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STUDENTS' SYNOPSIS SERIES

PHARMACOLOGY 7/6 Douglas Cow

DENTISTRY 9/6 A. B. G. Underwood

HYGIENE 18/- W. W. Jameson and

F. T. Marchant

SURGERY 12/6 Ivor Back and

A. Tudor Edwards

PHYSIOLOGY 10/6 Ffrangcon Roberts

ANATOMY 12/6 T.B.Johnston

MATERIA MEDICA 4/6 J. Burnet

SURGICAL PATHOLOGY 6/.

Eric Pearce Gould

SURGICAL DIAGNOSIS 8/6

W, H. C. Romanis

J. & A. CHURCHILL

[STUDENTS' SYNOPSIS SERIES'^

PHYSIOLOGY

FFRANGCON ROBERTS

M.A., M.D. (Cambridge), M.R.C.P. (London)

FELLOW AND LECTURER IN PHYSIOLOGY, CLARE COLLEGE, CAMBRIDGE

Pf'ITH 73 ILLUSTRATIONS

LONDON

J. & A. CHURCHILL

7 GREAT MARLBOROUGH STREET
1920

PREFACE

This book is an attempt to describe as briefly as possible
how the body works. It is definitely addressed to those
who are already acquainted with the elements of the
subject, and is intended to supplement the larger text-
books. In writing it I have therefore omitted to describe
the physical and chemical processes upon which physiology
is so largely based, and I have assumed that the reader
is familiar with the experiments commonly performed in
the elementary class. For the same reason I have treated
histology only incidentally, and have not described
systematically the general structure of the central nervous
system.

I admit to a plagiarism from Foster in the opening
words. I know no. better way of introducmg the subject.

I wish to offer my warmest thanks to Dr. Marshall,
Mr. Barcroft, Dr. Hele, Dr. Hartridge and Dr. Peters for
their khidness in lookmg over different parts of the
manuscript and proofs and for their many helpful sugges-
tions. I am indebted, too, to Professor Hopkins for his
advice upon numerous points in Biochemistry.

I wish to thank Prof. Langley (editor of the Journal of
Physiology), Prof. Schafer, Prof. Starling, Prof. Keith,
Prof. Sherrington, Dr. Marshall and Mr. Barcroft for
kindly allowing me the use of figures.

My thanks are due to my wife for helping me with the
index.

Ff. Roberts.

Cainhriflqe,
October 1920.

CONTENTS

CHAP.
I.

Introduction "

PAGE

II.

Enzymes

III.

Blood

IV.

Contractility ......

The Heart ......

VI.

The Circut,ation op the Blood

VII.

Respiration .....

VIII.

Digestion

120

IX.

General Metabolism

146

Intermediate Metabolism :

1. Methods of Investigation

155

2. Proteins .....

157

3. Purines .....

169

4. Creatine and Creatinine

. 177

5. Sulphur .....

6. Carbohydrates ....

7. Fats

179

181

. 194

8. Oxidation Process

. 203

Nutrition

. 206

XII.

Urine

. 214

XIII.

Internal Secretion ....

. 229

viii CONTENTS

CHAP. PAGE

XIV. The Regulation of Temperature . . 248

XV. The Nervous System :

Part I. The Neurone and the Nervous

Impulse .... 252

Part II. The Central Nervous System . 264

Part III. Reflex Action . . .272

Part IV. The Exteroceptive System . 281

1. Cutaneous and Deep Sensation . 282

2. Vision . . . . .286

3. Hearing ..... 300

4. Smell and Taste . . . .307

5. Motor Functions of the Cortex . 309

6. Speech . . . . .311

7. The Functions of the Cerebrum . 314
Part V. The Proprioceptive System . 318
Part VI. The Autonomic System . . 327

XVI. Muscular Activity and Fatigue . . 336

XVII. Reproduction 342

XVIII. Defence 368

Index ....... 379

SYNOPSIS OF PHYSIOLOGY

CHAPTER I

INTRODUCTION

M When a single-celled organism such as Amoeba is studied
it is found to possess certain features which distinguish
it from non-hving things. (1) It is able to change its
shape, to envelop particles of food-material and to move
from place to place. These functions it performs by
virtue of the contractility of the protoplasm of which
it is composed. (2) It responds in an active manner to
certain stimuli. It has therefore the property of irrita-
bility. (3) It has the power of ingesting or dissolving
particles of certain organic substances and of incorporating
them into its own architecture. This is the process of
assimilation or anabolism. (4) It is also able to oxidise
the complex substances formed in anaboUsm. This pro-
cess is known as catabolism, the combined processes of
anabohsm and catabolism being termed metabolism. (5) It
is able to expel from its body certain substances. These
are of two kinds — particles which it has enveloped but
cannot digest, and end-products of the catabolic changes.
This function is known as excretion. (6) Lastly, it has
the capacity for reproducing itself.

These fundamental properties are found also in multi-
cellular animals, but with this difference, that in the latter
the different cells of which the individual is composed

2 INTRODUCTION

have become specially endowed with one or other of these
properties. In other words, there is a division of labour,
all the cells contributing their share for the good of the
whole, the cells which possess the same property being
grouped together into units known as tissues. The mus-
cular tissues are cells speciahsed in contractihty ; the
nervous tissues in irritabihty ; the digestive tissues in
assimilation. Special tissues exist also for excretion and
reproduction.

Yet, though the one property has been exalted at the
expense of the others, these have not entirely disappeared.
All cells are assimilative ; muscle, though primarily con-
tractile, is irritable. Those properties other than the one
which is characteristic of the tissue have sunk to a
secondary position — they may be latent, but they are not
necessarily completely abolished.

From the grouping together of a number of cells certain
consequences follow. The first is the need for binding the
cells together. A number of structures are developed to
play this passive role. Such are the connective-tissues —
bones, hgaments, and fibrous tissue. The second conse-
quence is that as the individual increases in size the
number of cells which are in direct contact with the sur-
rounding medium becomes smaller. In Amoeba, the cell
being completely surrounded with water, there is ample
opportunity for interchange of food and excretions. In
multi-cellular organisms, on the other hand, only the few
cells on the surface can be nourished and drained in this
way. As a means of overcoming this difficulty there is
developed a transport system — the blood. Each cell in our
bodies is bathed in a salt solution just as freely as though it
floated independently, and this salt solution brings it the
nourishment which it needs and removes the waste products
which it excretes.

In the animal economy a factor of supreme importance
is the rapidity of the circulation. This is what we are
most apt to forget — possibly because we are unconscious

INTRODUCTION 3

of the movement of our own blood. Yet over four litres
are leaving each ventricle per minute and passing through
the aorta with a velocity of about eighteen centimetres
per second.

The rapidity with which the blood flows and its indis-
criminate distribution among the tissues have certain
important results. Any abnormaUty in the metabohsm
of one tissue immediately affects, through the blood,
the whole body. While the circulation is free there can
be no locahsation of a substance soluble in the blood.
This freedom of the circulation is made use of for the purpose
of co-ordinating the activities of the different organs. In
the first place, the accumulation of normal products of
metabohsm leads to a series of changes in other organs.
In the second place, certain organs have become specialised
solely to produce substances which quicken or retard some
general bodily function. These substances are known as
internal secretions or hormones.

This chemical method of co-ordination has at once an
advantage and a disadvantage. .The advantage lies in the
nicety of adjustment which is possible, due partly to the
potency of the chemical substance formed, partly to the sen-
sitiveness of the organ upon which it acts. The respira-
tory centre, for instance, is a far more dehcate indicator
of the reaction of the blood than any known chemical
reagent. Again, adrenahn exerts its effects in the strength
of one part in a million. The disadvantage of the chemical
method is the time which it takes to work its effects.
Rapid as the circulation is, it is not sufficiently rapid for
the proper co-ordinated response where time is an important
factor.

For rapid co-ordination Nature makes use of the irrita-
bihty of protoplasm. The nerve cells, some of them cells
of great length, are specially adapted to conduct disturb-
ances arising in one part to different parts of the body.
The grouping of nerve cells to form the central nervous
system is for the purpose of effecting rapidly, in response

4 INTRODUCTION

to a change in the environment, an appropriate physiological
reaction.

One difference, then, between the chemical and the
nervous co-ordination is a difference of speed. Another
difference lies in the greater variety of response which the
intricate nature of the nervous system makes possible.

It is sometimes stated that life is simpler in a single-
celled than in a multi-cellular animal. It may be ques-
tioned which is the more complex, an organism in which
different functions are pigeon-holed in different tissues,
admirably co-ordinated though these be, or an organism
in which all the animal functions are performed in an
orderly manner in one cell. Specialisation of function does
not necessarily mean greater complexity of the biological
process. In what sense, then, is a multi-cellular animal
such as a mammal " higher " than a unicellular organism
such as Amoeba? Simply in this, that with division of
labour goes an increase of stability in face of changes in
the environment, an increase in the power of response to
external disturbing factors, an indifference to adverse cir-
cumstances. The Amoeba is completely at the mercy of
the shghtest changes in the physical and chemical con-
dition of the water in which it hves. Its hold upon life
is of the slenderest. Contrast with this the comparative
security of hfe possessed by the mammal. In the follow-
ing pages we shall have reason to see the extraordinary
stability possessed by different bodily systems. The
reaction of the blood, the volume of the blood, the
arterial blood-pressure are, within wide limits, maintained
constant in spite of external forces tending to disturb them.
Another example is seen in the regulation of body
temperature.

But the most potent factor in the stabilising of the body
is the evolution of the central nervous system — the develop-
ment of instincts, memory, association of ideas, and other
intellectual processes. It is to the greater security of hfe

INTRODUCTION 5

which these bring that man owes his pre-eminent position
among all hving beings. The problem before us is to
show the bodily mechanisms by which man triumphs over
his environment.

The study of function in the higher animals will there-
fore have to be considered from three aspects : —

1. The mechanism possessed inherently by each organ,

e.g. the mechanism of the heart-beat.

2. The co-ordination of different mechanisms into bodily

functions, e.g. the co-ordination of heart, lungs and
brain in the supply of oxygen to the tissues during
exercise.

3. The protective reactions of the body to changes in

its environment.

In the following pages we shall try to develop the study
of function from this threefold point of view.

CHAPTER II
ENZYMES

A LARGE number of the chemical changes which occur
in hving tissues can be imitated in the laboratory only
by means of high temperatures or violent reagents. With-
out these the changes occur at so slow a rate that they can
be practically regarded as not occurring at all. Such
reactions can, however, be brought about with great rapidity
in the presence of certain substances which can be prepared
from the hving cells. These substances, which in the
hving body are responsible for facilitating otherwise difficult
reactions, are called enzymes or ferments. Enzymes may
act either within or without the cell in which they are
produced — a distinction of no biological significance.

Enzymes do not influence the energy changes which are
inherent to the reactions which they bring about. Although
it is possible that they act by forming compounds with the
substrate (as the substance upon which they act is called),
such compounds have but a momentary existence, the
enzymes appearing at the end of the reaction unaltered,
unless they happen to be destroyed by a secondary reaction.
Enzymes merely change the rate of a reaction.

It is clear from the above description that the part played
by enzymes corresponds to that played by catalytic agents
in inorganic reactions. Enzymes may indeed be defined
as catalysts produced by living tissues.

As to the chemical constitution of enzymes, little is
known. They are definitely not protein. They contain
nitrogen and probably a carbohydrate group.

Physically, enzymes belong to the emulsoid class of

NATURE OF ENZYMES 7

colloids. When in " solution " in water they exist as
particles containing a small amount of water suspended
in water. vSome of their properties are, as we shall see,
referable to their colloidal nature. There is considerable
evidence to show that they act by providing a large surface
upon which the molecules of the substrate are adsorbed.
The concentration of the substrate thus brought about
leads, by the law of mass action, to the acceleration of a
reaction which otherwise would take place only at an
infinitely slow rate. In favour of the existence of ad sorption
compounds as an intermediate stage, is the fact that some-
times an enzyme is more resistant to heat when in presence
of its substrate. Again, the fact that certain enzymes
may function even in a medium in which they are insoluble,
is best explained on the assumption that adsorption com-
pounds are formed.

In their surface effects enzymes strongly resemble the
metals in a finely divided state. Colloidal platinum effects
a rapid combination of hydrogen and oxygen ; colloidal iron
greatly accelerates the oxidising action of hydrogen peroxide.

We now have to consider the factors which influence
enzyme action, showing how they lend support to the idea
that enzymes are colloidal in structure and catalytic in
function.

1. The effect of temperature. — At 0° C, enzymes are
reduced to inactivity, but are not destroyed. As the
temperature rises they become more active. This, however,
is only one particular instance of the general rule that
molecular activity increases with rise of temperature.
At a temperature equal to or shghtly above body-tempera-
ture, enzymes display their maximum activity. This is
the so-called optimum temperature. Beyond this point
their activity wanes, owing to their gradual destruction.

Destruction by heat does not constitute any distinction
between enzymes and inorganic catalysts. It is a property
of the enzyme, which is shared by some inorganic catalysts
of colloidal nature — for instance, colloidal platinum,

8 ENZYMES

2. The action of electrolytes. — All enzymes are very sensi-
tive to the reaction of the medium in which they work.
There is for every enzyme a certain H-ion concentration
in which it displays a maximum activity. This is readily
understood when we consider the effect of electrolytes
upon the colloid particles. Agglomeration of particles
must lead to diminution of surface upon which adsorption
can take place.

3. Specificity. — This is a characteristic feature of enzymes.
Each enzyme brings about only one kind of reaction, and
acts either upon only one particular substance or only one
class of substances. Enzymes are indeed commonly named
after the bodies upon which they act. There are the proteo-
lytic enzymes, which hydrolyse proteins ; lactase, which
acts upon lactose; arginase, which hydrolyses arginine.
In this respect enzymes differ from inorganic catalysts
only in degree. The specificity of enzymes is not absolute,
as was once supposed. Further, specificity is found among
inorganic catalysts, although to a far less extent.

The high specificity of enzymes is beUeved by some to
depend upon a close structural resemblance between enzyme
and substrate, these fitting hke lock and key. The view
is also held that an enzyme consists of two parts — an active
principle related structurally to the substrate, and a non-
specific colloid which merely serves to provide a surface
upon which the active principle can come into contact
with the substrate.

4. Reversibility of Action. — When a reaction is reversible,
an inorganic catalyst which quickens it in one direction
quickens it in the other to the same extent. The catalyst,
therefore, does not influence the equihbrium point. For
instance, in the reaction —

Ethyl acetate + water '^ ethyl alcohol + acetic acid,

the equiUbrium-point is the same whatever the amount
of the catalyst HCl present. It depends only upon the
relative velocity of the two reactions, that is to say, upon

VELOCITY OF REACTION 9

the active mass of the components of the system. If
water is present in abundance, the equiUbrium-point will
be almost at complete hydrolysis. But if ethyl acetate
be removed from the.system as soon as it is formed, complete
synthesis will take place.

The question now arises whether enzymes behave hke
inorganic catalysts in this respect. Many reactions occur
reversibly in the body : the saponification and synthesis
of fats ; the intercon version of glycogen and glucose. Rever-
sibility of action has been proved for certain enzymes,
particularly for maltase and lipase. It is therefore probable
that in the body an enzyme accelerates a reversible reaction
in both directions, but that the actual change which takes
place depends upon the removal of certain products from
the sphere of action as soon as they are formed. When fat
is saponified in the intestine by the action of Upase the
process is complete, because the products of saponification
are rapidly absorbed. Within the intestinal epithehum
these accumulated products are resynthesised, probably
by the lipase which formed them.

5. Velocity of Reaction. — When the amount of enzyme
is small compared with the amount of substrate, the rate
of reaction is, in the initial stages, directly proportional
to the amount of enzyme, and independent of the amount
of substrate. The enzyme, in other words, can only deal
with a certain amount of substrate at a time. But the
final result, given sufficient time, is the same whatever the
amount of enzyme ; that is to say, there is no quantitative
relation between the amount of enzyme and the amount
of substrate. This constitutes a useful criterion in deciding
whether a substance is a ferment or not.

When the amount of enzyme is relatively large, the
velocity of the reaction undergoes a progressive diminution.
This is to be expected from the law of mass action, since
the concentration of the substrate is undergoing a constant
diminution. The falhng off, however, is usually more
rapid than would be expected from theoretical considera-

10 ENZYMES

tions. Several factors contribute to this. There is the
gradual development of the reverse reaction. The enzyme
may be killed by the products of its own action. Again,
the products may cause a change in the reaction of the
medium which itself inhibits the action of the enzyme.
In the tryptic digestion of proteins, for instance, the amino-
acids formed, being many of them distinctly acidic, increase
the H-ion concentration, and thus tend to retard the action
of the enzyme.

Is all metabolic activity due to the action of enzymes ?
At present this question cannot be answered decisively.
There are certain reactions which can be brought about
by hving cells, but not by enzymes. No enzymes, for
instance, have been discovered in the mammary gland
capable of forming the organic constituents of milk. Again,
antiseptics of a certain concentration are lethal to proto-
plasm but not to enzymes. It is possible that all stages
exist between simple enzyme action and protoplasmic
activity.

CHAPTER III
BLOOD

When blood is centiifugalised, means having been taken
to prevent it clotting, it separates into three layers : the
lowest layer composed of the red corpuscles in an almost
soUd mass ; above this a thin layer consisting of the
leucocytes; above this, again, a clear fluid, the blood-
plasma.

THE PLASMA

Blood-plasma has a specific gravity of 1'06.

Its saline constituents amount to 0-85 per cent. Of
these, the most abundant is sodium chloride ; potassium,
calcium, magnesium, phosphates, carbonates and sulphates
also occur.

Plasma contains the following proteins —

1. Fibrinogen, belonging to the class of globuhns.

2. Serum-albumin.

3. Serum-globuhns {p^f^aogbbuhn.

4. ( ? ) Thrombogen.

Besides the above substances, plasma contains dextrose
fats, cholesterin, lecithin, urea and other nitrogenous sub-
stances, amino acids and innumerable substances of un-
known composition such as antitoxins.

THE RED BLOOD CORPUSCLES

Structure and Composition

The Red Blood Corpuscles, of which there are about
5,000,000 to every c.mm. in men and rather less in women,

BLOOD

are circular, biconcave, non -nucleated discs of a yellowish
colour. They consist of a stroma containing hsemoglobin.
This is probably surrounded by an envelope of lecithin
and cholesterin. The corpuscles are flexible, and by alter-
ing their shape can squeeze through apertures smaller
than themselves. They are pervious only to substances

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Fig. 1. — The spectra of haemoglobin and its derivatives. 1-4, Oxy-
hsemoglobin in increasing concentration ; 5, reduced haemoglobin ;
6, carboxyhsemoglobin. (After Preyer and Gamgee, from Starling's
Princi'plcs of Physiology.)

such as alcohol, chloroform, urea, which are soluble in
lecithin and cholesterin. They are impervious to inorganic
salts. In standing blood the corpuscles tend to clump
together into roulettes. Concentration of the saline con-
stituents of the plasma causes a shrinking of the corpuscle,
while dilation causes the reverse, viz. swelhng up and burst-
ing with hberation of the haemoglobin. The latter process,
known as " haemolysis," can also be brought about by treat-

HEMOGLOBIN 13

ment with ether, bile salts and the serum of an animal of a
different species.

The stroma, consists of nucleoprotein, lecithin and cho-
lesterin. Oxyhcemoglobin, the loose combination of haemo-
globin and oxygen, can be obtained in crystalhne form.
It has a molecular weight of about 16,600 and contains
•3 per cent, of iron. It is easily dissociated into haemo-
globin and oxygen. The oxygen can be replaced by carbon
monoxide, which forms a far more stable compound. The
absorption bands of haemoglobin and its derivatives are
seen in Fig. 1. Oxyhaemoglobin gives a narrow band at
A 579, and a broader band at X 544. Reduced haemoglobin
gives a broad band at X 555. Carboxyhaemoglobin, which
is brighter in colour than oxyhaemoglobin, resembles spectro-
scopically oxyhaemoglobin, but both bands are slightly
nearer the red end, and the second band is better defined.

Methcemoglohin, isomeric with oxyhaemoglobin, is, how-
ever, a more stable compound. It occurs pathologically
wherever there is excessive breakdown of red blood cor-
puscles. Its importance lies in the fact that it can be
formed by treating haemoglobin with potassium ferri-
cyanide. Alt>hough the resulting product contains the
same amount of oxygen as oxyhaemoglobin, the original
oxygen of the oxyhaemoglobin is quantitatively liberated.
This is, therefore, a method for determining the amount of
oxygen in blood.

It has been suggested that oxyhaemoglobin has the
formula —

Hb(|

while methaemoglobin has the formula —

Hb(

Haemoglobin is composed of haematin (C34H34N405Fe),

14 BLOOD

and a protein, known as globin. While the composi-
tion of hsematin is constant, the globin varies in difierent
animals.

Life-history

Nucleated red corpuscles circulate in the human embryo
as early as the third week. From the eighth week, non-
nucleated cells begin to take their place. By the time of
birth, nucleated forms have disappeared.

The corpuscles first appear in the yolk sac, and soon after
in the chorion and wherever blood-vessels are being formed.
Their development is indeed contemporaneous with that
of the blood-vessels, both being derived from the same
syncytial masses of mesoderm. From the tenth day, the
liver is for some time the seat of formation, while after
the sixth week, the same function is performed by the
spleen. By birth the seat of formation is transferred to
the red bone-marrow, where it remains throughout life.
Here all stages of formation can be seen in the cells between
the blood sinuses. The activity of the marrow is increased
by haemorrhage, diminished by impoverisation of the diet.
When the formation of corpuscles is rapid, nucleated forms
(erythroblasts) appear in the blood.

After circulating in the blood for an unknown period,
the corpuscles are destroyed by phagocytes, chiefly in the
spleen and hsemolymph glands. The hberated haemoglobin
is transferred to the liver, where it is decomposed and the
haematin formed converted into the bile-pigments, bilirvbin
and biliverdin. These are excreted in the bile into the
duodenum. They are partly converted into stercobilin,
the colouring matter of the faeces, partly reabsorbed and
excreted in the urine as urobilin.

THE LEUCOCYTES

The leucocytes normally number from 6000-8000 per
c.mm. of blood. The number is increased during digestion
and in nearly all inflammatory conditions.

LEUCOCYTES 15

Classification

The following different kinds of leucocytes are described.

1. Polymorphonuclear Cells.- — In size 10-12/<. The
nucleus varies considerably in shape, being usually either
three-lobed or horse-shoe. The cell-body contains fine
granules, which stain, some with acid, others with basic
dyes, the result on double staining giving a purple effect.
Hence the name neutrophile sometimes given to them.
These cells are actively amoeboid. They constitute 60-70
per cent, of the total leucocytes.

2. Coarsely-granular or Eosinophile Cells.- — In size and
in the shape of the nucleus, these resemble the polymorpho-
nuclear cells. They differ from them in containing coarse
granules, which stain deeply with eosin. They are only
found to the extent of 1 per cent.

3. Lymphocytes. — These are smaller than the above
varieties, having a diameter of 7-5. The cell is spherical
and is almost filled with the nucleus, which is often kidney-
shaped. The cytoplasm stains a pale blue, and is free
from granules. Occasionally large forms are seen. These
cells are not amoeboid. About 25 per cent, of the leucocytes
are of this class.

4. Mononuclear or Hyaline Cells. — These are large— up
to 25/<, and round or ovoid in shape. The nucleus is ill-
defined and feebly staining. The cell-body is shghtly
basophile and non-granular. The cells are slightly amoeboid.
These form about 2 per cent, of the leucocytes.

5. Basophile or " Mast " Cells. — In size they are about
10/<. The nucleus is tri-lobed, and the cell-body contains
basophile granules. They are difficult to find, forming
less than 1 per cent.

