it has now become evi-
dent that the neutrophiles are intrusted with this function, for
Macallum used albuminate of iron. The intestinal leucocytes
of his previously starved animals evidently took this substance
up as they would the proteids of their usual food. Barker's

85 L. F. Barker: Johns Hopkins Hospital Bulletin, Oct., 1894.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 707

observation, however, adds another link to the chain of evi-
dence which unites the eosinophiles to the neutrophiles, for,
in addition to being both nucleo-proteid carriers, they now
become also iron-carriers. By tracing the itinerary of this iron
we may, therefore, obtain a clue to the true identity of its
cellular host.

The phagocytes seen by Macallum to ingest the albuminate
of iron, being assimilated to those charged at all times with
the duty of selecting proteids from the intestinal foodstuffs, it
becomes a question as to where they can part with their iron
in order to facilitate its absorption into the haemoglobin mole-
cule, of which, as is well known, it forms an important con-
stituent. From the intestine the iron is carried to the portal
system, thence into the hepatic lobule. It must be here that
the phagocytic leucocytes must take part in some process re-
lated to the elaboration of hemoglobin, for we have seen on
page 335 that in the spleen the leucocytes are formed in situ,
pass out into the pulp-tfhannels, take up the iron-pigment
(probably that of disorganized red corpuscles), and carry it to
the liver. Again, and for reasons which are there given, we
were led to conclude (page 339) that bilirubin and iron were
used to build up the hemoglobin in the lobular (hepatic) capil-
laries. The liver, therefore, seems to receive iron from both
directions — intestine and spleen — a normal mechanism when
we consider that the liver's blood passes almost directly to the
heart, and thence to the lungs.

How do the eosinophile (non-phagocytic) leucocytes ac-
quire their iron? We can hardly imagine that when the splenic
or intestinal leucocytes reach the hepatic lobule their contents
or any part thereof is disgorged to enable another cell to ap-
propriate it. Indeed, there is not the slightest evidence that
such a process occurs, although the eosinophile has already
been shown to contain not only iron, but also the other main
constituents of the neutrophile cell. There exists a physiolog-
ical process, however, through which the eosinophile can ac-
quire all the attributes of the latter: i.e., by mitosis, a mode
of cell-multiplication known to apply to leucocytes and par-
ticularly to neutrophiles. Gulland refers to this feature in the
following lines: "The cells which one sees dividing or about

708 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

to divide have generally the appearance of medium-sized hy-
aline cells, with a relatively large rounded nucleus and a com-
paratively small cell-body in which the mitoma is not easily
made out. But tKere is no doubt that cells with horseshoe-
shaped nuclei [the eosinophiles] divide, and that the nuclei
may even advance as far as the spirem stage without altering
their shape. Cells with more markedly polymorphous nuclei,
as, for instance, the ordinary oxyphile cells, certainly divide also,
but they seem generally to go through a preliminary rest-
ing stage in which the polymorphous nucleus returns to the
rounded form."

In Gulland's plate, Figs. 3 and 6, which refer to eosinophiles
from newt's blood, graphically portray a secondary process
through which these cells can subdivide, or rather yield a por-
tion of their substance. In 3, a spherical pseudopod is in the
act of being formed; in 6, three similar masses appear, the
lowest of which is on the point of being separated by the
mother-cell. Referring to the bridges that connect net-works
of granules with basophile leucocytes, Gulland remarks: "I
have little doubt that when that stage is reached [he associates
the phenomenon with a supposed process of degeneration] these
bridges are torn across and the granules are actually left be-
hind. This forms an exact parallel to what happens in the
eosinophiles of the newt's blood."

It thus becomes evident that recognized cytological phe-
nomena sustain the conclusion that neutrophile leucocytes are
the parent-cells of eosinophile leucocytes, and that eosinophiles can
part with segments of their cell-substance.

But does the process of neutrophilic mitosis actually occur
in the liver? M. Duval,36 in his study of the haematopoietic
functions of this organ, refers to the proportion of the red to
the white corpuscles in the blood of the portal vein as com-
pared to that in the hepatic vein, and writes: "Researches in
this connection give as result: 1 white corpuscle to 746 red in
the portal vein, and 1 white corpuscle to 170 red in the sub-
hepatic veins. This difference can only be due to a production
of white corpuscles in the liver or to a destruction of red cor-

M. Duval: "Cours de Physiologic," p. 200.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 709

puscles." That red-corpuscle destruction is a function of the
spleen is sustained by the presence "in the spleen-pulp," using
Foster's words, of red corpuscles "in various stages of disor-
ganization, some of them lying within the substance of large
colorless corpuscles, and, as it were, being eaten by them."
The presence of blood-pigments in the liver has been thought
to indicate that red corpuscles were destroyed in this organ;
we have seen, on the contrary, that it is the seat of a recon-
structive process of which hemoglobin is the product. Though
the liver may be a seat of destruction for red-cell fragments,
the likelihood that any., entire corpuscle leaves the capillaries
of the hepatic lobules to penetrate the cells is so remote that
it can be left out of question. On the other hand, we have seen
that these capillaries are the seat of the more important proc-
esses connected with the blood. It seems evident to us, there-
fore, that the liver, owing in part to the inordinate temperature
of its lobular channels (106° F.; 41.9° C.), is also the seat of
the mitotic process.

"At a certain period," write Bohm, Davidoff, and Huber,37
"the embryonic blood consists principally of nucleated red cells,
which proliferate in the circulation by indirect division. The
colorless blood-cells, the development of which is not yet fully
understood, appear later. It is possible that they also are ele-
ments of the blood-islands, which do not contain any haemo-
globin. In a later period of embryonic life the liver becomes a
blood-forming organ. Eecent investigations have shown, how-
ever, that it does not take a direct part in the formation of
the blood, but only serves as an area in which the Uood-corpus-
cles proliferate during their slow passage through its vessels.
The Hind, sac-like endings of the venous capillaries seem to be
particularly adapted for this purpose, as in them the blood-
current stagnates, and it is here that the greater number of
blood-cells reveal mitotic figures. The newly-formed elements
are finally swept away by the blood-stream and enter the gen-
eral circulation (Van der Stricht, 92; v. Kostanecki, 92, III)."

Gulland likewise states that the eosinophile cell is derived
from the "finely-granular acidophile" (the neutrophile), and

37 Bohm, Davidoff, and Huber: Loc. cit., p. 168.

710 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

the latter is itself traced back to the lymphocyte. "The transi-
tion-forms between the finely-granular and the coarsely-gran-
ular acidophile cells are seen much more frequently in the
bone-marrow than in the blood," says this investigator, "and
it seems certain that both from this source and from mitotic
division the main source of the eosinophile cells is in the bone-
marrow." That there is ample margin for our view that mitosis
may occur in the liver is also suggested by the following addi-
tional lines: "They must arise elsewhere, however, in abun-
dance,™ for Schaffer39 and I40 have shown that they are present
in the thymus and in lymphatic glands before either bone or
bone-marrow is properly formed at all, and Engel41 has seen
them in the chick's blood on the fifth day of incubation. In
the transition-forms (see Figs. 2, 8, 11) there is little in the
general shape of the cell and nucleus to distinguish them from
the preceding stage." All the evidence tends to show, there-
fore, that the process of mitosis through which eosinophile leuco-
cytes are formed from neutrophile leucocytes, is carried on in the
capillaries of the hepatic lobules, though it can also occur elsewhere
in the organism.

We have referred to the direct path which leucocytes can
follow from the liver to the heart and thence to the lungs. If
eosinophiles are formed in the liver, therefore, the lungs should
show indications of the presence of these leucocytes. Proof that
such is actually the case is obtainable with the aid of pathol-
ogy: i.e., the significant fact that in several pulmonary diseases
eosinophile cells are to be found in the sputum. Teichmiiller,42
for instance, has not only found this to be the case in pulmo-
nary tuberculosis, but considers an increase of these cells favor-
able from the standpoint of prognosis. In asthma, though a
non-ulcerative process is present, eosinophiles are to be found
in abundance in the sputum, and Gollasch43 states that they are
connected with the formation of the Charcot-Leyden crystals.

88 The italics are our own.

» Schaffer: Centralbl. fur die med. Wissen., 1891.
"Gulland: Journal of Path, and Bacteriol., 1894.
41 Engel: Archiv f. mikr. Anat., vol. Ixiv, 1894.

"H. Lenhartz: "Manual of Clinical Microscopy," advance pages of transla-
tion by H. T. Brooks, Post-graduate, July, 1902.
"Gollasch: Fortschritte der Med., vol. 1889.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 711

Lenhartz44 states that "it is not improbable that the majority
of cells designated as 'alveolar epithelia7 are variously altered
forms of leucocytes. The protoplasm very frequently shows
fine or coarsely-granular fatty metamorphosis, which is charac-
terized by the strongly refractive index."

The irregularity of the granules, and the manner in which
they form fibrin, as described by Eanvier, and the peculiar
color of the granules is recalled by the following description
of the Charcot-Leyden crystals by Lenhartz: "The Charcot-
Leyden crystals are delicate, very sharply pointed octahedra
which occur in very variable size. They present a sometimes
water-clear, transparent, sometimes a slightly yellowish-green,
Ehine-wine color; they occur either isolated or in dense col-
lections, which here and there are jumbled together, or in
uniform rows, following the mucous shreds." The same author
also says: "The crystals were first found in the sputum by
Friedreich in croupous bronchitis. On the other hand, Leyden
had drawn attention to their frequent occurrence in asthmatic
expectoration."

The association with various pulmonary diseases obviously
suggests that their presence is pathological, whereas we con-
sider their presence in the lung as normal, and their elimination
in their recognizable form as an accompaniment of the morbid
state. That such is the case is shown by the fact emphasized
by Lenhartz that: "The longer the asthmatic subject is free
from paroxysms, — that is, the more time allowed for the forma-
tion of the crystals, — the more densely the spirals are studded
with these crystals."

While all these facts sustain our opinion that the lungs
show ample evidence of the presence in them of eosinophile
cells and of their granules, their identity as offsprings of
the neutrophiles should be demonstrable here, as elsewhere,
through their chemical properties. Indeed, their identity as
daughter-cells of neutrophile leucocytes does not disappear
even in the lungs, for both acids and alkalies can dissolve them,
while the test common to both neutrophile and eosinophile
granules, i.e., insolubility in alcohol, is also applicable here.

** Lenhartz: Loc. cit.

712 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

Lenhartz not only confirms this assertion by saying, in refer-
ence to the crystals: "They are readily dissolved in warm
water, acids, and alkalies, but are insoluble46 in alcohol"; but
we also, it seems to us, can consider, as confirmation of our
interpretation of the identity of the granules from which the
crystals were derived, his statement that: "fixation of the air-
dried preparation for one hour in absolute alcohol and subse-
quent staining with Chenzinsky's eosw-methylene-blue solution
also gives very good results."

All these facts further confirm the origin of the eosino-
phile leucocytes from the liver, for there is no other path that
would have brought them to the lungs. They also seem to us
to clearly show that, after their formation by mitosis in the liver,
eosinophile leucocytes are carried to the pulmonary lobules.

What are the physiological functions of eosinophile leuco-
cytes? In the ninth chapter (page 481) we suggested that the
nervo-vascular mechanism of the lungs was composed of two
autonomous, though correlated, systems: the respiratory and
bronchial. The respiratory system, according to our concep-
tion, is composed of (a) the pulmonary lobules, in the walls of
which the blood is oxygenated; (b) the pulmonary artery and
its subdivisions, which bring venous blood, adrenal secretion,
and hepatic sugar to the capillaries of the lobules; (c) the pul-
monary venules and veins, which return the arterialized blood
to the heart. The bronchial nervo-vascular system, on the
other hand, has for its purpose to supply the oxidizing sub-
stance, which, by meeting the hepatic sugar contained in the
blood of the lobular capillary, liberates the necessary energy
upon which the local functions depend. It thus becomes evi-
dent that the lobule is the seat of the respiratory process, and
that all correlated organs of the respiratory system, from the
nasal cavities down to the terminal bronchial ramifications,
are but accessory structures.

This question has already engaged the attention of pathol-
ogists, including Virchow, Wagner, and Cohnheim. Lenhartz's
view is fully sustained by our own investigations, however,
when he says: "It is not improbable that the majority of the

These italics are Dr. Lenhartz's.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 713

cells designated as 'alveolar epithelia' are variously altered
forms of leucocytes. The protoplasm very frequently shows
fine- or coarsely- granular fatty metamorphosis, and is charac-
terized by the strongly refractive index" Again, while Len-
hartz expresses his belief that the positive identification of
the "alveolar epithelia" is "extremely difficult," he states that
he understands thereby "the large oval or round polygonal
cells, three to six times as large as a white blood-corpuscle,
which are found in almost every sputum. The usually large
cell-body is coarsely granular, and contains one or several
vesicle-like nuclei." The true identity of epithelium of the
alveoli and, therefore, of the lobule of which they form part,
now seems clear, if interpreted in the light of the data we have
submitted: The cells to which Lenhartz refers, i.e., the lolular
epithelial cells, are aggregates of the polynuclear neutrophiles and
of the daughter-cells of the latter, the eosinophiles.

We have seen that the neutrophiles start from the intes-
tinal canal; that Macallum and L. F. Barker found leucocytes
gorged with iron in this region; and, finally, that some bilirubin
at least is recovered from the intestine — obviously, now, by leu-
cocytes. We have traced the latter from the intestinal canal,
through the portal system, liver, hepatic veins, heart, thence
to the alveoli. After giving the formula of haemoglobin, Pro-
fessor Foster writes: "It will thus be seen that haemoglobin
contains, in addition to the other elements usually present in
proteid substances, a certain amount of iron; that is to say, the
element iron is a distinct part of the haemoglobin molecule, a
fact which of itself renders haemoglobin remarkable among the
chemical substances present in the animal body." Kanthack
and Hardy noted, as previously stated, that "in fluid prepara-
tions the granules have a brilliant, greenish luster" — a charac-
teristic of fine haemoglobin crystals. Haemoglobin is readily
soluble in blood-serum, as are the granules, we have seen.
Ether coagulates haemoglobin; it caused, in Milroy and Mal-
colm's experiments,46 the granules to lose a part of their re-
fractive power, even when boiling ether was used. The proteid
constituents of the granules of the neutrophiles, myosinogen
and fibrinogen, belong to the globulin group.

" Milroy and Malcolm: Loc. cit., p. 112.

714 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

This recalls our statement (page 440) in respect to the
manner in which the heart-muscle is supplied with its myo-
sinogen. We then said, referring to the present analysis:
"Paradoxical as the statement may seem, we were led to con-
clude that the minute granules referred to on page 433" — a
general outline of the prevailing views concerning the histology
of the myocardium, in which the minute pigment-granules,
easily seen therein microscopically, are mentioned — "were act-
ually supplied to the heart through the intermediary of leuco-
cytes. These cells were found to migrate from the liver (also
through the hepatic veins) to the inferior vena cava, where they
meet the adrenal secretion and proceed with it to the right
ventricle."

We can now readily understand how the granules of the
neutrophiles are supplied to the muscle-fibers by quoting an-
other of our own statements (page 434) concerning the dis-
tribution of fluids in the intimate structure of the heart:
"Fluids can penetrate through the maze of cellular tissue to
the bare muscular fibers; the sheaths that include the columns
or chains of muscular bundles afford a peculiar system of cana-
lization through which the liquids can easily gain access to them.
The canals — the lacunae of Henle — are the intervals between
the columns of secondary bundles, or their sheaths, rather,
which are placed in longitudinal apposition. Schweigger-Seidel
and Kanvier having observed that interstitial injections of col-
ored substances penetrated the lymphatic vessels; the lacunae
have been considered as adjuncts, or extensions, of the latter."
In this sense, therefore, the Thebesian channels are adjuncts of
the lymphatic system, for it is through their intermediary that
the lacunae of Henle are supplied with myosinogen granules and
— a feature we wish to emphasize — their nutritional peptones
and their fibrinogen. All of these jointly supply the heart with
its working energy, when acted upon by the oxidizing substance
of the blood-stream.

The bulk of the venous blood which enters the heart is
sent, we have seen, along with its adrenal secretion and its leu-
cocytes— neutrophile and eosinophile — to the lungs, Virchow,
Friedreich, Leyden, Cohnheim, Wagner, Lenhartz, and other
investigators having found them in the sputum, and histology

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 715

having demonstrated their presence in the alveoli. Again, the
path for these leucocytes from the intestine to the true respira-
tory areas of the lungs is comparatively direct: features which
distinctly suggest that the protective functions in the respira-
tory tract resemble those in the intestinal canal, as regards the
eosinophilic granules and the phagocytic functions of the neu-
trophiles, both kinds of cells being present, as we have seen.
Of course, the intestinal lymph-follicles being the source of
these cells, another arrangement prevails in the pulmonary
lobules: i.e., that to which we referred on page 713, to the effect
that the lobular epithelium per se is an aggregate of neutro-
philes and eosinophiles.

We can readily understand, now, why the eosinophiles de-
plete themselves of their granules in the alveoli: i.e., to dis-
solve them in the plasma prior to their absorption by the red
corpuscles. Indeed, the reticular structure of red corpuscles,
"the same as that of colorless blood-corpuscles,"47 observed
by Louis Elsberg in 1879, seems to us to present all the feat-
ures that have led us to consider as canaliculi the threads that
constitute this reticulum in the latter cells. That the red-
corpuscle "granulations," "platelets," or "haematoblasts" de-
rived from them are mere droplets of oxidizing substance
poured out through these canaliculi is shown by the fact that
the characteristic affinity (requiring oxygen and alkaline salts,
according to Ehrlich) for methylene-blue again appears: i.e.,
as manifested by the deep-blue stain which we found in other
structures, the axis-cylinder, neuroglia, etc., and in the leuco-
cytes themselves. This fact was also noted by Litten.48 That
the droplets pass out through centrifugal channels in the cell,
and that the latter presents the general mechanical character-
istics of leucocytes, is also suggested by the researches of
Hirschfeld,49 who observed that the "blood-plates" are first
seen as circular disks occupying the center of the cell, then
move very slowly toward the periphery, and finally drop out
of the cell through a minute aperture, which closes up again.

*7 M. L. Holbrook: "Proceedings of the American Microscopical Society,"
vol. 1894.

"Litten: Deutsche med. Wochenschrift, Nov. 2, 1899.
"Hirschfeld: Virchow's Archiv, vol. clxvl, 1901.

716 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

As the "plate" leaves the cell the external portion gradually
increases in size and is connected with the rest by a thread.
Several of these may leave the cell together from different parts
of the periphery. He also found them to stain with methylene-
blue and h&matoxylin. It is evident that we have in the red
corpuscle a diminutive nucleated sponge capable of absorbing
haemoglobin from the serum of the pulmonary alveoli and of
dealing it out in the blood-stream as needed by the plasma.
This feature and the functions of the leucocytes just
described introduce complemental factors in the respiratory
process as we interpreted it in the second chapter. It now
seems to us that the whole process is summarized in the fol-
lowing conclusions: —

1. The true respiratory areas in the pulmonary lobules are
composed of the alveolar endothelial plates (the non-nucleated epi-
thelium) and groups of eosinophile leucocytes (the nucleated epithe-
lium) interposed between the former.

2. The eosinophile cells are the bodies in which hcemoglobin
is formed from the proteids, bilirubin, and iron, absorbed by their
parent-cells, the neutrophiles, in the intestinal canal.

8. When the eosinophile leucocytes reach the alveoli from the
liver via the heart they assume an orderly arrangement and alter
their shape, so as to form the alveolar epithelium.

4. The eosinophile leucocytes supply the adjacent plasma with
their hemoglobin, and the latter is absorbed by the underlying red
corpuscles along with the oxygenized secretion (oxidizing sub-
stance).

5. Leucocy to genesis being governed by the adrenal system, the
main factors of the above respiratory process, the production of
eosinophile cells and of adrenal secretion, are thus dependent upon
the functional integrity of this system.

6. The neutrophile leucocytes which accompany the eosino-
philes migrate from the capillaries of the pulmonary artery to the
perialveolar lymphatics, and supply the interlobular structures
with their nutritional and functional elements: i.e., peptones,
myosinogen, and fibrinogen.

7. During certain diseases neutrophile and basophile leuco-
cytes may also penetrate into the alveoli and be found in the
sputum.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 717

THE BASOPHILE LEUCOCYTES. — These cells show the di-
vision into two groups, "finely-granular" and "coarsely-gran-
ular/' which characterizes those just reviewed. They seem to
differ from the latter in every other way, however, for, while
these are amoeboid, basophiles are not considered so by most
histologists. Gulland — rightly, in our opinion — contends that
they are, the variations of shape that they show and the man-
ner in which they are scattered throughout the body being
adduced as main reasons. The nucleus is round, oval, or kid-
ney-like; is less clearly differentiated from the cell-substance;
and stains with much greater difficulty than that of the neu-
trophile.

As regards their distribution, Ehrlich and Eanvier found
them in the peritoneal, pleural, and pericardial cavities, and
also in the connective tissue, but, as emphasized by Kanthack
and Hardy, the cells in the connective tissue differ somewhat
in shape and size from those in the three cavities mentioned.
The latter investigators also found the coarsely-granular baso-
philes "exceedingly numerous in connective-tissue spaces, where
they form sometimes an almost complete sheath for the lymph-
capillaries." Their distribution furthermore resembles that of
the eosinophiles in the fact that they are relatively very scarce
in the blood.

The chemical characteristics of the basophile granules is
suggested by a curious phenomenon which is especially notice-
able in animals, and to which Kanthack and Hardy refer in the
following words: "The unstable, or explosive nature of the
coarsely-granular basophile cells in certain animals is one of
their most remarkable characters. In the rat and mouse per-
fect preparations of these cells may be very easily made, but
in the guinea-pig and rabbit they can be preserved only with
the most rapid fixation by heat or absolute alcohol. In these
animals the mere exposure of the coelomic fluid to the air, or
to contact with a cover-slip for a few seconds, is sufficient to
cause their complete disappearance. Cells characterized by
great instability have been described elsewhere in astacus50 as
the 'explosive' cell of that animal, and the basophile cells of

60 Hardy: Journal of Physiology, Noa. 1 and 2, vol. xiii.

718 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

the guinea-pig and rabbit might, with equal justice, be desig-
nated the explosive cells of those animals." A familiar histo-
logical fact will -'suggest the relationship between such a cell
and the oxidizing substance. Berdal,51 quoting Ranvier, says:
"The action of oxygen or of the air may be observed in an
extremely simple way: A lymph preparation which has served
for the examination of amoeboid movements is carefully sur-
rounded with paraffin and set aside for thirty-six hours. If,
at the end of that time, the lymphatic cells are examined, all
will be seen to have reassumed the spherical form and to no
longer project pseudopodia. Eemoval of the paraffin and rais-
ing of the disk so as to admit a small quantity of air will suffice
to cause the amoeboid motion to recur." The explosive nature
of the coarsely-granular basophile cell can only be due to the
one cause: the presence of large proportion of phosphorus,
both in its nuclein and granules.

In their paper upon the free granules derived from leuco-
cytes Stokes and Wegefarth review the investigations of H. F.
Miiller, of NothnageFs clinic.52 This observer found them both
in diseased and normal blood, and describes them as "highly
refractive, round or dumb-bell shaped bodies, which show a
dancing, molecular movement, but no independent motion."
When mounted in 1-per-cent. osmic acid "the reaction for fat
does not occur," nor can they be dissolved by acetic acid or
ether. An important feature in connection with our inquiry is
that Miiller is recorded as stating that "he does not consider
them as Ehrlich's neutrophilic granules escaped from leuco-
cytes" and that "the neutrophilic granules are dissolved by
dilute acetic acid, while the bodies which he has studied are not
dissolved by this acid." This is in perfect accord with the
chemical analyses of Milroy and Malcolm, who found that acids
dissolved eosinophile granules, and with the observations of
Lenhartz in respect to those found in sputum. Stokes and
Wegefarth further emphasize the dissimilarity of basophiles
from acidophiles in general, as viewed from our standpoint,
when they say, doubtless referring to Ranvier's interpretation
of the purpose of the granules of white globules: "They are

» Berdal: Loc. cit., p. 275.

"H. F. Miiller: Centralbl. fiir allg. Path. u. path. Anat., vol. viil, 1896.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 719

not concerned in the formation of fibrin, since they remain out-
side of the fibrinous net-work or are only accidentally attached
to it." We thus have evidence to the effect that basophiles are
different from neutrophiles, both chemically and functionally.

What is the nature of these granules? Miiller is stated to
disbelieve "that they are true particles of fat, since they do not
give a reaction with osmic acid," while he is credited with the
opinion "that they may be bodies resembling fat, but which
fail to show the osmic-acid stain." Indeed, the persistence
with which this characteristic appearance is noted by investi-
gators is noteworthy. Thus, Kolliker,53 Ranvier,54 Bizzorero,55
von Limbeck,56 and Hayem57 are referred to by Stokes and
Wegefarth as having also observed bodies resembling fat-gran-
ules in the blood of normal human beings, those of the last-
named investigator and others described by Schiefferdecker and
Kossel58 also as fat-granules being thought by Miiller to be
identical to those observed by him. That they are fat-Zifce, as
thought by Miiller, but not fat, seems to us quite clear.

Miiller, we have seen, refers (as do other investigators) to
the fact that these granules are "highly refractive." As this
sign also attends eosinophilic granules, it would appear to have
but little differential value; such is not the case, however,
when this property is jointly considered with the osmic-acid
reaction, for we have here the two main distinctive signs of
myelin. "It is extremely refringent," writes Berdal, referring
to the latter; and he also alludes to the familiar fact that
"myelin treated with osmic acid" stains black.

Still, if the granules are composed of myelin, the active
constituent of the latter, lecithin, should be present, since we
found this body not only in the myelin of nerves, but also in
that of the neuron and the interior of the dendrites. That
some granules do contain this body is evident, inasmuch as
Foster, in his review of the physiological chemistry of white
corpuscles, writes: "Next in importance to the proteids as con-

's3 Kolliker: "Handbuch der Gewebelehre des Menchen," 1867.
84 Ranvier: "Traite" Technique d'Histologie," 1875.
55 Bizzorero: "Handbuch der kiln. Med.," 1887.

66 Von Lunbeck: "Grundriss einer klinischen Pathologie des Blutes," 1896.

67 Hayem: "Du sang et de ses alterations anatcmiques," 1889.
" Schiefferdecker and Kossel: Gewebelehre, Bd. xi, 1891.

720 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

stant constituents of the white cells come certain fats. Among
these the most conspicuous is the complex fatty body, lecithin"
As we now know that the nuclei of all leucocytes are similar in
composition, this can only apply to their granules.