Origin of the Leucocytes

The polymorphonuclear cells and probably the eosino-
philes are formed in the bone-marrow from large cells
known as myelocytes. The lymphocytes are formed in

16 BLOOD

" lymphoid " tissue, which is widely distributed throughout
the body — particularly in relation to the ahmentary canal —
the tonsils, adenoids, and Peyer's patches. The thymus,
the Malpighian corpuscles of the spleen, and the lymphatic
glands are tissues of the same nature. In all these organs
lymphocyte-formation by mitosis can be seen.

Functions of the Leucocytes

Besides circulating in the blood, leucocytes wander
through the intercellular spaces of the tissues. Their
function is the destruction and digestion of foreign bodies,
such as bacteria, and the absorption of tissues which are
undergoing degeneration. This process is known as -phago-
cytosis. In acute inflammatory conditions, there is. a
mobihsation of leucocytes, particularly of the polymorpho-
nuclear variety, at the site of infection, and an increase
in the number circulating in the blood.

The ingestion of foreign bodies is carried out by the
polymorphonuclear and mononuclear cells. The part
played by the lymphocytes is unknown. They increase
in number in chronic affections such as tuberculosis. It
is beheved that from the granules of the coarsely granular
cells, both oxyphile and basophile, are excreted substances
which are toxic to bacteria.

BLOOD-PLATELETS

These are small bodies 1-5 /t in diameter. In form,
size and number they vary according to the way in which
the blood has been collected. They are usually circular
discs, containing fine granules. They number from 100,000-
500,000 per c.mm. In the circulating blood they are only
seen when the vessel-wall is injured. When blood is care-
fully collected, and kept at body temperature, no platelets
can be found. It is therefore beheved that they are not
present in normal circulating blood. How they are pro-
duced is uncertain, some observers beheving that they
arise from the disintegration of red-cells and leucocytes.

REACTION 17

Whatever their origin may be, they seem to play, as we
shall see, an important part in the process of coagulation.
They seem to be absent from avian and probably from
amphibian blood.

The specific gravity of blood, measured by taking the specific
gravity of a mixture of chloroform and benzene, in which blood
neither rises nor sinks, varies in man between 1057 and 1066 —
slightly less in women.

The viscositii, measured by its rate of flow through a capillary
tube, is five times that of water. It varies with the number of
red corpuscles.

The amount of hcemoglobin is best measured by the Haldane-
Gowers Hsemoglobinometer. Blood diluted 200 times is saturated
with CO and the colour tested against a sample made up from a
mixture of blood (similarly treated) from a number of healthy
individuals.

Proportion of Corpuscles to Plasma. — The proportion of corpuscles
to the total volume of blood is measured by the hematocrit. This
is a graduated tube, in which blood can be centrifugalised. The
corpuscles which settle at the bottom form normally about 37 per
cent, of the volume of the blood.

Number of Corpuscles.- — This is estimated by means of the
Thoma-Zeiss hsematocytometer.

REACTION OF THE BLOOD

The reaction of the blood is most conveniently expressed
in terms of the concentration of hydrogen ions. Pure water
is very shghtly ionised into hydrions and hydroxyl-ions —

H2O ;t H' + OHi .

at 21° C. the concentration of H and OH being each 10 "'^
gramme-ions per litre. If an acid such as HCl be added, this
is to a large extent dissociated into H- and CI -ions. The
H-ions in the system are therefore increased, let us say, to
10 " '^, the OH-ions being decreased, to a corresponding extent,
to 10"^. When an alkali is added the reverse takes place.
An acid is therefore a solution which has at 21° C. a H-ion
concentration greater than 10"'^, and an alkah is one
which has a H-ion concentration less than 10"'^. The differ-
2

18 BLOOD

ence between a strong and a weak acid is due to the greater
degree of ionisation of the former.

It is usual to express the hydrogen ion concentration
as the logarithm to base 10 of the hydrogen ion concentra-
tion, according to Sbrensen's method, the negative sign
being omitted for simphfication. This figure is known as
the " Ph."

When the H-ion concentration is 1 x 10"''' normal, Ph =
7-0. When it is 0-2 x 10- ^ normal, Ph = 7-7.

(Since log 10*2 = 0-30
.-. -2 X 10-7= 10-3o-7o^_7.7)_

In the case of blood, Ph • 7-0 and Ph 7-7 are the hmits
compatible with health. The figure for Ph decreases as
the H-ion concentration (and therefore the acidity) increases.

When an acid is added to the blood the H-ion concentra-
tion is not raised to anything like the same amount as
occurs when the acid is added to water. The stabihty
of the blood in this respect is called buffer action. Buffer
action may therefore be defined as the capacity to take
up acid without acquiring a corresponding acidity. The
substances responsible for buffer action, themselves known
as buffers, are chiefly inorganic salts, and to a less extent
proteins. Of the salts the most important is NaHCOg,
which for practical purposes may be considered to be the
only " buffer" normally called into play. When an acid
such as lactic is added to blood the following reaction
occurs —

NaHCOg -f Hi7= NaL-f H2CO3.

Since carbonic acid is hardly ionised at all, there is practi-
cally no change in Ph.

A solution of NaHCOg always contains a certain amount

of CO2 dissolved in it, and the Ph of such a solution is

TT r\r\

determined by the ratio ■vpTrT^- When, therefore, lactic
acid is added to circulating blood, the diminution in the

BUFFER ACTION

NaHCOg which we have seen take place would lead to a
decrease in Ph were it not for the fact that the body pos-

TT r\r\

sesses three methods for restoring the ratio „ \inr\ ? ^^^

so keeping the Ph constant.

1. The respiratory centre is extremely sensitive to the
H-ion concentration of the blood supplying it, responding
to the shghtest increase by increasing the pulmonary ventila-
tion. This reduces the COg in the alveolar air and therefore
the CO2 of the blood.

2. The kidney responds to increased H-ion concentration

Piasma.

Corpuscles

Fig. 2. — ^IMigration of chlorine ions.

by excreting acid sodium phosphate until the normal
reaction is restored.

3. The blood itself responds by an interaction of ions
between plasma and corpuscles. When COg is added to
the blood, chlorine ions migrate from the plasma to the
corpuscles, thus, as it were, releasing sodium to combine
with COg. This transference of chlorine ions is connected
with the fact that reduced haemoglobin (reduced in this
case in consequence of the addition of CO2) is less acid
than oxyhsemoglobin. The migration of chlorine ions from
plasma to corpuscles has the effect of increasing the
NaHCOg of the plasma by an amount corresponding to
the increase in CO,.

20 BLOOD

It will therefore be seen that the blood has the power
of carrying a varying amount of acid with practically no
change in the H-ion concentration, and that this power
depends almost entirely upon the buffer action of NaHCOg.
We see further that the blood possesses a store of NaHCOa,
a store fluctuating in amount. Sodium bicarbonate is
therefore termed the alkaline reserve. It serves the purpose
of stabilising the H-ion concentration. When a more
stable acid such as lactic appears in the blood, it com-
bines with sodium and therefore reduces the amount of
NaHCOg. In small amounts this causes only a very slight
change in the H-ion concentration, but by reducing the
alkaline reserve it brings the blood nearer the margin of
stability. Such a condition of reduced alkaline reserve
is called acidosis. The blood can therefore be in a state
of acidosis without any appreciable rise in its H-ion concen-
tration. As the lactic acid is oxidised the alkahne reserve
is restored.

Determination of the Allcaline Reserve : Van Slyl<e's Method

Blood is collected under a layer of paraffin and centrifuged.
The plasma is removed and exposed to a sample of alveolar air.
A known volume is then treated with excess of 5 per cent. H2SO4,
frothing being prevented by addition of a drop of caprylic alcohol.
It is then put under reduced pressure and the CO2 driven off is
measured. Since this is the CO, combined chemically in the plasma,
the amount of NaHCO;; can be calculated.

Determination of H-ion Concentration

Electrical Method.

Sorensen^s Method. — The plasma is treated with an indicator,
e. g. neutral red, and the colour matched with a series of phosphate
solution.

Barcroffs Method. — This depends upon the fact that H-ion
concentration determines the form of the dissociation curve of
oxyhsemoglobin (p. 101).

THE TOTAL AMOUNT OF BLOOD IN THE BODY

This is estimated by two methods.

BLOOD-VOLUME 21

1. Haldane's Carbon-monoxide Method

This method depends upon the fact that carbon monoxide
combines with haemoglobin to form a compound more
permanent and of a brighter tint than oxyhsemoglobin.
The following are the steps in the process- —

1. The oxygen capacity of the subject's blood is first
determined — that is to say, the amount of oxygen with
which 100 c.c. of blood can combine. This is estimated
most accurately by an indirect method. The oxygen
capacity of ox blood is determined directly by the ferri-
cyanide method. By means of the heemoglobinometer,
the haemoglobin content of the ox blood and of the sub-
ject's blood are compared. From this is calculated the
oxygen capacity of the subject's blood. Suppose 1 c.c.
of blood combines with a c.c. of oxygen.

2. The subject breathes a known volume (V) of carbon
monoxide. This turns out some of the oxygen from com-
bination with haemoglobin.

3. The percentage saturation of the blood with CO is
determined in the following way. A sample of blood taken
before CO inhalation, (A), and a sample taken after, (B), are
diluted to the same amount. The latter will be sUghtly
redder than the former. Another sample (C), similarly
diluted, is saturated with CO by bubbhng coal-gas through
it. This, of course, will be redder still. Carmine is now
added to A from a burette until the colour is the same as B.
Let the amount of carmine used be x. Addition of carmine
is then continued until the colour equals that of C. Let
the total amount of carmine added be y.

The amount of CO required to saturate the blood com-
pletely would therefore be - x V. Now a given weight

of haemoglobin combines with the same volume of oxygen
as it does with carbon monoxide. The amount of oxygen
required to saturate the whole of the haemoglobin is there-

22 BLOOD

fore - X V c.c. But we already know that 1 c.c.'of blood

combines with a c.c. of oxygen.
The volume of blood is therefore -

''x V

2. Vital-red Method

Vital-red is a non-toxic dye, which on injection colours
the plasma, but does not to any extent affect the corpuscles,

A known volume of dye, say 15 c.c, is injected into a
vein, a sample of blood being drawn before and after the
injection. Both samples are centrifugahsed, and the
plasma separated from the corpuscles. Two solutions
are now made up as follows —

r 1 part plasma before injection of dye.
„, , , 1 part dye solution diluted 200 times with
Standard. I isotonic NaCl.

2 parts isotonic NaCl.

rp f / 1 part plasma after injection of dye.

^ ^^^- \ 3 parts isotonic NaCl.

The intensity of the coloration of the two solutions is
then compared, that of the test being expressed as a per-
centage of that of the standard.

It is clear that if the two colours are of equal strength,
the total volume of plasma must be 15 X 200 c.c. = 3 htres.

If K. is the percentage reading of the test solution, the

volume of plasma — -^ x No. of c.c. of dye injected x

200.

From the volume of plasma, the volume of the blood is
obtained by means of the hsematocrit.

Prior to the discovery of these methods, the only estima-
tions of the amount of human blood were derived from

COAGULATION 23

experiments upon executed criminals. From these, the
weight of the blood had been found to be one-thirteenth
of the body weight. Haldane, however, puts the figure
at one-twenty fifth.

When the volume of the blood is disturbed, the body
reacts so as to restore it to its normal value. When fluid
enters the body from the intestine, it does not materially
increase the blood- volume, for the excess is immediately
excreted by the kidney. When blood is lost by haemorrhage,
the volume is recovered by the passage of fluid from the
lymph spaces into the circulation, the normal number of
red corpuscles being restored later by increased activity
of the bone-marrow.

At high altitudes the volume of the blood is diminished,
with the result that there is a relative concentration of
red blood corpuscles. This effect comes on within twenty-
four hours. After a few weeks the number of red corpuscles
is increased absolutely by heightened activity of the bone-
marrow.

THE COAGULATION OF BLOOD

The clotting of blood consists in the deposition in it
of a mesh work, consisting of a protein known as fibrin.
In this meshwork the corpuscles are entangled and from
it exudes a fluid — the serum. Clotting is essentially the
formation of fibrin.

The conditions which determine the occurrence or non-
occurrence of fibrin-formation are very diverse.

The process is hastened in drawn blood —

1. By mechanical distvirbance ;

2. By keeping it at body temperature ;

3. By addition of serum or clot ;

4. By addition of extracts of nuclear tissue ;

and in vivo —

5. By injury to the endothelial lining of the blood-vessel.

24 BLOOD

The process is retarded or prevented — ■

1. By addition of sodium oxalate, fluoride or citrate;

2. By cooling ;

3. By receiving it direct from the interior of a blood-

vessel into a vessel hned with paraffin ;

4. By addition of leech extract.

If freshly drawn blood is treated ^vith sodium oxalate,
fluoride or citrate, it fails to clot. Clotting can be induced
by addition of calcium in excess. Calcium, therefore, is
necessary for the formation of fibrin, the preventive action
of the oxalate and fluoride being due to the metal being
precipitated, that of the citrate being due to the metal
being converted into a non-ionised form.

From the oxalated plasma there can be precipitated,
by half -saturation with sodium chloride, a protein — fibrino-
gen. This, on being separated and redissolved, forms
fibrin as soon as calcium is added to it. Fibrinogen, then,
is or contains the precursor of fibrin.

If fibrinogen be purified by repeated precipitation, it no
longer clots on addition of calcium. Crude fibrinogen,
therefore, contains another substance essential to clotting.

Purified fibrinogen, on addition of serum or clot in the
absence of calcium, readily clots.

Purified fibrinogen, on the addition of fresh oxalated
plasma, does not clot.

From the above facts, these inferences can be drawn.

1. There is present in clot and serum, but not in fresh
blood, a substance which directly causes clotting, even
in the absence of calcium.

This substance is called thrombin.

2. Thrombin is evidently the substance removed from
crude fibrinogen in the process of purification,

3. Calcium is necessary, not for the conversion of fibri-
nogen into fibrin, but for a process anterior to this, the
formation of thrombin, from a parent-substance {thrombogen
or prothrombin).

COAGULATION 25

Thrombin was at one time universally believed to be a
ferment. There is evidence, however, that thrombin
unites quantitatively with fibrinogen. It is probably a
protein.

We have already seen that when blood is drawn direct
from the blood-vessel into a vessel fined with paraffin — that
is to say, without touching any tissue — clotting is retarded.
In the bird, under the same circumstances, it is prevented
altogether. In blood drawn in this way, clotting can be
readily induced by addition of almost any tissue-extract,
or of blood-clot. But if tissue-extract is added to pure
fibrinogen, clotting does not occur. The substance present
in tissue-extract is therefore not thrombin, though its
presence is necessary for the formation of thrombin. In
the formation of thrombin, therefore, two factors are neces-
sary, calcium and the substance present in tissue-extract.
The latter is a ferment called thrombokinase. Thrombo-
kinase, in addition to being present in tissues, occurs also
in the blood platelets, or rather, it would be more accurate
to say, is produced in the formation of the platelets. The
absence of platelet-formation in the bird is the reason why
uncontaminated blood does not clot in these animals.

The argument may be summarised thus : clotting takes
place in two stages : (1) the formation of thrombin from
thrombogen (present in plasma), by the action of the ferment
thrombokinase (present in tissues and blood-platelets), in
the presence of calcium. (2) The interaction of thrombin
and fibrinogen to form fibrin.

The view has been expressed that thrombokinase is not
a specific substance, the formation of thrombin being attri-
buted to the effect of the calcium ions upon the colloidal
thrombogen in the presence of any fine particles, such as
dust.

To explain why clotting does not occur in the intact
circulation, we must assume ' either that the endotheUal
fining of the vessels is devoid of thrombokinase, or that
an antithrombin is present. A similar hypothetical anti-

26 BLOOD

thrombin must be credited to the sahvary glands of the
leech.

The process of coagulation may be tabulated thus —

Prothrombin
(in plasma)
in presence of Ca
and of thrombo-
kinase (in all
tissues and plate-
lets).

Thrombin + Fibrinogen
I (in plasma).

Fibrin + Corpuscles.

Clot.

THE LYMPHATIC SYSTEM

In all parts of the body, with the exception of the spleen-
pulp, the tissue-cells are bathed in a fluid — the lymph (Fig,
3). This is contained in irregular spaces separating the cells
from one another, and from the walls of the blood-capillaries.
Through the lymph nutritive substances pass from the
blood to the cells, and waste-products pass from the cells
to the blood.

Lymph originates in the blood-plasma. It is continually
passing in and out through the capillary walls. A certain
amount, however, regains the blood indirectly by a system
of vessels — the lymphatics — comparable in structure to
the veins. Lymph-capillaries originate in the intercellular
spaces and join together to form larger vessels which again
unite to form on each side a duct which drains into the
blood at the junction of the subclavian and jugular veins.
The two ducts are very unequal in size and in the territory
from which they gain tributaries. That on the left is much

LYMPH

the larger, and is known as the thoracic duct. It drains
the left side of the head and neck and thorax, the left upper
and both lower hnibs, and the whole of the abdomen with
the exception of the upper surface of the hver. The
remainder of the body is drained by the rigM lymphatic duct.
The lymphatics originate not only in the interstitial spaces
of the tissues, but also in the serous membranes such as
the pleura, pericardium and peritoneum, and from the joints.

Fig. 3. — Showing diagrammatically the relation between cells, capillaries
and lymph. The lymph is shaded. The capillaries are shown, some
contracted, some distended.

In the vilU of the small intestine they arise as the central
lacteals. In this region the lymphatics have the special
function of transporting fat from the intestinal epitheUum.

In some part of their course the larger lymphatic vessels
are interrupted by the lymphatic glands. These consist
of masses of lymphocytes enclosed in a fibrous capsule.
The lymphocytes are here being formed ; they pass into
the circulation by the efferent lymphatics.

The flow of lymph along the lymphatics is very slow.
Even the thoracic duct only pours out about 1 c.c. per

28 BLOOD

minute. The rate of flow from any tissue varies with physio-
logical activity. When the body is at rest there is practically
no flow from the Hmbs, all the lymph being derived from
the viscera, particularly the liver.

Properties of Lymph

Lymph is usually a clear, alkahne fluid which clots slowly
on standing. It contains the same saline constituents
as blood plasma. Its protein content varies with its origin,
being much higher in lymph which comes from the viscera
than in that which is derived from the limbs. Normal
lymph always contains less protein than blood. The lymph
which comes from the intestine is known as chyle. During
digestion it is milky, due to fat held in suspension.

The Formation of Lymph

Whether lymph is formed by a physical process or by
secretion is an old controversy. Heidenhain argued that
it was due to secretion. He discovered that there were
certain substances which increased lymph formation. These
he called lymfhagogues. He divided them into two classes
— the first class consisting of protein substances —
such as peptones, mussel-extract; the second class con-
sisting of crystalloid bodies such as dextrose and urea.
Both these classes owed their effect, Heidenhain believed,
to a stimulating action upon the secretory process.

Foremost amongst the opponents of this view is Starling.
According to Starling, the action of the first class of
lymphagogues can be discounted because these substances
are toxic. The action of the second class is due to a dis-
turbance of osmotic relations. When these substances
are injected they raise the osmotic pressure of the blood
and thus cause withdrawal of water from the lymph-spaces
into the blood. As they themselves, being slightly diffusible,
pass into the lymph-spaces they cause a flow by osmosis
in the opposite direction — in this way causing an increased
flow of lymph.

FORMATION OF LYMPH 29

Under normal conditions, according to Starling, lymph
formation is influenced by two factors^ — the state of the
blood and the state of the tissue. As to the blood, the
lymph is exuded from it owing to the capillary pressure.
When this increases, other things being equal, the amount
of lymph formed increases also. In confirmation of this,
Starling found that the rate of lymph flow from the hver
was increased when the venous outflow was obstructed, and
diminished when the arterial supply was lowered. It can,
however, be argued that this efiect is produced indirectly
by the altered metabohsm due to the stagnation of the blood.
It is known that deficient oxygenation causes an excessive
flow of fluid into the tissue spaces (CEdema),

But the effect of blood pressure is partly counterbalanced
by the osmotic pressure of the plasma colloids, which pass
but slowly through the capillary walls. The importance
of the osmotic pressure of the plasma proteins as a factor
in restraining the passage of fluid from the blood is shown
by the therapeutic effect of infusions for severe haemorrhage.
It is now agreed that isotonic sahne is of little use for this
purpose, since, owing to the dilution of the plasma proteins,
capillary pressure exceeds osmotic pressure, so that all
the fluid injected passes into the tissues. To be retained, the
injecting fluid must have an osmotic pressure equal to that
of plasma. To this end a 6 per cent, solution of gum arable
is used. The effective force driving the lymph out of the
capillaries is therefore the capillary pressure minus the differ-
ence between the osmotic pressure of the plasma proteins and
the osmotic pressure of the lymph proteins.

But while this force drives the lymph a tergo, another
draws it a fronte. This is the activity of the tissue-cells.
In every tissue lymph-formation increases with activity.
In the hmbs lymph only flows when the muscles are working.
Starhng explains the coincidence of lymph-flow with
activity in this way. When the cells become active, large
molecules are broken down into smaller ones. The osmotic
pressure within the cells and tissue-spaces is thus raised.

30 BLOOD

This attracts fluid from the blood and causes an increase
of lymph. The difference in the amount and character
of lymph from the abdominal viscera and from the hmbs
is explained by assuming that the capillaries of the former
are the more permeable.

In the central nervous system the place of the lymph
is taken by the cerebrospinal fluid. It contains a small
amount of sugar but is almost free from proteins.
Secreted by the choroid plexus into the third ventricle,
it passes by the foramen of Majendie in the roof of the
fourth ventricle into the subarachnoid space. It passes
into the cerebral veins by the Pacchionian bodies.

THE SPLEEN

In the splenic pulp the blood-vessels take the form of
sinuses, the walls of which are incomplete. The blood,
therefore, passes out and mixes with the splenic cells. This
is the only situation in the body where the blood comes
into direct contact with tissue-cells without the intervention
of lymph.

In the adult spleen, two processes can be seen to take
place — destruction of red blood corpuscles and formation
of lymphocytes. The first is carried out by large phago-
cytic cells, which engulf and digest the red cells. The
hgemoglobin is not destroyed in the spleen, since destruction
of injected haemoglobin is unaffected by removal of the
organ. It is carried by the splenic vein to the hver, where
it is converted into bile-pigment.

The formation of lymphocytes takes place in the Mal-
fighian corjmscles, which are masses of lymphoid cells
situated around the small arteries and undergoing prolifera-
tion. Blood in the splenic vein is said to contain more
leucocytes than blood in the splenic artery.

In foetal life the spleen is said to be one of the seats of
formation of red cells. Whether this function is continued
after birth is a matter of dispute. Normally, no histological

THE SPLEEN 31

evidence of it can be made out, but it is said that after
severe loss of blood, red cells are to be seen in process of
formation. When the spleen is removed, there occurs
a diminution in the red cells of the circulating blood — a
fact which indicates either that the spleen does normally
form these cells, or that it provides a hormone which stimu-
lates this function elsewhere.

The high content of purine bases which occurs in the
spleen is incidental to the metabolism of leucocytes. There
is no evidence that, apart from this, the spleen has a special
function of purine formation.

The slow rhythmic contractions which the spleen under-
goes by virtue of its unstriated muscle-fibres, are evidently
for the purpose of propelhng the blood through the organ.
The spleen cannot form a reservoir for excess of blood.

From the fact that hfe can be continued normally after
removal of the spleen, it is clear that whatever function
it performs can be transferred to other organs. Of these
the most important are probably the hcemolymqjh glands,
which, scattered throughout the abdomen, are intermediate
in form between the spleen and the lymphatic glands.

CHAPTER IV
CONTRACTILITY

Introduction

Contractility is one of the fundamental attributes
of protoplasm. It is the means whereby the organism
changes its size and shape, and in the animal world its
position in space. It is seen in its simplqgt form in the
Amoeba, where by retraction here and protrusion there of
the undifferentiated protoplasm surrounding the nucleus,
the animal is enabled to ingest foreign particles and move
from one place to the other. This simple mode of locomo-
tion is known as amoeboid movement. Even in the highest
organism this method is retained. It is found for instance
in the leucocytes of the blood and in the pigment layers
of the retina.

Ascending in the animal scale we find certain cells
speciahsed to effect, through changes in their shape, move-
ments of certain organs or of the whole organism, such
movements showing the widest variation in their strength
and rate. This capacity for change in shape is associated
with the presence of fibrils which are laid down in the cell
substance. The fibrils are known as sarcosfyles, and the
protoplasm in which they lie, sarcoplasm. The cells in
which the power of contraction is most strongly developed
are characterised by a great complexity of the sarcostyles.

Broadly speaking, two types of muscle cell are found,
the unstriated and the striated, these terms being referable
to the absence or presence of transverse-striation in the

CONTRACTILITY 33

fibres. These two classes show certain difierences in form,
mode of contraction and function. The structural differ-
ences will be dealt with more fully in a subsequent para-
graph. It is only necessary to point out here that in
unstriated muscles the fibres are beheved to be connected
to one another by fine bridges of contractile tissue, the
consequence being that a state of contraction is propagated
from fibre to fibre throughout the whole muscle. In
striated muscle, on the other hand, each fibre receives a
nerve filament and is independent of its neighbours. On
account of this difference between the two types, an
unstriated muscle always contracts as a whole, whereas
in striated muscle the contraction can be graded by
varying the number of fibres brought into play.

As to the form of contraction, striated muscle differs
from unstriated in its greater rapidity and force of con-
traction. The other difference between striated and un-
striated muscle lies in their relation to the central nervous
system. The striated are usually, but not always, under
the control of the will. The unstriated are not directly
under voluntary control ; they usually subserve visceral
functions. The striated, highly speciahsed though they
are in contractile power, are incapable of any form of con-
traction except in obedience to impulses arriving from the
nervous centres, and, owing to a constant flow of impulses,
they are normally in a condition of partial contraction or
tonus. Cut off from these impulses, they become flabby
or toneless. Unstriated muscles on the other hand
have in large measure retained a power of contraction
independent of outside influences. Like the striated, they
are normally in a state of tonus, but the tonus is an inherent
property of the muscles themselves, being independent of
impulses arriving from the nervous centres. Besides tonus,
they often possess a power of rhythmic contraction, an
example of which is seen in the muscle of the intestinal
wall. But though capable of contraction independently
of the nervous system, their tonus and rhythm are still
3

34 CONTRACTILITY

subject to control by impulses arriving from the nervous
centres, these impulses serving either to increase or to
decrease the degree of tonus and the rate and force of the
rhythmic contractions.

Commonly, unstriated muscles are supplied by two
different nerves, one augmenting, the other suppressing a
pre-existing state of activity. Herein lies another distinc-
tion between the two classes, for variations in the con-
traction of striated muscles are brought about, so far as
is known, only by variation in one direction or the other
of a constant flow of impulses along one and the same
nerve.

Heart muscle occupies an intermediate position between
the two classes. Structurally it exhibits a faint cross-
striation and continuity from cell to cell. It resembles
unstriated muscle in its rhythmic power, in its independence
of the central nervous system, and in its double nerve-
supply. It resembles striated muscle in the strength of
its contraction.

Composition of Muscle

If muscle-tissue be minced at 0° C, extracted with
NaCl solution and the mixture filtered, a filtrate is obtained
which consists of an opalescent fluid^ — muscle plasma.
This consists of two proteins, an albumin and a globuhn,
which have been called myosinogen and 'paramyosinogen
respectively. On slightly raising the temperature this
fluid, hke blood-plasma, undergoes coagulation, the two
proteins being converted into an insoluble form — -fibrin.
From being neutral or slightly alkaline, the reaction becomes
acid — a change attributable to the development of sarcolactic
acid. The residue which is left behind on the filter-paper
consists principally of what may be called the incidental
constituents of muscle — fibrous and nuclear material and
sarco lemma.

The serum which can be squeezed out of the muscle
clot consists of a pigment, myohamatin (related to hsemo-

STRUCTURE OF MUSCLE 35

globin), extractives, creatine, hypoxanthine and xanthine,
fats, glycogen, inosite (the so-called muscle-sugar, but in
reahty a benzene derivative), and lactic acid.

When muscle loses its blood-supply it soon undergoes
a profound physical change. From being translucent and
elastic it becomes opaque and stil!. This alteration, hke
the clotting of muscle plasma, is accompanied by a develop-
ment of sarcolactic acid. The condition which the muscle
assumes is termed rigor mortis. A similar change may be
brought about if the muscle is slowly warmed above the
coagulation temperature of its proteins. Since the most
striking chemical change is the development of lactic acid,
the question arises whether the presence of this acid is the
cause or the result of the physical alteration in the muscle.
Lactic acid increases in muscle as the result of activity,
and the rate of onset of rigor is dependent upon the degree
of accumulation of the acid. Further, rigor can be pre-
vented even in a dead muscle if the accumulation of acid
is prevented by perfusion. The formation of lactic acid,
then, would seem to be the forerunner and the cause of
rigor.

Structure of Muscle

Unstriated muscle is composed of fusiform cells of
variable length. There is an oval nucleus. The sarco-
plasm is occupied with fibrils disposed longitudinally.

Striated muscle consists of fibres of 0-05 mm. diameter and
of varying length up to 3 cm. Each fibre is enveloped in an
elastic sheath, the sarcolemma. It is composed of discs
or sarcomeres of dark and Ught material alternately— an
arrangement which gives to this type of muscle its name.
In the middle of each Ught band is a row of granules con-
stituting the so-called Krauses membrane. The complete
disc therefore consists of a dark middle portion and a light
portion at each end, Krause's membrane being the surface
of union of adjacent discs. Each of these discs is broken
up longitudinally into a number of longitudinal fibrillse,

CONTRACTILITY

the sarcostyles, which are separated from one another by a
granular substance — sarcoplasm.

The relative amount of sarcostyle and sarcoplasm in a
fibre is variable, and confers upon the fibre its form of
contraction. Where the sarcoplasm is scanty {white fibre),
the contraction is in the form of a rapid twitch; where
abundant {red fibre), the contraction is slow and sustained.
While in some animals individual muscles are composed
exclusively of either red or white fibres, in man both types
of fibre are often found in the same muscle. There is some
evidence to show that both sarcostyle and sarcoplasm are
endowed with contractihty, the movement being rapid
in the case of the former, slow in the case of the latter.

^.'EA

SJL

Fio. 4. — Sarcomere (diagrammatic). A, relaxed; B, contracted.
- K, membrane of Krause ; H, line of Henle ; S.E., sarcostyle (Schafer)

When a muscle-fibre is observed under the microscope
the act of contraction is. seen to consist of a broadening of
the fibre and a thinning of the individual discs. At the
same time the dark band becomes hghter and the hght
band darker, until a complete reversal is obtained. When,
however, the fibre is observed through polarised hght the
dark bands are anisotropic, or doubly refracting, appearing
hght ; while the hght bands are isotropic, or singly refracting,
and appear dark. In contraction there is no reversal of
this effect, but an increase of the anisotropic at the expense
of the isotropic substance.

In the following pages we shall deal primarily with
striated muscle, indicating how cardiac and imstriated
muscle resemble or differ from it.

IRRITABILITY 3!?

The Irritability of Muscle

Striated muscle retains, to a considerable degree, the
primitive characteristic of protoplasm in general — irrita-
bihty — though this is normally masked by the superior
irritabihty of nerve. The inherent irritabiUty of muscle
is shown by the occurrence of contraction in strips of
muscle demonstrably free from nervous element. It is
shown most perfectly by Claude Bernard's classical experi-
ment. In a frog both sciatics were exposed and a ligature
tied round the right thigh so as to include all tissues except
the nerve. Curare was then injected into the lymph sacs.
In a few minutes stimulation of the left sciatic nerve was
without effect upon the gastrocnemius, while on the right
side a normal contraction was evoked. On both sides
the muscles continued to respond to direct stimulation.
The drug had therefore paralysed neither the muscles nor
the nerve-trunk, since the muscles had been exposed to its
action on the left side and the nerve-trunk on both sides.
It had acted upon the nerve-endings in the muscles.
These having been put out of action, direct stimulation
affected the muscle itself.

CHANGES ACCOMPANYING CONTRACTION

The changes which a muscle undergoes when it passes
from the uncontracted to the contracted state may be thus
enumerated—

1. Change of form.

2. Development of tension.

3. Change in excitabihty.

4. Chemical changes.

5. Electrical changes.

6. Thermal change.

We now have to consider each of these in turn, pointing
out how the information gained leads us to an understanding
of the nature of contraction.

38 CONTRACTILITY

1. The Change in Form

When a muscle such as the frog's gastrocnemius is con-
nected with recording apparatus and is stimulated by means
of a single induction shock apphed to its nerve, the
mechanical result consists of three parts^ — the latent period,
the period of contraction, and the period of relaxation.
The latent period is due partly to the inertia of the apparatus,
partly to the time occupied in the transmission of the
impulse along the nerve and across the nerve ending. But
when these have been discounted there remains an interval
of time, estimated at -0025 sec, during which changes
preparatory to contraction are taking place in the muscle
itself. This is known as the true latent period.

The period of contraction occupies about y^ sec, and
the period of relaxation shghtly longer — about xfo sec.
It is important to realise that the curve of contraction
obtained in this way is but a caricature of the actual change
in form, so great is the distortion caused by the inertia of
the recording apparatus.

Factors Modifying the Change in Form

1. Temperature. — On raising the temperature all three
constituents of the curve — ^latent period, upstroke and down-
stroke — are shortened. As commonly recorded there is,
in addition, an increase in the height of the curve. This,
however, can be shown by means of an arrested lever to
be instrumental in origin. Alterations in temperature,
therefore, do not influence the height of contraction.

2. Load. — Beginning with a very hght weight, increase
in the load is at first a stimulus to increased contraction.
Beyond a certain weight any further addition leads to a
diminution in the height to which it is hfted. There is
thus for every muscle a certain load which stimulates it to
the maximum work — work being the product of the
weight and the height to which the weight is raised.

3. Strength of Stimulus. — In the ordinary gastrocnemius

ALL-OR-NONE PRINCIPLE 39

preparation the height of contraction varies with the
strength of stimukis. Herein hes an apparent difference
between the behaviour of skeletal and of cardiac muscle,
for the latter, if it responds at all, responds with the
maximum contraction of which it is capable under the
circumstances — the all-or-none principle. In the striated
muscle which we are considering, a submaximal response
might conceivably be due either to the stimulation of some
of the fibres and not others, those which respond doing so
with a maximum contraction, or to the stimulation of all the
fibres to an equal but incomplete contraction. Keith
Lucas, using a muscle composed of very few fibres, showed
that on increasing the stimulus, the increase in response
took place in a number of stages never greater than the
number of fibres. The increased contraction at each stage
therefore appeared to be due to the imphcation of an
increasing number of fibres. It would seem, therefore,
that a striated muscle fibre obeys the all-or-none principle.
This feature of muscular contraction is more obvious in
the heart, because here all the fibres are knit together, the
contraction wave being conducted from one to the other.
The difference may be expressed in this way. Cardiac
muscle as a whole obeys the all-or-none principle because
the individual fibres do so, and any contraction involves
all the fibres. Striated muscle-fibres also obey the all-or-
none principle, but the muscles into which they are bound
do not do so, because a variable number of fibres may
contract, there being no cell-to-cell propagation of the
contracted state.

4. Frequency of Stimulation : Tetanus. — When a second
stimulus is thrown in before the contraction from a previous
stimulus has subsided, a second contraction occurs which
begins at whatever stage of contraction the muscle is in
as the result of the first, the height of the second contraction
being greatest if the second stimulus acts at the summit
of the first contraction. This phenomenon is known as
Summation.

40 CONTRACTILITY

With each succeeding stimulus the height of contraction
continues to increase, but the increase becomes progressively-
diminished until a constant level is reached. As the
interval between the stimuh is diminished, the individual
curves become more completely fused until all distinction
between them is lost. This is known as tetanus.

The question now arises whether a sustained voluntary
contraction is due to the reception by the muscle of a series
of interrupted stimuh from the central nervous system, or
to some kind of constant stimulus which we cannot imitate
experimentally. If non-polarisable electrodes be placed
on the forearm aitd connected with a string galvanometer,
on contraction of the flexor muscles the instrument will
show a response at the rate of about 50 per second. Volun-
tary contraction is therefore a form' of tetanus, and is due
to the arrival of frequently repeated stimuh from the
spinal cord.

The Constant Current. — When a muscle is stimulated
with the constant current, a single contraction occurs at
make of the current and to a lesser extent at break. During
the passage of the current there is usually no contraction.
Change in the current, then, and not the current itself, is
the effective stimulus. We shall study this more closely
in the case of nerve.

2. The Development of Tension

Paradoxical as it may seem, shortening is not an essential
part of muscular contraction. When a muscle is made to
pull against a weak spring the tension of which is approxi-
mately constant whatever its length, the contraction is said
to be isotonic. Under these circumstances the muscle
undergoes its maximum shortening, and energy is hberated
in the form of work and heat. But if the muscle be made
to pull against a strong spring practically no shortening
will occur. Yet the muscle has undergone a profound
change of state^i^ has developed tensian. This is known
as an isometric contraction. The difference between the

REFRACTORY PERIOD 41

relaxed muscle and the muscle contracted isometrically
has been aptly compared with the difference between a
stretched spiral of lead and a stretched spiral of steel. Since
practically no work is done in an isometric contraction all
the energy hberated appears in the form of heat.

As an example of an isometric contraction which occurs
physiologically we may take the contraction of the ventricle
before this chamber has begun to empty its contents into
the aorta.

3. The Change in Excitability

When a muscle has been stimulated to contraction there
occurs an interval of time during which it is incapable of
responding to a second stimulus. This is known as the
refractory period. In skeletal muscle the refractory period
is of shorter duration than the time occupied by a single
contraction. It is therefore too short to prevent the
fusion of repeated contractions into tetanus. In the case
of cardiac and unstriated muscle, on the other hand, the
refractory period outlasts contraction and relaxation com-
bined. It is upon the great length of the refractory period
in these types of muscle that the capacity for rhythmic
contraction depends, fusion into tetanus being impossible.

4. The Chemical Changes Accompanying Contraction

Dextrose fed to a beating heart disappears, but whether
it is oxidised or converted into glycogen we have no direct
evidence. Indirect evidence pointing to oxidation is
given by the rise which takes place in the respiratory
quotient (see p. 150). That the respiratory quotient is
subject to change according to the diet indicates that both
fat and carbohydrate can be oxidised.

During contraction there is no increase in protein meta-
bolism. There is a change in the non-protein N. meta-
bohsm, but depending upon the form of contraction|and
the manner in which it is produced. The amount of
creatinine and purine bodies has been shown to be increased

CONTRACTILITY

as the result of prolonged tonic contraction only. The
manner in which carbohydrates are broken down and the
significance of lactic acid will be dealt with below.

5. The Electrical Changes

If two non-polarisable electrodes are placed one on the

Fig. 5. — Showing three stages in the diphasic variation.

surface, the other on the cut end of a muscle and connected
with a galvanometer, the instrument shows a current
passing from the intact surface through the galvanometer
to the cut surface ; the injured part, that is to say, is electro-
negative to any other part. This electrical effect is pro-
duced even by the injury involved in the most careful

ELECTRICAL CHANGES

dissection — a fact which led Du Bois-Raymond to regard it
as a phenomenon not dependent upon injury, but a property
of uninjured resting muscle. Hence the name " current

■ - . ■ 1

. . . 1 ., . . .

»06

• OS

/|\

• 04.

/ ' \

•OD

f \

■ Oi

► 01'

STIM

J-

i \

0 '
-•01

•■08

* »

-03

-•O*

-H)5

-oeJ

, . , .1 .

. , i

•i,

t » ^

SEC.

Fig. 6. — Diphasic variation in frog's sartorius (Keith Lucas, from The

Jourruil of Physiology).

of rest " by which it was called. From Hermann, however,
came the demonstration that in the intact resting muscle,
and also in the dead muscle, the muscle is at the same
potential throughout, but that when a part of the muscle is

44 CONTRACTILITY

injured a difference of potential is set up between the
healthy and the injured part.

A similar difference of potential exists between uncon-
tracted and contracted parts of a muscle, the part which
is in contraction becoming, hke the injured part, electro-
negative.

Now a single contraction takes the form of a wave of
contraction which passes from one end of the muscle to
the other. If the two electrodes are placed one near each
end of the muscle there is first a deflection of the galvano-
meter, indicating negativity at the proximal electrode.
When the wave is equidistant between the electrodes, these
are at iso-potential. At this moment there is no current
flowing. As the wave approaches the distal electrode this
becomes negative; a current now passes through, the
galvanometer in the reverse direction. The total effect
is a diphasic variation and is known as the current of action.
It is represented graphically in Fig. 6.

For detecting these electrical changes two instruments
are used — the capillary electrometer and the string
galvanometer.

The capillary electrometer consists of a glass tube drawn
out into a fine point. The tube is filled with mercury,
which does not run as far as the point. The point of the
tube dips into dilute sulphuric acid in a wider vessel.
Beneath the acid is a layer of mercury. The mercury in
the capillary and in the vessel become the terminals of the
electric circuit. When the mercury in the vessel becomes
negative the lower end of the mercury in the capillary
moves downwards, and vice versa. The movements of the
mercury are recorded photographically.

In the string galvanometer a fine quartz fibre is suspended
in the field of a powerful electro-magnet. When a current
passes along the string the latter is deflected to one side or
the other according to the direction of the current. Oppo-
site the middle of the string a hole is bored through the

HEAT 45

magnet. A powerful beam of light is passed through this
hole and the movement of the shadow of the string photo-
graphed on a moving plate.

What is the relation between the electrical effect and the
change in form?

The rate of propagation of the electrical wave is the
same as that of the wave of contraction, any condition
which modifies the one, modifying the other in hke degree.
But whereas a wave of contraction is always accompanied
by the electrical change, it is possible to have the latter
without the former. The electrical change, too, occurs
earher than the mechanical change. During contraction,
therefore, two waves pass along the muscle, an electrical
wave followed by a mechanical wave, the electrical wave
being the sign of a molecular change preparatory to the
mechanical wave, though the latter wave itself may
miscarry.

The importance of this electrical response we shall see
in connection with the heart.

6. The Thermal Effects of Contraction

We have seen that the process of contraction consists
primarily in the assumption of a state of tension, and that
this state once attained, energ)^ may be hberated as work
if the muscle be allowed to shorten, as heat if shortening
be prevented. In warm-blooded animals the energy
which appears as heat, so far from being wasted, is the chief
factor in maintaining the temperature of the body above
that of the environment.

Since in isometric contraction the energy of tension is
all converted into one form — heat, we can by measuring
the heat evolved estimate the energy of tension.

For detecting the small elevation in temperature which
occurs two methods are employed — the thermopile or
thermo-electric couple, and the alteration in electrical
resistance of a copper wire.

46 CONTRACTILITY

The former method depends upon the fact that if a
circuit be formed of two different metals, any difference of
temperature between the two junctions will cause a current
to pass through the circuit. One junction is placed upon
the muscle which is to undergo contraction, the other upon
a muscle which remains inactive. The current is detected
by a galvanometer.

The bearing of the results obtained by these methods
upon the mechanical efficiency of muscle and upon the
nature of muscular contraction will be dealt with later. For
the moment it is only necessary to state the important
fact that the energy of tension varies directly with the length
of the tmiscle before it contracts.

THE NATURE OF CONTRACTION

Since all tissue activity is the result of oxidation, we may
study the effect of oxygen upon contraction. In the
presence of oxygen there is a utilisation of carbohydrate
and of oxygen, and evolution of COg. In absence of oxygen,
contraction occurs as before and carbohydrate is utiUsed,
but the outstanding chemical change is the accumulation,
of lactic acid. There is no evolution of CO2 other than can
be explained as produced secondarily by the action of the
lactic acid upon the bicarbonates present.

Under these conditions, however, the muscle soon becomes
fatigued, recovery ensuing on the administration of oxygen.

Oxygen therefore, while essential for the continued
activity and well-being of the muscle, is not necessary for
the actual contractile process. Nor is anaerobic contraction
due to the consumption of a kind of intramuscular store
of oxygen, otherwise there would be a considerable evolution
of COg. The act of contraction, therefore, is associated
chemically not with an oxidative process but with the
formation of lactic acid. The uncontracted muscle con-
tains within it a store of potential energy which in the
assumption of the contracted state is capable of transforma-

NATURE OF CONTRACTION 47

tion into work or heat, and the part played by oxygen Ues
not in effecting this transformation of energy but in the
restoration of the condition of high potential. What is the
nature of the oxidation involved in the secondary process
of restoring the muscle to the state of high potential ?

In this process there is no disappearance of sugar,
whereas carbohydrate does disappear in the act of con-
traction both in the presence and in the absence of oxygen,
lactic acid appearing in the latter case but not in the
former. The conclusion is therefore drawn that the
energy for the recuperation of muscle into its high potential
state is derived from the oxidation of lactic acid formed in
the act of contraction.

Can it be shown that the energy thus obtained from the
oxidation of lactic acid is sufficient ? One gram of acid
on oxidation gives out 3,700 calories, whereas in the process
of recovery the utihsation of the same amount of acid
corresponds to the production of only 450 calories. The
source of energy, therefore, is amply sufficient.

Returning now to the process of contraction, if this
is not produced chemically by oxidation, as in the case of
an internal combustion engine, to what is it due ? It
cannot be due to the conversion of carbohydrates into
lactic acid, for this reaction is practically isothermic.
There are, indeed, strong reasons against its being a
chemical reaction at all. The mechanical efficiency of the
process has been estimated at practically 100 per cent.,
a degree of efficiency which is not approached by any
known form of chemical energy.

If the energy appears not to be chemical there is some
evidence to indicate that it is physical. We have seen in
discussing isometric contractions that although there is
practically no deformation, there is a very profound change
— a change of tension. The degree of tension developed,
and therefore of heat evolved, is greater in an isometric
than in aii isotonic contraction, and varies directly, not
with the volume, but ivith the length of the fibres, that is to

48 CONTRACTILITY

say, with the area of longitudinal surfaces within the
muscle. This indicates that contraction is dependent upon
change in tension between two surfaces, probably between
sarcostyles and sarcoplasm. The development of lactic
acid may be the factor determining the change of tension.

But surface tension is not the only property influenced
by contraction. A fatigued muscle has a higher osmotic
pressure than resting muscle. Upon this fact is based
a theory which attributes contraction to an aggrega-
tion of colloid particles, with consequent hberation of
electrolytes. The increased concentration of these causes,
by osmosis, a flow of water in a particular direction.

We may thus sum up what we have said above. Muscular
activity consists of two alternating phases : (1) ^ fhase
of contraction which, though associated with the formation
of lactic acid, is essentially a physical process involving
surface and osmotic phenomena. No gaseous metabohsm
is involved. (2) A 'phase of recovery consisting in the
restoration of a state of high potential. It is in this phase
that oxygen is used.

The Mechanical Efficiency of Contraction

It has been found that the energy of tension may have
an efficiency of 100 per cent. But in the phase of recovery
an amount of heat is produced equal to that produced in
the phase of contraction. This reduces the efficiency of
the whole contractile process to 50 per cent. In sustained
contraction, or tetanus, the efficiency becomes very much
diminished ; the form of contraction is therefore an important
factor. The average efficiency of contraction has been
estimated at about 25 per cent.