This involves the necessity of differentiating between the
two kinds of granules present, the acidophiles (neutrophiles and
eosinophiles) and basophiles. Professor Poster points to this
distinction, it seems to us, when he says: "next in importance
to the proteids; etc." The basophilic granules are evidently not
composed of nucleo-proteids: a fact which eliminates the acido-
phile cells and their granules. Indeed, we have confirmatory
evidence that it is not the latter which contain lecithin in the
following allusion to both kinds of acidophile granules by
Milroy and Malcolm: "The fact that neither alcohol nor ether
dissolves the granules excludes the possibility that they consist
of fat or lecithin."

How do basophile cells acquire their lecithin-building con-
stituents? As is well known, emulsified fats also penetrate the
intestinal villi, but, instead of entering as do nucleo-proteids
into the venules, they enter the lymphatic circulation directly,
by way of the lacteals. Are they absorbed by the villi, and then
by the lacteals, or are they also taken up by leucocytes and
carried into the latter? Inasmuch as the lymph contained in
the lymphatic vessels is itself crowded with leucocytes similar
to some of those found in the blood-stream, we must first ascer-
tain whether these leucocytes in any way leave the lymphatic
circulation in the intestine as they evidently do when the
lymph-ducts open into the general venous system at the junc-
tion of the internal jugular and the subclavian veins on both
sides.

It may prove useful, however, to first recall the fact that
the so-called "chyme" and "chyle" represent the same liquid,
i.e., the lymph, and that these terms were suggested by a tem-
porary quantitative difference in the constituents of the lymph
in the mesenteric lymphatics, which are greatly increased dur-
ing the process of absorption. Again, it may also be well to
refer to the fact that lymph is merely blood-plasma practically
devoid of red corpuscles, but containing lymphocytes and
coarsely-granular basophile leucocytes, and, besides, minute fat-

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 721

globules which show an active Browrdan movement, though
covered with a thin layer of protoplasm to prevent their run-
ning together as fat-drops are wont to do.

"Lymph also contains fibrin/7 writes Professor Duval, "but
a fibrin which is slow to coagulate spontaneously; indeed, lymph
removed from the vessel begins, after a quarter of an hour or
so, to harden into a colorless jelly, from which a reticulated mass
soon becomes separated as does blood-fibrin undergoing coagu-
lation." The cause of this delay seems to us but a natural
result of the absence of both varieties of acidophile leucocytes,
while the slow coagulation is but a normal consequence of the
fact that the lymph is plasma which, though derived from the
blood, and deprived of neutrophile leucocytes, nevertheless con-
tains more or less fibrinogen. "More. or less" is applicable in
a double sense here, for lymph taken from the lymphatics of
the extremities, for instance, coagulates more rapidly than that
taken from some vessels of the trunk. Lymph also contains
serum-albumin and serum-globulin in reduced quantity, and
relatively very small proportions of urea, neutral fats, and
sugar, as compared to the blood. Such is not the case, however,
as regards inorganic salts, which are present in the lymph and
blood in similar proportions.

What is the nature of the process through which fats are
taken up from the intestine and their itinerary in the blood-
stream until they are used for the elaboration of basophile
granules?

Stewart,59 referring to the nature of this process, says:
"The common view has long been that the greater part of the
fat escapes decomposition, and, after emulsification by the soaps
formed from the liberated fatty acids, is absorbed as neutral
fat by the epithelial cells covering the villi. If an animal is
killed during digestion of a fatty meal, these cells are found
to contain globules of different sizes, which stain black with
osmic acid, and dissolved out by ether, leaving vacuoles in the
cell-substance, and are therefore fat. It has always been diffi-
cult to explain how droplets of emulsified fat could get into
the interior of the epithelial cells, and yet it certainly passes

69 Stewart: Loc. cit., p. 370.

722 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

into them, and not between them." Foster also refers to this
feature in the following quotations: "It has, it is true, been
maintained by some that they [the neutral fats] pass between™
the cells, and not into them, but the evidence is distinctly
against this view." Alluding to the rods of the striated border,
he says: "We may imagine that the globules pass into the cell-
substance by help, in some way, of these rods through amoeboid
movements comparable with the ingestive movements of the
body of an amoeba; but we have no positive evidence to support
this view." . . . "Within the columnar cell, the fat may
be seen, both in osmic-acid preparations and in fresh living
cells, to be disposed in globules of various sizes, some large and
some small, each globule placed in a space of the protoplasmic
cell-substance. It does not follow that the fat actually entered
the cell exactly in the form of these globules; it may be that
the fat passes the striated border in very minute spherules,
which, reaching the body of the cell, run together into larger
globules; but whether this is so or not we do not know."

All this seems to pointedly suggest that the epithelial cells
take up minute fat-particles to submit them to some local proc-
ess. Bohm and von Davidoff61 emphasize the feature of the
process when they say, referring to the fat-globules in the
epithelial cells: "It seemed most probable that protoplasmic
threads (pseudopodia) were thrown out from each through its
cuticular zone, which, after taking up the fat, withdrew with it
again into the cell. But when it was shown that, after feeding
with fatty acids or soaps, globules of fats still appeared in the
epithelial cells as before, and that the chyle also contained fat,
the hypothesis was suggested that the fat is split up by the
pancreatic juice into glycerin and fatty acids, and that the
fatty acids are then dissolved by the bile and the alkalies of
the intestinal juice only again to combine with the glycerin to
form fat within the epithelial cells." Stewart further states
that "when an animal is fed with fatty acids they are not only
absorbed, but appear as neutral fats in the chyle of the thoracic
duct, having combined with glycerin in the intestinal wall,
and the epithelial cells contain globules of fat, just as they

80 All italics below this word are our own.

81 Bohm and von Davidoff : Loc. cit., p. 256.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 723

do when the animal is fed with neutral fat." It seems clear,
from these and other available data, that the epithelial cells of
the villi capture fat-globules from the intestinal contents and if
need le convert this fat into neutral fats.

We have seen, however, that the villi also take up the
leucocytes which ingest proteids. It is important, in this con-
nection, to clearly distinguish the two mechanisms involved
one from the other. Bohm and von Davidoff testify to the
passage of such cells into the villi by stating: "Leucocytes are
sometimes found within the epithelial cells, but more usually
between them, and, according to Stb'hr, when seen in these
positions are in the act of migrating into the lumen of the in-
testine." Stewart, however, remarks, in this connection: "Leu-
cocytes have been asserted to be the active agents in the ab-
sorption of fats. They have been described as pushing their
way between the epithelial cells, fishing, as it were, for fatty
particles in the juices of the intestine, and then traveling back
to discharge their cargo into the lymph. This view, however,
is erroneous." It is erroneous, but only in one respect, in our
opinion, i.e., their direct connection with the absorption of
fats, for, as stated, the functions of these wandering cells is
to carry proteids to the intravillous venules. These do not,
therefore, enter the intravillous lacteals. But other leucocytes
penetrate the latter with the neutral fat-globules. "Although
the leucocytes do not aid in the absorption of fat from the
intestine" says Stewart, "they appear to take it up from the
epithelial cells, conveying it through the spaces of the net-work
of adenoid tissue that occupies the interior of the villus, to dis-
charge it into the central lacteal, where it mingles with the
lymph." The distinction we suggest in this connection appears
to us to remove the confusion that exists in the literature of the
subject. Briefly, our conception of the process is as follows:
While the leucocytes which ingest proteids from the intestinal food-
stuffs pass between the epithelial cells and enter the venules, the leu-
cocytes which ingest fats only carry the latter from the inner limits
of {he epithelial cells to the interior of the lacteal, and deposit them
therein.

Professor Foster expresses the opinion that the number
of leucocytes found to contain any appreciable degree of fat is

46

724 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

too small to account for the amount of fat absorbed. But it
seems to us that, if these only transfer the fat from the epi-
thelial cells to the lacteals, the to-and-fro excursions of each
cell and the enormous number of villi over which the food of a
single meal has. to pass amply compensate for the apparent
paucity of cells. An additional reason adduced by Professor
Foster is the fact that the administration of a saline such as
magnesium sulphate "produces effects the very reverse of ab-
sorption," these cells being present in unusual numbers. As
interpreted from our standpoint, and as will be shown when
the action of purgatives- is studied, these agents greatly increase
the flow of serum into the intestinal canal by reflex action and
crowd its walls with defensive agencies, including leucocytes.
We are dealing here, not with a normal process, such as is the
fat-absorbing function, but with an engorgement by protective
elements.

The axial contraction and relaxation which occurs in the
villus to cause its various contents to gravitate into their re-
spective channels may, however, be instrumental in causing fat-
particles that have already passed the epithelium to enter, not
only the lacteal, but the venules also, fat-globules, or what pur-
ported to be such, having been found in the blood. This feat-
ure, and the manner in which fat-globules reach the general
lymphatic circulation, are exemplified in the following lines by
Stewart: "The contraction of the smooth muscular fibers of
the villus and the peristaltic movements of the intestinal walls
alter the capacity of the lacteal chamber, and so alternately
fill it from the lymph of the adenoid reticulum and empty it
into the lymphatic vessel with which it is connected. By this
kind of pumping action the passage of fat and other substances
into the lymphatics is aided. In the dog no fat is absorbed
by the blood-vessels, except perhaps a small quantity in the
form of soaps; it nearly all goes into the lacteals, and thence
by the general lymph-stream through the thoracic duct into
the blood."

An interesting feature now asserts itself. Again are all
the basophiles poured into a channel, the left subclavian vein,
which empties into a large venous trunk, the superior vena
cava, which in turn carries them to the right heart. We have

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 725

practically a repetition of the process witnessed in the case of
the neutrophiles with the exception of the passage through the
liver, the basophiles being directly transmitted to the heart,
and therefore likewise to the pulmonary lobules.

Indeed, we find our view that the granules of these cells
are myelin amply confirmed in this connection, for, while Len-
hartz alludes to the neutrophilic granules found in colorless
sputum, and to the fact that the sputum of asthmatics contains
"numerous eosinophile and quite numerous basophile leuco-
cytes," he also refers, when reviewing the characteristics of
the cells observed microscopically in this connection, to cells
that "present considerable coarse granulation," and remarks:
"Here, however, the spherules show a decidedly dull appear-
ance, resembling that seen in crushed nerve-substances. For
this reason they were designated by Yirchow as myelin drop-
lets'' Moreover, Lenhartz62 publishes a colored plate, one of
the figures of which represents what he terms with E. Wag-
ner "heart-lesion cells" found in the lungs. The granules of
these, he says, "are similar to myelin, and, occasionally, more
refringent than fat."

Evidently the nervous system is supplied with its myelin
precisely as the muscles are supplied with their myosinogen.
Kanthack and Hardy state that the coarsely-granular cells are
not only rare, but completely absent from the blood, while the
finely-granular are relatively rare in the latter except some
hours after a meal. "To say that these cells are found in the
body only in very small numbers, being confined to the blood
and scanty even there," remark these investigators, referring
to the finely-granular basophiles, "is probably only equivalent
to saying that we are at present very ignorant as to their his-
tory, distribution, and significance. However, since we find
this cell in the blood, but do not find it either in the coelomic
fluid or in the interstitial spaces of the tissues (except, per-
haps, in those of the mucous coat of the alimentary canal), we
must, until further facts are forthcoming, regard it as the baso-
phile cell of the blood." Still, they refer to the coarsely-gran-
ular cells as "occurring only in the extravascular spaces" and
in the "interstices of the connective tissue."

62 Lenhartz: "Mikroskopie und Chemie am Krankenbett," 1900.

726 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

It seems to us that we have in the finely-granular cell the
freshly-laden cell on its way, when in the blood, to its normal
habitat, the connective-tissue spaces, where their granules de-
velop into their normal size. Indeed, Gulland alludes to a
basophile cell, represented in one of his plates, of which he
says: "The leucocyte was seen to have been fixed in the act of
passing through a narrow hole between two bundles of connective
tissue." This cell is furthermore accompanied by a large num-
ber of granules held 'in a net-work of fibers, which the cell
appears to drag along in its travels. It is of this variety of
leucocyte that Gulland says: "It has often been remarked that
these cells show a great tendency to leave their granules be-
hind them," etc., and the one which, in the portion of this
section devoted to a review of the general properties of leuco-
cytes, stands pre-eminently as a free-granule producer.

That the cell in migrating from the vessels and passing
through connective-tissue interstices has for its purpose to
reach the myelin spaces of nerves is clearly suggested by the
manner in which the lymphatic spaces are arranged even in the
finer ramifications. "In its course Henle's sheath is not ap-
plied against the nerve-tube," writes Berdal63; "there is between
it and the nerve-tube a space occupied by lymph-plasma which
has for its purpose to supply the cylinder-axis with its nutri-
tion." If this statement is interpreted from the standpoint of
our views, it is more than nutrition, but myelin-granules, which
insinuate themselves — through chemical affinity, doubtless —
wherever there is need for them: i.e., wherever their consump-
tion has been greatest. "Medullated nerve-fibers, when exam-
ined, frequently present a beaded or varicose appearance," say
Pick and Howden64; "this is due to manipulation and pressure
causing the oily matter to collect into drops, and in consequence
of the extreme delicacy of the primitive sheath even slight
pressure will cause the transudation of fatty matter, which
collects in drops of oil outside the membrane." Evidently we
are not dealing with a fixed mass, but with one made up of
extremely mobile particles, which to us, at least, represent as
many basophile granules. If the space between Henle's sheath

«« Berdal: Loc. cit., p. 152.

°*Pick and Howden: Loc. cit., p. 1117.

THE LEUCOCYTES IN ORGANIC FUNCTIONS. 727

contains lymph supplied with myelin-granules, what is the dif-
ference between a nerve thus supplied with its primary source
of energy and a "medullated" nerve? None, it seems to us.
Such a nerve as a non-medullated nerve does not exist, therefore;
since a nerve deprived of myelin, if interpreted from our stand-
point, would become a mere plasma-channel.

The pathway to all nerves becomes greatly simplified down
to their terminal ramifications, it seems to us, in the presence
of Gulland's observation concerning the passage of a basophile
leucocyte "through a narrow hole between two bundles of con-
nective tissue." Indeed "the lymphatic vessels do not exist as
distinct channels in the interfascicular connective tissue," says
Berdal. "There is no lymphatic vessel in the thickness of the
nervous bundles nor in the sheath surrounding them (Ran-
vier). The circulation of the lymph, in the interior of the
bundles, is insured by the arrangement of the interfascicular
connective tissue, the meshes of which represent lymphatic
cavities communicating with the vessels of the interfascicular
tissue through holes in the lamellar sheaths." On the whole,
therefore, it seems to us permissible to conclude that: —

1. The physiological function of the basophile leucocyte is to
convert fats derived from the intestinal foodstuffs into myelin-
granules, and to distribute the latter to all parts of the nervous
system, including the brain.

2. The basophile leucocytes thus supply the entire nervous sys-
tem with the lecithin-containing compound which combines with the
oxidizing substance of the blood-plasma of axis-cylinders, neuroglia
fibrils, etc., in the production of nervous energy.

LEUCOCYTES AND THEIR RELATIONS TO VITAL AND FUNC-
TIONAL PROCESSES. — The varieties of leucocytes reviewed rep-
resent, it seems to us, the only three adult functional types,
the lymphocytes and hyalines being, as stated, immature cells.
This does not mean, however, that the latter are functionless;
indeed, we have seen that when an active process is initiated
these younger cells rapidly increase in the blood and intestinal
tract to replace the large number of their elders that have dis-
appeared to take part in this process. Their development must
be extremely rapid, therefore, and their number commensurate
with the number of adult leucocytes brought into action,

728 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

whether this be to distribute (1) the neutrophilic peptones,
myosinogen and fibrinogen granules; (2) the eosinophilic hem-
oglobin granules; or (3) the basophilic myelin granules.

On page 668 we said: "The closer is the intimate nature
of the leucocyte examined, the more does it become evident that
this cell must be endowed with functions greatly exceeding in
importance any as yet ascribed to it." The results of our anal-
ysis seem to us to have fully sustained this assertion. Indeed,
if the functions subserved by these cells are enumerated, it will
be found that they supply the entire organism with the agencies
which combine with the oxidizing substance to insure the contin-
uation of life and the efficiency of all organic functions.

THE FUNCTIONS OF LEUCOCYTES IN IMMUNITY.

In the preceding chapter we ventured the opinion that
Ehrlich's side-chain theory did not, in its present form, account
for the protective phenomena witnessed in the organism, and
that the solution of the problem required research in other
directions. The complexity of this hypothetical process; the
need of specific toxophoric atoms to counteract as many spe-
cific toxins; the implied necessity of an antenatal arrangement
of the molecular elements of the cells, with adjustment to
the requirements of existence in disease-ridden communities;
Ehrlich's own investigations showing that immunity is not
transferred to progeny through the germinal cell, etc., were
adduced as fundamental reasons for the position taken. What
work we have done since has but emphasized these objections,
especially as regards the multiplicity of antitoxins, cytolysins,
and haptophore groups. But it has also brought to light, it
seems to us, those features of his invaluable researches which
are beyond the domain of pure conjecture.

Professor Welch, in his masterly Harvey Lecture, quotes
Behring's terse definition of Ehrlich's theory: i.e., "The same
substance which, when incorporated in the cells of the living
body, is the prerequisite and condition for an intoxication, be-
comes the means of cure when it exists in the circulating blood."
As, in the light of our own views, the cell involved is a leuco-
cyte, the prophylactic function would thus be exercised by gran-
ules formed mainly of products of digestion. If the foods in-

THE LEUCOCYTES IN IMMUNITY. 729

gested by this cell included bacteria, these would become, there-
fore, the source of the bactericidal granules, according to
Ehrlich's theory. That such is not the case we have seen.

To the question: "What is the physiological mechanism
called into action in the processes resulting in the production
of antitoxins, cytolysins, and similar bodies?" Ehrlich is stated
by Welch, however, to answer: "The mechanism is one physio-
logically employed for the assimilation by the cells of food.
The receptors are in the Icells, not for the purpose of linking
poisons to the cells, but to seize certain foodstuffs, particularly
the proteids, and the toxins and bacterial and other foreign
cellular substances, if capable of inducing the immunizing re-
action, chance to have the requisite combining affinities for the
food-receptors." There is obviously considerable analogy be-
tween this and our own interpretation, although the latter is
devoid of the complex questions introduced by specific affinities.
The cellular trypsin seems to us to be endowed with all the
bactericidal and toxin-destroying power required. Indeed,
trypsins appear to us to embody the functions attributed to all
the complements: Buchner^s alexin, and Metchnikoff's cytase,
while the oxidizing substance corresponds with Ehrlich's am-
boceptor: i.e., Bordet's sensitizing substance, or fixative.

We are also vividly reminded of the fluctuations of adrenal
activity by the following words of Professor Welch's: "We
know that the content of the blood in specific anti-bodies, and
especially in complements, varies in significant ways under di-
verse conditions, as in infancy and in adult life, in health, in
different states of nutrition, under the influence of fatigue, of
inanition, of pain, of interference with respiration, of alcohol,
and in disease."

We likewise find confirmation of the view we have sub-
mitted as to the causes of the vulnerability of children to in-
fectious diseases: i.e., inadequate protection through lack of
adrenal development, in the following lines by the same au-
thor: "The infant comes into the world with protective anti-
bodies in the blood smaller in amount and less energetic than
those possessed by the healthy adult. It is an important func-
tion of the mother to transfer to the suckling through her milk
immunizing bodies, and the infant's stomach has the capacity,

730 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

which is afterward lost, of absorbing these substances in an
active state. The relative richness of the suckling's blood in
protective anti-bodies, as contrasted with the artificially fed
infant, explains the greater freedom of the former from in-
fectious diseases:" Evidently the importance we have attached
to the immunizing constituents of the mother's milk was not
groundless. What a holocaust of lives to be charged to the so-
called infant-foods T

Finally, the general protective process as we have con-
ceived it seems to us sustained. We have suggested that accu-
mulation in the blood of toxic waste-products occurred when,
owing to advanced insufficiency of the adrenals, the oxidizing
substance was inadequately formed. Obviously, the reduction
of all oxidation processes inhibits leucocy to genesis and the spleno-
pancreatic functions, and, as a result, bacteria, their toxins,
toxic waste-products, etc., are no longer antagonized. "One of
the earliest results of the systematic bacteriological examina-
tions which we make at all necropsies at the Johns Hopkins
Hospital," writes Professor Welch, "was the recognition of the
great frequency of terminal infections, formerly often unde-
tected by the clinician, in chronic diseases, particularly of the
heart, the blood-vessels, and the kidneys. Dr. Longcope finds,
although not regularly, still in many cases of these diseases, a
marked reduction in the quantity of complements, which may
amount to a total loss of the colon complements. The analysis
of the cases brings out unmistakably a definite relation between
this loss of complement and the predisposition to infection."

If the full meaning of these few quotations is grasped, it
will become apparent that the newer conceptions we have in-
corporated in this work are vividly reflected in the modern con-
tributions to our knowledge of immunity.

The adrenal system, as suggested by the foregoing quota-
tions, stands out prominently in all problems concerned with
immunity. The oxidizing substance may be said, therefore, to
occupy the same relative position.

Bordet in a series of exhaustive experiments65 ascertained
that the destruction of bacteria was due to the action of two

66 Bordet: Annales de 1'Institut Pasteur, vol. ix, 1895, and vol. x,

THE LEUCOCYTES IN IMMUNITY. 731

substances: (1) Buchner's alexin, a product of leucocytes; (2)
a body which, though present in small quantities in the plasma
during health, i.e., under normal conditions, was found to
greatly increase in quantity in infected animals. Referring to
these investigations, and to those of Pfeiffer, reviewed in our
eleventh chapter, Metchnikoff66 writes: "The researches of M.
Bordet67 have definitely elucidated this question. This scien-
tist has demonstrated that* Pf eiffer's phenomenon is produced
by all sera with the aid of the same substances, which are the
cytases (alexin, or Ehrlich's "complement). But in the serum
of vaccinated animals there is added to them the fixative (the
substance sensibilisatrice of Bordet or immunizing body, Ehr-
lich's amboceptor), which itself shows specific properties. After
having well distinguished one from the other, the two sub-
stances that intervene in the granular transformation of vibrios,
M. Bordet has proven that in vaccinated animals it is the
fixative which increases in quantity, while the cytase (alexin)
remains as to quantity in about the same proportion as that
observed in normal animals." . . . "While the cytase does
not increase as the result of vaccinal injections, the fixative, on
the contrary, becomes more and more abundant. It is this
second soluble ferment which imposes its characteristic upon
the blood-stream."

If this fixative, amboceptor, intermediary body, etc., is the
oxidizing substance, are we justified in granting it a position
in immunity overtopping that of all other agencies? In other
words, does Buchner's alexin, Ehrlich's complement, Metch-
nikoff's cytase, etc., play as insignificant a role as the experi-
ments referred to suggest?

We have furnished evidence to the effect that the bac-
tericidal phagocytes, the neutrophiles, absorbed trypsin (the
spleno-pancreatic secretion) not only in the intestinal canal,
but likewise in the portal vein. To this secretion we ascribed
the destruction of all toxic albuminoids, toxins, vegetable poi-
sons, venoms, etc. Bacteria being likewise ingested, they nat-
urally find their doom in the digestive vacuoles of the pha-
gocytic neutrophiles, through the effects upon them of the

66 Metchnikoff: L'lmmunitS dans les Maladies Infectieuses," p. 204, 1901.

67 M. Bordet: Annales de 1'Institut Pasteur, vol. ix, p. 462, 1895.

732 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

trypsin absorbed by the latter. "Just as amceba? digest their
prey with the aid of amibodiastase, a soluble ferment belonging
to the group of trypsins," writes Metchnikoff,68 "white corpus-
cles submit the foreign bodies they inglobe to the action of
cytases. These cytases (the alexins or complements of other
authors) are the soluble ferments which also belong to the
category of trypsins." It is necessary to bear in mind, how-
ever, that, the physiological role of the neutrophile as we have
conceived it is foreign to immunity, i.e., to the production of
myosinogen and fibrinogen, and that what trypsin penetrates
into this cell acts only under normal conditions as a digestant
upon the bacilli, and is not, therefore, eliminated as such by
the cell. It seems evident, therefore, that Metchnikoff is right
when, as stated by Welch, he "strenuously insists . . . that
the complement or cytase is within the leucocytes, from which
it is not secreted." Still, this does not give us the clue to the
manner in which the general blood-stream is supplied with pro-
tective toxin-destroying bodies.

The neutrophiles, which represent three-fourths of all
white cells found in the blood, appear as the normal agents for
this purpose; but how reconcile the fact emphasized by Metch-
nikoff that his trypsin-laden cytase does not leave these cells?
This is perhaps explained by another quotation from his text69:
i.e., "The cytases must be classed among soluble ferments
which do not leave the phagocytes while these remain intact.
But as soon as these cells are injured they allow a portion of
their cytases to escape from their contents." If this is the only
process through which the blood is supplied with its trypsin, we
are led to the deduction that in all intoxications due to albumi-
noid bodies injury to neutrophiles is necessary: an inapplicable
mechanism in the general blood-stream when general infections
are present. Indeed, we have not been able to find in this
distinguished zoologist's work evidence that the phagocytes
at any time part with their cytase for the purpose of distribut-
ing it throughout the organism. He only refers to the elimina-
tion of the trypsin-containing substance as passing out of the
cells after these have been taken from the organism: i.e., extra

68 Metchnikoff: Loc. cit., p. 573.
•• Ibid.

THE LEUCOCYTES IN IMMUNITY. 733

corpore. Thus, he remarks (incidentally, though indirectly, con-
firming our view that neutrophiles are the source of fibrinogen
granules): "In blood removed from the body the white cells
allow plasmane, which causes coagulation of fibrin and the for-
mation of the clot, to pass into the liquid. But at the same
time these cells abandon a portion of their cytase, which com-
municates to the serum its ha^molytic and bactericidal qualities."
In the body, however, the need of injury to liberate the cytase,
and the stated fact that this- trypsin-laden body (alexin) is
strictly intracellular, represent the features of the question
that are especially emphasized by Metchnikoff.

This is accounted for by an important feature of this in-
vestigator's views: i.e., he regards the intermediary substance,
Bordet's fixative, Ehrlich's amboceptor (our oxidizing sub-
stance), as a product of these cells, as shown by the following
lines: "The cytases are essentially intracellular soluble fer-
ments; the fixatives are, on the contrary, true humoral soluble
ferments. But, though circulating in the plasma, the fixatives
are unquestionably of cellular origin. This fact was first shown
by Pfeiffer and Marx, who found the specific fixative of cholera
vibrios in the 'haematopoietic organs/ that is to say, the spleen,
the lymphatic ganglia, and the bone-marrow at a period when
none were present in the blood."