CHAPTER V
THE HEART

THE NATURE OF THE HEART-BEAT

Inve.stigation into the nature of the heart-beat may be
said to have been inaugurated in 1852 wnth the experi-
ments of Stannius upon the frog's heart. Previous to this,
all that was known with certainty was that the beat was
independent both of connection with the central nervous
system, and of the presence of blood in the cavities.
Stannius found that when a hgature was tied at the junction
of the sinus and auricle (Stannius's First Ligature) the sinus
continued to beat while the auricle and ventricle stopped.
This he attributed to paralysis of Remak's ganghon
situated at the site of the Hgature. On applying a ligature
between the auricle and ventricle (Stannius's Second
Ligature) he found that while the auricle remained quiescent,
the ventricle resumed beating. This he considered to be
due to a stimulation of Bidder's ganglion situated at the
junction of these two chambers. Stannius's experiment,
therefore, seemed to confirm the view already held that the
cause of the beat lay in the activity of the nerve-cells
embedded in the heart- wall.

In 1881, the accuracy of these experiments and the
interpretation put upon them by Stannius were called in
question by Gaskell. Gaskell drew attention to the fact
that the stoppage of auricle and ventricle following the
first ligature was only temporary, and was soon followed
by the development of rhythmic contraction of these
chambers slower than and independent of the contraction
4 ' 49

50 THE HEART

of the sinus. Stannius had observed this, but had paid no
attention to it. Gaskell further found that if the second
hgature were replaced by slow compression of the auriculo-
ventricular junction the ventricle first stopped beating, but
afterwards began to beat with a rhythm slower again than
that of the auricle. Gaskell was therefore led to the view
that the origin of the beat was to be found in the inherent
property of rhythmicity possessed by the heart-muscle.
In other words, he founded the Myogenic Theory of the
Heart-beat.

In confirmation of this view came the later observations
that the heart of the developing chick begins to beat before
any nerves have migrated into it, and that the separated
apex of the frog's ventricle, demonstrably free from nerves,
continues to beat if properly nourished.

Rhythmic contraction then, being a property of heart-
muscle, what is the cause of the conduction of the beat
from the sinus to the ventricle ? Gaskell proved that the
conduction of the beat was muscular by two experiments
performed on the heart of the tortoise. In this animal sinus
and ventricle are connected together by a band of auricular
tissue. When a series of interdigitating cuts is made into
the band the conduction of the beat is unaffected. This
would not be the case if the conduction were due to nerves.
Again, if this band is little by little cut almost completely
across (Fig. 7), a stage is reached when the part of the
auricle distal to the cut responds only to every alternate
beat of the proximal part. On cutting further, it responds
only to every third beat, and so on until eventually the
bridge of tissue becomes so much narrowed that no wave
can pass along it. The distal part then develops a rhythm
of its own. Clearly, therefore, conduction is dependent
upon and due to the integrity of the muscle itself.

Both the origin and the conduction of the beat being
myogenic, why does the beat travel from sinus to ventricle
and not in any other direction ? Gaskell showed that this
was due to a greater rhythmicity possessed by the sinus.

THE PACE-MAKER

When all three chambers are beating independently, the
rhythm is quickest at the sinus, slowest at the ventricle,
and intermediate at the auricle. Normally therefore, the
inherent rhythm of the auricle and ventricle is not called
into play, for its effect is anticipated by contraction of
these chambers, due to the arrival of a wave from the
sinus. The auricle and ventricle, therefore, contract at

Fig. 7. — Heart of tortoise prepared to show partial heart-block,
auricular tissue is cut between As and Av (Gaskell).

The

the rate set by the sinus. For this reason the sinus is called
the pace-maker of the heart. To confirm this view, Gaskell
cooled the sinus and warmed the ventricle. By so doing
he lowered the rhythmicity of the former and raised the
rhythmicity of the latter. The result was that the beat
passed from ventricle to sinus. The progression of the
beat is therefore due to the fact that different parts of
the heart possess different degrees of rhythmicity.

It will be noticed that the rhythmicity is greatest in that

THE HEART

part of the heart which has the feeblest contraction, and
is least in that part where contraction is strongest. Here
then is a partial differentiation of the two fundamental
properties of heart-muscle — rhythmicity and contractiUty.j
It now remains to us to show how far this explanation
of the nature of the heart-beat is apphcable to the more

Fig. 8. — A generalised type of vertebrate heart (Keith), a, sinus
venosus ; b, sino-auricular canal ; c, auricle ; d, ventricle ; c, bulbus
cordis; f, aorta.

comphcated heart of the mammal. A g'enerahsed form of
primitive vertebrate heart is shown in Fig. 8. It is
composed of four serial chambers : (a) the sinus, (b) the
auricular canal, part of which is invaginated into (d) the
ventricle, (e) the bulbus cordis. The auricle is a lateral
diverticulum of the auricular canal. The sinus and
auricular canal may be regarded as forming the rhythmic,
the auricle and ventricle the contractile parts.

THE JUNCTIONAL TISSUE 53

This differentiation in function is associated with a
differentiation in structure, the rhythmic fibres retaining
their embryonic form and circular disposition, the con-
tractile fibres undergoing an approximation to the skeletal
form in developing a partial cross-striation.

As this type of heart develops into the mammahan form,
the sinus and auricular canal become lost as separate
chambers, and their tissues are submerged by the great
hypertrophy of the auricle and ventricle. But they do not
disappear. They persist, retaining their embryonic nature,
and forming the following structures —

Developed from the Sinus.

1. The sino-auricular node.i

2. Part of the interauricular septum.

3. The opening of the coronary sinus. ,

Developed from the Sino-auricular Canal.

4. The auriculo-ventricular junctional tissue, con-
sisting of —

(a) Fibres from the auricular septum to

(b) The auriculo-ventricular node.

His) and its two branches.
{d) The fibres of Purkinje.

So important to the modern conception of the heart-
beat has been the discovery of these remnants that it is
necessary to describe their anatomical disposition, and to
show how they differ structurally from the ordinary heart-
muscle.

Disposition and Structure of the Junctional Tissue

The ordinary cardiac muscle is composed of columns of
short cyhndrical fibres, united irregularly to those of

^ The sino-auricular node of the mammalian heart must not be
confused with the sino-auricular canal of the primitive vertebrate
heart.

THE HEART

adjacent columns. Cross striation is present, but not to
the same degree as in skeletal fibres. The single nucleus
is centrally situated. Longitudinal fibres appear not only
in the individual cells, but also traversing the partitions
between them.
The sino-auricular node, 2 mm. in thickness, begins at

SINO-AUR.ICUbAR. NODE

AUR.ICUL/^R.-VENTRICUL/^R-

BUNDLE OF HI5 AND
1T5 TWO BRANCHED

FIBR.E5 OF PURKINJE

Fig. 9. — Diagrammatic coronal section of the heart to show the
junctional tissue. The position of the sino-auricular node is shown
on the surface.

the junction of the superior vena cava and the right auricle,
and extends about 2 cm. along the sulcus terminalis. The
cells are fusiform, striated, and plentifully surrounded by
connective tissue. They are in intimate association with
nerve-fibres and nerve-cells, through which connections
can be traced with the vagus and sympathetic.

The auriculo-ventricular junctional tissue begins in the
form of fibres from the region of the coronary sinus, and

THE JUNCTIONAL TISSUE 55

from the inter-auricular septum. These converge upon the
auriculo- ventricular node, a mass of tissue lying on the right
border of the septum in the neighbourhood of the coronary
sinus. From this node emerges the auriculo- ventricular
bundle, which passes forward, still on the right side, to the
central fibrous body of the heart. At the anterior end of the
pars membranacea of the interventricular septum, it
divides into two branches, the right branch passing imme-
diately beneatli the endocardium to the papillary muscles,
where it arborises. The left branch, after piercing the pars
membranacea, proceeds downwards along the left side of
the septum, where it arborises. The extensive arborisations
on both sides are known as the Purkinje fibres. These,
ramifying in the subendocardial tissue, eventually terminate
by becoming continuous with the ventricular substance,
and in particular with the papillary muscles.

It is important to realise that throughout its course
the fibres of the junctional system are surrounded by
connective tissue which isolates them from the main
ventricular mass until their termination is reached.

At the auriculo- ventricular bundle, the fibres resemble
those of the sino-auricular node in their shape, and in their
isolation by connective tissue. But as they are traced
downwards, the cells come to have a less plexiform, more
parallel disposition, they become paler and larger, the
nucleus is multiple, and the striation is confined to the
periphery of the cells.

Chemically, the junctional tissue differs from the con-
tractile in containing a high percentage of glycogen.

The auricido-ventricular bundle forms the only connection,
other than fibrous, between auricles and ventricles.

The Function of the Junctional Tissue

The Sino-auricular Node is the Pace-maker of the Heart

We have seen that when a wave of contraction passes
along a muscle, the part which is in contraction is electro-

56 THE HEART

negative to the rest of the muscle. The part which is the
earhest to become electro-negative is therefore the part
which is earhest to contract. Lewis, by systematically
exploring the auricle, placing the electrodes on various
points, found that the region which first becomes negative
is the sino-auricular node.

Not only is the sino-auricular node the site of origin of
the impulse, but it is the part most sensitive to local
influences. Coohng slows the rhythm only when apphed
here. It is clear, therefore, that the sino-auricular node
plays the same part in the mammalian heart as the sinus,
from which the node is derived, plays in the amphibian
organ.

The Auriculo-Ventricular Bundle

It is now proved that the proper conduction of the
impulse from the auricle to the ventricle is dependent upon
the integrity of this structure. When the bundle is injured
the following effects are produced according to the degree
of the injury.

1. Prolongation of the interval between the auricular
and ventricular contractions.

2. An occasional ventricular lapse.

3. Response of the ventricle only to alternate or to
every third auricular beat. (Partial Heart-block.)

4. Complete failure of conduction from auricle to
ventricle, the latter chamber beating independently.
(Complete Heart-block.)

The same changes occur when the bundle is diseased, the
condition being known as Stokes- Adams' disease.

It will be seen that the effects produced by injury to the
bundle are the exact counterpart of those obtained in
Gaskell's experiment upon the heart of the tortoise. The
bundle performs the same function as the sino-auricular
canal from which it is developed.

INTRACARDIAC PRESSURE 57

THE CARDIAC CYCLE

Intracardiac Pressure

When the heart is beating at its normal rate — 72 beats
per minute — the complete cycle of changes occupies about
0-8 sec. and consists of three phases —

Auricular systole , . .0*1 sec.
Ventricular systole . . .0-3 sec.
Diastole .... 0-4 sec.

The pressure changes occurring in the heart during the
cycle have been investigated by the direct introduction

Fig. 10. — Piper's manometer (from Starling's Principles of Physiology).

into the chambers of specially-constructed manometers.
Of the many forms of these which have been invented, the
one which most effectively eliminates instrumental error is
Pij)ers (Fig. 10). It consists of a cannula B, fitted with a
trocar A. At one side of the cannula, at E, is an elastic
membrane, upon which is fixed a mirror F. C is a tap
which when open admits the passage of the trocar. The
manometer is inserted direct into the desired chamber of
the heart, the point of the trocar piercing through the wall.
The trocar is then withdrawn and C closed. Changes in
pressure in the chamber cause alternate stretching and
slackening of the membrane, these movements being
recorded in a magnified form by hght thrown on the
mirror. The results obtained when manometers are thrust

THE HEART

simultaneously into the auricle, ventricle and aorta are
shown diagrammatically in Fig. 11.

Systole begins with a sUght rise of pressure (at 1) in the
auricle due to contraction of this chamber. Immediately
afterwards the ventricular pressure rises, slowly at first,
then more rapidly. As it rises, there occurs (at 2) a second

Fig. 11. — Changes in pressure during a complete heart-beat in the left
auricle, left ventricle, and aorta (modified from Piper).

rise in the auricular pressure brought about by the sudden
closure of the auriculo- ventricular or mitral valve. At 3,
the ventricular pressure is sufficient to force open the
aortic valve. As the blood flows into the aorta the ven-
tricular pressure describes a rounded summit known as
the systohc plateau. This terminates in a sharp fall of
pressure, at the middle of which the aortic valve closes,
the point of closure being marked by the secondary rise

VENOUS PULSE 59

(at 4) of the aortic pressure, due to the rebound of the
aortic blood from the closed valve. During the early part
of the fall in ventricular pressure, the auricular pressure
undergoes a third rise attributed to gradual filhng.

The Venous Pulse

Measurement of the intracardiac pressure is a means of
finding out what the several chambers are doing, but it is
a means which from its nature can only be used upon
animals. We have no method of discovering the intra-
cardiac pressure in the human subject, but we can trace to
some extent the changes which are occurring in the right
auricle.

ac , ac

Jug.

Fig. 12. — Tracing of jugular pulse (from Starling's Principles of

Physiology).

When a tambour is pressed on the right side of the
neck opposite the jugular vein, and the movement trans-
mitted to recording apparatus, each beat is found to be
accompanied by three waves, known as the a, c, and v
waves. These are shown in Fig. 12. The a wave occurs
immediately after the first auricular wave, and is an expres-
sion of the rise in auricular pressure which is produced either
by the holding up of the blood in the auricle, or by the
regurgitation of some of the blood into the vein, the superior
vena cava having no valve. The c wave coincides with the
zenith of ventricular and aortic pressure. It depends
upon and is a measure of the ventricular contraction. It
is produced either by the transmission of the impulse from
the carotid artery through the tissues of the neck or by the
closure of the auriculo- ventricular valve. The v wave is

60 THE HEART

usually attributed, like the third auricular wave, to the
gradual filling of the auricle, the auriculo-ventricular valve
being closed.

The a wave is therefore an index of auricular, and the
c wave an index of ventricular contraction, while the
distance between them is a measure of the rate of con-
duction from the auricle to the ventricle.

The Heart-Sounds

At each beat two sounds are normally heard. The first
is best heard at the apex and is due to the contraction of
the ventricles and to the closure of the mitral valve. The
second sound, shorter and sharper than the first, is
also audible at the apex, but is heard best at the base. It
is caused by the sudden closure of the aortic valve. When
the valves are destroyed by disease, the eddies set up and
the flow of blood in abnormal directions cause the normal
sounds to be replaced by '" murmurs.

Electrical Changes in the Heart

The apparatus used for the detection of the current of
action of the heart in situ is an adaptation of the string
galvanometer — known as the electro-cardiograph (see p. 44).
Owing to the sahne content of the tissues and tissue-fluids,
the body conducts an electric current as though it consisted
merely of salt solution. When a diflerence of potential
occurs anywhere within the body, as in the heart, this can
by appropriate means be detected at the surface. Owing
to the obhque disposition of the heart, a potential at the
base tends to spread upwards and to the right, a potential
at the apex downwards and to the left. The subject is put
into circuit with the galvanometer by having his right hand
and left foot inserted into pots containing salt solution
wired up with the two ends of the string. The axis of the
heart is then more or less in line with the circuit, and any
difference of potential between base and apex of the heart
is recorded by the string.

THE ELECTROCARDIOGRAM

It is conventional to take the records in such a manner
that negativity at the base is shown on the photographic
record by a deflection upwards.

All electrocardiogram thus obtained is shown in Fig. 13.
It will be seen to differ considerably from the simple
diphasic variation of skeletal muscle. There are two
reasons for this discrepancy. First, the right hand and left
foot do not accurately represent the base and apex of the
heart respectively; secondly, the heart is far from being
a simple muscle.

Fig. 13. — Human electrocardiogram (from Starling's Principles of

Physiology).

The record usually consists of five waves, to which are
given the conventional names, P, Q, R, S, and T. Of these
three, P, Q, and T indicate base-negative currents; the
remaining two, Q and S, base-positive.

The interpretation of the electrocardiogram is a matter
of considerable difificulty. The wave P is admittedly of
auricular origin. During the iso-electric period following
it, neither auricle nor ventricle is contracting, the impulse
passing from the one to the other along the auriculo-
ventricular bundle. Q is of inconstant recurrence and
uncertain origin. R, which is always the most striking
feature of the electrocardiogram, indicates contraction at

62 THE HEART

the base of the ventricles. S is due to contraction at
the apex. Then follows a prolonged iso-electric period
which is succeeded by the slow base-negative wave T.
As to the nature of this last wave, there is much uncertainty.
It may be due to the ventricular contraction ending at the
base, at the opening of the aorta.

THE WORK OF THE HEART

The aorta and large arteries may be said to form a
reservoir at high pressure from which blood is suppUed
to the various tissues. The needs of the tissues for blood
are constantly fluctuating according to physiological
activity. We shall see how in the different tissues the
supply is made to meet the demands. It is only necessary
to say here that the fluctuation is greatest in the abdomen
and hmbs, least in the brain. It follows that if there were
no compensating mechanism, the arterial blood-pressure
would vary as the flood-gates into the tissues^ — for instance,
the muscles — were open or shut, and the brain would be
exposed indirectly to a diminution in its blood-supplv at
the very time when this organ would need blood most for
the increased cerebral activity which accompanies physical
exertion. But in the intact animal when the arterial
reservoir is being drained abnormally rapidly the pressure
within it, so far from falhng, actually rises. There exists,
therefore, a mechanism which seems to have for its object
the proper nourishment of the brain under all circumstances.

In whatever this mechanism may be found to consist,
it must involve ultimately a variation in the output of the
heart, since it is only by an alteration in the amount of
blood which enters the arterial reservoir that the pressure
here can be maintained constant in the face of alterations
in the rate at which blood leaves the reservoir.

The work done by the heart may therefore be said to
consist in the maintenance of a constant or nearly constant
arterial pressure. From a mechanical point of view, this

WORK 63 •

work consists in raising the blood from a region of low to a
region of high pressure, and in imparting to the same
blood a certain velocity. The work performed by the left
side of the heart, at each beat, is expressed approximately
by the formula —

W = QR + "^

where W is the work, Q the quantity of blood driven out
at each beat, R the average arterial resistance, w the mass
of blood moved, V its velocity immediately after it has been
discharged, and g the acceleration due to gravity. A
similar formula gives the work done by the right side, the
only factor which is different being R.

On the basis of this formula, the work done by the resting
heart at each beat has been estimated at 100 grammeters
per beat, or about 7,200 grammeters per minute. During
exercise, this figure is greatly increased owing to the
increased output, the increased arterial pressure, and the
increased velocity imparted to the blood.

For measuring the output' of the ventricle at each beat
in the intact animal, only indirect methods are available.
One of these is Zuntz's Method.

Two data are necessary — -

1. The amount of oxygen leaving the lung in a given time.

2. The difference in the oxygen content of arterial and
venous blood. In the case of a horse, it was found that
the arterial blood contained 10-33 per cent, more oxygen
than venous blood, or in other words that 100 c.c. of blood
in passing through the lungs had absorbed 10-33 c.c. of
oxygen. Since 2732 c.c. of oxygen was absorbed from the
lungs in one minute, the amount of blood which flowed
through the lungs in that period was —

100x2733 ^.,.„,.,
— ^K^r, — = 26-457 litres.
lU-oo

-. 64 THE HEART

Arguing from a comparison of the body-weight it is
estimated that in man the average output of each ventricle
per beat at rest is 60 c.c.

The same figure has been arrived at by another method
due to Krogh. This method is apphcable to man. The
subject breathes a certain volume of nitrous oxide and an
estimation is made of the amount which is absorbed in a
certain time. The rate of absorption of the gas at the
same pressure as it exists in the lungs is then determined
in vitro. From this is calculated the volume of the blood
passing through the lungs in a given time.

ADAPTATION OF THE HEART

It is estimated that the output of the heart per minute
varies from 3 htres during rest to 21 Htres during violent
exercise. The heart therefore has a very considerable
power of responding to the demands made upon it. Varia-
tions in the output can be brought about in two ways —

1. By an increase in the rate of the beat, and

2. By an increase in the output per beat ; that is to say,
by alteration in the capacity oi the heart at each diastole.

In considering how the heart thus adapts itself it will
be most convenient to inquire first how far the capacity
for adaptation is inherent to the heart itself, and expresses
itself independently of nervous connections, and secondly
how this inherent tendency, if it exists, is modified or
supplemented by the agency of the central nervous system.

The Isolated Heart

The behaviour of the heart when freed from its nervous
connections is best studied by means of the heart-hmg
^ preparation invented by Starling. Here is Starhng's
description of the apparatus.

" Artificial respiration being maintained, the chest is opened
under an anaesthetic. The arteries coming from the arch of the
aorta — in the cat, the innominate and the left subclavian — are

HEART-LUNG PREPARATION

then ligatured, thus cutting off the whole blood- supply to the
brain, so that the anaesthetic can be discontinued. Cannulse are
placed in the innominate artery and the superior vena cava. The
cannulse are filled beforehand with a solution of hirudin in normal
salt solution, so as to prevent clotting of the blood during the
experiment. The descending aorta is closed by a ligature. The

Fig. 14. — The heart-lung preparation. (From The Journal of Physiology.)

only path left for the blood is by the ascending aorta, and the
cannula CA in the innominate artery. The arterial cannula com-
municates by a T-tube with a mercurial manometer M^ to record
the mean arterial pressure, and passes to another T-tube ?; one
limb of which projects into the test-tube- B. The air in this test-
tube will be compressed with a I'ise of pressure, and will serve as
a driving force for the blood through the resistance. It thus takes
the part of the resilient arterial wall. The other limb of the test-
5

66 THE HEART

tube passes to a resistance R. This consists of a thin-walled tube
(e. (J. a rubber finger-stall) which passes through a wide glass tube
provided with two lateral tubulures u\, tv^. One of these is con-
nected with a mercurial manometer, M2, and the other with an air
reservoir into which air can be pumped. When air is injected
into the outer tube, the tube B coUapses, and will remain collapsed
until the pressure of the blood within it is equal or superior to the
pressure in the air surrounding it. It is thus possible to vary at
will tlie resistance to the outflow of the blood from the arterial
side. From the peripheral end of R, blood passes at a low pressure
through a spiral immersed in warm water, into a large glass reservoir.
From the reservoir a wide india-rubber tube leads to a cannula
which .is placed in the superior vena cava, SVC, all the branches
of which have been tied. This cannula is provided with a ther-
mometer to show the temperature of the blood supplied to the
heart. A tube placed in the inferior vena cava and connected
with a water manometer shows the pressure in the light auricle.
On the recording suiface we thus have a record of the arterial
pressure and of the pressure within the right auricle. The output
of the whole system can be measured at any time by opening the
tube X, clamping Y, and allowing the blood to flow for a given
numljer of seconds into a graduated cylinder. . . .

" The output . . . represents the ventricular output minus the
blood-flow through the coronary arteries. It is possible, however,
to insei't a cannula into the coronary sinus, and so to measure the
blood-flow through the heart-muscle." Artificial respiration is
continued throughout the experiment.

The volume of the heart is measured by means of a
cardiometer, a glass vessel which encloses the organ. By
a side tube it is connected with a tambour, the movement
of which is recorded on a drum.

The oxygen consumption of the heart is estimated from
the oxygen absorbed by the lungs.

We may now briefly discuss how the output is affected by
changing any of the conditions.

1. Temperature of the Blood. — The beat increases in rate
with rise of temperature.

2. Reaction of the Blood. — At a certain reaction of the
blood, the output of the heart is maximum. Slight increa.se

VARIATIONS IN OUTPUT

in H ion concentration diminishes the amplitude of the
beat, the rate being unaffected.

3. Adrenalin. — Adrenahn, the substance produced by the
suprarenal glands, causes an acceleration and augmentation
of the beat.

4, Changes in the Arterial Pressure. — The effect of chang-
ing the arterial pressure is shown in Fig. 15 and in this
Table :—

Arterial
Pressure.

Systemic

output

c.c. per min.

Total Coron-
ary output
(calculated).

Total

output of

Left Heart.

Venous
Pressure.

84
140

208

811

770
COO

40-80

70-75

260-30

851-80
840-75
860-30

9-6-12-4

8-0-11-2

120-22-0

It will be seen that the output of the heart and the rate
of the beat are unaffected. A gin nee at Fig. 15 will show
that as the arterial pressure rises the volume of the heart
increases (downward movement of the cardiometer curve),
and that this increase occurs by a slight distension at each
beat until the new volume is acquired. Another change is
the great increase in the blood-flow through the coronary
circulation, associated with a rise in the amount of oxygen
used. How these occur is as follows. Suppose the mean
arterial pressure is 80 (systohc pressure 100, diastohc 60).
Suppose 8 c.c. is the amount of blood expelled at each beat,
the ventricle being completely emptied. Blood begins
to flow from the ventricle when the pressure in this chamber
just exceeds 60, and in order that the ventricle may be
completely discharged the pressure within it must finally
exceed 100. Suppose that the mean arterial pressure is now
artificially raised to 110 (systohc 130, diastolic 90). At the
next beat following the change no blood leaves the ventricle
until the intraventricular pressure exceeds 90 ; for the
ventricle to be completely discharged, a pressure exceeding
130 is necessary. But systole terminates as before, when

THE HEART

the pressure just exceeds 100. for the heart is, as it were,
unprepared for the extra call made upon it. At this beat
only a part of the 8 c.c. — let us say 4 c.c. — is discharged.

Fig. 15. — The effect of increased arterial pressure on the heart.
C, cardiometer ; B.P., arterial blood i^ressure; V.P., pressure in
inferior vena cava. — 100 and — 80 indicate height of blood
pressure in mm. Hg. (From Starling's Principles of Phyniology .)

The heart at the end of systole contains 4 c.c. During the
subsequent diastole, another 8 c.c. flows in. To accommo-
date 12 c.c, the volume of the ventricle during diastole is

VARIATIONS IN OUTPUT

increased by distension. The next systole is stronger, and
results in, say, 6 c.c. being expelled, 6 c.c. remaining in the
ventricle. At the next diastole, the distension is greater

Fig. 16. — Effect of alterations in venous supply on the heart. The
curved line on the left shows the ventricular capacity in c.c. (From
Starling's Princi'ples of Physiology.)

still, 6 c.c. -f 8 c.c. = 14 c.c, and is followed by a still
stronger systole, which probably succeeds in expelhng
8 c.c, leaving 6 c.c. in the ventricle. The normal output
is thus restored ; the only difference lying in the diastolic

70 THE HEART

and systolic capacities of the ventricle, which, instead of
being 8 c.c. and 0 c.c. respectively, are now 14 c.c, and
6 c.c. The increased work of the heart is associated with
increased distension at diastole and incoinjdete emptying at
systole.

5. Changes in the Venous Inflow. — The result of changing
the venous inflow is seen in Fig. 16. It will be seen that
rise of venous pressure, like rise of arterial pressure, causes
a gradual distension and again no change in the rate of the
beat. The difference is that there is now an increase in
the output per beat, shown in the increased excursion of the
cardiometer.

The factors which these two experiments have in common
are the increased work performed by the heart, and the
increased distension at diastole. How arc these factors
related ? The greater energy of contraction cannot be
due to the stretching of the fibres owing to increased
tension through abnormal filling, for no such increase in
tension exists. As the blood flows in, the ventricle wall
simply gives, the pressure at the end of diastole being
practically nil whatever the capacity of the chamber.

In discussing skeletal muscle we have seen that the
energy of contraction varies directly with the initial length
of the fibre (p. 46). The same rule applies to the heart,
and is the cause of the phenomena we have been discussing.
This is called by Starling the Law of the Heart. " Within
physiological limits the larger the volume of the heart, the
greater are the energy of its contractions and the amount of
chemical change at each contraction.''' It must be remem-
bered, however, that with the heart in situ, the amount of
dilatation which it can undergo is limited by the inextensible
pericardium.

The Influence of the Nervous System upon the Heart

Having shown the power of adaptation possessed by the
isolated heart, we pass on to consider what further modifica-

NERVE-SUPPLY 71

tions in the heart's activity occur through the intervention
of the central nervous system.

The Efferent Nerves of the Heart

The heart receives efferent fibres from two sources, the
vagus and the sympathetic.
The Vagus —

1. Slows the beat and stops it on strong stimulation;

2. Diminishes the amphtude of the beat;

3. Prolongs the auriculo-vcntricular interval, by de-

pressing the conductivity of the bundle of His.

The Sym/pathetic, the fibres of which emerge from the
upper thoracic segments of the cord, is in every way
antagonistic to the vagus. It therefore —

1. Quickens the beat;

2. Increases its amplitude ;

3. Decreases the auriculo-vcntricular interval.

The centre for the control of the heart resides in the
medulla at the nuclei of origin of the vagus. This region
probably controls the spinal centres from which the
sympathetic fibres issue.

The efferent nerves may be called into play reflexly by
stimulation of sensory nerves, by impulses from the higher
centres, and by changes in the blood bathing the centre.

Cardiac Reflexes

Stimulation of almost any sensory nerve has the effect
of altering the rate of the beat in one direction or the other.
The most important reflexes, however, are those arising in
the heart itself and in the lungs.

Reflexes originatmg in the Heart. — The heart is liberally
suppUed with afferent fibres, which travel up in the vagus,
and probably also in the sympathetic. Arising at the base
of the heart, and at the root of the aorta, are the depressor

72 THE HEART

fibres. These in the rabbit form a separate nerve, the
depressor nerve, in the neck, but in most animals are in-
corporated throughout mth the vagus. On stimulating
the central end of the depressor nerve in the rabbit, there
occur slomng of the heart and fall of blood-pressure, the
former due to impulses travelhng down the vagus, the
latter to dilatation of the peripheral blood-vessels — chiefly
those of the abdomen.

We saw that in the heart-lung preparation, rise in the
arterial pressure, though it caused dilatation of the heart
with unaltered output, did not affect the frequency.
Wlien the arterial pressure is increased in the intact animal,
the heart is slowed (Marey's Law). The rise in pressure is
a stimulus to the depressor nerve-endings. Here then is
a protective mechanism whereby the heart is eased of a
load which is too great for it.

But the afferent fibres do not all stimulate the vagus
centre. We saw that in the isolated heart, the output
increased with the venous inflow, but the frequency of the
beat was unchanged. There is evidence to show that
abnormal distension of the right auricle stimulates efferent
nerve-endings to produce reflex quickening of the heart.

Reflexes originating in the Lungs. — -The beat is quickened
during inspiration, and slowed during expiration. This
phenomenon, which is known as sinus arrythmia, is abolished
when the vagi are cut. In children it occurs with normal
breathing ; in adults usually only during excessive respira-
tory movement.

The Influence of the Higher Centres upon the Medulla

Certain mental states, such as strong emotions, affect the
cardiac centre directly. The quickening of the beat
which occurs at the beginning of exercise is also produced
by the direct action upon the medulla of impulses originat-
ing in the cerebral centres and called into play by the
psychological process of attention.

NERVOUS CONTROL 73

Influence of the Blood-Supply upon the Cardiac Centre

Rise in the arterial pressure within the skull causes reflex
slowing of the heart by stimulating the vagus centre.
Increase in the hydrogen ion content of the blood has the
same effect.

From what has been said, it is clear that, owing to its
being controlled by the central nervous system, the heart
possesses a much greater latitude of adaptation than if it
were independent. The function of the cardiac centre
is to regulate the output of the heart according to the needs
of the body as a whole. It must be remembered however
that we are here dealing with only one aspect of a complex
story. The greatest increase in the activity of the heart
occurs as the result of an unusual demand for oxygen by
the tissues, and this demand is met not only by a quickening
of the circulation but by changes in other systems. Until
these have been separately considered, we shall not be in
a position to understand fully the significance to the
animal economy of the factors affecting the activity of
the heart.

CHAPTER VI
THE CIRCULATION OF THE BLOOD

THE SYSTEMIC CIRCULATION

The Velocity of the Blood

Whenever an artery divides, the branches, though
individually smaller than the parent-trunk, have collectively
a larger area of cross-section. The combined area of cross-
section of the capillaries is many hundred times greater
than that of the aorta. Similarly, as the veins converge,
the total area of the tributaries becomes smaller. Blood
is therefore flowing away from the heart in a stream which
is ever widening, and back to the heart in a stream which is
ever narrowing. On this account the velocity of the blood
diminishes as it travels along the arteries, reaches its
minimum in the capillaries and quickens again in the
veins.

We have no means of measuring the velocity of the blood
directly in the human subject. An indirect calculation can,
however, be made of the rate at which it travels through
the aortic orifice. The output of the left ventricle per beat
while the body is at rest we have seen to be on an average
60 c.c. At a pulse rate of 72, this gives 4320 c.c. per
minute. The area of cross-section of the aorta is 4 sq.
cm. In one minute, therefore, a column of 1080 cm.
passes along the aorta. Were the flow continuous, this
would give a velocity of 18 cm. per sec.

Many instruments have been invented for measuring
the velocity of the blood in animals. For use in arteries

VELOCITY

a record must be made not only of the average rate of
flow but also of the fluctuations due to the heart-beat. One
of the simplest instruments for showing this is Chauveau's
haemadromograph, a diagram of which is given.

The apparatus is shown in Fig. 17. The horizontal part of
the tube is inserted into the cut artery, c being attached to the

Fig. 17. — Chauveau's htcmadromograpli. (From Starling'ti Principles of

Physiology. )

central and p to the peripheral end. Into the tube is suspended
the pendulum pi, the movements of which are transmitted to the
tambour k, and by this recorded on a blackened surface. The
instrument is first calibrated on a stream of known velocity.

The capillary velocity can|^be measured microscopically
in thin tissues such as the frog's mesentery.

76 THE CIRCULATION OF THE BLOOD

The Pulse

Blood enters the arterial system intermittently and
leaves it at a constant rate. The arteries, therefore, at
each beat of the heart accommodate their capacity to an
increase in the volume of their contents. This they do
through the elasticity of their walls. Every time the
ventricle discharges its contents into the aorta part of the
kinetic energy imparted to the blood is spent in distend-
ing the part of the aorta nearest the heart. The distended
wall, in returning to its normal size, owing to its elasticity,
exerts a pressure upon the blood — a pressure which is trans-
mitted to the next segment of the aorta, which is distended
in consequence. In this way is caused a wave of dis-
tension known as the pulse- wave, which travels peri-
pherally at the rate of about seven metres per second.
The transmission of the pulse-wave is therefore a purely
mechanical effect, and is independent of any nervous
agency, except in so far as the latter may influence the
arterial tonus upon which the elasticity depends. The -pulse-
wave has nothing to do with the velocity of the blood,
being much faster. As it travels towards the periphery
the pulse-wave becomes less perceptible, the flow of blood
from the arterioles into the capillaries being perfectly
uniform.

The nature of the pulse-wave is investigated by means
of the sphygmograph. This consists essentially of a spring
which is pressed upon the radial artery at the wrist. The
expansion of the artery is transmitted through the spring,
magnified by a system of levers, and recorded on blackened
paper which is moved by clockwork. Such a record is
shown in Fig. 18. The wave will be seen to consist of a
sharp upstroke and a slower downstroke. Upon the latter
there is invariably a smaller elevation. This is known as
the dicrotic wave (e), the notch preceding it {d) being called
the dicrotic notch. The notch is due to the fall in pressure
consequent upon the cessation of the outflow from the

BLOOD-PRESSURE 77

ventricle. The dicrotic wave is due to a rebound from the
closed aortic valve. It cannot be due to reflected waves
from the periphery, since there is always the same interval
between it and the main wave, whatever the distance from
the heart. The dicrotic wave corresponds to the rise at
4 in the aortic-pressure tracing of Fig. 10.

The sphygmographic record is subject to considerable
variation even in normal individuals. Secondary waves
may appear, due to reflected waves from the periphery, to
vibration of the arterial wall, and to instrumental error.
When there is a high blood-pressure owing to resistance to
the outflow of blood from the arteries, the upstroke is more
prolonged and may show upon it a secondary wave : such

•

Fig. 18. — Radial pulse. (From Starling's Principles of Physiology.)

a pulse is called anacrotic. When the outflow is freer the
upstroke tends to be sharper, and a secondary wave
appears in a pre-dicrotic position on the downstroke — a
catacrotic pulse. Secondary waves which are post-dicrotic
in position are of instrumental origin.

BLOOD-PRESSURE

Measurement

The arterial blood-pressure is measured directly in
animals by the insertion of a cannula into the artery. This
is connected with a mercury manometer. On the open
surface of the mercury there is a float which holds a writing
pointer. The cannula and tube between the blood and the
mercury are filled with sodium sulphate, which prevents
clotting.

78 THE CIRCULATION OF THE BLOOD

Clinical Methods

For clinical purposes the sphygmomanometer is employed.
The Riva-Rocci pattern, which is the one most commonly
used, consists of a canvas band which is tied round the
upper arm. On the inner side of the band is a rubber bag
which, on being inflated with air, compresses the arm. The
air inside the bag communicates with a pump, with a
mercurial or spring manometer, and through a valve with
the external air. Air is pumped in until the radial pulse
can no longer be felt. The pressure is then gradually
released by opening the valve, and the reading of the
manometer noted at which the pulse just becomes per-
ceptible. This gives the systolic pressure.

By an adaptation of this instrument it is possible to
estimate the diastohc as well as the systohc pressure.
When the pressure as recorded by the manometer is such
that the pulse is barely perceptible, it means that the
brachial artery is completely compressed except at systole,
when the pressure within the artery is just sufficient to
overcome the pressure tending to obliterate the artery.
As the external pressure is gradually reduced the systohc
pressure comes through more easily, the artery being still
compressed at diastole. It is obvious that when the external
pressure is just sufficient to compress the artery at diastole,
the extra pressure produced in the artery by systole will
exert its maximum dilating effect. If the oscillations of
the manometer be recorded on a writing surface, as in
Gibson's apparatus, the point at which the excursion of
the lever is greatest marks the diastohc pressure.

The diastohc pressure can also be estimated by hstening
through a stethoscope placed over the brachial artery at
the elbow. Beginning with complete obhteration of the
pulse, as the pressure is released faint sounds are heard
when the systohc wave begins to come through. With further
lowering of the pressure a stage is reached at which the
sounds suddenly become louder and sharper. From this

VENOUS PRESSURE

point they first become still more intense and then suddenly-
become faint. The reading of the manometer at which
the sounds are loudest is the diastolic pressure.

The mean pressure is the mean between the systolic and
the diastohc pressure. The pulse-pressure is the difference
between the systolic and diastolic pressures. It is a
measure of the output of the heart.

A rough indication of the arterial pressure can be obtained
by placing two fingers upon the radial artery. The
proximal finger exerts the pressure and the distal finger
detects whether the pulse comes through or not. Certain
characteristics of the pulse are recognised clinically. The

Fig. 19. — (From Starling's Princi'ples of Physiology.)

volume is the difference between the diastohc and systohc
pressure ; it is therefore identical \vith pulse-pressure.
The tension is the pressure during diastole.

The Measurement of Venous and Capillary Pressure

A rough estimate of the pressure in the subcutaneous
veins of the upper hmb can be obtained by raising the
arm and noting the height above the heart level at which
they become blanched. Another method is by means of
the apparatus shown in Fig. 19. It consists of a rubber
bag, on the opposite sides of which are two holes. The
bag is placed on the skin so that one hole is opposite a
vein. Over the other hole is placed a plate of glass. The
junction between bag and skin and between bag and

80 THE CIRCULATION OF THE BLOOD

plate are made air-tight by greasing. The bag is con-
nected with a pump and manometer. At a certain pres-
sure the blue colour of the vein disappears. A similar
apparatus of smaller size is used for subcutaneous capil-
laries. This method does not give accurate results, since
the resistance of the skin is unknown. The same objection
apphes to von Kries's method for measuring capillary
pressure. In this method a glass plate of a certain area
is pressed upon the skin and weighted until the skin is
blanched. On dividing the weight by the area of the
plate the pressure upon unit area of skin is obtained.

The Regulation of Blood-pressure

In young adults the systohc pressure in the brachial
artery is about 110 mm. Hg., the diastolic 70, giving a
mean pressure of 90. In the horizontal position the blood-
press vire is almost uniform in large and small arteries. In
the arterioles the blood meets with considerable resistance
owing to the narrow cahbre of the vessels. The consequence
is that between the small arteries and the capillaries there
is a considerable drop in pressure, from 90 in the former,
to anything between 40 and 15 in the latter. The pressure
in the veins is lower again than that in the capillaries. It
varies between 10 and 0 mm. Hg., and in the great veins
entering the heart may even have a negative sign. It
will be seen that as the blood flows through the systemic
circulation the pressure which it exerts upon the vessel
walls does not fall uniformly. The greatest resistance to
the flow of blood is met at the junction of the arterioles
with the capillaries. In overcoming this resistance the
blood falls from a region of high pressure in the arteries to
a region of low pressure in the capillaries and veins. On
this account we may regard the arterial system as a kind of
reservoir. The purpose which such a reservoir serves will
become clear when we consider under what conditions and
by what mechanism the pressure of blood within it is liable
to alteration. For the moment it will suffice to point out

THE REGULATION OF BLOOD-PRESSURE 81

that the maintenance of the normal blood -pressure is of
the greatest importance, and that the body possesses an
elaborate mechanism for maintaining a constant blood-
pressure in the face of any tendency to disturb it.

It will be convenient here to consider in a general way
the factors upon which arterial blood-pressure depends.

For a proper understanding of this question it is neces-
sary not to lose sight of the fact that the blood is circulating
at a considerable rate — that we are dealing with a dynamic
and not a static condition. Blood-pressure is caused by
the heart-beat, and is supported by the resistance in the
arterioles.

Blood-pressure depends upon four primary factors —

1. The output of the heart.

2. The peripheral resistance.

3. The volume of the circulating blood.

4. The relative distribution of the blood, at any given

moment, between the heart, arteries, capillaries
and veins.

1 . The Output of the Heart. — If the peripheral resistance
is unaltered the arterial pressure will vary directly with the
output of the heart. If the latter is increased the blood-
pressure will rise.

2. The Peripheral Resistance. — This is the resultant of
two factors — the viscosity of the blood and the calibre of
the arterioles. Of these the latter is the more important.
The output of the heart being constant, the blood-pressure
varies directly with the resistance.

3. The Volume of the Circulating Blood. — The pressure
will vary with the volume of the blood, provided that the
distribution of the blood between the several parts of the
circulation is undisturbed.

4. The Distribution of the Blood. — The capillaries and
veins are, as we shall see, capable of considerable alteration
in capacity at low pressures. A change in the capacity of
the capillaries does not constitute a change in the peri-

82 THE CIRCULATION OF THE BLOOD

pheral resistance, for the capillaries are beyond the site at
which this resistance principally occurs — the arterioles.
If two reservoirs at different levels are connected together
with a narrow pipe, the resistance which the water meets in
passing through the pipe is unaffected by the size of the
lower reservoir. The variations in the capacity of the
circulation other than the arterial part will affect the blood-
pressure only by altering the proportion of the blood which
is in the arteries at any given moment. We shall see that
under certain circumstances a low blood-pressure may even
be associated with constriction of the arterioles, when the
capillaries are greatly distended. Under these conditions
the blood is nearly all in the capillaries.

Such being the effect upon blood-pressure of changes in
any one of the factors upon which it depends, the position
becomes more comphcated when more than one factor
varies at a time. If the output of the heart and the
peripheral resistance increase simultaneously, it is to be
expected that the resulting rise in pressure will be greater
than if either of these factors were to act alone. But if
an increase in the cardiac output takes place concurrently
with a decrease in the peripheral resistance, the two changes
may so antagonise one another as to leave the blood-
pressure unaltered. The net effect upon the circulation
is an increase in the velocity of the blood.

The above effects can readily be imitated on an artificial
schema of the circulation. But in the hving body the
effects may be very different owing to the close inter-
relation between the several factors. This interrelation
is partly direct, partly indirect through the interven-
tion of the central nervous system. If, for instance, the
arterioles be constricted all over the body, the pressure in
the arteries is raised, that in the capillaries and veins
lowered. The raised arterial pressure causes, reflexly,
slowing of the heart {Mareys Law). But this is not the
only way in which the heart is affected. The lowering of
the venous pressure, as we have seen, causes by a direct

THE PERIPHERAL RESISTANCE 83

effect upon the heart-muscle a decrease in the output per
beat (p. 70) and, reflexly through the vagus, slowing of
the heart. The peripheral resistance may therefore be said
to influence the heart in two ways, backwards through the
arteries and forwards through the veins.

THE PERIPHERAL RESISTANCE

As already stated, the peripheral resistance is the resultant
of two factors, the viscosity of the blood and the cahbre
of the arterioles. The viscosity of the blood is due partly
to the plasma, partly to the corpuscles. It decreases with
rise of temperature and increases with the COg content.
In the present state of our knowledge it is impossible to
assess what effect such variations will have upon the
resistance under physiological conditions.

Concerning variations in the calibre of the blood-vessels,
our knowledge is much more extensive. In thin tissues,
like the frog's mesentery or the rabbit's ear, such variation
can be directly observed. In organs such as the intestines,
kidney or limbs, changes in the capacity of the blood-
vessels are inferred from changes in the volume of the
whole organ. The organ is inserted into a plethysmograph,
which consists of a box opening equatorially. In the box
are two holes. One is for the blood-vessels. This is made
water-tight by packing with vasehne. The other hole is
to convey oil with which the organ is surrounded to a
tambour connected with recording apparatus. When the
organ expands oil is driven out of the box and raises the
recording lever. A special form of plethysmograph used
for the kidney is called an oncometer, and for the heart a
cardiometer.

Another method apphcable to small tissues is to
measure the venous outflow. This has the disadvantage
of entailing a loss of blood.

The factors controlUng the calibre of the blood-vessels
are two — nervous and chemical.

84 THE CIRCULATION OF THE BLOOD

THE NERVOUS CONTROL OF THE BLOOD-VESSELS

Vaso-Constrictor Nerves

In 1852 Claude Bernard showed that in the rabbit
when the cervical sympathetic was cut, the arteries of the
ear dilated, and when the peripheral end of the nerve was
stimulated, the vessels contracted. He thus demon-
strated not only that the sympathetic conveyed vaso-
constrictor fibres, but that these exerted upon the vessels
a constant tonic action, removed by section of the nerve.
Vaso-constriction is now known to be a function of the
whole sympathetic system, and the origin of the impulses
has been traced to a centre — the " vaso-motor " centre,
situated in the floor of the fourth ventricle. From this
region impulses are constantly passing down the cord, which
they leave by the sympathetic outflow in the thoracico-
lumbar region. When the cord is transected at the seventh
cervical segment or higher, a maximal fall of blood-pressure
occurs, and any organ inserted in a plethysmograph under-
goes an increase in volume, owing to withdrawal of this
vaso-constrictor influence from all the blood-vessels in the
body which are provided with sympathetic fibres. When
the cord is transected at the third lumbar segment the
blood-pressure is unaffected, showing that no vaso-con-
strictor fibres issue from the cord below this level. The
blood-pressure is similarly unaffected when the brain-stem
is cut above the fourth ventricle, proving that the con-
trolling centre is below this level. But when the fourth
ventricle is itself destroyed complete fall of blood-pressure
results. A region in the fourth ventricle therefore presides
over the condition of the arterioles, and determines the
resistance which these vessels present to the outflow of
blood from the arterial reservoir.