We have shown the direct functional relationship between
the adrenal system and leucocytosis. That the oxidizing sub-
stance, which invades the entire blood-stream in increased quan-
tity under the influence of a toxic, should have reached the
structures mentioned at an early stage of the morbid process
is quite plain. Indeed, the proof adduced by Metchnikoff is
easily accounted for without in any way attributing to the leu-
cocytes themselves the production of the fixative. We have
seen, for instance, that the splenic artery, as a branch of the
cceliac axis, is one of the first to receive freshly oxygenized
blood; the lymphatic system, which has a serum-containing ca-
pacity twice that of the entire blood-system, receives fresh
serum from the pulmonary lymphatics, etc., before it even has
time to penetrate the blood, etc. Again, none of the leucocytes
we have studied afford a single physical or chemical feature
tending to suggest that the fixative is a product of these cells.

734 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

We must frankly claim, on the other hand, that its production
— as oxidizing substance — through the intermediary of the ad-
renal system has been supported in this entire work by a wealth
of evidence seldom equaled in the annals of medicine when an
entirely new line of thought was being submitted for the first
time.

The oxidizing substance has affirmed its identity on all
sides as the reagent which, by combining with products, so to
say, stored in the cellular elements — through the agency of
the leucocytes — causes the liberation of functional energy.
Wherever in the organism we witness vital or functional phe-
nomena, these must be accounted for by a reaction in which the
oxidizing substance takes part. To insure the liberation of this
energy in the organism itself, the presence of the two sources
of energy are necessary for the reaction. When blood is re-
moved from the body, therefore, it is only when both are pres-
ent that bacteria, red blood-corpuscles, etc., can be chemically
disintegrated. The multitude of contradictory phenomena con-
nected with experimental germ- and blood-cell- destruction re-
corded in literature seem to us to find their explanation in the
fact that this fundamental feature of the processes involved has
been totally overlooked.

Metchnikoff, as just stated, found that in blood removed
from the body, the leucocytes allow what he terms "plasmane"
(because it coagulates fibrin, he thinks) to pass into the liquid.
"At the same time," he asserts, "these cells abandon a portion
of their cytase, which communicates to the serum its haBmo-
lytic and bactericidal qualities." It is evident that M. Metch-
nikoff considers plasmane as the cause of coagulation of fibrin,
whereas we consider the cells as the source of the agent which
becomes coagulated by what remains of oxidizing substance in
the extravasated blood. In other words, what M. Metchnikoff
deems the causative factor of coagulation is a substance which
he regards as a product of the cell, whereas we consider this
cellular product as the one acted upon by an agency in the
plasma. Of course, coagulation in one sense is due to the
ultimate absence of oxidizing substance, because its existence
as fibrin is due to the fact that it is not completely consumed
by the oxygen. But to become coagulated at all it requires the

THE LEUCOCYTES IN IMMUNITY. 735

momentary exposure to the action of the oxidizing substance.
A sudden arrest of the supply of the latter to the blood, as
occurs when a large dose of venom causes the functions of the
adrenal system to cease, for example, accounts for the liquid
blood witnessed under such circumstances. The tissues, con-
tinuing the consumption of oxygen, soon deplete the blood of
this gas, leaving none to carry on the partial oxidation of the
fibrinogen to which the formaiion of fibrin is due. We have
evidence here, therefore, through the fact alluded to by Metch-
nikoff, that coagulation occurs in the extravasated blood, of
the presence in it of at least a small quantity of oxidizing sub-
stance. As we view the composition of this extravasated blood,
therefore, it embodies (1) fibrinogen, (2) the oxidizing sub-
stance, and (3) the cytase, including its trypsin, as factors of
the process through which bacteria and blood-cells are disin-
tegrated.

An application of the principles we have submitted will
serve to illustrate our meaning. Keferring to the labors of
Bordet, Metchnikoff70 states that "whenever the serum of a
prepared animal is deprived of its haemolytic properties by heat-
ing to 55° or 56° C., this property can be restored to it with
certainty by adding to it a little normal serum incapable itself
of causing haemolysis. The heated serum of prepared animals
completely loses its power of dissolving its red corpuscles, but
it preserves its other acquired property of agglutinating the
latter. The red corpuscles in voluminous masses visible with
the naked eye remain intact indefinitely if allowed to remain
in the prepared and heated serum. But if a small proportion
of normal blood (obtained from many species of vertebrates) is
added, dissolution of the corpuscles soon follows. There is
initiated under these conditions a process in which two sub-
stances take part, one of which was present in the heated serum
of the prepared animal, and the other in the non-heated normal
serum. The first of these substances which resists not only the
temperature of 55° to 56° C., but stands, without undergoing
alteration, heating up to 60° to 65° C. corresponds with the
intermediary substance of M. Ehrlich [our oxidizing substance] .

™ Metchnikoff: Loc. cit., p. 97.

736 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

It has been designated by M. Bordet under the name of 'sensi-
tizing substance' [fixative]. The second insignificant ['banale']
substance, that found in normal sera, is the alexin of Buchner
and Bordet, or Ehrlich's complement."

What is the active cytolytic constituent of the normal
serum? A material difference between Buchner's alexins and
Bordet's fixative, that is to say, between the trypsin-laden
cytase and the oxidizing substance, is the fact, recognized by
all, that the alexin, or cytase, is destroyed when exposed to a
temperature of about 56° C., while the fixative, or oxidizing
substance, can stand without harm a temperature of about 65°
C. It becomes evident, therefore, that the agency disabled "by
heating to 55° to 56° C.," referred to by Metchnikoff, must
have been the alexin. But how did the addition of "a little
normal serum incapable itself of causing hcemolysis" restore the
serum's hsemolytic powers? It is clear that there must have
been something in the latter with which it could combine to
bring about the reaction necessary for the liberation of func-
tional energy to which we have referred. And what is the
nature of this required agency? The second portion of the
quotation furnishes a clue to its identity: i.e., the fact that,
while losing its power of dissolving red corpuscles, the serum
of a prepared or infected animal preserves its property of ag-
glutinating the latter. Indeed, this agglutination points to the
presence of fibrin, which, as interpreted from our standpoint,
is a phosphorus-laden body. But, then, how did haemolysis occur
when the normal serum was added? The fibrin on being ex-
posed to the action of the oxidizing substance could only have
liberated the agglutinated blood-corpuscles by causing dissolu-
tion of the fibrinous filaments, and without affecting the red
cells. The process evidently requires another agency: a body
which only becomes active in the blood when aided by the
energy liberated by the combination of fibrinogen and oxidizing
substance.

Again, "M. Bordet has shown," writes Metchnikoff, "that
the serum of animals injected at various times with the blood
of foreign species contains almost the same quantity of alexin
as does normal serum. But, on the other hand, it is the sen-
sitizing substance [the fixative, oxidizing substance, etc.] which

THE LEUCOCYTES IN IMMUNITY. 737

appears in very great quantity as a result of these injections.
M. de Dugern71 has confirmed this observation,, and has added
the interesting fact that the sensitizing substance is found in
great excess in the serum of prepared animals. When fresh,
non-heated blood is added to this serum, the haemolysis produced
is thirty times more active than occurs with the serum of the
prepared animal alone." How could haemolysis be increased
thirty times simply by adding" the sensitizing substance, — our
oxidizing substance, — "which," using MetchnikofFs words,
"fixes itself to the red corpuscle without ever dissolving it,"
a feature which, he adds, "is accepted by everyone and may be
regarded as definitely settled"? In the light of our statements
regarding fibrinogen, this body cannot be considered as the
haBmolytic agent, since the blood-cells remained intact when
in the first experiment they had been set free by the addition
of fresh serum. In the latter experiment, however, the pres-
ence of alexin, the trypsin-containing body, is alluded to, even
though supposed to be present only in normal quantities. This
suggests that this trypsin may have played a role in the process
not only in this, but likewise in the former experiment.

This is further sustained by the need of an agglutinating
agent, for we have seen that, although heating caused the serum
of an injected animal to lose its corpuscle-destroying character,
its agglutinating power remained. We know the peculiar man-
ner in which trypsin attacks albuminoids; it does not disin-
tegrate them as do some other bodies by abstracting one or
more of their constituents; it fairly corrodes the substances
vulnerable to it, first melting corners, edges, etc., and softening
the surface until the entire fragment has disappeared as would
a gum-drop in water. Agglutination seems a normal outcome
of such changes. Under these circumstances, however, trypsin
cannot, as an agglutinant, be considered as a part of the alexin
destroyed by heating to 55° C. or thereabouts, and must have,
in the foregoing experiments, been liberated from the alexin
by the heating process, thus being free to act when fibrinogen
and oxidizing substance were present. In other words, it must
also have been able to stand without harm the higher tempera-

71 M. de Dugern: Miinchener med. Wochenschrift, No. 20, p. 677, 1900.

738 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

ture — at least that of the oxidizing substance. Evidence of this
is fortunately available. "It was supposed that the sensitizing
or intermediary substance was likewise the substance which
produced agglutination of the red corpuscles," writes Metch-
nikoff,72 "but .searching investigations have thoroughly estab-
lished the difference between these two substances, which have
as a common characteristic the fact that they both resist heat-
ing at 55° to 60° C. and beyond." Evidently trypsin is not only
the agglutinating agency, but likewise that which destroys red
corpuscles, bacteria, toxins, etc.

But if, as stated by Bordet, the alexin is not increased in
the serum of periodically injected animals and it is only the
sensitizing substance, our oxidizing substance, which appears
in "very great quantity," how can we account for the thirty-
fold hsemolytic power noted by de Dugern? It seems plain that
a relatively small quantity of trypsin should be quickly disposed
of under such circumstances, the haemolytic process ceasing
with corresponding promptness. But the fact that alexin can
so easily part with its trypsin as suggested by the first experi-
ments reviewed, on the one hand, and the correspondence be-
tween the temperature resistances of trypsin and the oxidizing
substance, on the other, point to the fact that the alexin ratio
of a serum may not in the least represent that of the trypsin
ratio. The blood of the injected animal may thus have con-
tained an ample supply to account for the great increase of
haemolytic power without showing an increase of alexin.

Indeed, we must not, in all this, lose sight of the fact that
the conditions that prevail in extravasated blood do not portray
conditions as they exist in living blood, and that such experi-
ments can only be of value if, as in those referred to in the fore-
going pages, all the elements introduced by the separation of
the specimen from the intra corpore blood are taken into ac-
count. Thus, Martin and Cherry,73 of Melbourne, refer to ex-
periments by Calmette74 which led him to conclude that "the
toxin of snake-venom does not interact with its antitoxin in
vitro, but only in corpore, and, therefore, that its action cannot

« Metchnikoff : Loc. cit., p. 98.

73 Martin and Cherry: British Medical Journal, Oct. 15, 1898.

»* Calmette: Annales de 1'Institut Pasteur, p. 250, 1895.

THE LEUCOCYTES IN IMMUNITY. 739

be explained as a simple chemical operation between the two."
A similar observation is credited to Wassermann75 in respect
to the bacillus pyocyaneus. Metchnikoff's statement that in
cxtravasated blood the leucocytes allow their "plasmane" and
a part of their cytases, "which/7 he says, "communicate to the
serum its hamolytic and 'bactericidal qualities/' to escape,
therefore, is not applicable to the living blood-stream. Indeed,
he emphatically asserts, as we have seen, that the cytase, the
trypsin-containing body, exists under normal conditions solely
within the leucocytes. The blood-stream, therefore, must find
itself deprived of trypsin: the body which we have seen plays
the primary role in the destruction of toxins and other toxic
albuminoids. Still, this statement must be qualified.

We have seen, when the spleen and pancreas were analyzed,
that the internal secretion of these organs was poured into the
blood-stream about four hours after meals. Between-times its
presence could hardly be detected experimentally. Again, post-
prandial leucocytosis is a close companion of spleno-pancreatic
functions; it also appears some time after a meal. The direct
connection between the two is emphasized by the best possible
proof: the presence, within the leucocyte, of the spleno-pan-
creatic secretion: i.e., trypsin. The marked leucocytosis — of
neutrophiles only as regards the blood-stream — that occurs
after acute infections has been sufficiently emphasized. The
question to determine is whether this secretion, which is poured
into the portal vein by the splenic vein, is entirely absorbed
by the leucocytes that pass the splenic veins' orifice when in
the portal vein, or whether some is allowed to pass into the
blood-stream.

The experimental evidence adduced in the preceding pages
clearly illustrates the baneful results of free trypsin in the
presence of the oxidizing substance and fibrinogen. As soon
as these three agents are together, their destructive effects can
even, we have seen, destroy red blood-corpuscles under appro-
priate conditions. The hepatic capillaries receive fresh arterial
blood through the hepatic arteries, which arterial blood is
mixed with the portal blood in the minute channels of the

75 Wassermann : Zeitschrift fur Hygiene, Bd. xxii, p. 521, 1896.

47

740 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

hepatic cells. We therefore have, in the latter, oxidizing sub-
stance and fihrinogen in active reaction: a fact demonstrated
by the elevated temperature of the organ's parenchyma: i.&.t
106° F. That tile delicate protoplasmic structures of the he-
patic cells would be exposed to destruction were any considerable
amount of free trypsin present in the blood seems obvious.
Still, it is evident that a certain amount must be allowed to
penetrate the organ to assist therein in the destruction of
albuminoid toxics that have reached it through the digestive
canal. When we consider the enormous number of channels
which the liver contains, it is probable that considerable tryp-
sin is distributed to this organ in a free state. Beyond the
liver, however, and under normal conditions, analysis of the
question again supports Metchnikoff, when he states that the
trypsin-laden alexin is inclosed within the precincts of the leu-
cocyte. But we must now lay stress upon the fact that this
only applies to normal conditions, for, as soon as abnormal con-
ditions prevail, another order of things is inaugurated.

Heat we have seen is the predominating factor of the proc-
ess through which trypsin is enabled to enact its bactericidal
and antitoxic functions. The intracellular functions of leuco-
cytes, as we have interpreted them in this work, are depend-
ent upon the same initial feature. Referring to the action of
pancreatic juice, Foster states76: "The activity of the juice in
thus converting proteids into peptone is favored by increase of
temperature up to 40° C. [104° F.] or thereabouts, and hin-
dered by low temperature." 7T That this likewise applies to the
trypsin of the pancreatic juice is clearly shown in the following
lines from Metchnikoff 7s pen: "From all their ingenious ex-
periments Ehrlich and Morgenroth conclude that the fixative
[Ehrlich's intermediary body or amboceptor; our oxidizing
substance] is endowed with two different affinities: one for
the red corpuscles and another for the complement [the tryp-
sin-laden alexin]. Of these two affinities, the stronger is that
which combines it with the red corpuscle, for it occurs at a
very low temperature. In order that the fixative be enabled to

*• Foster: Loc. cit., p. 282.
77 All italics are our own.

THE LEUCOCYTES IN IMMUNITY.

741

combine with the complement, a much higher temperature is
necessary."

In the light of our conception of the functions of the red
corpuscles — i.e., that it is merely a carrier of haemoglobin, from
which the serum can replenish itself with oxidizing substance
as fast as this is used — the relationship between cell and oxidiz-
ing substance, or intermediary substance, logically coincides
with the observations of Ehrlich and Morgenroth. The sub-
stance simply adheres to its feeder regardless of the tempera-
ture. Not so with the trypsin-laden alexin, however, for here
the temperature-ratios of its trypsin and of the oxidizing sub-
stance are, as we have seen, practically co-equal, and, as trypsin
requires a certain temperature to insure adequate functional
activity, its £0-substance, the oxidizing substance, must itself
be brought to this temperature: i.e., the "much higher tem-
perature" to which Ehrlich and Morgenroth refer. We have
seen how this purpose is reached, viz.: mainly by the phos-
phorus (absorbed by the leucocytes from the alkaline phos-
phates of the plasma) in the fibrinogen,78 the blood's own source
of heat. The direct part played by the fibrinogen and oxidizing
substance in the haemolytic process has caused some investiga-
tors to term "hasmolytic complement" the bodies which are
constantly present in the blood-stream and increase in quantity
when toxics are administered: i.e., these two substances. It
now seems obvious that, although they do take part in the
hsemolytic process, they are only heat-producing auxiliaries,
the true haemolytic substance being the trypsin.

But the process involves the necessity of a mechanical
combination capable of insuring the presence in the blood-
stream of just enough trypsin to correspond with the fibrinogen
in the blood-stream. How could this object be better subserved
than, as is the case, by combining in the same cell, the neutro-
phile leucocyte, the two active constituents? Again, what more
precise mechanism could we obtain than a granule of fibrinogen
stopping up, as it were, a canaliculus leading up to the central
or perinuclear vacuole in which the trypsin is stored and sud-

78 We must emphasize the fact that the term "flbrinogen," as we understand
it, is not intended to represent the body recognized as such by physiological
chemists, though considerable kinship between the two exists. — S.

742 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

denly allowing enough of the latter to escape? As the need
asserts itself, — impressed by the surrounding fluids upon the
sentient exposecl protoplasm of the leucocyte, thence commu-
nicated to its centrosphere — one, two, or many granules are
unloaded, each being followed by a jet of the trypsin-laden fluid,
but a jet only commensurate with the potential of the granule.

And experimental evidence is not lacking to show that such
a process must prevail when toxics stimulate the adrenal sys-
tem: "Under the influence of the repeated doses of pilocar-
pine," writes George Wilkinson,79 in a study of the action of
drugs on the leucocytes of the blood, "the granules become
gradually less distinct, and eventually the protoplasm appears
perfectly homogeneous and takes up the stain very feebly. In
one of the animals this change was found to be very pronounced
in so short a time as fifteen minutes after the first dose of the
drug." All the work done in connection with cytolysis, espe-
cially that bearing upon red corpuscles, emphasizes not only
the need of the mechanism we have outlined, but its presence.
Indeed, all cells would be submitted to the destructive process
to which these cells succumb when "fresh serum" is added even
in vitro to the blood of "prepared" animals were it absent.
In the light of our own views, we have here merely an exag-
gerated phenomenon, but a true picture of what would occur
were fibrinogen, trypsin, and the oxidizing substance promis-
cuously mixed, as they are in extra cor pore experiments. Here
many red corpuscles, gorged perhaps with oxyhaBmoglobin and
enmeshed in fibrin filaments replete with phosphorus, suddenly
find themselves imbedded, when fresh serum is added, in what
is to them a seething mass. The leucocytes contributing their
trypsin in the manner defined by Metchnikoff, and the ag-
gressiveness of this corroding body being suddenly multiplied
thirtyfold, as observed by de Dugern, the red cell soon suc-
cumbs, adding its own oxyhaemoglobin to the destructive me-
dium surrounding it as soon as its stroma has been sufficiently
disintegrated.

Such a fate for all vulnerable elements we deemed in-
evitable when, in the foregoing chapter, we discussed Buchner's

79 George Wilkinson: British Medical Journal, Sept. 26, 1896.

THE LEUCOCYTES IN IMMUNITY. 743

views as to the action of alexins. It is now plain that general
destruction of cellular elements would prevail were the physio-
logical co-ordination of all functions, including those of the
blood, not as perfect as it is. Buchner's interpretation of the
destructive action of alexins and of bacterial products is never-
theless justified; but it lacks the all-important controlling
factors we have described to -restrain this action within proper
limits. Indeed, our organism produces trypsin to destroy bac-
teria which also produce kindred toxins capable of destroying
us. It is primarily upon the integrity of our adrenal system
and of the protective agencies that it governs, therefore, that
our safety depends when bacteria, their toxins, vegetable poi-
sons, and venoms penetrate the blood-stream, notwithstanding
the barriers with which the intestinal and respiratory tracts are
supplied to oppose their entrance therein.

But do the trypsin and the oxidizing substance simulta-
neously accumulate in the blood-stream? Trypsin being, as
previously stated, the agglutinating body and the fixative the
oxidizing substance, the following additional quotation from
MetchnikofFs work80 will show that such is the case: "The pres-
ence of the fixative, this other important element in immunity,
could only be demonstrated in normal humors in exceptional
cases and in small quantities. The agglutinating properties of
these humors also showed themselves as but slightly developed,
and devoid of importance in natural immunity. In acquired
immunity against microbes we see, on the contrary, the bac-
tericidal and agglutinative powers of the humors increased to a
great proportion."8* As viewed from our standpoint, however,
the bactericidal and agglutinative properties are both inherent
in the trypsin; the oxidizing substance plays as elsewhere in
the organism its role as a reagent, with the fibrinogen as the
primary source of energy. This energy, manifested as heat,
endows the trypsin not only with the power to convert toxins
and diastases secreted by bacteria, toxalbumins, including vege-
table poisons and venoms, into harmless products, as stated in
the previous chapter, but it also enables it to destroy bacteria.

*> Metchnikoff: Loc. cit., p. 264.
81 All italics are our own.

744 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

All the foregoing facts seem to us to warrant the following
conclusions as the manner in which bacteria, their toxins, and
all other albuminoid poisons, whether the latter be traceable to
imperfect physiological processes or to the introduction of these
poisons from without, are converted in the organism into benign
products: —

1. When the adrenal system, stimulated to unusual activity
by a poison, increases the production of oxidizing substance, all
the functions of the organism are correspondingly activated, in-
cluding (1) those of the leucocytogenic structures, thus causing
leucocytosis, and (2) those of the spleno-pancreatic system, thus
giving rise to an excessive production of trypsin.

2. The general blood-stream thus becomes supplied with (1)
an excess of oxidizing substance and (2) a larger proportion of
neutrophile leucocytes which, on their way to the hepatic cells, ab-
sorb (3) a portion of the trypsin carried to the portal vein by the
splenic vein.

3. The trypsin absorbed by the neutrophile leucocytes is mainly
stored in their perinuclear digestive vacuole, into which most of
the bacteria and other materials ingested by these phagocytic cells
are digested.

4- An excess of heat-energy being necessary to insure the
prompt and adequate digestion of these substances by the trypsin,
this is provided for by a reaction in the canaliculi of the nucleus,
between the oxidizing substance absorbed by the cell with the plasma
and the phosphorus of the nuclein.

5. The trypsin which serves to destroy bacteria, toxins, etc.,
in the blood-stream, is derived from the neutrophile leucocytes and
is secreted simultaneously with their fibrinogen granules, when
their naked peripheral protoplasm is chemotactically stimulated
by the toxic bodies in the plasma.

6. An excess of heat-energy being also necessary in the blood-
stream to insure prompt and adequate disintegration, by the tryp-
sin, of the bacteria, toxins, etc., present therein, this is provided
for by a reaction between phosphorus-laden granules of fibrinogen
discharged by the neutrophile leucocytes and the oxidizing substance
of the surrounding plasma.

7. Both phagocytosis, carried on by wandering, endothelial,
and other fixed cells, and the foregoing protective process carried

THE ACTION OF ANTITOXIC SERUM. 745

on in the blood-stream, thus owe their ability to convert bacteria
and their toxins into harmless products to trypsin.

THE PHYSIOLOGICAL ACTION OF ANTITOXIC SERUM.

At the end of the previous chapter we stated that, judging
from the stage of our analysis then reached, antitoxin con-
tained blood-serum, alexins, trypsin, and oxidizing substance.
In the light of the data submitted in the foregoing pages, each
of the constituents of antitoxin seems to us to have acquired its
due position as a physio-chemical agency.

The oxidizing substance, irrespective of its functions in the
blood-stream when it combines with the fibrinogen, subserves
all the other functions of the organism. Hence, the plasma
must contain — and we have seen that it does — a constant sup-
ply of oxidizing substance over and above that utilized in the
blood itself. The fibrinogen granules being supplied by leuco-
cytes, they are doubtless distributed in measured quantities, as
it were — just enough to sustain the blood's normal temperature
or raise this if albuminoid poisons are present in the blood-
stream. The increase of oxidizing substance insured by the
adrenal overactivity which the poison itself causes compensates
for extra oxygen used under these circumstances. Still, leuco-
cytogenesis being commensurate with the surplus of adrenal
activity, it becomes evident that at least the greater part of
the oxidizing substance supplied to the blood-stream combines
with the excess of fibrinogen formed to liberate heat-energy.
It follows, therefore, that, while some oxidizing substance may
be present in antitoxin, it cannot be considered as a prominent
constituent of the substance. This does not prevent its dis-
ruptive influence upon toxics that are converted by oxidation
into harmless products. Indeed, we have seen that phagocytic
leucocytes absorb plasma, and with it oxidizing substance. As
it is these cells which carry drugs, poisons, etc., introduced in
the digestive canal, into the body itself, it is within their di-
gestive vacuole that the poison first meets its foe. If a bacillus
or an albuminoid: a toxin, a vegetable poison, etc., it is at-
tacked by the trypsin; if an oxidizable body, by the oxidizing
substance.

Buchner's alexin has likewise suffered from the analysis

746 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

submitted in the foregoing pages. Trypsin, we have seen, is
the bactericidal agent of this body, the complement, the cytase,
etc. To give alexin an autonomous position in our analysis does
not, therefore, seem necessary.

THE ACTIVE PRINCIPLE OF ANTITOXIN. — The oxidizing
substance and the alexins are thus eliminated from the list of
agencies upon which the title of "active principle" might be
bestowed. Trypsin, on the other hand, remains, having shown
itself, indeed, as an autonomous body, distributed throughout
the entire organism, endowed with all the attributes that an
agency destined to chemically dissociate bacilli, their toxins,
and other albuminoid poisons should possess. Though its full
efficiency in the organism requires the heat-energy developed
by the reaction between fibrinogen and the oxidizing substance,
all the evidence points to trypsin as the active principle of anti-
toxin.

Though this coincides with Bordet's view that there is but
one complement as against Ehrlich's that there is a multi-
plicity of them, our conception of the physio-chemical nature
of this body is evidently sustained by the latter scientist's chem-
ical analyses of this body, for "he believes," writes D. H.
Bergey,82 "the complement to be of the nature of an enzyme,
and, therefore, the substance by means of which the immune
body really brings about the solution of the corpuscles." That
trypsin is an enzyme and that it dissolves the corpuscles in
ha3molysis we have seen.