Details of the paths taken by vaso-constrictor fibres
are fully given in the section on the Autonomic System.
It is sufficient to state here that all these fibres emerge

VASO-DILATOR NERVES 85

from the cord between the first dorsal and third lumbar
segments, that the fibres which supply the abdominal and
pelvic viscera pass, without interruption, through the
sympathetic chain and have cell-stations in the collateral
gangha — the semilunar, superior and inferior mesenteric
gangha, and that fibres which supply the blood-vessels of
the skin have cell-stations in the sympathetic chain from
which post-ganglionic fibres emerge and travel to the
periphery bound up in the ordinary nerve-trunks.

There appears to be no vaso-motor control over the
arteries of the brain or the coronary arteries of the heart.
In the pulmonary vessels vaso-motor influence is indicated
by the constriction which occurs on the administration of
adrenalin.

When a vaso-constrictor nerve is stimulated it will
produce a double effect — first, a diminution in the blood-
supply to the part of the body to which it is distributed ;
secondly, if the distribution of the nerve is sufficiently
extensive, stimulation will, by diminishing the outflow from
the arteries, tend to raise the general blood-pressure.

Vaso-dilator Nerves

Claude Bernard showed that the chorda tympani nerve
on stimulation caused dilatation of the blood-vessels to
the submaxillary gland, and that this occurred indepen-
dently of secretion. This was the first demonstration that
there exist nerves which on stimulation cause an inhibition
of the tonus of the vessels. Vaso-dilator fibres occur also
in the nervus erigens supplying the penis. In both these
cases the vaso-dilator effect is sufficiently striking to
warrant our beheving the existence of nerves having this
special function.

When we turn to the blood-vessels in general we find
ourselves on more debatable ground. Do the sympathetic
nerves convey vaso-dilator as well as vaso-constrictor
impulses? The only positive information we have on

86 THE CIRCULATION OF THE BLOOD

this point is the isolated fact that stimulation of the cervical
sympathetic in the dog causes vaso-dilatation of the gums
and soft palate.

After the administration of the drug, ergotoxine, stimula-
tion of the abdominal sympathetic causes vaso-dilatation.
This may be interpreted in two ways. The drug may
paralyse the vaso-constrictors, and so bring out the action
of the vaso-dilators, previously masked by the greater
power of their opponents. On the other hand, it may be
argued that ergotoxine acts by converting an excitor into
an inhibitor effect, in the same way as strychnine converts
an inhibitor into an excitor efiect.

Passing to the somatic system, we find more certain
evidence of the existence of vaso-dilator nerves.

It is possible to demonstrate that in the nerves supplying
the Hmbs, vaso-dilator as well as vaso-constrictor impulses
are conveyed. In the first place, the two sets of fibres are
susceptible to different modes of stimulation. When the
peripheral end of the cut nerve is stimulated by the ordinary-
interrupted current, vaso-constriction occurs; when by
slowly repeated induction shocks, vaso-dilatation is the
result. Again, when the nerve is stimulated two or three
days after section, vaso-dilatation invariably occurs,
pointing to a difference in the rate of degeneration between
the two sets.

How do the vaso-dilator fibres emerge from the cord?
Are they part of the sympathetic or not ? When the
posterior root of a segmental nerve is cut and its peripheral
end stimulated, vaso-dilatation occurs over the area of
distribution of the nerve. This cannot be due to stimula-
tion of the sympathetic, since sympathetic fibres join the
nerve more distally. There is here, then, a contradiction
of Bell's Law, according to which the posterior root was
regarded as purely afferent. The question which we now
have to decide is this : Does the posterior root contain
two kinds of fibres, afferent conveying sensation and
efferent conveying vaso-dilator impulses, or are there but

ANTIDROMIC IMPULSES 87

one set of fibres capable of conveying impulses in both
directions ?

When the skin in any part is irritated, the underlying
vessels are dilated, as is well known. This might be regarded
as a simple reflex action were it not for the fact that the
effect occurs even after section of the nerve-trunk. But
when the peripheral part of the nerve has degenerated, the
effect is abolished. Here, then, is a mechanism which
clearly involves the nerve-trunk, but neither the posterior
root ganglion nor the spinal cord. The effect can only be
explained by assuming that each of the fibres in the
posterior root divides^ into two branches, one supplying
the skin, the other the vessels lying beneath. When the
cutaneous nerve-ending is stimulated the disturbance is
propagated not only centrally but throughout the whole
fibre, and an inhibition of the tonus of the blood-vessel
results. This is therefore termed an axon-reflex. (Fig. 20,
p. 88).

It would seem therefore that the posterior root contains
not two kinds of fibres but one kind, which usually convey
impulses in both directions. The impulses passing towards
the periphery are termed antidromic.

Is there a nervous centre which on stimulation produces
vaso -dilatation ? Such a centre has been stated to exist
in the fourth ventricle, distinct from the vaso-constrictor
centre, but this observation is not confirmed.

We may now summarise the position with regard to the
nervous control of the blood-vessels. Nearly all the
arterioles of the body are under the control of nerves which
have a constrictor effect upon them. These nerves belong
to the sympathetic system. Some arterioles, particularly
those of the somatic system, are in addition suppUed with
nerves which have an inhibitory effect. These nerves are
identical with the sensory nerves {see Fig. 20). In such
vessels the tonus of the muscular coat is determined by the
relative strength of these two antagonistic impulses, and
it so happens that vaso-constrictor influences are usually

THE CIRCULATION OF THE BLOOD

far the stronger. When a vaso-constrictor nerve is cut,
impulses which were previously passing down it are
aboUshed, and the arterioles which it supphes are dilated.
But when a vaso-dilator nerve is cut there is hardly
any constriction. The vaso-dilators, then, under normal
conditions exert but a feeble, if any, effect.

Does the wall of the arteriole possess an inherent
tonus independent of any nervous influence ? It would

Fig. 20.
B = Posterior Root Fibre, the axon dividing distally, one part

supplying the skin, the other a blood-vessel A which it dilates.
C = Motor Fibre to muscle M.
D = Sympathetic pre-ganglionic fibre.
E = Post-ganglionic fibre arising in a sympathetic ganglia. Distally

it supplies the blood-vessel with vaso-constrictor fibres and

innervates the hairs and sweat glands.

seem that it does, because when a nerve is cut the blood-
vessels which it supplies, after first undergoing paralytic
dilatation, acquire a certain degree of constriction.

Vaso-motor Reflexes

We now pass on to consider under what conditions these
efferent mechanisms are brought into play. The vaso-
motor centre or centres can influence, in two directions,
the outflow of blood from the arteries. The tonus of the
arterioles may be increased throughout the greater part

VASO-MOTOR REFLEXES 89

of the body. The blood is therefore held up in the arteries,
and if the output of the heart is unaltered a rise in the
arterial blood-pressure must result. This is called a pressor
effect. On the other hand, a pre-existing normal degree
of tonus may be reduced. Blood rushes out more quickly
from the arteries, and the heart continuing unaltered, the
blood-pressure must fall. This is known as a depressor
effect.

It is to be expected that since the majority of arterioles
receive a double nerve supply, constrictor and inhibitor, a
pressor effect will involve both an excitation of the vaso-
constrictors and an inhibition of the vaso-dilators, and
similarly that a depressor effect will involve both an
excitation of the dilators and inhibition of the vaso-con-
strictors. In other words, when the medulla is stimulated
the changes in the cahbre of the arterioles are produced
by reciprocal innervation, in exactly the same way as
movement at a joint. There is evidence that this is the
case, but under normal conditions the vaso-constrictors
are much more active than their antagonists, the latter
appearing to play a minor role. Vaso-constriction may
therefore be said to be produced principally by stimulation of
the centre, vaso-dilatation by inhibition of the same centre.

The factors influencing the vaso-motor centre are of
two kinds — nervous and chemical. Of the former it may
be said that stimulation of any sensory nerve causes
universal vaso-constriction. If a posterior root is stimu-
lated an efferent antidromic impulse causes vaso-dilatation
in the part supphed by the nerve, and an afferent impulse
causes reflex vaso-constriction throughout the rest of the
body, with consequent rise of arterial blood-pressure.
In these two ways the part innervated by the nerve
receives an increased blood-supply at the expense of the
remainder of the body.

Among the nervous influences affecting the centre are
the psychical. As is well known, vaso-constriction is one
of the physiological expressions of emotional states.

90 THE CIRCULATION OF THE BLOOD

But of all the factors which influence the vaso-motor
centre, the one which in man is probably most often called
into play is the blood-supply to the brain. It is evident that
gravity must exert its influence upon the circulating blood.
According to the position of the body, the pressure in the
tibial artery varies from 165 mm. when the body is vertical,
to about 105 mm. when it is horizontal. Yet the pressure
in the brachial artery remains unaltered. It has already
been mentioned that there is no evidence of the existence
of vaso-motor fibres to the cerebral vessels. Alterations in
the intracranial blood-pressure, due to gravity, are com-
pensated by alteration in the facihty with which blood
can escape from the arteries in other parts of the body,
chiefly the abdomen.

The chemical influence playing upon the centre consists
in the reaction of the blood. In its extreme form this is
seen if we asphyxiate an animal, having primarily cut the
vagi to eliminate the effect of any action upon the heart.
There occurs a rapid rise of pressure due, not to the specific
action of carbonic acid, but to the increase in hydrogen
ion concentration, for the effect can be imitated by injec-
tion of lactic acid into the blood-stream.

Depressor Reflexes

We have already seen that from the heart and begin-
ning of the aorta arise afferent fibres which reflexly slow
the heart. The same fibres reflexly produce fall of blood-
pressure. This is not entirely due to slowing of the heart,
since it occurs after section of the vagi. It is due to
universal vaso-dilatation. Under what circumstances is
this nerve normally brought into play ? Of this we have
no direct evidence, but it is assumed that the depressor
nerve-endings are sensitive to conditions of excessive tension
in the heart and aorta, and that when stimulated they
reflexly ease the strain to which these organs are put.
It is known that the rise in pressure during asphyxia
is much less when the vagi are intact than when these

CHEMICAL CONTROL 91

nerves are cut, but this difference can be explained as due
to the direct stimulating effect of the carbonic acid upon
the vagus centre.

THE CHEMICAL CONTROL OF THE BLOOD-VESSELS

(a) Metabolites. — It has long been known that blood
percolates more freely through an organ as its content of
CO2 rises. Other acids — as, for example, lactic acid —
have a like effect. This is due to a direct effect upon the
arterioles and, as we shall see later on, the capillaries.
When a tissue such as a muscle or gland becomes active,
the acids produced dilate the neighbouring blood-vessels.
But the same substances passing into the blood-stream
stimulate the vaso-motor centre. These acids therefore
produce two contrary effects- — a dilator effect, which is
local, and a constrictor effect, which is general. Locally,
the dilator effect is greater than the constrictor. The result
will therefore be an increased flow of blood through the
active organ, and a decreased flow through the inactive
tissues — in particular the viscera. More blood is diverted
to the tissues which require it.

(6) Pressor Substances. — ^Adrenalin, the product of the
suprarenal glands, has the same effect upon any organ as
stimulation of the sympathetic nerve. It is itself dis-
charged into the blood-stream when the sympathetic fibres
to the suprarenal are stimulated. It follows, therefore, that
when the sympathetic system enters upon a state of
increased activity, as in emotional states or asphyxia,
the physiological effect may be caused directly by nervous
impulses passing to the various organs, or indirectly to
the secretion of adrenalin. There is evidence that in the
resulting rise of blood-pressure both factors contribute.
It is sometimes found that in asphyxia rise of blood-
pressure occurs in two stages : the first due to stimulation
of the vaso-constrictor fibres, the second due to the action
of adrenahn poured into the circulation.

92 THE CIRCULATION OF THE BLOOD

But the rise of pressure which occurs on injection of
adrenahn after the vagi have been cut is not entirely due
to vaso-constriction. Adrenahn has also a direct action
upon the heart, quickening it and increasing the amphtude
of each beat. To the diminished output from the arteries
is therefore added increased output from the heart.

THE CIRCULATION IN THE CAPILLARIES

We have seen that the arterioles, owing to their muscular
walls, present to the flow of blood a resistance which can
be varied by nervous and chemical means. The terminal
arterioles lead into the capillaries — dehcate tubes, about
0-5 mm. in length, composed of a single layer of flattened
endothehal cells. These capillaries he in a bed of lymph
which separates them from the tissue-cells.

In the mesentery of the frog the circulation in the
capillaries can be readily observed and compared with the
circulation in the arterioles. In the latter it will be seen
that the red corpuscles, owing to their greater specific
gravity, run in the axis of the vessel where the stream is
fastest. Surrounding the corpuscular column is a clear
layer composed of plasma. Here the white corpuscles can
be seen rolhng in a leisurely manner along the inner wall
of the tubes. When the capillaries are reached, owing to
the narrowness of these vessels there is only one layer,
the corpuscles passing one by one. Here the blood flows
with great irregularity, stopping and rushing on alter-
nately. There is no pulsation, this having been effectively
damped by the terminal arterioles. Here, where the blood-
flow is at its slowest, occur the transference of food material
from the blood across the lymph to the cells, and of waste
products from the cells to the blood, the exudation of
lymph, and the migration of leucocytes into the tissue
spaces. At present, however, we are concerned not with
these nor Avith the dramatic changes which occur as the
result of injury, but only with such modifications in the

THE CAPILLARIES 93

capillaries as directly or indirectly affect the rest of the
circulation.

Direct observation of the capillaries in the thin tissues
of the frog has shown that they are capable of considerable
variation in calibre. In a resting muscle they are con-
stantly contracting and expanding, the great majority
being at any one time contracted to complete obliteration
of their lumen. The course of the blood is constantly
changing; it flows now through this tube, now through
that. The capillaries therefore possess a considerable
power of contraction, and experiment shows that this power
is independent of nervous influences, being an inherent
property of the endothelial cells of which the capillaries are
composed.

When a muscle becomes active there occurs a simul-
taneous opening up of all the capillaries, so that the blood
supply may be increased several hundred times. The
capillaries respond readily to chemical agents. On the
direct appHcation of acids they are dilated. It is there-
fore probable that the acids produced in activity are the
cause of the dilatation.

It should be reahsed that the degree of t07ius of the capil-
laries is not dependent upon the hlood-pressure. The
capillaries are not necessarily distended by a rise in the
pressure of blood supplying them. Adrenahn, in addition
to constricting the arterioles, in weak doses dilates the
capillaries. Similarly, histamine, a base derived from the
amino-acid histidine (by removal of COg), constricts arterioles
and at the same time dilates capillaries.

Shock

Confirmatory evidence of the changes in caUbre under-
gone by the capillaries is forthcoming from a study of the
chnical condition of shock. This is characterised by a
great fall of blood-pressure. It is brought on by trauma
or haemorrhage, especially under conditions of exposure to
cold, excitement and deprivation of food.

94 THE CIRCULATION OF THE BLOOD

The question arises, what has happened to the blood ?
It is not in the arteries, for these are constricted ; it is not
in the veins, for surgeons testify that these are not dilated.
It must therefore be in the capillaries. In the paralysed
and greatly distended capillaries a large proportion of the
blood is accommodated. The blood corpuscles are to a
great extent immobihsed, hke railway wagons on a siding.
Secondary changes then occur owing to the deficient oxida-
tion of the tissues. The stagnated blood, too, becomes
concentrated in corpuscles owing to the excessive transuda-
tion of plasma into the tissue-spaces.

As regards the cause of the capillary paralysis, it has been
found, as the result of observations on men wounded
in the late War, that a relationship exists between the
tendency to shock and the degree to which muscle is
involved in the injury. Shock can indeed be produced
experimentally by crushing muscles. It is therefore beheved
that substances resembling histamine in action are, in the
destruction of tissue, hberated into the blood-stream.
These paralyse the capillaries and lead to the stagnation
of blood above described.

To what degree the capillaries, hke the arterioles, are
under nervous control is not determined. It is possible
that the antidromic impulses which we have seen to con-
stitute axon reflexes travel to the capillaries, and not
merely to the arterioles.

THE CIRCULATION IN THE VEINS

In the veins the blood-pressure is 10 mm. Hg., and lower
as the heart is approached. The blood is driven along the
veins by two forces : the pressure of the blood behind it —
that is to say, the kinetic energy communicated to it by the
contraction of the left ventricle — and the negative pressure
in front created by the contraction and relaxation of the
right auricle. Two accessory factors combine in giving a
further impetus to the venous flow. The first consists of

THE PULMONARY CIRCULATION 95

muscular contraction whereby blood is pumped through
the capillaries into the venules. The second is the movement
of the diaphragm — this muscle in descending tends to
decrease the already negative pressure in the thorax and to
increase the pressure in the abdomen. Most of the veins
being provided with valves, muscular contraction in general,
and contraction of the diaphragm in particular, are effective
only in one direction — towards the heart. On account
of the factors above described, the pressure in the great
veins may be negative. Blood may be sucked rather than
pushed into the heart. This is especially liable to occur
during deep inspiration, for under these circumstances,
to the negative pressure within the heart is added the
negative pressure within the thorax, which tends to draw
open the intrathoracic veins.

The nature of the jugular pulse has already been
discussed.

THE PULMONARY CIRCULATION

The pulmonary circulation differs from the systemic
in two important respects. First, the peripheral resistance
is considerably smaller in the lungs than in the rest of the
body. For this reason a smaller pressure is required to
drive the blood through the capillaries. It is on this
account that the right side of the heart is much less muscular
than the left. In the second place, the capacity of the
pulmonary circulation is continually undergoing rhythmic
alteration, due to the alternate expansion and retraction
of the lung tissue which occur in respiration. This influ-
ences the systemic circulation in two ways. First, each
inspiratory movement of the chest aids the flow of blood
along the extra-thoracic veins, in the manner above
described. Secondly, in ansesthetised animals there is an
effect upon the arterial pressure. During inspiration there
is a quickening of the heart-beat due, as we have already
noted, to diminution of vagus control. The effect upon

96 THE CIRCULATION OF THE BLOOD

the blood-pressure is independent of the vagus and is
purely mechanical in origin. There is a rise in blood-
pressure during inspiration, and a fall during expiration.
The blood-pressure and respiratory changes are, however,
not synchronous^ — the blood-pressure is at its highest just
after the end of inspiration, and at its lowest just after the
end of expiration. With the distension of the pulmonary
circulation more blood is presented to the left side of the
heart, the output of the left ventricle is increased, and the
blood-pressure in this way raised. The delay in the rise
of pressure is due to the fact that at the beginning of
inspiration blood first has to occupy the increased capacity
of the pulmonary circulation before it affects the left side
of the heart.

With the diminution in the capacity of the lung capil-
laries which occurs in expiration, there is first a further
increase of the blood reaching the left auricle. Later, as
the piilmonary vessels have constricted, the amount of
blood fed to the left side of the heart' is diminished and
the blood-pressure falls.

These effects are reinforced by the movement of the
diaphragm. As this muscle contracts it forces blood from
the abdomen into the thorax, as already described.

In man the effects of the respiratory movement upon
blood-pressure are exceedingly complex, varying with the
form and depth of respiration.

Whether or no the pulmonary arterioles are subject to
nervous control was for long a matter of controversy.
By direct stimulation of nerves no positive evidence can
be procured. Since, however, the vessels constrict to
adrenalin, it is inferred that they receive constrictor fibres
from the sympathetic.

CHAPTER VII
RESPIRATION

Introduction

Respiration is the exchange of oxygen and carbonic acid
between the organism and its surroundings. In evolu-
tion a special mechanism for the transport of these gases
makes its appearance as soon as any of the tissues are
excluded from direct contact with the medium in which
the animal lives. A separate tissue, the blood, is developed
principally, though not exclusively, for this function ;
the blood serving to carry oxygen from the external cells
which can supply it to the internal cells which need it, and
to drain the internal cells of the COg which is constantly
being formed within them.

With the appearance of land animals the process becomes
comphcated, owing to the fact that gaseous exchange now
involves a change of state. Oxygen taken from the air
has to be brought into solution, and COg has to pass from
solution into the free state. Moreover, the exchange of
oxygen and carbonic acid between the animal and its
environment occurs no longer on the surface of the body
but in its interior — ^in the lungs. There are therefore no
less than four stages in the process of assimilating oxygen.
In the first, oxygen passes from the atmosphere to the air
in the lung ; in the second it passes into the blood ; in
the third it is transported in the blood to the whole body ;
in the fourth it passes from the blood to the tissues. Four
corresponding stages occur in the removal of carbonic acid.
7 97

98 RESPIRATION

In considering how the cell acquires oxygen and rids
itself of CO2 we must bear this fact in mind — that the
extent of its gaseous interchange is determined not by the
amount of oxygen presented to it by the blood, but by its own
inherent need arising out of its metabolic activity. It is
the cell and not the blood which sets the pace for oxida-
tion. The amount of oxygen which the cell utilises is
therefore a measure of the work which the cell is performing.
When the body as a whole is at rest the blood contains
more than sufficient oxygen for its needs.

The problem of respiration resolves itself into two ques-
tions:— -First, how are the supply of oxygen and the removal
of CO2 effected? Secondly, how do these vary according
to the varying needs of the body? Consider the task which
the blood performs. It conveys two gases in opposite
directions, one of these gases being relatively insoluble
in aqueous solution. This double transport of gases is
carried out undisturbed by the many other functions which
the blood performs.

THE TRANSPORT OF OXYGEN

Haemoglobin

Haemoglobin is a complex substance present in red blood
coxpuscles. It is a combination of hsematin and a protein
known as globin, and has a molecular weight of about
16,600. Its haematin component contains iron, each
molecule of haemoglobin containing one atom of this metal.
Haemoglobin possesses the property of forming with oxygen
a loose compound known as oxy haemoglobin. As each
molecule of haemoglobin combines with two atoms of oxygen,
it follows that in oxyhaemoglobin there are two atoms of
oxygen for every atom of iron. Haemoglobin must there-
fore be regarded teleologically as a means of utihsing the
oxygen-combining property of iron, the great size of the
haemoglobin molecule overcoming the high specific gravity

TRANSPORT OF OXYGEN 99

of the metal. In other words, haemoglobin is a kind of boat
in which iron is enabled to float in the blood.

When oxyhsemoglobin is treated with potassium ferri-
cyanide its oxygen is quantitatively evolved. The nature
of the reaction is very compHcated, for the oxyhsemoglobin
is not reduced but is converted into a substance known as
methsemoglobin, which contains just as much oxygen as
oxyhsemoglobin. The oxygen, however, is in more perma-
nent combination. Notwithstanding its complex nature,
the process provides what is now the standard method for
estimating the amount of oxygen originally present.

The combination of haemoglobin with oxygen is a
reversible reaction, the direction in which the reaction
proceeds being determined by the pressure of oxygen to
which the haemoglobin is exposed.

The relation between the degree of combination and the
oxygen pressure can be estimated by exposing a solution
of pure haemoglobin to different pressures of oxygen and
estimating by the ferricyanide method the amount of the
gas which has entered into combination. The result is
expressed in the accompanying curve (Fig. 21 H), which is
seen to be a rectangular hyperbola. It corresponds to
the curve which is obtained theoretically from the equation

Hb + 0., Z HbO^.

The respiratory function of haemoglobin therefore Hes in
its capacity for combining with oxygen when the pressure
of oxygen is high, as in the lungs, and of parting with the
gas when the pressure is low, as in the tissues.

If, however, the dissociation curve of haemoglobin in the
blood resembled the curve for pure haemoglobin, this sub-
stance would but inefficiently fulfil its function. Reference
to Fig. 20 will show that even at as low an oxygen pressure
as 10 mm. Hg the blood would still be 55 per cent, saturated ;
in other words, the affinity of haemoglobin for oxygen
would be too great for the transference of an adequate
amount of blood to the tissues. In the body, however,

100

RESPIRATION

several factors contribute to modify considerably the
combination of hsemoglobin with oxygen. These we shall
now consider.

Factors Influencing the Dissociation of Oxyhsemoglobin

A. Inorganic Salts. — When the curves of dissociation of
pure haemoglobin and of blood are compared (Fig. 21), a

100

40 oO CO 70 00 £50 100

Fig. 21. — The dissociation curves of haemoglobin (H) and of Blood (B).
Ordinates; percentage saturation of haemoglobin ; abscissae: pres-
sure of oxygen in mm. (From Barcroft, The Respiratory Functions
of the Blood.)

great difference is noted between them. While the former
is rectangular the latter is more complex, the two differing
in such a manner that at low oxygen tension dissociation
takes place more easily from blood than from haemoglobin,
while at high oxygen tension more oxygen is in combination
with the blood than with haemoglobin. This means that
the oxygen-carrying power of the blood from a place of

TRANSPORT OF OXYGEN 101

high to a place of low oxygen tension is superior to that
of pure haemoglobin.

This difference is due to the electrolytes, as is shown
by the follo\ving facts —

1. If to haemoglobin, salts are added, the dissociation
curve approaches that of blood in the measure that the
amount of salts present approaches that which obtains in
blood.

2. The form of the dissociation curve of blood varies
sHghtly, as does the saline content, in animals of different
species. If to the hajmoglobin of an animal A are added
salts as they occur in an animal B of another species, the
curve obtained corresponds with the blood of B. Therefore
the differences in the curves found in different species are
due to differences not in the haemoglobin, but in the sahne
constituents.

The salts are beheved to exert their influence by causing
a clumping together of the haemoglobin molecules.

B. The Reaction of the Blood. — That the curve is
materially affected by the degree of acidity of the blood
is shown in Fig. 22, which gives the effect of varying
amounts of COg. Acidity increases the tendency to
dissociation, the greatest effect being at an oxygen tension
of 20 mm. At tensions of 80 mm. and over the difference is
but shght. All acids have the same effect, the degree of
their influence varying with the extent to which they form
free hydrogen ions in blood.

C. Temperature. — The effect of temperature is shown in
Fig. 22. With rise of temperature goes increased dis-
sociation, an increase which is greatest at low oxygen
tension.

We therefore see first that the combination of haemoglobin
with oxygen is of such a nature that it is readily influenced
by three factors : the presence of salts, hydrogen ion con-
centration and temperature. We see, secondly, that these
factors exert their greatest influence at low tensions of
oxygen. We know, too, that of the three factors favouring

102

RESPIRATION

dissociation, two, namely rise of temperature and increased
hydrogen ion concentration, and perhaps the third, altera-
tion in the quantity of electrolytes, occur as the result of
cellular activity. When the cell needs more oxygen, then
the thermal and chemical effects of its activity are such as
to increase the tendency of the blood to part with its oxygen
to the tissues.

—

"Z^-"

1 —

^,,-'

h--;

1
t

1 1

t 1

}

t
*

l/j

/■

10.
Fig.

50 60

80 90 100 HO no 110 IW

22. — Dissociation curve of oxyhemoglobin with different tensions
of COo. The lowest curve is at a CO, tension of 420 mm. Hg.

The Transport of CO2

As this problem is intimately connected with the ques-
tion of the reaction of the blood the reader is advised to
refer to pp. 17-20. Here we may say that COg is not
carried in the blood as NaHCOg and dissociated in the lungs,
for under the conditions in which it exists in the blood

TRANSPORT OF CARBONIC ACID 103

NaHCOg is not dissociated. Nor is there conclusive
evidence for the behef that CO2 combines with hsemoglobin.
There are two mechanisms whereby the blood accom-
modates itself to varying amomits of COg. The first is due
to the proteins of the -plasma. A protein, by virtue of the
H atom of the COOH group, is an acid and is capable of
combining \vith sodium according to the amount of sodium
available, this in turn being determined by the amount
of sodium required to combine with COg. The sodium,
in other words, shifts to and fro between the CO2 and the
proteins, the direction of the movement being determined
by the amount of CO2 present. Here is a diagrammatic
representation — ■

CO. CO^ CO. Protein Protein Protein Protein

Na Na Na Na Na

CO2 CO. CO,, CO. CO. Protein Protein Protein Protein

Na Na Na Na Na

Since the proteins are very weak acids, the amount of free
protein does not affect the H. ion concentration.

The second method is the interaction between plasma and
corpuscles already described (p. 19). When CO2 is added to
the blood, CI ions pass from the plasma to the corpuscles,
thus allowing sodium to enter into combination with the
acid.

THE PASSAGE OF OXYGEN INTO THE BLOOD

From the alveoh of the lungs oxygen gains the blood by
passing through the flattened cells of the lung epithehum,
across the lymphatic space and through the endothehal
wall of the capillaries. Is this process one of diffusion or
is it due to active secretion of oxygen into the blood by
the lung epithehum? If the process is to be explained
by diffusion it is necessary to show that the tension of

104 RESPIRATION

oxygen in the blood leaving the lung is not higher than the
partial pressure of oxygen in the alveoh. If, on the other
hand, the pulmonary epithehum is capable of actively
secreting oxygen into the blood, then the relation between
the tension of oxygen in the blood and the partial pressure
in the alveoh is of no importance.

Before proceeding further it is necessary that we should
be quite clear as to what we mean by the tension of oxygen
in the blood. The tension of a gas in a liquid is the
pressure which it exerts in an atmosphere in equihbrium
with that liquid, such pressure being independent of the
pressure of any other gas present. Suppose that a sample
of blood on exposure to air containing oxygen at a pressure
of 30 mm. neither loses nor acquires oxygen, the number of
molecules which enter the blood and the number which
leave it in a given period being equal; then the tension
of oxygen in the blood is said to be 30 mm. Such blood
can only acquire oxygen by being exposed to a pressure of
that gas greater than 30 mm.

Now suppose that there hes on the surface of the blood
a membrane which has the power of absorbing oxygen from
the air and passing it into the blood. Then the tension
of oxygen in the blood will be higher than it would if no
membrane intervened. The question before us is whether
the lung behaves actively, hke this membrane, or whether
it is merely an inert partition freely permeable to oxygen.
It is at once obvious that diffusion, if this occurs, must
become more difficult as the pressure of oxygen in the
alveoli becomes less. What happens at ten or fifteen
thousand feet above sea-level wher© the pressure of oxygen
is considerably diminished? Is the oxygen in these
circumstances at a higher pressure in the alveoh than in
the arterial blood? Further, supposing that the body is at
the same time performing strenuous muscular work, will
diffusion in a rarefied atmosphere allow of the passage into
the blood of the increased amount of oxygen required ?
It is of course conceivable that both processes occur,

ALVEOLAR AIR 105

diffusion at high and secretion at low atmospheric pressure.
There are therefore three possibihties ; the process may be —

1 . Entirely due to secretion ;

2. Due to chffusion supplemented under special circum-
stances by secretion ; or

3. Due to diffusion under all conditions.

That the lung should be capable of secreting oxygen is
not an unreasonable supposition. Such a process is known
to occur in the swim-bladder of the fish, which may con-
tain as much as 80 per cent, of oxygen. At the same time,
the swim-bladder is not a lung either in structure or in
function.

In order to decide the nature of oxygen absorption two
data are required, the partial pressure of oxygen in the
alveoh and the tension of oxygen in the arterial blood.

The Composition of the Alveolar Air

This is determined by two methods.

Haldanes Method. — The apparatus consists of a tube
one inch in diameter and several feet in length. At one
end is fitted a mouthpiece, while two inches from it a short
side-tube leads into a gas-receiver which is fitted at each
end with a tap. At the beginning of the experiment the
receiver is filled with mercury. The subject, after taking a
normal inspiration, breathes into the tube as forcibly and
as deeply as he can, and then stops the mouthpiece with
his tongue. The end of the tube nearest to him now
contains air which may be regarded as coming from the
alveoh. On opening the taps this flows into the receiver,
from which it can be analysed. The experiment is now
repeated, but with this difference, that the forcible expira-
tion into the tube takes place not after an inspiration,
but after a normal expiration. The mean between the
two samples is taken as the composition of the alveolar
air. The normal oxygen pressure is found to be about
100 mm. of mercury.

Krogh and Lindhard's Method. — The subject breathes

106 RESPIRATION

normally through a tube provided with valves so arranged
that the exhaled and inhaled air are kept separate. At
the termination of each expiration the last fraction of air
expired is collected in a side-tube. This method is said
to give better results than Haldane's when strenuous
exercise is being performed.

The Tension of Oxygen in the Blood

This can be determined in animals with a high degree
of accuracy by means of Krogh's Microtonometer.

This is shown in Fig. 23.

The blood enters from the proximal end of the cut artery
by the inner tube 1 (Fig. 23 a) and returns to the circulation
by the tube 7. The stream issuing from 1 plays upon a
small gas bubble 2 in such a manner as to agitate it violently.
From time to time the bubble is drawn up into the graduated
capillary tube by means of the screw tap 4 and its length
measured. When this no longer changes, it shows that
blood and bubble are in equihbrium. The bubble is now
analysed in the apparatus by exposure in turn to caustic
soda and pyrogalHc acid.

The advantages of this apparatus he in the relatively
slight disturbance of the blood, in the small amount of air
used — a bubble of only 2 mm. diameter^and in the rela-
tively large surface exposed to the blood. Its disadvan-
tages are that it is inapphcable to man, and that even in
animals it cannot be used to determine the effect of exercise
and other natural conditions. A further disadvantage is
that in animals one cannot determine the composition of
the alveolar air. Krogh had to be content with taking a
sample of air from the bifurcation of the trachea.

Experiments conducted with this apparatus, so far as
they go, show that the pressure of oxygen is always higher
in the lungs than in the arterial blood — thus supporting
the diffusion theory.

OXYGEN -TENSION

107

The Carbon Monoxide Method

Some years ago Haldane invented the following method
for finding the tension of oxygen in human blood. The

r^^-"^<

Fig. 23. — Krogh's microtonometer. A, lower part showing the gas
bubble; B, upper part showing the fine tube into which the
bubble is drawn for measurement.

subject breathes air containing a known amount of carbon
monoxide. After a short time equihbrium is attained
between the CO in the blood and the CO in the alveoU.

108 RESPIRATION

Some blood is then withdrawn and a sample of alveolar
air taken. To this alveolar air is exposed in vitro blood
taken from the subject before the experiment began.
The amount of CO in combination with hgemoglobin in each
case is estimated colorimetrically. There are therefore
two samples of blood, both in equihbrium with CO and
oxygen, but with this difference, that in one case the
blood and alveoh were separated by the lung epithelium,
in the other they were in direct contact. In both cases
the CO and oxygen may be regarded as competing for
the haemoglobin. An imaginary example will make this
clear.

Supposing the partition of the two gases in the blood in
vivo were —

HbO.2 80 per cent.

HbCO 20 „ „
and in vitro

HbOg 75 per cent.

HbCO 25 „ „

Such a result would show that the intervention of the
pulmonary epithelium has caused more oxygen to enter
the blood than if no epithelium existed. In other words,
the epithehum has actively secreted oxygen into the
blood.

The results which Haldane obtained by this method
suggested that diffusion occurs at normal oxygen pressure
when the body is at rest, but secretion when the oxygen
is rarefied. But Hart ridge, using a modification of the same
method, found that the process could under all circum-
stances be explained by diffusion. This method therefore
failed to decide the question.

Barcroft's Experiment

Recently a determination of the alveolar air and of the
oxygen in the arterial blood at low oxygen pressures has
been made by Barcroft in an experiment performed upon

EXCRETION OF CARBONIC ACID 109

himself. Barcroft lived for six days in a chamber in which
the oxygen pressure was gradually reduced, the CO2
exhaled being absorbed. On the sixth day samples of
blood were taken from the radial artery during rest and
after a period of work on a bicycle ergometer. The results
show that at a reduced oxygen pressure corresponding to an
altitude of 18,000 feet, while work is being done, the arterial
blood is 834 per cent, saturated with oxygen, but when
the same blood was exposed in vitro to a sample of alveolar
air its oxygen content rose to 88*6 per cent. — a difierence
of 5-2 per cent. This corresponds to a difference of about
7*5 mm. between the pressure of oxygen in the alveolar air
and the tension of oxygen in the arterial blood. During
the exercise 750 c.c. of oxygen were used per minute.
In this experiment then the oxygen tension in the arterial
blood was lower than in the alveolar air — ^that is to say, the
passage of oxygen into the blood even under extreme
conditions could be explained by diffusion.

The Excretion of Carbonic Acid

The passage of carbonic acid out of the blood presents
no problem comparable with the entry of oxygen. The
pressure of COg in venous blood is always higher than in
the alveolar air, although the difference may sometimes
be very shght. But taking into account the rapidity of
diffusion of this gas, there is no difficulty in explaining
its exit from the blood by diffusion.

THE INTERCHANGE OF GASES BETWEEN BLOOD
AND THE TISSUES

Since there is no evidence of any storage of oxygen
within the cell, we may assume that the passage of oxygen
from the blood into the tissues is due to diffusion. In the
case of carbonic acid there is a tension of this gas within
the cell. We cannot estimate it directly, but we can arrive
at some idea of it from the tension of COg in the fluid

110 RESPIRATION

secretions, such as the lymph or urine. In these it may
amount to as much as 70 mm. In the tissues it must be
higher than this, since the greater part of the COg is
washed away by the blood and excreted in the lungs.
We may safely say, therefore, that the passage of COg out
of the tissues, hke the entry of oxygen, is due to diffusion.
We have seen that the dissociation of haemoglobin is
facilitated by rise in the hydrogen ion concentration and
by rise in temperature. When the cell becomes active the
increased tension of CO2 and the rise in temperature which
result affect the blood in such a manner as to make it
more easily part with its oxygen. In other words, the
chemical and thermal effects of increased consumption of
oxygen cause an increased supply of oxygen.

LUNG VENTILATION

The ventilation of the lungs is effected by co-ordinated
muscular movements which cause a rhythmic alteration
in the capacity of the thoracic cavity. To this alteration
the lungs adapt themselves owing to the elasticity of the
lung tissue and to the potential vacuum of the pleural
cavity.

The Muscular Mechanism

From a respiratory point of view the chest can be
divided into two parts — an upper part, conical in shape,
corresponding externally to the upper five ribs and inter-
nally to the upper lobe of the lung, and a lower part,
almost cyhndrical in shape, corresponding externally to
the lower ribs and internally to the lower lobe. The
changes in capacity which these two parts undergo differ
both in kind and in the manner in which they are produced.

In the lower part of the chest the principal muscle
involved is the diaphragm, which is aided in its action by
the abdominal and the lower intercostal and interchondral
muscles. The diaphragm is attached posteriorly to the
spine by the crura and arcuate hgaments, and anteriorly

RESPIRATORY MOVEMENTS 111

and laterally to the sternum and the lower ribs respectively.
In its concavity he the hver and stomach. In any down-
ward movement of the diaphragm the abdominal viscera
are depressed, and being incompressible must be accom-
modated by protrusion of the abdomen. The diaphragm
and abdominal muscles are therefore antagonistic. If the
abdominal wall is fixed, then the dome of the diaphragm
cannot be depressed. Under such circumstances contrac-
tion of the diaphragm will have the effect of drawing the
anterior and lateral attachment of the muscle up towards
the dome. The attachment of the diaphragm to the lower
costal cartilages draws the antero-lateral part of the lower
ribs outwards and forwards, the subcostal angle being
increased. Thus there is brought about an increase in the
capacity of this part of the chest. Since the abdominal
contents offer a certain resistance to the descent of the
diaphragm, contraction of this muscle results not merely
in a depression of its dome, but also in an elevation of
its circumferential attachment. That is to say that in
inspiration neither the dome nor the circumference is
fixed, but the former moves downwards and the latter
upwards.

Movement of the ribs is due mainly to the action of the
intercostal and interchondral muscles, but owing to the
variation in the size, shape and disposition of the different
ribs no general rule can be laid down as to the manner in
which these muscles act.

In the lower or cyhndrical part of the chest the external
intercostals, running as they do downwards and forwards,
reduce the obhquity of the ribs and in this way assist
inspiration. The internal intercostals, on the other hand,
since they are directed downwards and backwards, cause
expiration by increasing the obhquity of the ribs. This
will be clear from the accompanying figures. A and B
represent spine and sternum respectively, C and D two
ribs. In the upper figure xy represents an external inter-
costal muscle. Imagine the four corners of the parallelo-

112

RESPIRATION

gram to be hinged. When xy contracts it must cause the
ribs to^move upwards in the direction shown, since such

Ftg. 24.^ — ^Action of the intercostal muscles.

movement will cause the ends of the muscle to approximate.
The area of the parallelogram will be increased.

EXPANSION OF THE LUNG 113

In the lower figure, rs represents an internal intercostal
muscle. When this contracts the ribs are depressed, the
area of the parallelogram becoming diminished.

But in the upper conical part of the chest the above
considerations do not apply, for the costal movement con-
sists during inspiration in a closing up of the upper six
ribs towards the first, which is fixed. This is brought
about by simultaneous contraction of the external and
internal intercostals. As each rib is an arc of a wider
circle than the one above it, this movement causes an
increase in the capacity of this part of the chest.

The capacity of the chest is further increased in inspiration
by extension of the spine.

Expiration is due not to a passive recoil, but to a co-
ordinated muscular movement the reverse of that which
causes inspiration.

Expansion of the Lung

The movement of the lung takes place fro7n the apex
downwards, forwards and outwards. In this movement
the root of the lung participates. Indeed it is only owing
to this movement of the root that any expansion can occur
in that part of the lung which lies between the root and the
posterior wall of the thorax.

During expansion and retraction the posterior part of
the apex remains practically stationary. From the com-
parative disuse of this part of the lung arises its great
hability to tuberculous infection.

The degree of expansion increases from the apex where
it is shght, to the base where it is considerable.

In the upper conical part of the chest there is no relative
movement between the chest wall and the lungs, but in
the lower part the lungs glide up and down beneath the ribs.

The whole of the lung tissue does not expand equally.

The root and the tissues in its neighbourhood expand least,

whilst the greatest expansion occurs in the infundibula

into which the alveoh open. The amount of air breathed

114

RESPIRATION

in and out at each respiratory excursion being smaller than
the total capacity of the lungs, a complete interchange
between the atmosphere and the lungs does not take
place at each respiration. The result of this is that the
temperature of the entering air is raised by that of the
outgoing air, so that the former is almost at body tempera-
ture by the time it reaches the alveoli.

The walls of the bronchi are held open by the pull upon
them of the elastic lung tissue, in antagonism to which
are the constrictor muscles of the bronchi, which tend to
keep the passages shut. The bronchial muscles are under
the control of the vagus, which exerts a constant tonic
influence over them. On stimulation of the peripheral
end of the vagus these muscles are contracted.

During inspiration the passages are dilated by the
increased pull of the lung tissue, and during expiration
slightly constricted. In asthma the bronchial muscles
undergo spasmodic contractions. The patient therefore
makes violent inspiratory efforts to keep the tubes open.

The Exchange of Gases between the Lungs and the

Atmosphere

The composition of inspired air, expired air and alveolar
air is here shown, excluding water vapour, w^th which
expired and alveolar air are saturated.

Inspired Air.

Expired Air.

Alveolar Air.

Oxygen ....
Nitrogen and allied elements
\j\J2 • • . • .

20-96

79-00

004

16-4

79-5
41

150

79-0

6-0

The following are the volume changes induced —
The volume breathed in normal inspiration = 300-
500 c.c. {Tidal air).

The volume which can be inhaled by an effort, super-

REGULATION OF RESPIRATION 115

imposed upon a normal inspiration {Complemental air) =
1500-2000 c.c.

The vokinie which can be exhaled by an effort after a
normal expiration {Sitpple^nenfal air) = 1500-2000 c.c.

The total change of capacity, full inspiration and full
expiration {Vital capacity) = 3300-4500 c.c.

Even after the greatest expiratory effort, the residual
air remains, measuring 1500-2000 c.c.

THE REGULATION OF RESPIRATION

For the proper ventilation of the lungs two things are
necessary, an orderly alternation of inspiration and expira-
tion and an adaptation either of the extent or the rapidity
of the movement to the needs of the body. We therefore
have to consider how the rhythm is maintained and how
it undergoes variation.

Respiration is dependent ultimately upon the integrity
of a centre situated in the floor of the fourth ventricle
near the nuclei of the vagus. When this centre is destroyed
respiration immediately ceases. But respiration is a co-
ordinated muscular act, and must therefore be due to the
stimulation of motor centres in the cord — ^the centre for
the phrenic nerve in the third, fourth and fifth cervical
segments, those for the intercostal nerves in the thoracic
region. The co-ordinated action of these centres is due
to stimuli which they receive from the medulla, since the
intercostal movements are abolished' after section of the
cord in the lower part of the cervical region, and both
intercostal and diaphragmatic movements are paralysed
after section through the upper part of the cervical region.
Section of the brain-stem above the medulla is without
effect upon the respiratory movements.

Respiration is under the control of the will only to a
Umited extent. We may cease breathing for a time or
we may breathe excessively, but in either case the effort is
short-hved and is followed by a compensatory effect,

116 JRESPIRATION

hyperpnoea or apnoea, as the case may be. Voluntary efiort,
therefore, though it may affect the respiratory movements
temporarily, does not affect the ultimate gaseous exchange.
The increased respiratory movements which accompany
a great need for oxygen, as in exercise, are brought about
involuntarily.

In 1905 Haldane and Priestley showed conclusively that
the activity of the respiratory centre is influenced by the
composition of the blood supplying it. Their results may
be thus summarised —

1. The partial pressure of COg in the alveolar air is
constant for each individual when in the resting state.
It is about 40 mm.

2. The tension of COg in the blood leaving the lung is
equal to its pressure in the ah^eolar air.

3. Any change induced in the pressure of COg in the
alveoh is transmitted to the arterial blood.

4. "When COg is injected into the blood supplying the
medulla respiration is increased.

5. A very shght rise of COg alveolar pressure causes
increased depth and rate of respiration.

The chain of evidence is therefore complete that the extent
of pulmonary ventilation depends upon the tension of COg
in the arterial blood.

Carbonic acid, however, is not the only substance which
affects the medulla. Any acid has a similar effect. The
responsible factor is now known to be the hydrogen ion
concentration of the blood.

The question now arises whether the tension of oxygen
has also an effect upon the respiratory centre. Haldane
and Priestley found that the tension of oxygen had to be
very considerably diminished before any respiratory dis-
turbance was produced. When increased respiration does
occur under these circumstances, it is attributed not to
deficiency of oxygen directly, but to accumulation of acids
in the centres themselves owing to incomplete oxidation.

The comparative indifference of the respiratory centre

REGULATION OF RESPIRATION 117

to the tension of oxygen leads to the phenomenon known as
Cheyne-Stokes respiration, in which periods of breath-
ing alternate with periods of respiratory rest. It occurs
after the period of apnoea which follows excessive breathing.
It is explained in this way. Owing to the excessive breath-
ing which has just occurred CO.^ is to a great extent washed
out of the body. The centre is then stimulated to activity
by oxygen- want. By the respiratory movement thus
caused the need for oxygen *s immediately satisfied. The
tension of CO2, being meanwhile still below normal, respira-
tion ceases. This process is repeated until the tension
of CO2 regains its normal level and resumes the function of
regulating the centre.

Cheyne-Stokes respiration is also found in certain toxic
states. It is then attributed to the influence of the toxin
upon the centre.

But the chemical constitution of the blood is not the only
factor influencing lung ventilation. It is a matter of
everyday knowledge that the orderly sequence of the
respiratory movements may be interrupted by reflex
stimulation. The stimulus may be emotional or it may be
sensory, in the latter case originating from the surface
of the body or from the respiratory passages. Since the
most potent stimuli arise from the respiratory passages
themselves, it would be natural to seek an effect upon
respiration from the pulmonary nerve endings in the vagus.