The role of trypsin and its relationship with the functions
of the adrenal system as influenced by toxics is well shown by
the experimental work of A. C. Abbott. Bergey, in the article
previously quoted, also says: "It has been known for a long
time that under the influence of fasting, excessive exercise, loss
of sleep, etc., the organism is less resistant to disease than when
functioning normally. It has been pointed out by Abbott83
that, through the influence of alcohol, rabbits could be made
more susceptible to infection by means of staphylococci and
streptococci." In experiments by both of the above-named

82 D. H. Bergey: American Medicine, Oct. 11, 1902.

83 Abbott: Journal of Experimental Medicine, vol. 1896.

THE ACTION OF ANTITOXIC SERUM. 747

observers84 the following conclusions, among others, were
reached: "The daily administration of alcohol per os to rabbits
brings about a reduction in their circulating blood of haemo-
lytic complement [our trypsin] . . . . The administration
of alcohol to rabbits induces not only a marked reduction in
the complement content of their blood, but may cause, at the
same time, a reduction in the specific hsemolytic receptor [our
oxidizing substance] in the blood of rabbits artificially immu-
nized against an alien blood. . . . The diminished comple-
ment content of the blood-alcoholized rabbits renders the ani-
mal more susceptible to the toxic action by an alien blood."
It is plain, therefore, that insufficiency of the adrenals induced
by a poison reduces the bactericidal and antitoxic agency, the
complement: i.e., the trypsin.

As' previously stated, Metchnikoff credits the antitoxic
properties to Bordet's fixatives (the oxidizing substance). The
properties he ascribes to the latter bodies in the following lines
are, therefore, those of the trypsin: "The fixatives offer many
points of analogy with the antitoxins," says this author; "they
are just as resistant to heating; they likewise show rather
marked specificity; and, as is the case with fixatives, they are
dispersed throughout the plasma." The same modifications of
his interpretation of the nature of these substances is also
applicable, however, when he writes: "Notwithstanding so
many data in favor of the phagocytic origin of antitoxins, it is
impossible to base this supposition upon rigorous and easily
interpreted facts such as those possessed by science in favor
of the phagocytic origin of fixatives." While the latter word,
to meet our conception, should read "trypsin," Metchnikoff, we
have seen, found that the diastase in the digestive vacuoles of
his phagocytes was a trypsin, and that it was this body, there-
fore, which destroyed bacteria. Our analysis having shown that
this process also applied to toxins and all other albuminoid
poisons, and that, when one of these pathogenic agencies en-
tered the organism, the trypsin was increased in the blood-
plasma through the operation of three dominant factors: (1)
primary overactivity of the adrenal system, (2) secondary over-

M D. H. Bergey and A. C. Abbott: University of Pennsylvania Medical Bul-
letin, Aug.-Sept., 1902.

748 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

activity of the spleno-pancreatic system, and (3) secondary over
activity of the leucocytogenic structures, and that the trypsin
supplied to the blood-plasma originated from leucocytes, it
seems to us that we can legitimately conclude that: —

Bacilli, their toxins, and all other albuminoid poisons are
converted into benign products by the same agency, trypsin, both
in the leucocytes and in the blood-plasma.

This conclusion, however, awakens a question as to the
manner in which antitoxic serum obtained from animals by
means of repeated and gradually increased doses of injected
toxins accumulates in the blood-stream. It would normally
seem that the adrenal system, stimulated by the poisons, should,
by loading the circulation with oxidizing substance, cause the
liberation of considerable heat-energy, and give rise to an in-
crease of the trypsin's activity sufficient to involve the destruc-
tion of all cellular elements. But we must not lose sight of
the fact that, while leucocytosis and a marked increase of tryp-
sin-production are caused by an excess of oxidizing substance
in the plasma, the leucocytes obtain from the intestinal canal
the necessary proteids to create not only fibrinogen, but also
the myosinogen, lecithin, hemoglobin, etc., required by the
organism's general routine work — since we refer to presumably
healthy animals. The formation of fibrinogen is, therefore,
commensurate with the proportion of proteids ingested; and
the primary source of heat-energy, that with which the oxidiz-
ing substance combines, is thus only just sufficient to preserve
the blood's normal temperature.

A proof of this is afforded by Widal's reaction. We have
shown that agglutination was a property of trypsin. Typhoid
fever we shall see in the next volume is essentially a disease
in which the absorption of proteids is inhibited mainly through
impaired leucocytogenesis, owing to disease of the intestinal
lymph-follicles: a fact itself demonstrated by the identity of
the disease as the only one among the greater febrile processes
in which, in cases following their regular course, the proportion
of leucocytes in the blood is decreased. As a result, the quan-
tity of fibrinogen in the blood-stream is limited in proportion
as the number of lymph-follicles involved is great. Neverthe-
less the oxidizing substance, an internal secretion, the trypsin,

THE ACTION OF ANTITOXIC SERUM. 749

an internal secretion, are continuously produced in excess, the
former only burning up what fibrinogen is formed by the small
contingent of available leucocytes, and the protective destruc-
tion of bacteria, toxins, catabolic products, etc., being corre-
spondingly reduced. But heat-energy is a measurable quantity,
and that produced through the combination of fibrinogen and
the oxidizing substance can only enhance the activity of a pro-
portionally limited amount of trypsin, thus leaving a surplus
which accumulates in the blood-stream. The blood of a
typhoid-fever case thus contains a proportion of trypsin which
no other disease (owing to the absence of lesions of the lym-
phatic follicles and particularly of the agminated follicles or
Peyer's patches) shows, and in Widal's test trypsin acts upon
the bacilli when added to a culture precisely as trypsin does
upon any albuminoid body extra corpore. The movements of
the germs cease as soon as their surface is being softened by
the trypsin; this softening causes this surface to become adhe-
sive, and they therefore adhere to one another: i.e., become
agglutinated, forming "clumps."

While further indicating the great value of Widal's re-
action as a diagnostic feature, it seems evident to us that, if
the general frame-work of our conception of all the physiolog-
ical and pathological phenomena involved did not rest upon a
solid foundation, it could hardly be accounted for without
indulging in hypothetical conjectures. Again, if the entire
field of the physio-chemistry of the blood is scrutinized, — as we
have done, — it will be found that the only agency that it could
contain to which this action upon bacteria and other albu-
minoid bodies could be ascribed is trypsin. It seems to us,
therefore, that we can confidently conclude that: —

Trypsin is the dominant active principle of antitoxin.

THE UNIFORMITY OF ALL ANTITOXIC SEKA. — This deduc-
tion involves another which tends greatly to simplify the entire
problem of serum-therapy, both as to the production of serum
and its use in disease. We have fully shown, we believe, the
relationship between the adrenal system and poisons. That a
poison capable of stimulating the anterior pituitary body always
gives rise to the excessive production of the oxidizing substance,
trypsin, and leucocytes, — when the organs represented are nor-

750 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

mal, — need hardly be repeated. Again, we have seen that the
quantity of oxidizing substance produced by the adrenal sys-
tem is commensurate with the stimulating activity the poison
injected can excite in that system. As the quantity of oxidizing
substance produced correspondingly enhances the functional
activities of the spleno-pancreatic system and of the leucocy-
togenic structures (all else being normal), it is evident that the
toxic that will most actively stimulate the adrenal system with-
out causing adrenal insufficiency will produce the greatest quan-
tity of trypsin. This body in turn being dissolved in a given
quantity of blood-serum, the efficiency of antitoxic serum ob-
tained as to units will correspond with the stimulating power
of the toxic employed. In other words: —

The injection of different toxins into healthy animals, as now
practiced to obtain immunizing sera of various kinds, including
antitoxin, always leads to the same result: i.e., to the production
of a serum containing trypsin as its dominant active principle.

The proportion of trypsin in a serum thus obtained is com-
mensurate with the stimulation of the adrenal system that the toxic
injected can cause without giving rise to adrenal insufficiency.

Again, the use of toxins to obtain antitoxic serum — a
feature which limits the therapeutical use of the latter by in-
spiring fear of complications — is not necessary in the light of
our views. Indeed, Ehrlich has immunized animals by means
of injections of ricin and abrin to the effects of fatal doses of
these poisons: a proof that these agents greatly increased the
production of trypsin in the experimental animals. Since all
poisons capable of safely stimulating the adrenal system pro-
duce a serum containing trypsin, we may therefore conclude
that:—

Bacterial toxins may be replaced by equally active toxalbumins
or vegetable alkaloids to obtain antitoxic serum from animals.

This raises a question as to whether a more efficacious
agent than antitoxin could not be obtained by toxics capable of
raising the adrenal functions to a higher potential, thus in-
creasing the proportion of trypsin in a given quantity of serum.
The answer seems to us, at least, to be embodied in the follow-
ing editorial comment85: —

88 Journal of the American Medical Association, Ncv. 1, 1902.

THE LIMITS OF SERUM-THERAPY. 751

"It will be remembered that when the soluble bacterial
toxins of the bacillus of diphtheria and of the bacillus of tet-
anus were discovered the hopes ran high that in this way would
be explained the action of all pathogenic bacteria; but soon
these hopes met with disappointment. With this disappoint-
ment also fell to the ground the hope that specific antitoxic
serums could be produced for all or most of the bacterial dis-
eases, just as in the case of diphtheria or tetanus. The con-
ditions did not prove to be so simple as first thought. . . ."
Indeed, the specificity that a serum was supposed to possess,
when obtained with a specific toxin, seems to us to have proven
misleading. But it is not upon a high potential that our hopes
for better results must rest, but upon a more scientific adjust-
ment of the serum to morbid conditions.

THE LIMITS OF SERUM-THERAPY.

What we mean by scientific adjustment of a serum to mor-
bid conditions is the judicious use of the dominant triad upon
which the organism depends to counteract the morbid effects
of bacteria, their toxins, and other poisons: i.e.., (I) trypsin, (2)
fibrinogen, and (3) the oxidizing substance. This will be illus-
trated by briefly reviewing their role in the more important of
the general infections.

Typhoid Fever and the Typhoid State. — In an excellent re-
view of the present status of serum-therapy F. A. Packard and
E. N. Willson86 introduce the following remarks: "A great
hindrance to the development of serum-treatment up to the
present time has been the failure to consider the constant lack
in infections of sufficient quantities of both the binding body
[our oxidizing substance] and the complement [our trypsin],
though Wassermann has, as stated, shown in a series of experi-
ments, that they can be supplied, and that, by means of their
addition, results can be obtained that have heretofore seemed
impossible. He has found that, by injecting normal serum
(thus supplying the end-body and complement) together with
immune serum, he can immunize against virulent cultures and
toxins that produce early death when combated by the immune

88 F. A. Packard and R. N. Willson: American Journal of the Medical Sci-
ences, Dec., 1902.

752 INTERNAL SECRETIONS AND PRESERVATION OP LIFE.

sera alone, which contain little else than the immune body or
the binding substance. ... He found that normal serum
from cattle (beef) could be used with typhoid immune serum —
e.g., that guinea-pigs injected with three loops of living culture
(typhoid) and in a half-hour with 0.5 cubic centimeter of ty-
phoid immune serum mixed with 4 cubic centimeters of fresh
normal ox-serum, all survived in good health, while control ani-
mals injected with normal serum or immune serum alone all
died in twenty-four hours."87 This series of experiments seems
to us to demonstrate the correctness of our views. Indeed, it
is obvious that, while the immune serum furnished trypsin, the
normal serum furnished fibrinogen (the oxidizing substance being
too limited in quantity to add energy to the animal's living
blood); this fibrinogen, by combining with the oxidizing sub-
stance in the injected animal's blood, liberated enough heat to
raise the trypsin's energy to the required level, and it chem-
ically dissociated not only the bacteria, but their toxins.

But herein lies the adjustment to which we have referred:
WidaPs test has enabled us to show that fibrinogen is precisely
the missing agency in typhoid fever; the ox-serum, therefore,
supplied this substance. But we have also seen that it is the
only disease in which the fibrinogen is lacking to such a marked
degree, and that Widal's test owes its value to this fact. What,
then, about all other diseases?

If the morbid process in typhoid fever is now traced to
its source, it will become evident that it is partly ascribable to
inhibited phagocytosis, and not altogether to the fact that the
number of cells that are able to take up proteids in the intes-
tinal canal is more or less reduced. Fibrinogen is thus inade-
quately furnished to the blood-stream. Indeed, were the cells
produced, as they are when leucocytosis occurs, even though
they could not reach the intestinal foodstuffs, fibrinogen would
be formed in the neutrophile cells. In the light of the analysis
we have submitted, the heat which energizes the trypsin in the
digestive vacuole of a phagocyte is mainly due to the reaction
between the nuclein of its nucleus and the oxidizing substance
absorbed by the cell with the plasma. The cell, therefore, does
not require fibrinogen, but the bacteria it ingulfs are them-

87 All italics are our own.

THE LIMITS OF SERUM-THERAPY. 753

selves digested and converted into useful secretions, one of
which is fibrinogen, its phosphorus being acquired from the
alkaline phosphates of the plasma.

This exemplifies an exceedingly beautiful provision of
Nature,, if examined closely. Indeed, leucocytosis, when not in-
hibited as it is in typhoid fever, being commensurate with the
degree of intoxication (the adrenal system acting as touch-
stone, as it were, for the morbid process) the fibrinogen derived
from the bacteria ingested by the surplus of phagocytes is evi-
dently intended to supply the needs of the febrile process, thus
avoiding a derangement of the general mechanism of all func-
tions. As it is only inhibited to a marked extent in typhoid
fever, however, it becomes evident that in all other febrile
processes and intoxications that are not sufficiently severe to
overwhelm the adrenal system and cause immediate insuffi-
ciency (in which bacteria penetrate the blood-stream) the addi-
tional fibrinogen required for the febrile process is obtained at
the expense of the bacilli ingested by the surplus of phago-
cytes, besides that acquired from proteids; the trypsin through
overactivity of the spleno-pancreatic system; the oxidizing sub-
stance through overactivity of the adrenal system. In other
words, the dominant triad of the protective process is always
available in diseases in which pathogenic organisms penetrate
into the blood. On the whole, it seems clear to us that: —

When leucocy to genesis is not inhibited: —

1. The plasma is provided with the three agencies, fibrin-
ogen, trypsin, and oxidizing substance, that enable it to dissociate
the bacteria that phagocytes do not ingest and digest.

2. The bacteria ingested by phagocytes are converted in
these cells into peptones, myosinogen, and fibrinogen, the phos-
phorus being derived from the alkaline salts of the plasma.

8. The system is thus supplied with the surplus of fibrin-
ogen required to sustain the febrile process, even though the proteids
obtained from the intestinal canal by the cells be small.

When leucocytogenesis is inhibited to any marked extent, as
it is in typhoid fever: —

1. The absorption of proteids from the intestinal canal
and phagocytosis are correspondingly reduced and the formation
of fibrinogen is inadequate.

754 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

2. The oxidizing substance and the trypsin is neverthe-
less formed in excess owing to the prophylactic functional activity
of the adrenal system.

8. The 'trypsin being deprived of the heat-energy of which
fd>rinogen is the primary source, it remains unused and accumu-
lates in the organism, as shown by the Widal reaction.

4. The excess of oxidizing substance produced propor-
tionally enhances general cellular metabolism, and, the formation
of peptones and myosinogen being reduced owing to inhibited leu-
cocytogenesis, the {( typhoid state" is engendered.

That these conclusions are based on sound premises is
shown by the following quotations from two papers, one by
Naegeli,88 the other by M. L. Eichardson.89 The former in-
vestigator found that "the neutrophile cells decrease rapidly in
the first stage of typhoid fever, soon reach the half of their
usual number, and gradually further decrease up to the stage
of defervescence. In the convalescence they begin to increase,
at first slowly, and then rapidly. It is usually only after many
weeks that the normal figures are regained.'7

The absence of fibrinogen, by depriving the trypsin of its
bactericidal properties, must necessarily give free sway to the
latter. Richardson writes as follows: "If we take the fresh
blood-serum from a typhoid patient at any stage of the disease
or convalescence and combine it, for example, with an equal
quantity of a bouillon culture of the typhoid bacillus, we get,
in the vast majority of cases, not destruction, but abundant mul-
tiplication of the typhoid organisms." Still, if all our estimates
of the manner in which the results of the experiments in vitro
previously analyzed are sound, normal serum should supply the
heat necessary to energize the trypsin. Richardson also satis-
fies this feature of the problem by the following remark: "If
we introduce the mixture of serum and bacilli into the peri-
toneal cavity of a normal guinea-pig, we find that there is not
only a complete absence of multiplication of the bacilli, but
there is absolute destruction and disappearance of the organ-
isms": i.e., Pfeiffer's phenomenon.

It now becomes apparent that it is not by adding an anti-

MNaegeli: Correspondenz-blatt fur Schweizer Aerzte, No. 18, 1899.

89 M. L. Richardson: The Journal of Medical Research, vol. vi, July, 1901.

THE LIMITS OF SERUM-THERAPY. 755

toxic serum, the active principle of which is trypsin, to a blood-
stream already overburdened with trypsin that we can hope to
overcome typhoid fever and kindred disorders in which fibrin-
ogen is inadequately formed. If, in addition, we realize that
an active febrile process (the organism's main protective re-
source against bacilli and their toxins) indicates that the ad-
renal system is in full activity, and that the plasma contains
an ample proportion of oxidizing substance besides trypsin, it
seems but logical to conclude that: —

In febrile diseases attended with hypoleucocytosis and in
which an excess of trypsin is found to exist (by the Widal or other
tests) a serum rich in FIBRINOGEN should be administered.

Indeed, Eichardson90 found, in his observations in forty-
one typhoid patients at different stages of the disease, that "in
the stage of convalescence or falling temperature, the normal
element returns apparently to the blood, and a corresponding
destruction of bacilli takes place." He also remarks almost
prophetically, — if our views are sound, — though he ascribes the
hypothetical effects, in accord with Ehrlich and others, to the
"immune substance" (our oxidizing substance): "We can, there-
fore, hazard a guess why serum-therapy in typhoid fever and
allied diseases has made so little progress. We have been giving
a serum loaded with immune element with which the patient
was perhaps already surfeited, and we have neglected to give
the element that was necessary to make active powerful agen-
cies already present in the patient's blood. Apparently, there-
fore, we should give to most of our typhoids normal serum."
We have seen, by Wassermann's experiments, that fresh ox-
serum sufficed to save infected guinea-pigs.

Can we use fresh serum in human beings? The cytolytic
action of the serum of one species when introduced into the
blood-stream of animals of another species is well known. In
the light of our analysis this is accounted for by the fact that
the blood introduced too suddenly augments the proportion of
trypsin in the host's blood (trypsin being practically limited,
we have seen, to the leucocytes during health), and, finding the
fibrinogen and oxidizing substance necessary to greatly increase
its dissociating energy, it attacks the red corpuscles as it would

*> Richardson: Loc. cit., p. 199.

48

756 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

bacteria. That this is true is shown by the fact recorded by
Bordet01 that agglutination was the first effect of haemolysis
produced in this manner. The quantity of serum injected and
the intervals between the injections thus become the ruling
factors of the use of normal serum. This is sustained by the
experiments of Cantacuzene92 and others.

But we refer in this connection only to normal serum, as
against that of immunized animals or animals in which even
the blood of another species has been injected. Indeed, as is
well known the latter acquires through the procedure a marked
increase of haemolytic power, simply through the fact, in our
opinion, that the alien serum acts as a toxic upon the adrenal
system and gives rise to an active production of the blood's
protective bodies: a feature which can be clinically utilized to
great advantage by avoiding large doses.

Eichet and Hericourt (who also first suggested immuniza-
tion by means of the blood-serum of immunized animals) found
experimentally, as is well known, that the injections of dog-
serum were completely non-toxic if collected with due care.
Eichet93 used hypodermic injections of this serum in tuber-
culosis, pulmonary and laryngeal. Both the local and general
phenomena were improved, the patients gaining several pounds
in weight. The serum proved absolutely harmless physiologic-
ally. Eoger94 experimentally found that the treatment reduced
the virulence of the bacillus. Semmola95 obtained beneficial
results in but two out of ten cases. This is readily accounted
for in the light of our views, for the serum can only be valuable
in the advanced stages: i.e., when hypoleucocytosis by wasting,
a febrile process, etc., are present owing to involvement of the
leucocytogenic glands. Our aim, however, is to show that the
blood of some lower animals can be safely used in human beings.
Immunized horse-serum and goat-serum have also been em-
ployed without giving rise to untoward phenomena, and the
use by Wassermann of ox-serum in guinea-pigs suggests that
this readily-obtained serum can likewise be used with due pre-

91 Bordet: Annales de 1'Institut Pasteur, vol. 1896.

92 CantacuzSne: Annales de 1'Institut Pasteur, vol. 1900.
83 Richet: La Semaine MSdicale, Jan. 28, 1891.

94 Roger: Bulletin de la Phthisie Pulmonaire, Paris, No. 3, 1891.
96 Semmola: Internationale klinische Rundschau, Nos. 25, 26, 1891.

THE LIMITS OF SERUM-THERAPY. 757

cautions. Brodie has found, however, that, of all sera obtained
from domestic animals, horse-serum was the least toxic. On
the whole, the literature of *thie therapeutic method and the
foregoing line of reasoning seem to us to warrant the following
conclusions: —

The normal serum of certain animals, particularly the horse,
ox, cow, goat, and dog, contains enough fibrinogen to render its use
in small and frequently repeated doses advantageous in febrile
processes attended with hypoleucocytosis and an excess of trypsin.
Horse-serum, being the least toxic, should be given the preference.

Diphtheria, the only disease which may be said to have
found in antitoxin, thanks mainly to the splendid labors of
Behring, a specific antagonist, presents, it seems to us, patho-
logical characteristics of an opposite order. Here leucocytosis
is a prominent feature of the morbid process, — as long as the
adrenal system is functionally overactive, — and, since antitoxin
does prove unquestionably effective when the whole subject is
studied with due care, it follows, if our views are sound, that
the neutrophiles are able to furnish the blood with enough
fibrinogen to afford, in conjunction with the oxidizing sub-
stance, the heat-energy required by the trypsin which the in-
jected antitoxin contains. Such being the case, the disease
must follow a lethal course merely because of the lack of tryp-
sin. How is this absence of trypsin engendered, or, if there
is trypsin in the child's plasma, why does it fail to antagonize
the pathogenic elements?

A feature emphasized by Metchnikoff, and that our anal-
ysis has sustained, is the absence of trypsin from the plasma.
According to our own interpretation of experimentally demon-
strated facts, such a condition of the blood only occurs when
it is completely devoid of morbific products of digestion wastes
which the leucocytes themselves cannot submit to complete
cleavage. Briefly, it may be said that under normal conditions
the blood does not contain trypsin. And this may be demon-
strated by a very familiar bacteriological fact: i.e., that, using
Stengel's words, "the most characteristic cultures are obtained
upon blood-serum."

A direct application of this fact, however, would mislead
us. In other words, we cannot say that it is because the blood

758 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

contains no trypsin that the bacilli increase rapidly in a
diphtheritic child's plasma; indeed, diphtheria presents the
characteristic, in Jiuman beings and during life, of showing but
few bacteria in the blood-stream. "It is a local infection, due
to the presence and development of the bacilli in the pseudo-
membrane," writes McFarland, "but is accompanied by a gen-
eral toxaemia resulting from the absorption of a violently toxic
substance produced by the bacilli. The bacilli are found only
in the membranous exudation, and most plentifully in its older
portions." And were it otherwise, the presence of bacteria in
the blood-stream would not account for the absence of trypsin.
There is, therefore, another cause for this phenomenon.

"We have submitted the reasons that have led us to con-
clude that the leucocytes, when on their way to the liver, absorb
the greater part of the trypsin poured into the portal system
by the splenic vein. The excessive hepatic functional activity
which accompanies a corresponding activity of the adrenal sys-
tem, renders the probability that any trypsin finds its way into
the general circulation very remote. It is, therefore, impris-
oned in the leucocytes. But another blood-cell has experi-
mentally shown considerable affinity for trypsin: i.e., the red
corpuscle. Indeed, Ehrlich and Morgenroth and Bordet have
demonstrated that the alexins are absorbed by these cells, and
we have seen that Metchnikoff found the active body of the
alexins to be trypsin. Another feature of the whole process
upon which Bordet lays stress is embodied in the following
words: "It is proper, therefore, to ascribe to the stroma the
property that red cells show of absorbing alexin in the presence
of sensitizing substance" (our oxidizing substance).96 It thus
becomes evident, seeing that the blood-stream always contains
oxidizing substance, that whatever vestige of trypsin may
happen to pass beyond the portals of the liver is at once taken
up by the red corpuscles. That under such circumstances the
child's plasma should be completely deprived of trypsin is
evident.

Still, why do the leucocytes, gorged with trypsin as they are,
not convert the toxins in the blood-stream into benign cleav-

86 Renault: Archives Generates de M6decine, Dec., 1900.

THE LIMITS OF SERUM-THERAPY. 759

age products? Being greatly augmented in number through
adrenal overactivity, it would seem as if they should be capable
of doing so. Such is the case in mild infections or when the
child's thymus and partly developed adrenal system can suffi-
ciently prolong the fray. But when they cannot, another cause
appears, one that illustrates vividly the scientific value of Metch-
nikoff's labors: i.e., the phagocytes are unable to reach and
destroy the source of the toxins. Indeed, the bacilli are in the
false membrane. Multitudes of cells crowd to the respiratory
passages or other surfaces to destroy the local focus of infec-
tion. And the pseudomembrane is itself but an extensive ceme-
tery of protective cells in which the cadavers are more numer-
ous than the particles of soil! But what is this exposed surface
when compared with the vast immunizing field which the capil-
lary system represents and into which the contraction of the
central vascular trunks incident upon adrenal overactivity
forces, not only the poison, but the laboratory in which it is
formed?

We can now understand, it seems to us, why the virulent
toxins of the diphtheria bacillus accumulate so rapidly in the
blood-stream and soon cause what any other virulent poison
does: i.e., arrest of adrenal functions, after the preliminary
signs which denote the stage of insufficiency. . . . "The pal-
lor is extreme; the face has an ashen-gray hue," writes Osier;
"the pulse is rapid and feeble, and the temperature sinks
below normal." We can understand also how antitoxin acts and
why delay in its use compromises the issue; indeed, why it in-
sures death in a severe case. The trypsin of the antitoxin finds
in the plasma the fibrinogen and oxidizing substance it requires
to develop its full energy, and it soon converts the toxins into
harmless agencies. But this only occurs when organic lesions
have not been given time to hamper the mechanism of the vital
processes; that is to say, when necrotic foci in the liver, heart,
pancreas, spleen, etc., have not been given time to form, and
while the adrenal system is still able to recover its functions.

And we have evidence of the adrenal system's work in
some cases; for what are the eruptions and other untoward
phenomena that occasionally follow the use of antitoxin but
evidences that the blood is loaded with waste-products that the

760 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

normal channels cannot eliminate with sufficient speed? In-
deed, these eruptions show that the scales have been turned;
that antitoxin — devoid itself of all toxic attributes when pure
— has conquered its foe, and that the immunizing field, the
peripheral capillary system, is ridding itself of the remains of
the fray. That the following conclusions are warranted seems
to us evident: —

While the Hood-stream in diphtheria is adequately supplied
with oxidizing substance and fiHrinogen, it is deficient in trypsin;
hence, toxins rapidly accumulate.

The active principle of antitoxin being trypsin, it becomes
active in the Wood-stream owing to the presence therein of the
fibrinogen and oxidizing substance, and converts the toxins into
benign cleavage products.

Antitoxin is curative if used sufficiently early in diphtheria,
and harmless if used in any disease with which diphtheria may be
confounded.

Tetanus. — This is another disease in which bacilli have
been found only at the seat of inoculation, but not in the
blood. The toxins are developed so rapidly, however, that, as
shown by Kitasato, only animals from which the inoculated area
had been excised one-half hour after inoculation remained well.
All the conditions reviewed under the last heading, namely:

(1) the absorption of trypsin by leucocytes and erythrocytes,

(2) the impossibility on the part of the phagocytes to protect
the system by destroying the source of the toxins, prevail, there-
fore, and it is the only disease which has afforded any evidence
of remote kinship with diphtheria as regards the effects of anti-
toxin when used early.

But here another course of events is inaugurated. We are
not dealing with a poison which tends first to stimulate the
adrenal system and then, by exhausting the anterior pituitary
body, to bring on insufficiency soon followed by arrest of adre-
nal functions, but with a virulent toxin which does not, to
any extent, primarily stimulate this system. Insidiously, and
almost from the start, it gives rise to adrenal insufficiency, and
steadily the products of metabolism accumulate in the blood.
We have throughout this work given reasons that seem to us
to demonstrate that the toxin is not the direct cause of the

THE LIMITS OP SERUM-THERAPY. 761

tetanic convulsions, but that these should be ascribed to the
accumulation of products of metabolism incident upon in-
hibited oxidation. Tetanus neonatorum, epilepsy, hydrophobia,
eclampsia, etc., are kindred conditions, as we shall see in an-
other volume. Care must be taken, however, not to confound
the convulsions induced by these various forms of sepsis with
those observed in strychnine poisoning. This form of "tetanic"
convulsions is due, we have seen, to hyperoxidation.

Tetanus antitoxin would undoubtedly show far better
results than can now be credited to it judging from the litera-
ture of the subject, could it be used, not when the convulsions
have begun — the second stage — as is now generally the case,
but very soon after the receipt of the injury: i.e., before the
adrenal functions are seriously compromised. But how distin-
guish the exposed cases when we know that even slight injuries
may initiate the morbid process when received in stable-yards,
gardens, roads, etc., the bacillus being a common saprophyte
found in manure, dust, soil, etc.? Better means may perhaps
suggest themselves in the next subdivision of immunity to be
considered.

What shall we say of the multiplicity of other sera that
have been introduced from time to time: the antistreptococcic,
antipneumococcic, antituberculous, antivenomous, and the
more recently introduced sera calculated to combat the plague,
dysentery, yellow fever, scarlatina, anthrax, leprosy, glanders,
pertussis, syphilis, malaria, and other disorders? Herein lies,
it seems to us, the misleading factor which has suggested that
specificity could be considered as an element of these various
sera. Indeed, all these agents are beneficial because they all
stimulate the adrenal system — as does any active agency intro-
duced into the blood-stream. But they are not specific, if our
views are sound; they only differ essentially in the proportion
of trypsin they contain: the unused product of the artificially
stimulated adrenal system of the purveying animal.

Briefly the following conclusions seem to be warranted by
the foregoing data: —

1. Precisely as is the case with drugs, so do the different
toxins stimulate the anterior pituitary body with more or less vigor,
or depress its functions.

762 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

2. Precisely as is the case with drugs, so are the different
toxins endowed with specific attributes, each toxin reacting prima-
rily upon the anterior pituitary body in its characteristic way.

3. The various sera introduced, including antitoxin, are all
similar in the sense that they contain the same constituents, the
dominant active principle in all being trypsin.

Still, the use of the many sera introduced has shown that
they differ from one another symptomatically, and in a way
which trypsin, alone, in the light of our statements, could not
explain. Even a cursory review of these effects will show, how-
ever, that we are dealing with symptoms that denote a mere
increase in dosage of certain secondary constituents — a feature
which accounts for our use of the word "dominant" in respect
to trypsin as an active principle. Which are these secondary
constituents? "We have emphasized the fact that an increased
production of trypsin was caused when a toxin or any other
poison in the blood-stream enhanced the functional activity of
the adrenal system, because that of the spleen and pancreas
was also enhanced, though secondarily. That the functions of
the thyroid gland, under these circumstances are likewise raised
to inordinate activity is self-evident. The use of a specific
toxin, therefore, must indirectly cause this organ to supply the
blood with a proportion of thyro-iodine commensurate with its
ability to stimulate the adrenal system. It seems clear to us,
therefore, that: —

4. The various antitoxic sera are more or less active in pro-
portion as the quantity of thyro-iodine contained in them is great.

5. The proportion of thyro-iodine in a given serum is com-
mensurate with the degree of stimulation to which the adrenal
system of the supply-animal is subjected by the toxin employed to
obtain this serum.

But this introduces another factor: i.e., the part played
in the effects of the serum by the agencies added to it to insure
its preservation, i.e., carbolic acid (Behring), camphor (Roux),
trikresol (Aronson), etc. They are all adrenal stimulants, fort-
unately, and can only, therefore, enhance its effectiveness.
Still, they are all capable of giving rise to phenomena that
may suggest specific qualities quite foreign to the serum itself,
and which drugs, judiciously handled, can replace with advan-

ARTIFICIALLY PRODUCED IMMUNITY. 763

tage. It seems to us, therefore, that we can legitimately con-
clude that: —

6. The use of antitoxic serum or of the various sera intro-
duced is only indicated in morbid processes characterized by a de-
ficiency of trypsin.

In all other pathological conditions drugs are productive
of better effects, because these can be scientifically controlled.

ARTIFICIALLY PRODUCED IMMUNITY.

The foregoing deduction seems to us to embody a far-
reaching meaning in connection with the subject which is now
to claim our attention. If the entire domain of immunity is
scrutinized, it will become apparent that the effects of all
inoculations are similar: they all react more or less promptly
and more or less vigorously upon the adrenal system; and
upon the character of this stimulation depends the duration of
degree of the protection conferred upon the inoculate^ sub-
ject. Here we no longer have as active factors benign sera of
varying strengths which require two complementary bodies in
joint action to manifest their beneficial activity; we are deal-
ing with toxalbumins, far more active than many of the more
potent alkaloids of our pharmacopoeia, but which present the
same physiological attributes as alkaloids and all drugs and
toxins.

Still, a distinction asserts itself in this connection, which
will serve to give each of the forms of immunity artificially
produced its true physiological bearing. Indeed, we' must not
lose sight of the fact that there is a difference of vast practical
importance between the action of a dose of toxins introduced
artificially into the blood-stream and the manner in which a
disease is developed in the organism either through the en-
trance of pathogenic germs directly into the blood or, as in
diphtheria and tetanus, through the intermediary of a periph-
eral focus of these germs. Whether these myriads of toxin
laboratories be in the blood or outside of it matters little as
long as their products enter the blood. Disease means the in-
troduction of these sources of toxins, which rapidly increase in
number in blood devoid of trypsin, while artificial immuniza-

764 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

tion means the introduction not of the bacteria, but of their
products: the toxins themselves. These do not reproduce any
more than the alkaloids of plants reproduce; they react with
more or less vigor upon the adrenal system, precisely as do
these alkaloids or other drugs. Indeed, if, instead of "toxins,"
they were called, as are alkaloids, "medicines," their use would
inspire no more fear of complications than do the former, and
their true, position in therapeutics would be accorded them.

Hydrophobia. — The distinction may perhaps be more
clearly shown by briefly submitting our interpretation of the
manner in which this dread disease is developed in the organ-
ism, and the difference between this process and that following
vaccination against rabies, as practiced at the Pasteur Institute
of Paris.

Have we in the wound, as in the case of tetanus, a focus
from which toxins are gradually developed? Bacteriologists
have not as yet determined the nature of the exciting agent of
rabies, but the development of the disease recalls that of tet-
anus. As is the case with the toxins of the tetanus bacillus, the
potential of the toxic body of rabies is such that the stage of
adrenal stimulation passes practically unperceived, and the ad-
renal system gradually lapses into insufficiency. The amount
of trypsin, oxidizing substance, and fibrinogen in the blood
and cells is reduced in proportion, though life's processes con-
tinue, and waste-products are continuously being elaborated.
The day finally comes, however, when the accumulation of phys-
iological poisons is such that the usual symptoms, including con-
vulsive paroxysms, i.e., the rabies, appear. But why does the
blood of a rabid animal never contain the virus?

We are incidentally afforded another proof of the correct-
ness of our views in two of the leading newer conceptions we
have submitted: i.e., the principle that toxic elements are de-
stroyed in the peripheral capillaries by contraction of the mus-
cular vessels from which they receive their supply; and the
identity of the minute elements of the central nervous system
as blood-channels. That the cerebro-spinal system is the seat
of accumulation of the virus of hydrophobia, and that Pasteur,
whose genius will serve as beacon for all generations, employed
the desiccated medulla of rabbits in his vaccination against

ARTIFICIALLY PRODUCED IMMUNITY. 765

rabies, need hardly be recalled, — any more than the fact that
by using medullas in various stages of desiccation he was able,
with Eoux and Chamberland,' to completely immunize dogs
from the bites of rabid animals.

When the method is employed in human beings, a small
piece of desiccated cord is rubbed up in sterile bouillon and
some of the fluid thus prepared is injected at intervals.
Wherein does this method differ, in the light of our views,
from injections of an equally active alkaloid? Simply in this:
We have seen that poisons differ as regards the energy with
which they stimulate the adrenal system; by using the toxin
of a given bacillus we are at least reasonably certain that the
vigor with which the adrenal system will be stimulated will
prove adequate to cause the production of sufficient oxidizing
substance, fibrinogen, and trypsin to fully master the morbid
process: a result which a weaker agency might fail to insure.
There is a degree of precision in the use of the methode in-
tensive, therefore, that the use of other agents to offset the
disease would not afford.

Still, we have only, so far, referred to the manner in which
the morbid effects of germs and toxins are counteracted; an-
other question presents itself, however: i.e., How is the im-
munity prolonged, as it is by vaccination against small-pox,
for example, and various diseases? This may be illustrated by
a brief reference to vaccination.

Vaccination against Small-pox. — In this method, as now
practiced, the "lymph" obtained from pocks of young calves is
the inoculating agent. The nature of the infecting agent as
in the case of rabies has remained undiscovered; but it evi-
dently differs as to its mode of action from that of the virus of
the latter disease, since, instead of insufficiency, it gives rise to
a febrile reaction and other phenomena of marked adrenal over-
activity. That this adrenal reaction sometimes exceeds its nor-
mal limits is illustrated by the cases of tetanus that have been
recently observed after vaccination. Under these circumstances
adrenal insufficiency occurs precisely as in true tetanus, but is
preceded by a primary stage of overactivity which the adrenals
of the various subjects are not able to stand.

We have clear evidence here that inordinate functional

766 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

activity of the adrenal system has been excited; but this means
that all organs concerned in the immunizing process, besides
the adrenals, the, spleen, pancreas, etc., and the various struct-
ures concerned in leucocytogenesis, have been roused. Indeed,
the period between the moment of inoculation and the entire
disappearance of the virus from the blood-stream represents a
continuous stage of greatly exaggerated function — akin to that
to which .the subject would have been submitted had he gone
through the disease. The adrenal system and all the other
organs the functions of which it energizes, have, during all this
time, been the seat of unusually active nutrition, and the return
to their previous condition is by no means sudden. Indeed, it
occupies years sometimes — the years during which the subject
is immune to the exciting agent of small-pox. Notwithstanding
the severity of the reaction, however, vaccination is likewise
benign because it does not introduce into the blood the source
of the poison, the micro-organism, but a minute dose of the
poison itself, which cannot therefore increase in quantity or
power.

The foregoing conception of the manner in which pre-
ventive "inoculations" — an unfortunate term, by the way —
produce their beneficial effects, seems to us applicable to all
measures of this kind, whatever be the disease from which pro-
tection is sought. The recent favorable evidence recorded by
British army surgeons as to the use of typhoid bacillus steril-
ized cultures in Africa is noteworthy, for we have seen that
fatigue and other untoward features to which a soldier is ex-
posed during campaigns tend greatly to weaken the functional
energy of the adrenal system and, therefore, his vulnerability
to disease. Haffkine's preventive inoculations against plague
have likewise demonstrated their value, etc. Briefly, all forms
of vaccination endow the inoculated subject with enhanced ac-
tivity of the adrenal system and, therefore, of all structures
which take part in the defense of the body.

Natural immunity, i.e., the innate power to resist disease,
is ascribable, it seems to us, to identically the same cause. Of
course, the susceptibility of some individuals to certain diseases
while they are immune to others is not to be overlooked; but this
introduces features of another kind that will receive attention

IMMUNIZING MEDICATION. 767

in another volume. These features, however, do not modify the
position of the adrenal system in all processes connected with
immunity and, we may add, with the pathogenesis of all gen-
eral intoxications. Indeed, all the testimony and lines of
reasoning we have adduced seem to us to warrant the conclu-
sion that: —

The power of the organism to antagonize the constitutional
effects of pathogenic germs, their toxins, and other poisons, is di-
rectly proportionate, all else being equal, to the functional efficiency
of the adrenal system.

IMMUNIZING MEDICATION.

The foregoing conclusion obviously suggests that since cer-
tain remedies greatly increase, even when administered by the
mouth, the functional activity of the adrenal system, we might,
by the judicious use of such remedies, protect the organism
against pathogenic germs, their toxins, and all poisons that
the protective apparatus can overcome when its efficiency is
raised to its highest potential. In other words, it suggests
that, prior to exposure to infectious diseases or during epi-
demics, after injuries received in places thought to contain
tetanus saprophytes, after bites from presumably rabid animals
or from venomous animals, etc., we might be able to cause,
in our blood-stream, a sufficient accumulation of phagocytes,
trypsin, fibrinogen, and oxidizing substance to offset the life-
destroying tendency which all these bodies exhibit. The con-
tents of this entire work seems to us to sustain such a de-
duction.

If we recall the energy with which certain agents: quinine,
for instance, force blood into the peripheral capillaries, by
causing contraction of the central vascular trunks and other
vessels supplied with muscular walls, it will become apparent
that the presence of this remedy in the blood not only excites
the adrenal system to unusual activity, but that the vast im-
munizing field of the organism is being utilized to destroy the
alkaloid. The headache and the superficial heat, the suffused
face, the hard pulse, etc., testify to this. But we are dealing
with an inoffensive agency, — if properly used, — and its value
as a prophylactic has been emphasized by those writers who

768 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

speak from the standpoint of experience, including Laveran and
Maurel. Now that the source of the parasite has been traced
to the mosquito,, we can readily understand the nature of the
prophylactic process, i.e., dissociation of the morbific agent in
the peripheral .capillaries into which the system's protective
agencies have accumulated. But quinine is not the only agent
capable of producing this effect: arsenic, ammonium muriate,
apiol, strychnine, and other drugs have each been lauded by
various observers and evidently on good ground, if, as we
believe, the majority of drugs more or less actively stimulate
the adrenal system.

Among the agents recommended for the same purpose,
i.e., as a febrifuge, is carbolic acid, Treulich,97 Declat,98 and
Einger," among others, having recognized its value as a proph-
ylactic. Though it is not to be recommended as such against
malaria, this agent is nevertheless shown by this feature of its
physiological action to also produce engorgement of the pe-
ripheral capillaries owing to its effect upon the adrenal system.

Packard and Willson,100 to whose article we have already
referred, speak of the treatment of tetanus in the following
terms: "Baccelli states that of 40 cases of tetanus treated with
carbolic acid subcutaneously only 1 died; and Pinna notes
statistics, compiled by Ascoli, of 33 cases treated by Baccelli's
method with only 1 death." While they correctly state that no
such results are reached in other countries, the fact remains
that results vouched for by an investigator of the rank of
Baccelli command confidence. It suggests that we should look
elsewhere for the untoward results obtained in other countries.
That the simultaneous or previous administration of cannabis
Indica, chloral, the bromides, etc., commonly used in tetanus,
and which, in the light of our views, react upon the adrenal
system much as does the tetanus toxin itself, account for these
untoward results seems to us very clear. Indeed, the use of
such remedies besides Baccelli's carbolic-acid treatment can have
but one result: i.e., adrenal insufficiency. If, on the other

"Treulich: Medical Age, vol. 1892.
w Declat: Gazette Hebdomadaire, vol. xvii, 1880.
99 Ringer: "Hand-book of Therapeutics," 1897.
100 Packard and Willson: Loc. cit., p. 1023.

IMMUNIZING MEDICATION. 76D

hand, Baccelli's method is alone resorted to, and the drug be
administered in doses no larger than those he recommends, we
feel confident, if our views are' sound, that the results obtained
in all countries will but coincide with his own. Suffering may
require the use of morphine; fortunately, this agent also stimu-
lates the adrenal system, when given in therapeutic doses.

But Baccelli's clinical experience with tetanus when coup-
led with our views seems to us to suggest a far-reaching appli-
cation of such energetic adrenal stimulation. Indeed, we have
fully emphasized throughout this work the kinship between all
conditions attended with convulsions. The main disorders which
may be classed as such are: epilepsy (other than purely traumatic),
puerperal and infantile convulsions, and hydrophobia. Though
the latter disease is the only one of the three which presents
a direct analogy to tetanus as regards primary cause, i.e., an
exogenous virus, the convulsion-producing factor is neverthe-
less the same in all: i.e., an accumulation in the blood-stream
of toxic waste-products incident upon adrenal insufficiency. It
follows, therefore, that a treatment similar to that which Bac-
celli employs in tetanus should also prove effective in all these
affections, since it becomes evident that carbolic acid is able
not only to counteract the insufficiency of the adrenal system,
and cause the latter to resume its normal functional activity,
but also to raise this activity ~beyond the normal, flood the cir-
culation with its defensive and offensive weapons, and convert
the enemies of the organism into benign elements.

Arsenic is another agent that has been found of great
value in malaria. Boudin,101 one of the pioneers in its use as
a prophylactic agency, introduces a suggestive remark which
acquires considerable weight when the fact that his experience
was acquired while surgeon-general of the French armies in the
field during the Algerian campaigns: "I am assured by suc-
cessive trials, which have been repeated with similar results by
many others, that arsenous acid preserves, in the somewhat
microscopical doses of 1/100 grain, all its medicinal energy, not
only in marsh-fevers, but also in a multitude of other diseases.
Further, I have obtained from 1/100 grain of this remedy the

101 Boudin: "Trait6 des FiSvres Intermittentes," Paris, 1842.

770 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

entire removal of fevers contracted in Algeria and Senegal and
which had previously resisted means of various kinds, including
quinine and change of climate." Indeed, when we consider the
large number of diseases in which arsenic is now recommended,
Boudin's reference to a "multitude" of diseases finds its veri-
fication. As a prophylactic its value has been extolled by C. F.
Bryan in various affections, including scarlatina.

Directly connected with our views is the fact that arsenic,
so extensively employed in skin diseases, is, as stated by Shoe-
maker,102 "valuable in proportion to the absence of irritation
or acute inflammation." It is obvious that a peripheral in-
flammatory process, in the light of our views, means the pres-
ence of the protective elements — indeed, an excessive propor-
tion of them — in the cutaneous tissues. In the so-called chronic
processes, on the contrary, some of which recall, by the dryness
of the skin, the same condition in myxcedema, cretinism, etc.,
the main pathogenic features are the absence of these pro-
tective elements and the lowered nutrition which this normally
involves. Hence the value of arsenic in cutaneous diseases in
which desquamation, dryness, etc., prevail: i.e., psoriasis, the
dry form of eczema, impetigo, etc. The connection of the
curative process with the adrenal system is well shown by the
results obtained by Byrom Bramwell103 in psoriasis with thy-
roid extract. Arsenic, as observed by Gautier (see page 156),
seems to be a normal constituent of various structures, and, we
have seen, is able to counteract the untoward effects of iodine.
If the experience of Boudin, Bryan, and others, which illus-
trates the value of arsenic in a large number of diseases, is
added to that of dermatologists as regards the pre-eminent
value of this remedy in cutaneous diseases in which nutrition
of the skin is impaired, — the whole being traceable, as shown
by BramwelFs cases, to the adrenal system, — the far-reaching
value of arsenic as an immunizing agent seems self-evident.

Of considerable interest in this connection is the stress
laid by C. E. Illingworth104 upon the use of the biniodide of

102 Shoemaker: "Materia Medica and Therapeutics," fifth edition, 1901.
*°» Byrom Bramwell: "Atlas of Clinical Medicine," Plate LXI.
104 C. R. Illingworth: "The Abortive Treatment of Specific Febrile Dis-
orders by the Biniodide of Mercury," London, 1888.

IMMUNIZING MEDICATION. 771

mercury with the view to aborting scarlatina, diphtheria, mea-
sles, variola, varicella, pertussis, parotitis, typhoid fever, typhus,
dengue, relapsing fever, pyaemia, puerperal fever, syphilis, lep-
rosy, the plague, hydrophobia, and yellow fever. In keeping
with some of the views that prevailed at the time, the author
ascribes infectious processes "to the exhausting depredations
of the germs more rapidly and extensively exerted than ordi-
narily upon the oxygen of the corpuscles of the blood"; he also
considers the salt as "germicidal and ha3matinic." While this
interpretation of the nature of the morbid and curative proc-
esses is not in accord with our own, the fact remains that
Illingworth is sustained by our views as regards the legitimacy
of his results. In other words, while he witnessed the results,
we show that such results can be reached, and how they are
reached. Indeed, we will see in another volume that the
biniodide of mercury occupies a high position among the stim-
ulants of the adrenal system, owing mainly to its haloid con-
stituent. The feature that we wish to emphasize by referring
to Illingworth's observations is the efficacy of stimulation of
the adrenal system in arresting incipient morbid processes.

"Abortive treatment" is a familiar expression, and its ap-
plicability is not only exemplified by the experience of the few
authors we have named, but by that of a multitude of them.
The multiplicity of ailments in which a single drug may be
used attests to this. It is, therefore, entitled to a prominent
position in therapeutics, precisely as is, it seems to us, "im-
munizing treatment," an expression which seems to us appli-
cable to the scientific use of remedies for the purpose of pre-
venting disease.

Sera, we have seen, are at best only able to supply two
constituents, i.e., the trypsin and fibrinogen, while appropriate
remedies, by enhancing the functions of the adrenal system,
awaken all the resources of the organism to inordinate activity.

Indeed, in the light of our views, nothing in our pharma-
copeia approaches antitoxin in value in the treatment of diph-
theria, simply because it supplies exactly the missing plasmatic
constituent: i.e.., trypsin. It is probable that the use of fresh
horse-serum will not be found inferior in the treatment of ty-
phoid fever to antitoxin in that of diphtheria, simply because

49

772 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

it supplies precisely the plasmatic constituent required in that
disease: i.e., fibrin ogen. In all other diseases, however, apart
from the unquestionable usefulness of fresh serum in all dis-
orders of an adynafnic type to temporarily compensate for some
component of the blood-stream that is morbidly reduced quan-
titatively, the use of drugs seems to us far preferable, while
essentially susceptible to scientific application. The history of
serum-therapy fully sustains, we believe, our statement regard-
ing the value of sera, but the aggregate of facts we will submit
in another volume seems to us to demonstrate that our con-
fidence in the therapeutic value of drugs is not misplaced.

If our views prove sound, we must frankly express our
belief that they will enable us, as physicians, to master the
greatest scourges of humanity. Indeed, the comparative list on
the opposite page will show that Asiatic cholera is in reality
but the gravest form of adrenal insufficiency, and that many
familiar morbid conditions are its prototypes, notwithstanding
the variety of causative factors.

Besides hygienic means, the prevention and arrest of the
choleraic process and all the kindred disorders mentioned
resolve themselves into these few words: stimulate the adrenal
system. But in doing this it is necessary to remember that
large doses cause insufficiency, while the average therapeutic
dose causes stimulation. We have not been able to master
cholera Asiatica because no agent has been used that was
capable of sufficiently stimulating the adrenal system. East
Indian empirics have found by experience, however, that snake-
venom could cure cholera. We have seen how rapidly venom
can overwhelm the adrenal system; that we have, among our
alkaloids, fully as potent agencies is probable. Trial alone,
however, can show which of these can raise the adrenal system
from the depths into which the cholera toxins — an aggregate
of them — have plunged it, precisely as Baccelli's carbolic-acid
treatment succeeds in doing in tetanus.

Pulmonary tuberculosis is another formidable enemy of
mankind which, in the light of our views, seems subject to a
different interpretation as regards intrinsic pathogenesis. The
vulnerability of the system to the bacillus of this disease is
readily accounted for if, as we believe, the adrenal system,

IMMUNIZING MEDICATION.

773

either through inherited or acquired insufficiency, is unable to
adequately maintain general nutrition. It is not in the lungs,
therefore, that the primary endogenous cause of the disease
must be sought, but in the adrenal system. Nor is it even in

Symptoms that follow : (1)
removal of both adrenals
in mammals ; (2) hem-
orrhage into both adre-
nals ; (3) sudden ces-
sation of adrenal
functions as a result of
organic disease.

Cardinal symptoms of
ASIATIC CHOLERA.

Cardinal symptoms of chol-
era in fan turn, cholera
nostras ; tartar emetic
and arsenic acute poi-
soning ; poisoning due to
ingestion of certain toxic
foods : meat, milk, fish,
and mushrooms (phal-
line) especially.

1. Great weakness,
with gradual loss of
muscular power.

1. Marked muscular
weakness.

1. Rapid loss of
strength.

2. Violent abdominal
pain.

2. Violent griping pain.

2. Abdominal discom-
fort and pain.

3. Great reduction of
vascular pressure;
pulse small and weak.

3. Pulse rapid and
weak ; sometimes in-
termittent.

3. Pulse rapid, weak,
and intermittent.

4. Temperature subnor-
mal just before death
especially.

4. Temperature in
mouth and on surface
very low, but 104° F.
in rectum.

4. Temperature subnor-
mal, but rectal tem-
perature 103° to 105°
F.

5. Raspiration frequent
and difficult ; dysp-
noea ; sometimes cy-
anosis.

5. Respiration frequent
and difficult, and cy-
anosis.

5. Rapid; labored;
Cheyne-Stokes type
sometimes.

6. Urine scanty.

6. Urine scanty ; some-
times suppressed.

6. Urine scanty ; some-
times complete anu-
ria.

7. Abundant liquid
stools.

7. Rice-water ; serous
stools.

7. At first bile-stained
stools, and then noth-
ing but serum.

8. Death ; coma ; con-
vulsions.

8. Coma ; convulsions.

8. Coma ; convulsions.

9. Proves fatal in from
20 minutes to 3 days.

9. Proves fatal in from
2 to 3 days.

9. Proves fatal in from
a few hours to 4 days.

the lungs that we must seek the explanation of the lesions in
them, for the element of specificity of the bacillus of tubercu-
losis does not, as is well known, include limitations to any
particular organ.

774 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

We have seen how dependent upon the adrenal functions
are»those of the heart. Even if the nutrient cells, the neutro-
philes, and the haemoglobin cells, the eosinophiles, were sup-
plied in sufficient numbers (leucocytogenesis being inadequate
when adrenal Insufficiency exists), what would it avail with a
weak heart to send them through their distributing channels?
Indeed, what there is produced of adrenal secretion, life's pabu-
lum, we may say, cannot even pass the alveoli with sufficient
speed to adequately supply not only the system at large, but
the pulmonary tissues themselves with oxygen. Indeed, we have
seen that the activity of function in any organ was commen-
surate with the speed with which the oxidizing substance passed
through that organ. That this also applies to the lungs is
strikingly illustrated by the beneficial effects of high altitudes,
which, by enforcing a marked increase of cardiac activity, pro-
portionally enhance general nutrition, not only of the lungs,
but also that of the adrenal system itself.

But the predominating feature of the morbid process as
regards systemic vulnerability to the disease is that connected
with the protective functions in the alveoli. Since our study of
the subject in the eleventh chapter was submitted, we ascer-
tained that all three varieties of adult leucocytes are present in
this most exposed portion of the organism, and that they all
contain trypsin. As this substance is ejected with their gran-
ules, the eosinophiles, in undergoing conversion into nucleated
epithelium, doubtless eliminate theirs along with their large
haemoglobin granules. The cavity of the lobule and the under-
lying serum must therefore be constantly supplied with this
bactericidal and antitoxic fluid (besides the phagocytic neutro-
philes), when the adrenal system is functionally normal.

Absolute integrity of the adrenal system thus asserts itself
as a sine qua non of perfect immunity against pulmonary tuber-
culosis, i.e., against the intrusion of pathogenic germs of any
kind (and particularly the tubercle bacillus) in the circulations,
not only of the lungs, but also of the intestines. We say "cir-
culations," because the lymph is at least as greatly exposed
to invasion as is the blood, and is a far better medium for the
rapid pullulation of bacteria. Insufficiency of the adrenal sys-
tem, whether inherited or acquired, when sufficiently advanced

IMMUNIZING MEDICATION. 775

to cause hypoleucocytosis, correspondingly weakens the func-
tional energy of the heart, and two cardinal factors thus unite
in rendering the lungs vulnerable to pathogenic elements. As
soon as the tubercle bacillus is admitted, it becomes an addi-
tional source of adrenal insufficiency, owing to the toxins it
generates, and which react upon the anterior pituitary body
precisely as would any other equally virulent poison.

All these features bear with equal force upon the intestinal
infection by this pathogenic micro-organism, for we must not
overlook the fact that trypsin is also secreted into the intestine
by the pancreas. If our views are sound, therefore, Koch is not
sustained when he says that human beings are not susceptible
to bovine tuberculosis; still, this is only true when the intes-
tinal protective functions, including the production of trypsin,
are impaired through adrenal insufficiency. On the other hand,
his views are sustained when perfectly protected human beings,
i.e., subjects possessed of an adrenal system in full functional
activity, form the basis of his deductions.

The value of immunizing medication seems to us to cover
a vast field of usefulness in this connection. The family his-
tory, and many other features considered as etiological factors
of tuberculosis, afford landmarks for the adoption of preventive
medication long before the morbid process has had time to
develop, — long, indeed, before infection can have occurred.
During adolescence, for example, particularly when the family
history is unfavorable, medication calculated to raise or de-
velop the functional activity of the adrenal system to a high
standard, must, in the light of the views submitted, not only
prevent the development of pulmonary or any other form of
tuberculosis, but arrest it in its earlier stages.

Pneumonia, the mortality of which remains the same not-
withstanding the material improvement in that of phthisis, does
not present the characteristics of disease susceptible to preven-
tion. Indeed, lobar pneumonia, for instance, seems to us to
exemplify a process wherein death occurs owing to excessive
functional activity of the adrenal system. This is shown espe-
cially by the hyperleucocytosis, the high fever, the flushed face,
the high temperature, the bounding pulse, etc. The conception
is furthermore sustained by the remarkable results (a 2.64-per-

776 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

cent, mortality) reported by Petresco105 with very large doses
of infusion of digitalis, and by a large number of clinicians with
veratrum viride, but only when used during the sthenic stage.
In the light of our views these agents, which normally bring
on adrenal insufficiency, lower the excessive adrenal activity of
pneumonia sufficiently to prevent the dangerous engorgement
of the first stage, and, therefore, that of gray hepatization and
its main consequence: the asthenic stage. In the latter, of
course, the adrenal system must be supported, but with due
care, owing to the increased likelihood of adrenal insufficiency.

Insanity, when due to factors other than structural
changes, seems to us to present many phases that are directly
traceable to insufficiency or overactivity of the adrenal system.
The splendid studies of Andriezen and Berkley have enabled us
to show the morbid effects of adrenal overactivity as caused by
alcohol, ricin, etc., upon the neurons and the structures that
supply them with their plasma: i.e., with oxidizing substance.
Since then, we have seen that leucocytosis also means an ex-
cessive supply of the primary source of energy: i.e., of myelin
granules. We therefore have, as a result of the excessive use
of any agent capable of exciting the adrenal system, not only
the mechanical dilation or beading of the dendrites shown in
the plates we have reproduced, but excessive metabolism within
the neurons. That exaltation, the various forms of mania, etc.,
should develop under such conditions, particularly in individ-
uals predisposed to mental disorders through inherited cerebral
malnutrition, is self-evident. On the other hand, a similar pre-
disposition, or continued cerebral malnutrition incident upon a
debilitated adrenal system, can normally become a cause of the
various forms of melancholia, dementia, idiocy, etc. We have
traced cretinism to adrenal insufficiency, and have adduced evi-
dence tending to prove that absence of the thymus — the main
active factor of which is phosphorus — coincided with idiocy in
a large proportion of cases. What have we here but impaired
nutrition of the cerebral structures through insufficiency of
their main dynamic elements: phosphorus and oxygen?

Immunizing medication here can obviously render great

106 T. G. Ashton: "Sajous's Analytical Cyclopaedia of Practical Medicine,"
vol. v.

IMMUNIZING MEDICATION. 777

service, but only when the pathogenesis of each form is thor-
oughly established. Some cases of acute mania, for instance,
may require stimulation of th*e adrenal system, simply because
the engorgement of the neurons may find its cause, not in an
exogenous poison, but in accumulation of physiological toxics,
which, as is the case in epilepsy, tetanus, etc., give rise to sud-
den exacerbations of adrenal activity: i.e., to explosions of
functional activity calculated to rid the organism of the mor-
bific agencies by L process of active combustion.

Another feature which must not be overlooked in mental
disorders is the influence exerted upon them of fluctuations in
the functional activity of the posterior pituitary body. As the
sensorium commune, it necessarily takes part in all emotional
states. Indeed, hysteria appears to us to be essentially a dis-
order of the posterior pituitary body. This organ, as may
readily be surmised, is likewise the seat of perturbations at-
tended by a distinct line of symptoms. Influenza, hay fever,
neurasthenia, neuralgia, and several other obscure neuroses are
all, in fact, syndromes in which the posterior pituitary body
plays a leading part. In diseases of the heart, vascular system,
digestive apparatus arid skin, this organ necessarily takes part in
the production of the phenomena witnessed, owing to its iden-
tity as the general center of vagus.

Syphilis. — Although the influence of the posterior pituitary
body in all these processes has necessitated a special line of
analysis that will be submitted in another volume, we may here
refer to the fact that simultaneous impairment of the functions
of both the anterior and posterior pituitary bodies accounts for
the ravages of syphilis. Indeed, we have seen that these two
organs are the governing centers of all vital processes; it is
these, therefore, that this fell disease undermines. That such
is the case is not only suggested by the inquiry to which we
refer; it is also revealed by the character of the agency which
best overcomes its more advanced stages: i.e., the medicinal
prototype of Nature's own adrenal stimulant: iodine, — but so
combined with a normal constituent of the blood-stream, potas-
sium or sodium, as to further assist the vis medicatrix natures
itself.

Indeed, if our views are sound, the adrenal system is the

778 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

physician of the organism — one whose beneficient mission we
can govern at will by the many valuable agencies which science
has placed in our hands.

ALKALINITY OF THE BLOOD AND THE PRESERVATION
OF LIFE DURING DISEASE.

We began this chapter with an allusion to the remark-
able life-saving value of saline solution. As is well known,
the alkaline reaction of the blood is exceedingly marked,
and is mainly due to the sodium salts the serum contains.
Charrin106 gives this reaction the first place among the protect-
ive properties of the blood and body-fluids, and rightly deems
it an essential condition of normal life. When it is reduced
through alimentation, abnormal fermentation, the virulence
of various micro-organisms, and deviations from the normal
chemical reactions of which the body-fluids, etc., are the seat,
correspondingly marked disturbances in the blood occur, with
disease as a result.

Furthermore, the globulins, which normally contain 6
per cent, of potassium salts and e/io °f 1 Per cent, of sodium
salts, and the albumoses are kept in solution in the plasma by
these salts. Chloride of sodium, besides this role, facilitates
osmosis and diapedesis. When it is recalled that several
grammes of this salt pass out of the organism in the urine
daily, probably assisting in the excretion of waste-products,
besides the two grammes which are eliminated with sweat, its
role in the preservation of conditions favorable to the main-
tenance of tissue-metabolism becomes evident. The di-sodium
phosphates, found in all tissues and fluids, usually in asso-
ciation with the sodium carbonates, are active in insuring the
alkalinity of the plasma, the lymph, the pericardial fluid, the
cephalo-rachidian fluid, the mucus (excepting the vaginal), the
tears, the milk, the synovia, the spermatic juice, the aqueous
humor, the saliva, the bile, the pancreatic juice, and the large
intestine. The sulphates of sodium and potassium are also
found in the majority of the above fluids, along with other
salts in smaller proportions. This alkalinity is of great indirect
importance in another direction: i.e., it enables the blood to

108 Charrin: "Les Defenses Naturelles de 1'Organisme," 1898.

LIFE AND ALKALINITY OF THE BLOOD. 779

carry an adequate quantity of C02, and thus assists it in effi-
caciously ridding the organism of this gas.

The classical teachings in respect to the importance of the
blood's alkaline reaction in all vital functions are not only sus-
tained by our labors, but greatly emphasized in view of the
manner in which the various leucocytes we have studied dis-
tribute their granules of peptone, myosinogen, fibrinogen, hem-
oglobin, and myelin. Any modification in the fluidity and con-
stituents of the plasma must necessarily compromise this all-
important function, and, if we recall the fact that chloride of
sodium takes part in the intranuclear reaction of all leucocytes,
it will become apparent that the presence of this salt in ade-
quate proportion in the plasma is as paramount to the con-
tinuation of life's processes as is oxygen itself. Even trypsin
will, not act in the absence of salts. Metchnikoff, we have seen,
found that trypsin was the active body of the intraphagocytic
alexin; referring to the latter, he writes107: "It only acts in the
presence of salts. When relieved of its salts by dialysis, the
serum loses its haemolytic power, but, as soon as these salts are
restored to it, this power reappears."

The remarkable results obtained by the timely administra-
tion of saline solution either subcutaneously, intravenously, or
by way of the rectum in febrile diseases, uremia, puerperal
eclampsia and other infections, haemorrhage, etc., and which in
some cases have restored sufferers deemed to be in extremis, are
thus accounted for. Indeed, some of the instances reported
could almost be considered as resuscitations.

Experimental bacteriology forcibly shows the importance
of the alkaline reaction of the blood-fluids as a protective
factor. The experiments of Behring and Nissen108 led them
to conclude that the resistance of the white rat to anthrax was
due to the intense alkalinity of its blood; Paul109 not only
supported this view, but also found that, if the alkalinity of
rabbit's serum was neutralized, its germicidal powers disap-
peared.110 These observations were further sustained by von

107 Metchnikoff: Loc. cit., p. 93.

108 Behring and Nissen: Zeitschrift flir Hygiene, Bd. vii, 1890.

109 Paul: "Proceedings of the Royal Society," London, May 22, 1890.

110 McFarland: "Pathogenic Bacteria"; edition, 1900.

780 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

Fodor,111 who ascertained that this resistance to anthrax could
actually be increased in rabbits by the injection of an alkaline
solution, and by Blumenthal,112 who experimentally found that
the formation of bactericidal products in the circulation de-
pended upon the- degree of the blood's alkalinity. Calabrese,
of Naples/13 also conducted a series of valuable experiments in
this connection. He immunized animals with attenuated, viru-
lent cultures of bacterial toxins at different times, and deter-
mined the degree of alkalinity in each instance by an accu-
rate dosimetric method. He invariably found the alkalinity
of the blood to increase with the degree of immunization, and
the alkaline reaction only attained its maximum when the ani-
mal had become totally refractory/ The blood reacted toward
the toxic agent by a very gradual, though persistent, increase of
the alkalinity. Healthy, non-immunized animals, on the other
hand, first showed a more or less sudden evidence of alkalinity,
but this declined, and the fall became marked during the few
hours preceding death.

In the face of such evidence, to which much more could be
added, we can certainly ascribe to the alkaline salts of the
blood a most important part in the protective process. But
how do they exercise their function? Evidently not as neu-
tralizing factors, as already stated, but in virtue of an action
directly exercised upon the fluids or cellular elements. And
"cellular elements" mean more than the generally accepted
sense given these words, if our views are sound, for they in-
clude the leucocytes and erythrocytes, the general center of the
protective system itself, the anterior pituitary, and its co-center
in preserving vital functions: the posterior pituitary body.

Indeed, the adrenal system asserts itself in a new capacity
in this connection, for experimental evidence suggests that, in
addition to its other functions, it also governs the alkalinity of
the blood. Thus, von Fodor also found that, when rabbits
were infected with anthrax, typhoid, cholera, tuberculosis, and
erysipelas toxins, the alkalinity of their blood rose, but declined
as the effects of the disease became more marked. Cantani

"i Von. Fodor: Centralbl. fUr Bakt. u. Parasit., vol. vii, 1890.
"2 Blumenthal: Zeitschrift fur klin. Med., Bd. xxviii, 1895.
113 Calabrese: La Semaine M6dicale, Oct. 30, 1895.

LIFE AND ALKALINITY OF THE BLOOD. 781

observed the same phenomenon under the use of diphtheria tox-
ins. The influence of the adrenal system also becomes evident
through the facts (1) that the'increase of alkalinity only showed
itself two hours after the poison had been injected; and (2)
that it slowly increased until the twentieth hour had been
reached, then gradually fell, returning to the normal when a
period of three days had elapsed. In another series of experi-
ments, performed with the collaboration of Rigler,114 von Fodor
adduced suggestive evidence. In this series he observed that
the intensity of the symptoms varied with the dose of toxin
injected: moderate doses increasing the alkalinity, while very
large doses caused it to decrease. Again, an important clinical
feature: while the injection of diphtheria toxin lowered the
alkalinity of the blood, injections of antitoxin raised it. Finally,
we have shown how clearly leucocytogenesis was dependent
upon overactivity of the adrenal system: Lb'wy and Richter,115
in a series of experiments with hemialbumose, spermin, pep-
tone, and antitoxin in rabbits, noted that the increase of white
cells kept pace with that of alkalinity. It therefore seems clear
to us that: —

1. Both leucocytosis and increased alkalinity of the Uood are
concomitant results of the enhanced functional activity of the ad-
renal system induced by toxics.

2. It is only when the alkalinity and fluidity of the 'blood-
plasma are approximately normal that all cellular elements of the
organism, including the adrenal system and the posterior pituitary
body, can continue their functions.

The lethal tendency engendered by a deficiency of salines
in the blood during disease is not only due to the fact that
cellular metabolism is inhibited through the increased density
of fluids and cells, but there is another factor which contributes
materially to augment the morbid results of such a condition:
i.e., the primary prophylactic process itself. Indeed, in virtue
of the principle we now have so frequently emphasized, the
various poisons, toxins, toxalbumins, etc., awaken a defensive
reaction in the organism by primarily stimulating the adrenal
system. But in doing this it augments to an inordinate degree

114 Rigler: Centralbl. fur Bakter., Feb. 6, 1897.

118 Lowy and Richter: Deutsche med. Wochenschrift, No. 33, 1897.

782 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

the combustion processes and simultaneously the physiological
consumption of the salts.

If we now seek for a compensative supply, it soon becomes
evident that none is available.

During health the sodium chloride needed by the organism
is ingested with the food, both as a condiment and as a con-
stituent of meats, vegetables, etc.; the alkaline phosphates
and the sulphates likewise form part of our diet, the latter
salts being also obtained from most drinking-waters. As to
the alkaline carbonates, they are products of dissociation of
acids ingested with vegetables and fruits. All the alkaline
salts referred to are thus ingested with foods or beverages.
During disease, on the other hand, anorexia, the restricted or
modified diet, etc., involve, if anything, a marked reduction
in the amount of alkaline salts ingested. It thus becomes evi-
dent that a morbid cycle exists, in this connection, pernicious
in the extreme to the welfare of the patient in febrile disorders,
because, the source of these salts being external to the organism,
the latter is possessed of no intrinsic reserve. Steadily, as the
febrile process advances, the alkaline salts are consumed, and,
being inadequately renewed, the vital and defensive functions are
increasingly hampered until life ceases.

There is still another phase of the morbid process which
further increases the lethal tendency: i.e., the fact that, while
the alkaline salts are being reduced through the foregoing
factors, the increased prophylactic activity of the adrenals
correspondingly augments the vigor of tissue-metabolism and
causes accumulation of waste-products. We thus have a new
source of intoxication added to that incident upon the disease
itself.

Besides the aggravation of all symptoms which this engen-
ders,— a source of considerable confusion in diagnosis, — this
complication easily accounts for a perplexing experimental re-
sult reported by Charrin and Langlois to which we have already
referred: i.e., the fact that an animal from which one adrenal
has been removed lives longer after pyocyaneous culture in-
fection than a normal animal poisoned in the same way. Op-
penheim116 more recently confirmed this observation with diph-

116 Oppenheim: Comptes-rendus de la Soci€t6 de Biologic, March 16, 1901.

LIFE AND ALKALINITY OP THE BLOOD. ; 783

theria toxins. It seems to us that the animals deprived of one
adrenal were correspondingly less exposed to excessive tissue-
waste under the stimulating influence of a toxin than those
possessed of both their organs. Through the excessive metab-
olism at first induced in the latter, soon followed by adrenal
insufficiency and inhibition of all oxidation processes, toxic
waste-products were added to the toxin, thus submitting the
normal animals to the effects of two poisons, while the mu-
tilated ones suffered from those of only one.

If this factor is added to those previously described, the
absence of plasmatic salts not only hampers the vital and de-
fensive functions of the organism, but it soon becomes an in-
direct source of general toxcemia which insures a fatal result even
in relatively benign cases.

A disease in which the mortality has remained practically
unabated, notwithstanding the quantity of faithful work de-
voted to the elucidation of its pathology and treatment, is
pneumonia. This seems to us accounted for mainly by the fact
that the functional dependence of leucocytes upon the chlorides
has been entirely overlooked. Metchnikoff states, we have seen,
that trypsin only acts in the presence of salts, and that serum
loses its haemolytic power when relieved of them; again, we have
referred to the experiments of Kossel, which suggest that al-
kaline salts are factors in the intranuclear reactions. The rela-
tively enormous excess of leucocytes which invade the lungs
during the primary stage of this disease necessarily involves the
use of a correspondingly great quantity of these salts, the nu-
cleus and the trypsin soon appropriating all those available.
How are these salts replaced? The answer readily appears in
the light of the foregoing deduction: In a large proportion
of cases they are not replaced, and death occurs.

Frederick P. Henry, of Philadelphia, who was the first cli-
nician to resort to this measure (1889), says117: "The surest
method of conveying water to the tissues is by subcutaneous
injections of (deci-) normal saline solution: a solution of com-
mon salt of the strength of 50 grains to a pint. About three
years ago a number of cases of pneumonia at the Philadelphia

117 Frederick P. Henry: Hare's "System of Practical Therapeutics," first
edition, vol. ii, p. 290, 1892.

784 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

Hospital were treated by the writer in this manner and with
excellent results, both as regards palliation and cure."118 This
method was also used by him in the worst types of lobar pneu-
monia met with: i.e., those that occur in drunkards, alcoholic
intoxication, expo'sure and a debilitated adrenal system incident
to the alcohol habit, concurring to place the patient on the
brink of death almost from the start. After vividly describing
a case of this kind he remarks: "Such cases treated by ordinary
methods terminate, as a rule, with few exceptions, in death.
Such cases treated by hypodermoclysis terminate, as a rule, in
recovery." In the light of our investigations, the immediate
use of this measure, i.e., as soon as the diagnosis is established,
becomes imperative, and the fact that even during health about
V2 ounce of chloride of sodium alone is voided with the excre-
tions in twenty-four hours (Purdy), points to the need of its
frequent introduction into the organism during disease.

Again, it seems to us that the mortality of diphtheria
could still be further reduced were the saline solution consid-
ered as a necessary accompaniment of antitoxin injections. In
all the diseases to which we have referred in the foregoing
pages, tetanus, typhoid fever, scarlatina, and small-pox espe-
cially, a reduction of alkaline salts in the blood-stream can like-
wise, it seems to us, be distinctly discerned; and, if our inter-
pretation of the scheme of life is not erroneous, most of them
owe their lethal tendency mainly to this cause. Even apart
from the more exact solutions employed, mere rectal injections
of a solution composed of chloride of sodium, one drachm to
the pint of water, at 104° F. (40° C.), renewed once in awhile
have often kept death at bay and insured recovery. Why not
supply the system from the outset of a febrile disease, or, indeed,
any other general disorder, with the constituents that preserve
the mechanical freedom of all nutritional and protective func-
tions, including those of the adrenal system itself? The colon is
also provided with solitary lymph-follicles which supply leuco-
cytes capable of appropriating from the intestinal contents all
useful constituents. The presence of such a fluid in the colon,
judging from the promptness with which some patients revive
when it is used, evidently gives rise to marked activity in this

"8 Editorial, Medical News, July 6, 1901.

LIFE AND ALKALINITY OF THE BLOOD. 785

region, for the process requires rapid production of leucocytes,
followed by absorption of the»injected fluid by the cells and im-
mediate return of the latter to the blood-stream to distribute
their charge throughout the entire organism. In the so-called
"diathetic" diseases, including rheumatism, gout, and migraine,
the use of saline solution enemata, and, if need be, hypo-
dermoclysis, or of saline waters by the mouth, should prove
beneficial in addition to the remedies administered. Indeed,
the reputation acquired by many of the best-known watering-
resorts in Europe is admittedly due, as is well known, to the al-
kaline salts which the patients ingest in large quantities and to
the well-regulated regime prescribed for them by the local phy-
sicians. In the treatment of tuberculosis it constitutes an es-
sential measure.

Certain growths, particularly the more malignant forms,
sarcoma and carcinoma, seem closely connected with adrenal
insufficiency and its normal consequences. We have seen that
trypsin, fibrinogen, and the oxidizing substance were simulta-
neously necessary to insure the destruction of cells even in
vitro, and, furthermore, that this process required, in addition,
the presence of alkaline salts. That the destruction of worn-
out or degenerated cells is a function of these very elements in
the blood is evident. Insufficiency of the adrenals, therefore,
by reducing the relative proportion of these four constituents
in the blood-stream must correspondingly inhibit this physio-
logical process in all parts of the organism.

As to sarcoma, the similarity between the cellular elements
of the small round-celled variety and mononuclear leucocytes is
striking; each cell shows its nucleus, fibrils, and granules,
though, of course, more or less modified, owing to the abnormal
environment. The large round-cell sarcoma recalls the meta-
morphosis into epithelial cells which eosinophiles undergo in
the pulmonary alveoli; indeed, the cells of melanosarcoma con-
tain the blood-pigments themselves. Grouped as sarcomata are
now, according to the variety of connective tissue which forms
their frame-work, we have, as is well known, myo-, lympho-,
fibro-, myxo-, glio-, osteo-, chondro-, myelo-, melano-, angio-,
and finally neuro- sarcoma, all of which clearly indicate that
any part of the system in which nutrition is, from one cause

786 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

or another, relatively impaired, may become the seat of this
malignant growth, or rather of a local accumulation of the ab-
errant or worn-out cells which enter into its formation. The
great vascularity of these growths suggests an effort of Nature
to cause their elimination, but mitotic proliferation is alone in-
duced, the blood being deficient in the four constituents which
should insure destruction of the morbid cellular elements.

Apart, from the marked vascularization peculiar to sar-
coma, the same pathological process obtains, it seems to us, in
cancer, although here we are dealing with a localized accumu-
lation, retention, and proliferation of epithelial cells. Their
multiplication in situ occurs (as in sarcoma) partly in virtue of
the fact that they "cannot fully utilize the assimilated material
in. the performance of [their] specific functions" ( Adami119) and
partly because the potential energy of their nuclei becomes con-
verted into sufficient heat-energy (with what oxidizing sub-
stance reaches them) to induce proliferative activity, fitter120
found the nuclear chromatin to be precisely that of normal
tissue and the cellular karyokinesis to differ in no way from
that observed in the normal physiological process.

Adrenal insufficiency also accounts for the complications
witnessed. As the accumulated elements degenerate, toxic
products of decomposition enter the blood and, by lowering the
functional activity of the anterior pituitary body, finally bring
on the cachectic stage. The foci of retained cellular elements
becomes also more numerous: i.e., "metastasis" occurs in one or
more regions. That the adrenal system is primarily at fault
is also suggested by the predilection of the aged to malignant
growths, the recognized influence of "general debility," local-
ized malnutrition as a result of trauma, cicatrices, etc., and by
the fact that the only internal remedies that have proven of
any value whatever are powerful adrenal stimulants: erysipelas
toxins (Fehleisen), erysipelas and bacillus prodigiosus toxin?
(Coley), thyroid extract (Borland), lysol and iodine (Behle-
Luckau), sodium cacodylate (Benoit), and the better known ar-
senic, quinine, etc.

Owing to the adrenal stimulation induced, the four con-

u» J. George Adami: British Medical Journal, March 16,1901.
120 Ritter: Deutsche med. Wochenschrift, June, 1901.

LIFE AND ALKALINITY OF THE BLOOD. 787

stitucnts capable of disintegrating the morbid cellular elements,
trypsin, fibrinogen, oxidizing* substance, and alkaline salts, are
supplied to the blood, and these, under normal circumstances,
should cause disappearance of the growth. But unfortunately
such a result is but rarely reached even under the violent adre-
nal stimulation which Coley's toxins must cause. How account
for this? The Roentgen rays, as suggested by the results
already obtained, seem to us to supply one of the missing
factors upon which the curative process depends, i.e., a local
accumulation of heat-energy and a congestive process through
which neutrophile leucocytes (owing to their phagocytic and
fibrinogenic properties) are caused to immigrate into the growth
in large numbers, to convert the degenerated cellular elements
into benign products. Here again, however, the curative proc-
ess requires alkaline salts in addition to those normally utilized
by the organism, in order to insure the full haemolytic activity
of the tryptic intraphagocytic digestion. The frequent use -of
saline solution thus asserts itself as the remaining measure in-
dicated to insure success in the bloodless treatment of malig-
nant tumors.

In the light of our views, it seems evident that, notwith-
standing its simplicity, the use of saline solution represents
one of the most valuable measures in the domain of thera-
peutics, because it defeats the most ubiquitous and efficient
morbid influence with which the organism has to contend. On
the whole, our analysis of the question seems to us to have
shown that: —

1. In all febrile diseases the alkaline salts of the Hood and
cells are rapidly utilized, and, the organism depending upon the
salts ingested with foods for its supply, the anorexia and the re-
duced diet incident upon the disease tend greatly to aggravate the
morbid process.

2. The primary effect of deficiency of alkaline salts in the
liJood being to inhibit nutrition, impair the efficiency of, and finally
arrest, the organism's protective functions, it constitutes one of the
most active causes of death.

3. The use of saline solution may be beneficial even in des-
perate toxcemic cases when the functions of the adrenal system have
reached the lowest stage of insufficiency.

50

788 INTERNAL SECRETIONS AND PRESERVATION OF LIFE.

4- When a favorable reaction does not follow the use of saline
solution, it is because the adrenal system also requires direct stim-
ulation, such as that afforded by strychnine, digitalis, etc., admin-
istered subcutaneouslij.

5. The use of saline solutions is also indicated in general or
local chronic diseases due to, or associated with, insufficiency of
the adrenal system.

The pre-eminent part we ascribe to salt solution in the
preservation of the functional integrity of the cellular elements
and of the fluids by which they are surrounded becomes a nor-
mal consequence when, as suggested by modern cosmogony and
palaeontology, sustained by the teachings of comparative anat-
omy and embryology, the origin of cellular life is traced back
to the primitive seas. The many vestigial structures which
the human frame exhibits as relics of its evolutional past not
only include evidences of a primitive aquatic existence, the
embryonic branchial or gill- clefts and the pituitary bodies, for
instance; but the plasma in which all the cells of the organism
bathe may be said to also typify the original medium, and to
assert by its composition, its claim to recognition as a factor
of a problem which is destined to revolutionize every depart-
ment of human thought: i.e., the origin of species. At the
Thirteenth International Medical Congress, Rene Quinton
maintained that all aggregates of cells, such as those repre-
sented by our organs, were essentially colonies of marine cells,
which required as a sine qua non of their existence their original
environment. Sea-water, he also contended, differs little, if at
all, from the blood-plasma in composition. Our own labors
confirm this interpretation. Whether immersed in its primor-
dial fluid, as is the elementary marine cell, or traversed by its
prototype, the blood-plasma, as are the cellular colonies of
which all organs are built, matters little: All find in the saline
medium's constituents the agencies necessary to their continued
existence. Even the governing center of the adrenal system,
the anterior pituitary body, which differs from all other cellu-
lar aggregates and the elementary cell itself in that its func-
tional activity is upheld by a special agency, is dependent for the
latter upon a constituent of marine plants and sea-water: i.e.,
iodine.

INDEX TO VOLUME FIRST.

Abdominal vessels, dilation of, versus
contraction of capillaries, 19, 29, 31,
33, 36, 50, 51, 88, 153, 337, 573, 622.

Accelerator cardiac phenomena, 446.

Accessory adrenals, 85, 86.

Acetanilid poisoning, haemoglobin dis-
integration in, 97; muscular weak-
ness in, 41; temperature in, 51; vas-
cular pressure in, 46.

Acetonuria, as a symptom of adrenal
insufficiency, 154.

Aconite poisoning and haemoglobin dis-
integration, 97; muscular weakness
in, 41; temperature in, 51; vascular
pressure in, 46.

Acromegaly, adrenal stimulation in,
by waste-products, 199; the adrenals
and, 189, 192; pathogenesis of, 192;
pathological anatomy of, 516; the
posterior pituitary body in, 514;
symptoms of, 186, 196, 512-515; three
forms of, 207.

Addison's disease and insufficiency of
the adrenals, 86; pathogenesis of, 77.
(See also Bronzing.)

Adrenal extract and vascular pressure,
13.

Adrenal insufficiency as source of in-
creased vulnerability to disease, 633,
635.

Adrenal insufficiency, general prin-
ciples of, 19, 25, 165, 170.

Adrenal system, 186; alkalinity of the
blood and the, 781; and antitoxic
serum, 637; in cardiac functions, 421;
as source of engorgement of cerebro-
spinal plasma-channels, 573; as
governing center of oxidation proc-
esses 231; in insanity, 776; insuffi-
ciency of, and phthisis, 478; and
phagocytosis, 610; as the physician
of the organism, 778; as the govern-
ing center of protective processes,
621, 624; in pulmonary functions,
421; the tuberculin test and, 635;
vasomotor functions and, 233. (See
also Adrenals.)

Adrenal, unilateral removal of, 4, 19.

Adrenalin, 66.

Adrenals, accessory, 85, 86.

Adrenals, action of poisons on, 23, 34,
36, 61; effects of toxins on, 33, 36, 37,
39, 61, 62; effects of venoms on, 39;
functional activity of, regulated by
the dose of a toxic, 102; and mus-
cular weakness, 40; and respiration,
71, 76; and temperature, 50; and
vascular pressure, 44; as the source
of major symptoms in disease and
poisoning, 39, 633, 635.

Adrenals and blood-disintegration, 95,
102, 106, 128.

Adrenals, internal secretion of, 9; af-
finity for oxygen, 67, 76, 77 ; antitoxic
power of, 24; chemical properties of,
62; and the circulation, 18; as an
haemoglobin-binding agent, 78, 120,
714; action on the heart, 11, 13, 17,
71, 433, 441; and respiratory chem-
ism, 71, 76.

Adrenals, intrinsic pathology of, 34; in
Addison's disease, 86; advanced dis-
ease of, 21; in Asiatic cholera, 30;
in anuria, 58; atrophy of, 84; and
central congestion, 30, 33, 51; com-
pensative hypertrophy of, 23, 84; in
chlorosis, 87; in cretinism, 165, 170;
in diphtheria, 34, 35; fatty degenera-
tion of, 38, 78; haemorrhage into, 5;
hypertrophy of, in infections, 36;
in polyuria, 58; tuberculosis of, 8;
tumors of, 8.

Adrenals, nervous supply of, 8, 11, 12,
14, 17, 27, 37, 215, 2iio, 296; spino-ad-
renal communicating filaments, 225,
415; spino-adrenal communicating
filaments in early life, 607.

Adrenals, overactivity of, general ef-
fects, 33, 36, 37; in fever, 33, 51; in
leucocytosis, 616, 624; symptoms of,
152.

Adrenals, relations of, with anterior
pituitary, 215, 225; with the spinal
cord, 225, 415, 607; with the vagus,
12, 296: with the thymus, 171; witn
the thyroid, 146; with the vasomotor
system, 11, 14, 17.

Adrenals, removal of, in animals, ef-
fects of, 5; in man, 5, 6, 7, 29, 77;
removal of, and accumulation of

(789)

790

INDEX.

Adrenals (concluded).
toxic waste-products in the blood,
168; effects of removal of, on the
blood, 120; functions suppressed by
removal of, 9; effects o'f removal of,
on metabolism, 121; symptoms of re-
moval of, similar to -those of Asiatic
cholera, 773.

Adynamia as a result of adrenal insuf-
ficiency, 153, 167.

Agglutination, nature of phenomenon,
737.

Air-hunger as a symptom of adrenal
insufficiency, 154.

Albuminoid bodies reduced by trypsin,
655.

Albuminuria as a symptom of adrenal
insufficiency, 154.

Alcohol and haemoglobin -disintegra-
tion, 97; action of, on neurons, 522.

Alcohol poisoning, temperature in, 52;
and cerebral activity, 56; muscular
weakness in, 41; vascular pressure
in, 46.

Alcoholic insanity, neurons in, 590.

Algid stage of Asiatic cholera, nature
of, 74.

Alkaline salts as diuretics, 60.

Alkalinity of the blood, reduction of,
as a cause of death, 778, 782.

Alkalinity of the blood, the adrenals
as governing centers of, 780; in an-
thrax, 780; in cancer, 785; in cholera,
780; in diphtheria, 781, 784; in ery-
sipelas, 780; in febrile diseases, 779,
782; in gout, 785; in haemorrhage,
779; in pneumonia, 783; physiolog-
ical r61e of, 778; in puerperal
eclampsia, 779; reduced by acetan-
ilid, 97; and renal irritation, 59; re-
sistance to pathogenic germs and,
779; in rheumatism, 785; in sarcoma,
785; and sea-waters, 788; in scar-
latina, 784; in small-pox, 784; in
tetanus, 784; in tuberculosis, 780,
785; in typhoid fever, 784; in urae-
mia, 779.

Alloxuric bases, the adrenals and, 144;
how neutralized in the system, 141;
oxidation of, 139; as physiological
poisons, 139.

Alopecia and adrenal insufficiency, 167.

Amblyopia in acromegaly, 515.

Ammonia and haemoglobin disintegra-
tion, 98.

Ammonium chloride as immunizant,
768.

Ammonium picrate and haemoglobin
disintegration, 100.

Amyl nitrite and haemoglobin disin-
tegration, 100, 103, 104.

Amyotrophic lateral sclerosis, 515.

Anaesthesia as a symptom of acromeg-
aly, 514; retraction of neuron-gem-
mules during, 521, 578.

Anosmia and adrenal insufficiency, 169.

Anterior pituitary body as the govern-
ing center of the adrenals, 215; func-
tions of, 230; the sympathetic gan-
glionic chain and the, 218, 220; mi-
nute anatomy of, 215; the splanch-
nic nerve and, 219.

Anterior pituitary, the thyroid, and the
adrenals as an autonomous system,
186.

Anthrax, saline solution in, 780.

Antimony poisoning and haemoglobin
disintegration, 97; muscular weak-
ness in, 41; temperature in, 52; vas-
cular pressure in, 46.

Antipyretics, action of, 51.

Antipyrin poisoning, bronzing in, 52;
haemoglobin disintegration in, 101;
muscular weakness in, 41; tempera-
ture in, 52; vascular pressure in, 47.

Antitoxic sera, uniformity of all, 762;
use of, only indicated in diseases in
which trypsin is deficient, 763; and
the adrenal system, 637; physiolog-
ical action of, 745.

Antitoxin, action of, in diphtheria,
757; active principle of, 746, 749;
composition of, 652, 665, 666; forma-
tion of, in injected animals due to
excessive adrenal activity, 643; iden-
tity of, 652; oversensitiveness in in-
jected animals and adrenal insuffi-
ciency, 643; source of, 642.

Anuria, the adrenals and, 58; copper
and, 59; iodoform and, 59; opium
and, 59.

Apathy's neuro-fibrils as plasma-chan-
nels, 540, 544, 568.

Apiol as immunizant, 768.

Appendix vermiformis, functions of,
325.

Appetite, excessive, as a symptom of
adrenal overactivity, 153, 196; as a
symptom of acromegaly, 512; in gly-
cosuria, 363.

Arsenic as an adrenal stimulant, 769:
as a constituent of iodized nucleo-
proteids, 156, 167; as a constituent
of the thyroid gland, 156, 167; as an
antagonist to iodine and as a con-
trolling agent, 157, 167; and haemo-
globin d:sintegration, 97; effect of,
ou the skin, 770; as an immunizant,

INDEX.

791

Arsenic (concluded).
768, 769; as a lymphatic stimulant,
156, 167.

Arsenic poisoning, muscular weakness
in, 41; similarity to Asiatic cholera,
773; temperature in, 52; vascular
pressure in, 47.

Asiatic cholera. (See Cholera.)

Asphyxia as caused by venoms, 103.

Asthma as a symptom of acromegaly,
515; eosinophile leucocytes in the
sputum in, 710.

Ataxic gait and adrenal insufficiency,
167.

Atrophy of the adrenals, 84.

Atropine poisoning and cerebral ac-
tivity, 55; cystic paralysis in, 61;
muscular weakness in, 41; tempera-
ture in, 52; vascular pressure in, 47.

Augmentor cardiac phenomena, 446.

Axis-cylinders as plasma-channels, 543.

Bacteria, relations to liver, 341; free
trypsin as possible antitoxic and bac-
tericide in liver, 740; destruction of,
in peripheral capillaries, 622. (See
also Immunity and Phagocytosis.)

Bacterial toxins, effects on adrenals of,
33, 36, 37, 39. (See also Immunity
and Phagocytosis.)

Belladonna poisoning, muscular weak-
ness in, 41; temperature in, 52; vas-
cular pressure in, 47.

Bilirubin, formation of, 337; and
haemato'idin identical, 119, 128; and
haemoglobin synthesis, 119, 128; ori-
gin of, 115.

Biniodide of mercury as an adrenal
stimulant, 770; as immunizant, 770.

Blood, alkalinity of, and preservation
of life, 778.

Blood-clots, disintegration of, 338.

Blood-disintegration, the adrenals and,
95, 102, 106, 128; and poisons, 97, 102;
and venoms, 96, 99, 103.

Blood-plates, nature of, 715.

Bones, softening of, during growth,
and thyroid extract, 177.

Brain and cord, minute circulation of,
562.

Brain, lower, identity of, 483.

Brain, neuroglia-flbers as the capillary
system of, 583.

Brain, non-development of, and ad-
renal insufficiency, 166.

Bromide poisoning, muscular weakness
in, 41; temperature in, 52, 53; vas-
cular pressure in, 47.

Bromides, action on neurons, 523; con-
tra-indicated in tetanus, 768; and
haemoglobin disintegration, 98.

Broncho-pneumonia, the adrenals in,
35.

Bronzing, a symptom of advanced ad-
renal insufficiency, 77, 79, 80, 86, 153,
197, 515; a result of haemoglobin dis-
integration, 93; haematoidin in, 120;
melanin-formation in, 93; prognosis
of, 83; a symptom of many diseases,
78, 79, 84.

Buchner's alexins, 625, 666, 742, 745.

Buchu, action of, as a diuretic, 61.

Bulimia as a symptom of adrenal over-
activity, 153, 196; of acromegaly, 512;
in glycosuria, 363.

Cachexia strumipriva a direct result of
adrenal insufficiency, 152.

Calabar-bean poisoning, muscular
weakness in, 43.

Camphor poisoning, haemoglobin disin-
tegration in, 98; muscular weakness
in, 41; temperature in, 53; vascu-
lar pressure in, 48.

Cancer, adrenal insufficiency in, 786;
deficiency of alkaline salts in, 786;
pathogenesis of, 786; the Roentgen
rays in, 787.

Cannabis Indica and cerebral activity,
58; contra-indicated in tetanus, 768.

Capillaries, engorgement of peripheral,
as a symptom of adrenal overactiv-
ity, 153.

Capillaries of the periphery a vast im-
munizing field, 622.

Carbolic acid as an adrenal stimulant,
768; as immunizant, 768.

Carbolic-acid poisoning and haemoglo-
bin disintegration, 98; muscular
weakness in, 41; temperature in, 53;
vascular pressure in, 48.

Catalepsy and adrenal insufficiency,
169, 513.

Cerebral activity, the adrenals and, 55;
influence of poisons on, 55; in poison-
ing, 55; mania and, 152, 572, 590, 776,
777.

Cerebral suboxidation a result of ad-
renal insufficiency, 153, 169; melan-
cholia and, 153, 169, 513, 776.

Cerebro-spinal substance, minute cir-
culation of, 562.

Cerebro-spinal system, general center
of, 483, 591.

Cervico-thoracic ganglionic chain as
link between anterior pituitary and
adrenals, 225.

792

INDEX.

Chemical properties of adrenal secre-
tion, 62.

Chloral contra-indicated in tetanus,
768.

Chloral poisoning, haemoglobin disin-
tegration in, 98; muscular weakness
in, 42; temperature in; 53; vascular
pressure in, 48.

Chloral-camphor and haemoglobin dis-
integration, 98.

Chlorate of potassium and haemoglobin
disintegration, 100.

Chloride of sodium, its physiological
role, 59, 778.

Chloroform, action of, on neurons, 523.

Chloroform anaesthesia, temperature
in, 53.

Chloroform poisoning and haemoglobin
disintegration, 98; vascular pressure
in, 48.

Chlorosis, adrenals in, 87; blood-
changes in, 94; effects of remedies
in, 94; pathology of, 87.

Cholera Asiatica, adrenal insufficiency
in, 30, 35, 52, 772; immunizing medi-
cation in, 772; kindred disorders to,
773; lowered vascular pressure in,
47; respiratory symptoms in, 74;
saline solution in, 780.

Cholera infantum, lowered vascular
pressure in, 47; kinship with Asi-
atic cholera, 773.

Cholera morbus, lowered vascular
pressure in, 47; kinship with Asi-
atic cholera, 773.

Cloudy swelling in the adrenals, 37, 42.

Cocaine poisoning, muscular weakness
in, 42; temperature in, 53; vascular
pressure in, 48.

Cold, sensitiveness to, and adrenal in-
sufficiency, 197.

Coley's toxins, mode of action in ma-
lignant growths, 786.

Colliquative diarrhoea as a symptom of
adrenal insufficiency, 153.

Colloid substance, 156.

Copper and anuria, 59.

Copper poisoning, haemoglobin disin-
tegration in, 100; muscular weakness
in, 42; temperature in, 53; vascular
pressure in, 48.

Cord, minute anatomy of, 562; neu-
roglia-fibers as the capillary system
of, 583.

Cramped heart as a symptom of ad-
renal overactivity, 153, 1 :>."..

Cretinism and adrenal insufficiency,
165, 170; the posterior pituitary body

in, 514; the thymus generally per-
sistent in, 178.

Crisis, meaning of, in disease, 62.

Cumulative action of drugs, and arrest
of adrenal functions, 61.

Curare poisoning, the adrenals in, 36.

Deafness as a symptom of acromegaly,
513.

Death and deficient alkalinity of the
blood, 782, 783, 787.

Delirium tremens and cerebral over-
activity, 56.

Delusions as a symptom of acromeg-
aly, 512.

Dementia, adrenal insufficiency in, 776.

Dengue, immunizing medication in,
771.

Dental caries as a symptom of adrenal
insufficiency, 153.

Dentition, delayed, and adrenal insuf-
ficiency, 166.

Diabetic coma, 363.

Diabetes. (See Glycosuria.)

Diarrhoea, colliquative, as a symptom
of adrenal insufficiency, i53.

Diathetic diseases, use of saline solu-
tion in, 785.

Digestive apparatus, the posterior pit-
uitary body in diseases of the, 777;
dual nervous supply of, 296. (See
also Intestines, Liver, PUHCI-CUN, and
Ktomach.)

Digitalis, action on adrenal system,
227, 228; action of large doses in
pneumonia, 61, 775; action of, on
myocardium, 70; "cumulative ac-
tion," meaning of (foot-note), 61;
action of, as diuretic, 61.

Digitalis poisoning and haemoglobin
disintegration, 98; muscular weak-
ness in, 42; temperature in, 53; vas-
cular pressure in, 48.

Diphtheria, the adrenals in, 34, 35;
deficiency of trypsin in, 757; action
of antitoxin in, 757, 771; use of saline
solution indicated in, as adjunct to
antitoxin, 784; immunizing medica-
tion in, 771; saline solution in, 7<S1.

Diuresis, the adrenals in, 60.

Diuretic action of alkaline salts, 60;
of acetanilid, 61; of antipyrin, 61;
of buchu, 61; of digitalis, 61; of
sulphonal, 61; of uva ursi, 61.

Dyspna'si as a symptom of adrenal in-
sufficiency, 103; as a symptom of
adrenal overactivity, 153; as a symp-
tom of acromegaly, j!3, 515.

INDEX.

793

Eclampsia, puerperal, adrenal stimula-
tion indicated in, 769. (See Puer-
peral.)

Eczema, adrenal stimulation In, 770.

Ehrlich's side-chain theory, 637, 728.

Engorgement of central vessels of ad-
renal origin, 29, 51.

Epilepsy, accumulation of waste-prod-
ucts in, 222; adrenal stimulation in-
dicated in, 769; and cerebral activ-
ity, 56; as manifestations of excess-
ive motor activity, 508; effects of
sympathectomy on, 221.

Epinephrin, 66.

Epistaxis as a symptom of adrenal
overactivity, 153.

Erysipelas, saline solution in, 780.

Erythema, general, as a symptom of
adrenal overactivity, 153.

Erythrocytes, structure of, 715.

Erythromelalgia and acromegaly, 515.

Ether anaesthesia, muscular relaxa-
tion in, 42; temperature in, 54; vas-
cular pressure in, 49.

Excitability as a symptom of adrenal
overactivity, 152.

Exophthalmic goiter and adrenal over-
activity, 152, 153; cachectic stage
and adrenal insufficiency, 158, 164,
197; increased consumption of oxy-
gen in first stage of, 166; cachectic
stage and accumulation of waste-
products, 159, 163, 164; as caused by
thyroid extract, 155; as caused by
iodine, 163; the posterior pituitary
body in, 514; effects of sympathec-
tomy on, 221; the thyroid extract
useful in cachectic stage, 158, 160.

Fatty degeneration of the adrenals, 38.

Fever and adrenal overactivity, 33, 51;
alkalinity of the blood in, 782, 787;
phagocytosis during, 624; saline solu-
tion in, 779; stercobilinuria in, 114.

Fibrillary muscular tremor as a symp-
tom of adrenal overactivity, 153;
paretic, as a symptom of adrenal in-
sufficiency, 153, 167.

Fibrinogen in typhoid fever, 754, 755.

Fibrinogen, neutrophile leucocytes as
source of, 703, 733; and experimental
haemolysis, 735, 741.

Flushes due to exacerbations of ad-
renal activity, 161.

Fontanelles, non-closure of, and ad-
renal insufficiency, 166.

Foramina Thebesii in cardiac func-
tions, 421.

Functional activity, mechanism of gen-
eral, 294.

Functional activity of the brain NTMM
retraction of the neuron-gemmules,

577, 578.

Gastric disorders and adrenal insuf-
ficiency, 87.

Gastric juice, formation of, 297, 301, 310.

Gastroptosis and adrenal insuffi-
ciency, 87.

Gerlach's fibers as plasma-channels,
568.

Gigantism, pathogenesis of, 192.

Glycogen and its formation, 347, 356,
360.

Glycosuria as a symptom of adrenal
insufficiency, 154, 197, 365; coma in,
363; as a symptom of adrenal over-
activity, 363, 366; as a symptom of
excessive formation of dextrose, 367;
ptyalin and, 418; unconsumed sugar
and, 366; drugs as a cause of, 362.

Golgi's fibers as plasma-channels, 585.

Gout, saline solution in, 785.

Growth, retarded or arrested, and ad-
renal insufficiency, 166; thyroid ex-
tract and, 175.

Haematin, formation of, 89.

Haematoblasts, nature of, 715.

Haematoi'din and removal of adrenals,
120.

Haematoporphyrin, bilirubin, iron-free
haematin, and haematin as isomers,
113; formation of, 89; nature of,
106, 128; physiological chemistry of,
109, 113, 128.

Haematoporphyrinuria and adrenal in-
sufficiency, 96, 101, 102, 106, 128; a
symptom of various disorders, 89;
readily caused by drugs when the
adrenals are diseased, 107, 110.

Hae'maturia and adrenal overactivity,
95; quinine and, 59; opium and, 59.

Haemoglobin, adrenal secretion as
binding agent of, 78; formation of,
78, 87, 128, 335, 339; dissociation of,
128; dissociation of, in glycosuria,
365 ; dissociation of, in poisoning,
97; eosinophile leucocytes as source
of, 713, 716; molecule, formation of,
in the liver, 335, 339; power of, to
take up oxygen acquired from ad-
renal secretion, 122, 128; process of
dissociation of, when adrenals are
insufficient, 109.

Haemoglobinuria and adrenal insuffi-
ciency, 96.

794

INDEX.

Haemolysis, the adrenals in, 95; ex-
perimental, 735; and poisons, 97;
and venoms, 96, 99. /

Haemoptysis as a symptom of adrenal
overactivity, 153.

Haemorrhage and adrenal insufficiency,
166; and adrenal overactivity, 153;
saline solution in, 779.

Hair, coarseness of, and adrenal insuf-
ficiency, 166, 515.

Haller's fibers as plasma-channels, 568.

Hallucinations as a symptom of ad-
renal overactivity, 152.

Hay fever, the posterior pituitary body
in, 777.

Headache as a symptom of adrenal
overactivity, 152; pressure as a
source of, 198, 512.

Heart, active inhibition of, due to ex-
cessive vagal stimulation, 452; ac-
celerator phenomena of, 446; aug-
mentor phenomena of, 446; enlarge-
ment of, and adrenal insufficiency,
88; the foramina Thebesii in the
functions of, 421, 441; functional
mechanism of, 453; hypertrophy of,
512; impaired nutrition of, and tu-
berculosis, 774; innervation of, 444;
leucocytes and nutrition of, 434, 714;
murmurs and adrenal insufficiency,
88; non-existence of inhibitor fibers,
452; nutrition of, 434, 714; the ox-
idizing substance and the functions
of, 433, 441; "palpitations" of, 512,
515; passive inhibition of, due to ad-
renal insufficiency, 452; inhibitor
phenomena of, 449, 452; the posterior
pituitary in diseases of the, 777; re-
laxation of myocardium and adrenal
insufficiency, 88; the vagal system
in functions of, 421.

Heat, abnormal superficial, as a symp-
tom of adrenal overactivity, 196.

Hyaline leucocytes, 688.

Hydrochinone, action of, as diuretic,
61.

Hydrocyanic-acid poisoning and haemo-
globin disintegration, 99; tempera-
ture in, 54; muscular weakness in,
42; vascular pressure in, 49.

Hydrophobia, adrenal stimulation in-
dicated in, 769; immunizing medica-
tion, 764, 771; prevention of, in bit-
ten subjects, 767.

Hyperaesthesia and adrenal overactiv-
ity, 186, 196; the posterior pituitary
body and, 512.

Hyperthermia due to adrenal overac-
tivity, 50, 55.

Hypoleucocytosis, 613.

Hypophysin, 210.

Hypothermia and adrenal insufficiency,

50, 55, 166, 167.
Hysteria, the posterior pituitary body

in, 777.

Idiocy, absence of the thymus in, 175;
and disease of the pituitary bodies,
199, 204, 513; patLogenesis of, 776;
thyroid extract in, 175. (See also
Cretinism.)

Immunity, antitoxic serum, 637, 652,
655, 665, 746, 749; artificially pro-
duced, 763; Buchner's alexins, 625,
742, 745; Ehrlich's side-chain theory,
637, 728; the internal secretions and,

609, 667; the leucocytes in, 728, 744;
leucocytosis, 610; the oxidizing sub-
stance in, 666, 729, 745; phagocytosis,

610, 667; uniformity of all antitoxic
sera, 749.

Immunizing medication, 767.

Impetigo, adrenal stimulation in, 770.

Infantile convulsions, adrenal stimula-
tion in, 769.

Infectious diseases, causes of liability
of children to, 607, 632, 635.

Infections, saline solution in, 779.

Influenza, the posterior pituitary body
in, 777.

Inhibition, active, of heart due to ex-
cessive nervous stimulation, 450, 452.

Inhibition, passive, due to adrenal in-
sufficiency, 452.

Insanity, alcoholic, neurons in, 590.

Insanity and diseases of the pituitary
bodies, 198, 204; immunizing medica-
tion in, 776; pathogenesis of, 776;
the posterior pituitary body in, 512,
777.

Internal secretion of adrenals (see Ad-
renals); of the pancreas, 362, 392,
420; of the spleen, 362, 392, 420; of
the thymus gland, 171 (see Thinim*};
of the thyroid gland (see Thi/r<ii<l).

Internal secretions and immunity, 609.

Internal secretions and the preserva-
tion of life, 667.

Intestine as starting-point of blood-
pigments, 115; cytogenous tissue of,
316, 321; fenestrated subepithelial
membrane of, 321; general functional
mechanism of, 325; leucocytosis of,
88, 321; minute anatomy of, 310;
nervous supply of, 323, 326; phago-
cytes and their rfile in the, 322;
prophylactic functions of, 310; se-

INDEX.

795

Intestine (concluded).
creting glands of, 312, 315; villi and
lymph-follicles of, 315.

Intoxications, saline solution in, 779,
787.

Iodides, action in syphilis, 777.

Iodine, action of, in syphilis, 777; as
the basis of thyroid extractives,
156; as a cause of oedema, 59; as a
lymphatic stimulant, 156, 163; as the
physiological adrenal stimulant, 158,
163.

lodoform and anuria, 59.

lodothyrin, 156.

Iron, action on the adrenals of, 94;
intestinal absorption of, 88; leuco-
cytes as carriers of, 88, 335, 713;
physiological action of, 86, 713.

Irritability as a symptom of adrenal
overactivity, 152.

Kidneys, irritation of, and drugs, 58;
action of iodine on, 59.

Lacrymal glands, functional mechan-
ism of, 266.

Lacrymation as a symptom of adrendl
insufficiency, 167; pilocarpine and,
268.

Lecithin as the active body of myelin,
534, 543, 720.

Lepine's glycolytic ferment as the ox-
idizing substance, 411.

Leprosy, immunizing medication in,
771.

Leucocytes, basophile, as source of
myelin, 725, 727; basophile, functions
of, 717; classification of, 686; eosino-
phile, functions of, 703, 712; eosino-
phile, and the alveolar epithelium,
713; eosinophile, as source of haemo-
globin, 713, 716; formation of, 712;
functional mechanism of, 674; the
functions of, 668; the granules of, as
secretory products, 679; immature,
688; in immunity, 728; me mitoma
of, as canaliculi, 668; neutrophile, as
the source of peptones, myosinogen,
and flbrinogen, 703; neutrophile,
functions of, 688; physiological chem-
istry of, 682; in vital and organic
functions, 668, 727.

Leucocytosis, alkalinity of the blood
and, 781; and overactivity of the ad-
renal system, 612, 620; and phagocy-
tosis, 612; in pneumonia, 650.

Leucoderma as a symptom of adrenal
insufficiency, 153.

Lids, drooping of, and adrenal insuffi-
ciency, 167.

Life, leucocytes and, 668; alkalinity of
the blood and, 778; preservation of,
and the internal secretions, 667; as
sustained by the adrenal system, 232;
primordial seas and, 788; unity of
cellular, 609.

Life, the pituitary bodies as co-centers
in sustaining, 483, 606, 608.

Liver, blood-pigments of, 334, 360; the
hepatic artery, the functional vessel
of, 326; the hepatic cell-canaliculi,
340, 360; the hepatic cell a minia-
ture sponge, 339; minute anatomy of,
326, 360; pancreas and spleen, com-
bined functions of, 359; physico-
chemical functions, 326; pulsation cf,
as a symptom of adrenal overactiv-
ity, 153.

Lower brain, functions of, 483.

Lungs, innervation of, 455, 468; nervo-
vascular mechanism of, 468, 481; the
vagal system in functions of, 421.
(See also Respiration.)

Lymphatic system, arsenic and iodine
as stimulants in, 156, 158; and saline
solution, 667, 668.

Lymph-follicles, intestinal, functions
of, 315.

Lymphocytes, 688.

Malarial fever, enlargement of spleen,
and adrenal overactivity, 332; im-
munizing medication in, 767, 769.

Malignant growths, mode of action of
Coley's fluid in, 787; mode of action
of Roentgen rays in, 787; pathogen-
esis of, 785.

Mammary glands, functional mechan-
ism of, 285, 293.

Mania a potu and cerebral activity, 57.

Mania as a symptom of adrenal over-
activity, 152; pathogenesis of, 776,
777.

Marasmus as a symptom of adrenal in-
sufficiency, 153.

Measles, immunizing medication in,
771.

Medulla oblongata as a consociating
organ, 602.

Melancholia as a symptom of adrenal
insufficiency, 153, 169, 513, 776.

Mental apathy and adrenal insuffi-
ciency, 169.

Mental phenomena of acromegaly, 198,
512, 514.

Mentally-normal children, presence of
thymus in, 175.

796

INDEX.

Mentally-weak children, absence of
thymus in, 175; thyroid extract in,
175. (See also Idiocy.)

Mercurial poisoning, muscular weak-
ness in, 42; temperature in, 54; vas-
cular pressure in, 49.

Mercury, biniodide as adrenal stim-
ulant, 770; and immunizing medica-
tion, 770; and haemoglobin dissocia-
tion, 99.

Metabolism, reduction of, as a result
of adrenal insufficiency, 153, 167.

Methaemoglobin, nature of, 103, 128.

Methsemoglobinuria and adrenal insuf-
ficiency, 96, 99, 102, 128.

Migraine, saline solution in, 785.

Milk, fluid portion of, as an immuniz-
ing serum, 289, 607, 729.

Mineral poisons, action on adrenals, 39.

Mineral waters and alkalinity of the
blood, 785.

Morphine, action on neurons, 520, 522.

Morphine poisoning, temperature in, 54.

Motor areas of gray substance as sen-
sory areas, 508.

Motor nerves an autonomous system,
including vasomotors, 279; and mus-
cular contraction, 233, 247, 279; vaso-
constrictor function of, 253, 261; and
glandular secretion, 262.

Muscles not supplied with separate
vasoconstrictors, 253, 261.

Muscular atrophy in acromegaly, 514.

Muscular contraction, confusion in pre-
vailing views, 236; functional process
of, 261; and motor nerves, 233; source
of chemical energy in, 239.

Muscular hypernutrition and adrenal
overactivity, 186, 196, 512.

Muscular hypertrophy in acromegaly,
186, 196, 512.

Muscular tremor, fibrillary, as a symp-
tom of adrenal overactivity, 153.

Muscular twitchings due to exacerba-
tions of adrenal activity, 161.

Muscular weakness, the adrenals in,
40; and adrenal insufficiency, 153,
166, 197, 513.

Myolin and the functional energy of
nerves, 543; basophile leucocytes as
source of, 725, 727.

Myosinogen, functions of, in muscle-
fiber, 262; neutrophile leucocytes as
source of, 703; and the oxidizing
substance, 234; physiological chem-
istry of, 240.

Myxcedema and adrenal insufficiency,
165, 170; and cretinism, adrenal in-
sufficiency in, 165, 170; and cretinism,

difference between them, 167; the
posterior pituitary body in, 514; re-
duced tissue-metabolism in, 168.

Nails, brittleness and striation of, and
adrenal insufficiency, 166.

Narcolepsy in acromegaly, 513.

Nerves, myelin as source of energy in,
534, 536, 543; physiological chemistry
of, 532.

Nervous energy, source of, 533, 536, 543.

Nervous system, general center of, 483,
591.

Nervous system, including neurons,
composed of plasma-fibrils sur-
rounded by myelin, 560.

Neuralgia, the posterior pituitary body
in, 777; in acromegaly, 514.

Neurasthenia, the posterior pituitary
body in, 777.

Neuroglia-cells as links between cir-
culation and neurons, 570, 587.

Neuroglia-fibers as plasma-channels,
539, 543.

Neuroglia-fibrils of the brain and cord,
their capillary supply, 582.

Neuron, circulation of, 539, 559; direct
continuation of circulation by some
of its dendrites, 552; functions of
gemmules, 577; histology of, 518;
lecithin, the functional ground-sub-
stance of, 557; lymph-channels of,
586; physiology of, 519; physiological
chemistry of, 518, 519, 552; trans-
mission of vibrations between, 579,
581; varicosity of, in fatigue and
sleep, 522.

Nicotine poisoning, temperature in, 53;
vascular pressure in, 50.

Nitrite of amyl and haemoglobin dis-
integration, 100, 103, 104.

Nitroglycerin and haemoglobin disin-
tegration, 100, 104.

Numbness in cachectic stage of acro-
megaly, 514.

Nutrition, impaired, as a symptom of
adrenal insufficiency, 166.

(Edema, general, as a symptom of ad-
renal overactivity, 153.

(Edema, laryngeal, iodine as cause of,
59.

Ophthalmoplegia as a symptom of ad-
renal insufficiency, 154.

Opium and anuria, 59.

Opium poisoning and cerebral activ-
ity, 57; muscular weakness in, 42;
saline solution in, 667; temperature
in, 54; vascular pressure in, 49.

Optic atrophy in acromegaly, 515.

Oxalic-acid poisoning and haemoglobin
disintegration, 102; muscular weak-
ness in, 43; temperature in, 54; vas-
cular pressure in, 49.

Oxidation of toxics and products of
metabolism, 646, 649.

Oxidation-power of living tissues, 68.

Oxidizing substance and alloxuric bod-
ies, 139; chemistry of, 132; and the
digestive organs, 296; diminished
consumption of, and adrenal insuf-
ficiency, 166; as a constituent of
antitoxin, 666, 728, 744; and glandular
secretion, 262; and fibrinogen, 734,
741, 745, 753; and myosinogen, 234;
as a poison-destroying agent, 646,
649; as a reagent in all functional
processes, 145, 293; source of, 130;
and uric acid, 137.

Oxygen, absorption by tissues, 89; and
the adrenal secretion, 67; reduced
consumption of, and adrenal insuffi-
ciency, 166.

Pachymeningitis as a symptom of
acromegaly, 515.

Pain, abdominal, of adrenal origin, 22.

Pallor and central congestion, 33; and
adrenal insufficiency, 88, 167.

Pancreas, internal secretion of, 362,
420; functional mechanism of, 381,
385, 414; in the formation of glyco-
gen, 356, 369.

Paraesthesia, the posterior pituitary
body and, 513, 514.

Paralysis, adrenal insufficiency in, 44.

Paralysis agitans as a symptom of ad-
renal insufficiency, 153.

Paralysis and atropine poisoning, 56.

Parotitis, immunizing medication in,
771.

Peptones, neutrophile leucocytes as
source of, 703.

Pernicious anaemia, urobilin in, 114.

Pertussis, immunizing medication in,
771.

Peyer's patches, function of, 315, 322,
325.

Phagocytosis and the adrenal system,
610; and leucocytosis, 610; mechanism
of, 671, 676, 678, 679; neutrophile leu-
cocytes in, 688; trypsin as bacteri-
cidal agent in, 732.

Phenacetin and haemoglobin disinte-
gration, 100.

Phlegmasia alba uolens and adrenal
insufficiency, 94.

Phloridzin and glycosuria, 363.

INDEX. 797

,

Phosphorus, as active principle of leci-
thin, 177, 533; as active principle of
myeliu, 543; as active principle of
thymus gland, 179; basophile leu-
cocytes and, 718; cell-metabolism
and, 697; nervous energy and, 533,
536, 543; posterior pituitary body
and, 210, 213, 593; proportion of, in
nuclein, 532, 683; vital process and,
608.

Phosphorus poisoning, and haemoglo-
bin disintegration, 98; muscular
weakness in, 43; temperature in, 54;
vascular pressure in, 49.

Physostigma poisoning, and haemo-
globin dissociation, 99; muscular
weakness in, 43; temperature in, 54;
vascular pressure in, 50.

Pilocarpine and lacrymation, 268; and
sweating, 279.

Pituitary bodies, chemical constitu-
ents of, 188; as co-centers in sus-
taining vital processes, 483, 593, 606;
mutual relations of, 207, 213; phylo-
geny of, 491; effects of removal of,
187, 190; as the source of adrenal ac-
tivity, 215.

Pituitary body, anterior, as general
center of the adrenal system, 186,
207, 215; as governing center of ox-
idation processes, 606. (See also Ad-
renals and Adrenal system.)

Pituitary body, posterior, as an ag-
gregate of neurons, 596; as central
sensorium, 598; as center upon which
all emotions, shock, etc., react, 606;
as governing center of functional ac-
tivity, 606; histology of, 493, 500; as
general center of nervous system,
483, 511, 591; physiology of, 493, 591.

Pituitary extract, action of, 188, 189,
191.

Plague, immunizing medication in, 771.

Platelets, nature of, 715.

Pneumogastric, 421.

Pneumonia, absence of alkaline salts
as cause of death in, 783; adrenal
overactivity in, 775; action of dig-
italis in, 61; leucocytosis in, 650;
pathogenesis of, 775; prune-juice
sputum and haemoglobin dissociation,
99; stercobilinuria in, 114.

Poisoning, the adrenals in, 23, 27, 29,
34, 36, 37, 39; blood-disintegration in,
95, 102, 106; cerebral activity in, 55.

Poisons, how converted into harmless
bodies, 639, 646, 659; and haemolysis,

' 95, 102, 106; influence on tempera-
ture, 50; action on vascular pressure,

798

INDEX.

Poisons (concluded).
44; albuminoid, effects of trypsin on,
659.

Polydipsia in acromegaly, 515.

Polyuria and adrenal insufficiency, 58,
169, 512; as a symptom of adrenal
overactivity, 196.

Potassium chlorate and haemoglobin
dissociation, 100.

Psoriasis, adrenal stimulation in, 770.

Puerperal eclampsia, adrenal stimula-
tion indicated in, 769; immunizing
medication in, 771; saline solution in,
779.

Pulmonary system, innervation of, 455,
468. (See also Respiration and Re-
spiratory. )

Pulmonary tuberculosis and adrenal
insufficiency, 478. (See also Tuber-
culosis. )

Purpura, general, as a symptom of ad-
renal overactivity, 153.

Pyaemia, immunizing medication in,
771.

Quinine and adrenal insufficiency, 617;
and hsematuria, 59; as immunizant,
767, 768, 770.

Red corpuscles as carriers of oxygen
to supply the plasma its oxidizing
substance, 247; structure of, 715.

Relapsing fever, immunizing medica-
tion in, 771.

Respiration, arrest of, by venoms, 103;
eosinophile leucocytes as the source
of haemoglobin, 716; nervo-vascular
mechanism and, 468, 481; physiology
of, 71, 76, 120, 128, 455, 463, 468, 481,
716; prevailing views as to, 73, 75.

Respiratory center, identity of, 455;
non-existence of, in medulla, 463.

Respiratory interchanges, 481; de-
pendent upon adrenal secretion, 128;
diffusion of gases inadequate to ac-
count for, 122, 123, 127.

Respiratory muscles, innervation of,
464, 468.

Respiratory system, innervation of,
455.

Rheumatic pains in acromegaly, 512,
515; saline solution in, 785.

Rickets and adrenal insufficiency, 178,
515; and removal of thyroid, 178.

Rigor mortis, nature of, 240, 245.

Roentgen rays in cancer, nature of
curative process, 787.

Saline solution, action of, assisted by
adrenal stimulants, 788; in the de-
struction of pathogenic agents, 779;
in the prevention of death, 784;. itin-
erary of, in vascular system, 667;
physiological action of, 778; rectal
use of, 784.

Salivary glands, functional mechan-
ism of, 270, 275.

Salivation as a symptom of adrenal
overactivity, 153.

Santonin poisoning and haemoglobin
disintegration, 102; muscular weak-
ness in, 43; temperature in, 54; vas-
cular pressure in, 50.

Sarcoma, adrenal insufficiency in, 785;
deficiency of alkaline salts and, 785;
mode of action of Coley's fluid in,
787; mode of action of Roentgen rays
in, 787; pathogenesis of, 785.

Scarlatina, arsenic as a prophylactic,
770; immunizing medication, 770, 771;
salt solution in, 784.

Scleroderma as a symptom of adrenal
insufficiency, 153.

Seas, primordial, and alkalinity of the
blood, 788.

Sensation, impaired, and adrenal in-
sufficiency, 169.

Septic fevers, stercobilinuria in, 114.

Sera, all contain similar constituents,
762; uniformity of all, 749.

Serum-therapy, limits of, 751.

Sexual organs, retarded development
of, and adrenal insufficiency, 166.

Shock as a cause of acromegaly, 199;
removal of adrenals and, 3; the pos-
terior pituitary body and, 606.

Silver poisoning, muscular weakness
in, 43; temperature in, 54; vascular
pressure in, 50.

Skin, diseases of, effect of arsenic
partly due to adrenal stimulation,
770; dryness of, and adrenal insuffi-
ciency, 166; the posterior pituitary
body in diseases of the, 777; rough-
ness of, and adrenal insufficiency,
197.

Sleep and reduction of the cerebral
blood-supply, 526; retraction of the
neuron-gemmules during, 577, 578,

Small-pox, salt solution in, 784.

Snake-bites, prevention of morbid ef-
fects of, 767.

Splanchnic nerves, effects of division
of, 28; effects of stimulation of, 219;
as part of the adrenal system, 218,
225, 231.

INDEX.

Spleen as a leucocytogenic center, 333,
335.

Spleen, enlargement of, in malarial
fevers, 332; functional mechanism of,
390, 404; importance of functions of,
663; internal secretion of, 362, 420.

Spleen, post-prandial enlargement of,
and adrenal overactivity, 332.

Spleen, pulsation of, as a symptom of
adrenal overactivity, 153.

Splenic vein, path for spleno-pancre-
atic secretion, 367.

Spleno-pancreatic internal secretions,
367, 392; as a protective body against
action of toxins, toxalbumins, vege-
table poisons and venoms, 664; ac-
tion of, on albuminoid poisons, 369,
392,. 404, 664. (See also Trypsin.)

Stellwag's sign as a symptom of ad-
renal insufficiency, 154, 155.

Stercobilin, origin of, 114.

Stomach, disorders of, and adrenal in-
sufficiency, 87.

Stomach, effects of emotions on, 307;
functional mechanism of, 309; nerv-
ous supply of, 297; physico-chemical
functions of, 296; vascular supply of,
300.

Strontium salts as diuretics, 60.

Strychnine as immunizant, 768.

Strychnine poisoning, muscular weak-
ness in, 43; temperature in, 54; vas-
cular pressure in, 50.

Stumbling as a symptom of adrenal
insufficiency, 153.

Sudoriferous glands, functional mech-
anism of, 276, 280, 283.

Sulphonal and haematoporphyrinuria,
90, 106.

Sulphonal and haemoglobin disintegra-
tion, 101, 106.

Suprarenal apoplexy, 6.

Suprarenal glands. (See Ailrowl.)

Suprarenal haemorrhage, 5, 20, 22, 34.

Suprarenin, 66.

Sweating and adrenal insufficiency,
153, 197, 515; and pilocarpine, 280.

Swelling, superficial, and adrenal in-
sufficiency, 167.

Sympathectomy, morbid effects of, 220.

Sympathetic nerve, a part of general
motor system, 294; morbid effects of
section of, 220, 221.

Sympathetic system, non-existence of,
as separate entity, 218, 262.

Syphilis, immunizing medication in,
771; pathogenesis of, 777: the pitui-
tary bodies in, 777.

Syringomyelia and acromegaly, 514.

Teeth, brittleness of, and adrenal in-
sufficiency, 167.

Temperature, the adrenals and, 50,
166; influence of poisons on, 50; In-
fluence of venoms on, 50.

Tendon-reflex as a symptom of ad-
renal overactivity, l .".::.

Tetanic spasm due to hyperoxidation,
153, 234.

Tetanus due to accumulation of waste-
products, 167, 168; Baccelli's treat-
ment in, 768, 769; curative treatment,
768; dangers of chloral, cannabis
Indica, and similar drugs in, 768;
immunizing medication in, 767, 768;
morphine in, 769; prevention of, in
exposed subjects, 767; salt solution
in, 784; serum-therapy in, 760.

Tetanus due to adrenal overactivity,
167, 234; thermal phenomena in, 234,
236.

Thirst as a symptom of adrenal over-
activity, 196.

Thrombi and adrenal insufficiency, 94;
and haematoporphyrin, 94.

Thymus absent in mentally-weak chil-
dren, 175; present in normal ones,
175; the adrenals and the, 171; bone-
formation and the, 180, 182; extract,
action of, 171, 174; in foatal life, 180;
as a leucocytogenic organ, 181; as a
phosphorus purveyor for the cerebro-
spinal system during development,
179, 182, 185; lecithin as a constitu-
ent of, 177; physiology of, 183.

Thyreo-antitoxin, 156.

Thyreo-globulin, 156.

Thyroid, arsenic as a constituent of,
156.

Thyroid extract as an adrenal stim-
ulant, 166; in exophthalmic goiter,
158.

Thyroid gland and the adrenals, 146;
as an auxiliary organ to adrenals,
152; functions of, 230; itinerary of
the secretion of, 148; relation of,
with the pituitary bodies, 209; re-
moval of, and adrenalectomy, 150,
165; removal of, and rickets, 178;
transplantation of, 149; vascular
supply of, 148.

Thyroid secretion, 154, 163, 164; as a
constituent of antitoxin, 666; effects
on toxins, 148, 155.

Thyro-iodine as a constituent of anti-
toxic serum, 762.

Tobacco poisoning, muscular weakness
in, 4H; temperature in, 54; vascular
' pressure in, 50.

800

INDEX.

Toxic albuminoids, reduction of, 369,
392, 404, 420.

Toxic foods and adrenal insufficiency,
773.

Toxics, effects of continuous presence
of, in the blood, 153.

Toxins, action of, on the adrenals, 33,
36, 37, 39; action on -the adrenal sys-
tem similar to that of drugs, 762;
conversion of, into benign products,
369, 392, 404, 420; reduced to benign
products by trypsin, 655.

Tremors, paretic, as a symptom of ad-
renal insufficiency, 153, 167; as a
symptom of adrenal overactivity, 153.

Trional and haemoglobin disintegration,
102, 106.

Trypsin as the dominant active con-
stituent of antitoxin, 728, 745, 749;
action of, dependent upon presence of
alkaline salts, 779; as the spleno-
pancreatic secretion, 392, 404, 420; as
toxin-destroying agent, 655. (See
also Spleno-pancreatic secretion.)

Tuberculin test and the adrenal sys-
tem, 635.

Tuberculosis of the adrenals, 8.

Tuberculosis, pulmonary, adrenal in-
sufficiency in, 478, 772, 774; intestinal
infection in, 775; mode of infection
in, 774; prevention of, in exposed
subjects, 775; impaired nutrition and
cardiac adynamia, 774; saline solu-
tion in, 780.

Typhoid fever, immunizing medication
in, 771; fibrinogen and, 754, 755; leu-
cocytqsis in, 613; perforation in,
616, 624; saline solution in, 780, 784;
serum-therapy in, 751, 772; sterco-
bilinuria in, 114; Widal's reaction
in, nature of, 748.

Typhus, immunizing medication in,
771.

Unity of cellular life, 609.
Uraemia, saline solution in, 779.
Urea and its formation, 342, 346, 360.
Uric acid, a harmless body, 139; the

most highly oxidized of the alloxuric

bodies, 139; the oxidizing substance

and, 137.

Urobilin, origin of, 114.
Urticaria, general, as a symptom of

adrenal overactivity, 153.
Uva ursi, action of, as diuretic, 61.

Vaccination, nature of immunizing

process, 765.
Vagal system in cardiac functions, 421.

Varicella, immunizing medication and,
771.

Variola, immunizing medication in,
771.

Vascular pressure, adrenal extract
and, 13, 67; the adrenals and, 44;
in poisoning, 44.

Vascular system, the posterior pitui-
tary body in diseases of the, 777.

Vasoconstrictors as subdivisions of
general motor nerves, 253, 261.

Vasodilators, non-existence of, 259, 261.

Vasomotor center, non-existence of,
in medulla, 463.

Vasomotor functions and adrenal sys-
tem, 233.

Vasomotor impulses, the posterior pit-
uitary as the source of, 597, 598.

Vegetable poisons, action on adrenals,
39.

Veins, pulsation of, as a symptom of
adrenal overactivity, 153.

Venomous bites, immunizing medica-
tion in, 767.

Venoms, action on adrenals, 39; action
on vascular pressure, 44; and blood-
disintegration, 96, 99; action on tem-
perature, 50; action of the respira-
tory process, 103.

Venous hums and adrenal insuffi-
ciency, 88.

Veratrum poisoning, muscular weak-
ness in, 43; temperature in, 55; vas-
cular pressure in, 50.

Villi, intestinal functions of, 315.

Vital process, the pituitary bodies as
co-centers in sustaining, 483, 593.
(See also Life.)

Vitiligo, general, as a symptom of ad-
renal insufficiency, 153.

Vomiting as a symptom of adrenal
overactivity, 153.

Von Graefe's sign, as a symptom of
adrenal insufficiency, 154, 155.

White corpuscles. (See Leucocyte.)
Widal's reaction, nature of, 748.

X-rays in malignant growths, mode of
action of, 787.

Yellow fever, immunizing medication
in, 771.

Zinc poisoning and haemoglobin disin-
tegration, 100; muscular weakness
in, 43; temperature in, 55; vascular
pressure in, 50.

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