\Vhat happens when the vagi are cut ? On section of
one vagus, respiration becomes slower and deeper; on
section of both it becomes slower and deeper still, but the
alternation of movements is undisturbed. But another
change also occurs ; for increased CO2 tension now increases
the depth of respiration still further, but the rate of
respiration is unaltered. This would seem to show that
one function of the vagus is to regulate the rate and to
limit the extent of the respiratory excursion. What is
the cause of the stimulation of the vagus ? The answer to
this is given by Head's experiment, in which it was shown

118

RESPIRATION

that artificial inflation of the lung (Positive Ventilation)
caused cessation of breathing; standstill occvirring in the
expiratory position. Suction of air out of the lung, on

Positive ventilation.

Diuplirai-'ni.
I Seconds.
Fig. 25. — -Positive ventilation.

Ainspiration.
4' Expiration.

the other hand (Negative Ventilation), is followed by
cessation, but in the opposite phase; standstill now
occurring in inspiration. These effects were found to be
conditional upon the integrity of the vagi.

Negative ventilation.

at) 01

Diaphragm,

Alnspir;
^-Expiratioi

SeconUtJ.

Fig. 26. — -Necrative ventilation.

The results show that on distension of the lung an impulse
travels up the vagus which stimulates the medulla to
produce relaxation of the diaphragm, while relaxation of
the lung tissue, on the other hand, causes contraction of
the diaphragm.

Head then proceeded to stimulate the vagus. Using
the rabbit, where the nerve is free from depressor fibres,

REGULATION OF RESPIRATION 119

he found that, on stimulating with a strong current,
expiratory standstill was induced, but with a weak current
inspiratory standstill occurred. He therefore concluded
that the pulmonary branches of the vagus conveyed two
sets of fibres, differing both in their sensitivity to stimuH
and in their central effects.

Is the activity of the vagus thus experimentally pro-
duced a measure of what occurs normally ? The only way
in which this question can be answered is by testing the
vagus for current of action. This is done by placing two
non-polarisable electrodes on the trunk of the nerve and
connecting them with the string galvanometer. The
current of action waxes with inspiration and wanes with
expiration.

We have already seen that respiration is practically
unaffected by separation of the respiratory centre from
the higher parts of the brain. But when this operation
is combined with section of the va^ respiration ceases.
Evidently the centre is affected by nervous impulses from
two sources, normally from the vagus and vicariously from
the higher centres.

We may therefore summarise the mechanism of the
regulation of respiration as follows :■ — The respiratory centre
is played upon by afferent impulses of two kinds, the
chemical impulse of the hydrogen ion concentration of the
blood and nervous impulses arising in the pulmonary nerve
endings. Of these the latter have the effect of hmiting the
respiratory excursion, while the former is responsible for
the adaptation of lung ventilation to the needs of the body.
There is evidence, too, that impulses from the higher centres
increase the susceptibility of the respiratory centre to
the H. ion concentration of the blood. Whether the
alternation of movement is due to rhythmic variation in
the sensitiveness of one centre or to the alternating activity
of two centres, one inspiratory the other expiratory, we
do not know.

CHAPTER VIII
DIGESTION

Introduction

Food, in the form in which it is taken in by the mouth,
is incapable of being of service to the body : first, because
it is usually insoluble ; secondly, because even if soluble it
is not in such a form as to be absorbed by the gut. To
reduce the food into small molecules and to absorb these
into the blood-streajn are the functions of the digestive
system.

In the process of digestion three physiological mechanisms
may be said to be involved : the secretion of digestive
juices, the action of enzymes upon the food, and the
movements of the alimentary canal. As regards enzyme
action we need only say here that this is invariably of the
nature of hydrolysis, and that in the changes thus pro-
duced in the food-molecules there is no loss of potential
energy. As regards the movements of the gut, these
comprise an orderly sequence of co-ordinated movements.
They serve to mix the food with the digestive juices, to
propel the digesting mass along the canal, to expose it to
the absorbing surface, and finally to evacuate such remnants
as are not absorbed. As regards the secretion of digestive
juices, some general remarks are necessary at this stage.

The Nature of Secretion

The formation of a secretion by a gland is associated
with certain histological changes. When the fresh gland

120

SECRETION 121

is examined after a period of rest the cells are found to be
filled with granules. After secretion these granules are
much reduced in size and in number, those which are
present occupying only the part of the cell nearest the
lumen. The cell itself, instead of being distended as in
the resting phase, has undergone shrinkage. Secretion,
then, consists histologically of a breaking up of granules.
Sometimes these are themselves discharged from the
gland, but this is not usually the case, the secretion being
generally quite clear. The granules are regarded by some
authorities as constituting a store-house for the secretion,
by others as constituting not only the store-house but also
the seat of formation.

The act of secretion is accompanied by dilatation of
blood-vessels. Vaso -dilatation, however, is not the cause
of secretion, for at the onset of secretion there is usually
a transient diminution in the volume of the gland. More-
over, vaso-dilatation may be unaccompanied by secretion, -
as when the latter process is abohshed by drugs such as
atropine. The dilatation of blood-vessels seems to be due
to two factors : a direct effect of the stimulating agent,
be it nerve or hormone, upon the blood-vessels, and an
indirect effect due to the chemical products of secretory
activity.

In some cases, as in the salivary glands, secretion is
brought about by a reflex nervous action, in others, as
in the pancreas, by a hormone or chemical substance
elaborated elsewhere.

In the process of secretion there is, besides the formation
in the gland of the specific constituent of the fluid secreted,
a constant passage of water and other substances, from
the blood to the cell and from the cell to the lumen. This
cannot be due to filtration, for the secretion pressure in
the duct may be greater than the blood-pressure within
the gland. Attempts have been made to explain it by
osmosis. It is held that the first change in the cell is a
breakdown of molecules. This causes a rise in osmotic

122 DIGESTION

pressure, which in turn causes water to pass into tiie cell
from the blood. It is ditticult to understand how continued
secretion can thus be explained. Physical factors may play
a part in secretion, but they cannot cause it. The best
proof of this is that secretion is always accompanied by an
increase in the consumption of oxygen and in the production
of CO2. In the act of secretion, therefore, work is being
done by the cells of the gland.

The sahvary glands are innervated by branches from the
cranial nerves and by the sympathetic. In the case of
the submaxillary gland stimulation of the chorda tympaui
causes a secretion accompanied by vaso-dilatation, stimu-
lation of the sympathetic, secretion accompanied by vaso-
constriction. In some animals the chorda secretion is
thin and copious, while the sympathetic secretion is thick
and scanty. The question therefore arises whether this
difference in the character and amount of the secretion is
due to differences in the nerve fibres or to the accompanying
differences in the state of the blood-vessels. It was believed
by Heidenhain that each nerve contains two kinds of
fibres, " trophic " fibres which cause secretion of water
and salts, and " secretory " fibres which cause secretion
of organic substances; in the chorda trophic fibres, and
in the sympathetic secretory fibres preponderate. The
following facts seem to support' this view. The presence
of meat in the mouth causes a secretion much richer in
organic constituents than dOes the presence of acid. The
difference is just as marked after removal of the superior
cervical gangha, indicating that different nerve-fibres in the
chorda tympani are called into play.

Changes occurring in the Mouth

We habitually speak of the sight and smell and even of
the idea of food making the mouth water. To what extent
is this idea justified? For the full answer to this question
we are indebted to the researches of the Kussian physio-
logist, Pavlov. Pavlov diverted the duct of the dog's sub-

SALIVA 123

maxillary gland on to the outer surface of the cheek in
such a manner that the secretion could be collected. He
observed that, provided the dog desired food, sensations
arising from the presentation to it of food evoked a secre-
tion, even though the food did not come into contact with
the mouth. Pavlov further showed that stimuh which
normally were not connected with salivary activity could,
by prolonged association, become effective. If, for instance,
the exhibition of food was repeatedly accompanied by the
ringing of a bell, after a time ringing the bell alone caused
secretion. We can therefore readily understand how in
human beings, in whom association of ideas is so much
greater than it is in dogs, the range of stimuli may be
very wide. Not merely the sight and smell of food, but
the sounds and other sensations which we associate with
the immediate prospect of gratification will effectively
prepare the mouth for the reception of food.

The first cause of sahvary secretion, then, is the com-
bination of two stimuh : one, arising from within, the
need for food ; the other, arising from without, the sensation
associated with the prospect of gratification.

But the food having entered the mouth, a fresh path for
sensation becomes possible in the nerves of taste. These,
too, as has been shown by Pavlov, cause reflex secretion
of sahva.

In the sahvary glands there exist two kinds of cells,
differing in their histological appearances and in the
secretion which they produce. There are the mucous
cells, which secrete a viscid fluid containing mucin, and
the serous cells, which secrete an albuminous fluid con-
taining the enzyme ptyahn. The mixed secretion is
alkaline in reaction.

The character of the saliva varies with the nature of the
sensory stimulus from the mouth. Dry sand, for instance,
provokes a profuse thin, meat a scanty thick secretion.
It is said, too, that the amount of ptyahn increases with
the amount of carbohydrate eaten.

124 DIGESTION

The changes which the food undergoes in the mouth
consist in a grinding up into fragments of about 2 mm.
These, when impregnated and lubricated by the sahva,
are ready for transference to the stomach.

The function of ptyaUn is to convert starch into maltose,
the action of the ferment occurring almost entirely in the
stomach.

Deglutition

Deglutition is a complex process, or rather succession
of processes initiated by a muscular movement under
control of the will. The food is collected in a bolus on
the dorsum of the tongue. It has to be transferred to the
oesophagus, avoiding the nasopharynx and the larynx.
Return to the front part of the mouth is prevented by the
apposition of the upper surface of the tongue to the hard
palate. A quick contraction of the mylohyoid and hyo-
glossus muscles draws the tongue upwards and backwards.
At the same time the palatal muscles close the posterior
nares by drawing the soft palate back to the posterior wall
of the pharynx. The elevation of the hyoid bone, which
occurs simultaneously, raises the larynx, the upper opening
of which is closed by the descent of the epiglottis. By
this co-ordinated movement the bolus is pushed down past
the soft palate and posterior wall of the pharynx into the
upper end of the oesophagus, which is stretched open to
receive it. Coincidently with this there is an inhibition
of respiration. When the bolus enters the oesophagus it
passes out of voluntary control, and normally out of
consciousness.

The way in which food passes along the oesophagus
depends upon its consistency. The ordinary bolus is
carried down by a wave of contraction, which is initiated
refiexly by the contact of the food with the pharyngeal
wall. This wave becomes slower as it courses downwards.
In the case of a thin fluid the propulsive force of the volun-
tary part of deglutition is sufficient to drive it mth great

THE CARDIAC SPHINCTER 125

rapidity down to the lower end of the oesophagus, the
completion of its journey into the stomach being performed
more slowly. The fluid thus reaches the stomach before
the wave of contraction which it has initiated while in the
pharynx. This wave follows in the wake of the fluid,
and serves to propel any remnants into the stomach.

The oesophageal contraction is dependent upon the
discharge from the medulla of a succession of impulses
which travel down the vagi. This is shown by the fact
that the wave is interrupted by section of these nerves,
but not by section of the oesophagus itself. But this wave
of vagal origin is not the only form of contraction met
with in the oesophagus. The tube is divided into two parts
by differences in its muscular layer. There is an upper
region, where the muscle is striated, and a lower region,
where it is unstriated. When some days have elapsed
after section of the vagi, the unstriated part develops
the power of responding to pressure of food within it by
undergoing peristaltic waves. These waves, which are
quite independent of any voluntary act, eventually succeed
in conveying the food from the lower end of the oesophagus
into the stomach. The part played by these waves under
normal conditions is described below.

The Cardiac Sphincter

Normally the cardiac sphincter is closed, but it opens
on the approach of an oesophageal wave. When closed
the tonicity of the muscle is not great, for it can easily
be opened passively. It also opens on shght increase in
the intragastric pressure. The part which the vagus plays in
controlling the cardiac sj)hincter is complex, for on stimula-
tion this nerve causes increased tonus followed by relaxation.

But although the sphincter is normally closed it opens
rhythmically, and allows regurgitation of food into the
lower part of the oesophagus. From here the food is
returned to the stomach by a peristaltic wave originating
in the unstriated part of the oesophagus. This wave is

126 DIGESTION

independent of the act of swallowing and independent of
the vagus.

Two conditions in the stomach notably increase the
tonus of the cardiac orifice and inhibit its rhythmic relaxa-
tion— mechanical irritation and the presence of free acid
in the cardiac sac,

THE STOMACH

The functions of the stomach are principally to act
as a reservoir from which food can be discharged into the
intestine at a regular speed, and to begin the breakdown
of foodstuff and, in particular, of proteins. It possesses
but a shght absorptive power.

Form of the Stomach

The stomach consists essentially of two portions, the
cardiac and the pyloric, separated by the incisura angularis.
The cardiac portion is further divided into two parts, the
fundus or part above the level of the cardiac orifice, and the
body or part below the fundus. Similarly, the pyloric
part is subdivided into the pyloric vestibule — the main
proximal part — and the pyloric canal, which consists of
the distal 3 cm. and terminates at the pyloric sphincter.

The cardiac and the pyloric part of the stomach differ
in their shape, in the structure of the glands which hne
them, in the character of the fluid which they secrete, and
in the movements which they undergo.

All the gastric glands secrete pepsin, the principal
gastric enzyme, but only those of the cardiac part secrete
free hydrochloric acid, which is beheved to be formed in
the oxyntic cells.

The muscles of the stomach-wall are disposed in three
layers — -

1, An outermost longitudinal layer continuous with the
corresponding layer in the oesophagus, but separated by a
fibrous band from the longitudinal layer of the duodenum,

2. A middle circular layer forming a complete wall. It

THE STOMACH

127

is much thickened at the pylorus to form the pyloric
sphincter, and shghtly thickened at the cardiac end to
form the cardiac sphincter, and opposite the incisura
angularis to form the " transverse band."

Fig. 27. — ^Position of human stomach after a bismuth meal (Hertz,
from Starling's Principles of Physiology). 0, asophagus ; F, fundus ;
I. A, incisura angularis.

3. An innermost obUque layer forming two bands
passing from the cardia, one along the anterior, the other
along the posterior surface. Near the pylorus they termi-
nate in the circular layer.

The Secretion of Gastric Juice

As in the case of the sahvary glands, our knowledge of

128 DIGESTION

this process was put on a scientific basis by the experi-
ments of Pavlov. Pavlov's procedure was as follows.
He first cut the oesophagus in the neck, and brought the
two ends to the surface, to which he sutured them. When
he gave the dog food it merely fell out of the upper opening.
When he wished to feed the dog he inserted food into the
lower opening. He then made a permanent opening or
fistula into the stomach, and so sutured the mucous mem-
brane that the part of the stomach cavity which opened
by the fistula did not communicate with the main stomach,
but at the same time it preserved its normal nerve-supply.
In this way there was formed a small sac opening to the
exterior, the secretion of which was a measure of the
secretion in the whole organ. This sac did not become
contaminated with food. By this means Pavlov was able
to investigate the changes which occurred in the stomach
when food was shown to the animal, but not masti-
cated ; when it was masticated, but did not reach the
stomach ; when it was inserted into the stomach without
the animal's knowledge; and when it was masticated and
inserted into the stomach.

The results may be briefly stated. The same stimuli
which provoke secretion of the salivary glands — sight,
smell and taste of food — stimulate production of gastric
juice. When the vagi are cut this effect is abolished,
showing that these nerves form the efferent path of the
reflex. Gastric secretion, therefore, begins before food has
entered the stomach. It is important to notice that
psychical secretion only occurs when the stimulus is
associated with a pleasurable sensation. Mastication of
inedible substances, hke small stones, is ineffective.

The secretion of gastric juice continues long after the
food has been taken. This is no mere prolongation of the
reflex effect, for it occurs independently of the vagi when
these nerves are cut after the preliminary secretion has
begun. Nor is it due to the mechaniQal irritation of the
food against the stomach- wall. It is due to the action of

GASTRIC JUICE 129

the HCl and of the products of protein breakdown upon
the pyloric mucosa. The substance thus formed is absorbed
into the blood-stream, and, being conveyed back to the
stomach by the arterial blood, stimulates the glands to
continued activity.

In the process of gastric secretion there are therefore
two factors. The first is a nervous reflex which starts the
secretion ; the second is the stimulus of a chemical substance
or hormone which continues it. Thus the hormone which
is the cause of the continuation of secretion is produced
as the result of the initial secretion. This hormone has
been called gastrin or gastric secretin.

The gastric juice produced by the chemical method
differs from the juice of vagal origin in that it is adapted
to the kind of food present in the stomach. It is most
abundant with meat, while the presence of fats may alto-
gether inhibit its formation.

Gastric Juice

Gastric juice has the following active constituents — ■

1. Pepsin. — This is formed in the gastric glands in an
inactive form — pepsinogen, which is converted into pepsin
on contact with hydrochloric acid. Pepsin requires free
HCl, not only for its formation, but also for its digestive
action ; it is rapidly killed by alkahes. It causes an in-
complete hydrolysis of protein, the end-products formed
normally being proteoses and peptones.

2. Rennin. — This ferment, by converting the soluble
caseinogen to insoluble casein, causes the coagulation of
milk. Rennin is believed by some to be identical with
pepsin.

3. Gastric Lijjase. — Present in small quantities, it effects
hydrolysis of finely divided fat.

4. Hydrochloric Acid. — -This is secreted by the oxyntic
cells of the fundus. Its functions will be described later.

130 DIGESTION

Movements of the Stomach

As food enters it, the stomach expands in such a way
that the intragastric ])ressure is not raised. That is to say,
the stomach does not behave as though its walls were of
elastic. The pressure upon its contents is the same what-
ever the degree of dilatation. How this remarkable effect
is brought about is not known. The increase in circumfer-
ence is more than can be accounted for by an elongation
of the muscle fibres. It is therefore beheved that these
shde over one another in some way, the layers becoming
fewer.

The stomach fills up from the pylorus to the cardia. A
certain amount of air taken in at each deglutition is always
present in the fundus.

The stomach is divided physiologically into two parts :
the distal part, which undergoes peristaltic contraction, and
the proximal part or cardiac sac, which has no rhythmic
movement but which exerts a constant tonic contraction
upon its contents. Owing to the quiescence of the cardiac
sac and to the mucinous nature of the food, some con-
siderable time elapses before the food is permeated by the
gastric juice. During this period, which may last as long
as an hour, the hydrolysis of starch by jityalin continues
undisturbed, being stopped only when the ferment is
killed by the HCl.

Soon after the intake of food peristaltic waves appear
at the transverse band, travelling towards the pylorus,
about three waves occurring per minute. The seat of origin
of the waves shifts gradually backwards till it reaches the
middle of the body of the stomach. Each peristaltic wave
kneads deeper into the stomach as it proceeds, and as it
approaches the pylorus the longitudinal muscles contract
with the circular. The sudden increase in pressure thus
caused and the narrowness of the advancing ring causes
the food to be driven partly through the pylorus if the
sphincter allows, and partly backwards through the ring

THE PYLORIC SPHINCTER 131

of contraction. The effect of a succession of waves of this
sort upon the gastric contents was shown by Cannon,
who administered to an animal small capsules containing
a large quantity of bismuth in a meal containing a small
amount of bismuth. The capsules thus appeared by the
X-rays as dark shadows in a faint shadow. At each wave
the capsules were conveyed a short distance, until they
slipped back through the advancing ring. They thus
arrived by a to and fro movement at the pyloric vestibule.
Finally, a wave carried them up to the pylorus, from
which they were returned in the back-wash to the point
from which they first started.

It is thus evident that gastric peristalsis has the effect
of mixing very thoroughly the food and the gastric juice,
and incidentally of exposing the mixture to the pyloric
wall, thus favouring the formation of the gastric hormone
already described. The cardiac sac meanwhile, by exert-
ing a constant pressure upon its contents, keeps the gastric
mill supphed.

As the stomach empties, diminution in its size affects
first the middle of the body, which becomes tubular in
shape. The part above this then diminishes until it is
almost emptied. The pyloric part is the last to be
evacuated.

The vigour of the gastric movement varies directly with
the amount of HCl present, this acid, in fact, providing
the stimulus to peristalsis.

As to the cause of the gastric movements, it is not
certain how far they are myogenic and how far they are
to be ascribed to Auerbach's plexus.

The Pyloric Sphincter

The pylorus remains firmly contracted during the whole
of digestion except at regularly recurring intervals of
momentary duration, during which it opens and allows a
small part of the gastric contents to be squirted through.
When this has happened it immediately closes again.

.132 DIGESTION

Many experiments prove beyond doubt that for the open-
ing of the sphincter the presence of free acid on its gastric
side is essential. It is equally proved that its closure is
due to the presence of the same acid on its duodenal side —
a local reflex mediated through Auerbach's plexus. But
the action of the acid on the duodenal side is much the
stronger, so much so that the presence of a very small
amount of acid on this side is sufficient to counterbalance
the antagonistic action of the large amount of acid in the
stomach. The pylorus therefore opens only after the
acid in the duodenum has been neutrahsed by the alkah
secreted by intestine, pancreas and liver.

But the rate of emptying of the stomach varies with the
nature of the food. It is shghtly more rapid with carbo-
hydrates than with proteins, and much more rapid with
these than with fats. This difference has been shown by
Cannon to be due to the effect of these foodstuffs upon the
amount of free acid formed. Fats, as we have seen, inhibit
the secretion of gastric juice. The shght difference between
protein and carbohydrate is attributed to the combination
of part of the HCl with the former, the effective acidity
being thus reduced.

Absorption from the Stomach

The only substances known to be absorbed, and these
only in small amounts, are peptones, sugars and alcohol.
There is no absorption of water.

We may now summarise the digestive changes that
occur in the stomach.

1. The digestion of starch continues in the fundus until
the ptyahn is destroyed by HCl.

2. Proteins are hydrolysed incompletely to proteoses
and peptones.

3. Milk is clotted.

VOMITING 133

4. Fats are liberated by the proteolytic digestion of
their fibrous envelopes, and are to some extent hydrolysed
by the gastric lipase.

5. Cane sugar is inverted to dextrose and Isevulose.

6. In the early stage of digestion bacteria taken in with
food decompose carbohydrates with formation of lactic
acid.

7. These bacteria are destroyed by the HCl.

The Hydrochloric acid performs the following functions —

1. It activates pepsinogen and is necessary for the
proteolytic action of pepsin.

2. It inverts cane sugar.

3. It destroys bacteria.

4. It maintains the closure of the cardiac sphincter.

5. It stimulates the stomach to peristaltic contraction.

6. It governs the opening and closing of the pylorus.

7. As we shall see later, it is necessary for the activation
of the pancreas.

Vomiting

Vomiting is a reflex action induced by irritation of the
stomach or of certain other parts of the body, particularly
the ahmentary canal. It may also be excited by irritation
of the brain, as in tumours, or by emotions. It is usually
preceded by a free flow of saliva, which is swallowed.
Then come retching movements, which are really attempts
at inspiration with the glottis closed. These culminate
in the actual vomiting, which is a co-ordinated muscular
act. The stomach is compressed by the simultaneous
contraction of the diaphragm and the abdominal muscles.
At the same time its walls undergo contraction. The
gastric contents are thus driven out through the cardiac
orifice, which is dilated.

When vomiting is violent, antiperistalsis of the small
intestine may occur, driAdng the intestinal contents into
the stomach.

134 DIGESTION

THE SMALL INTESTINE

The small intestine is the seat of the greater part both
of digestion and of absorption. The digestive changes
are due to the action of juices derived from three sources,
the pancreas, the hver and the intestine itself.

THE PANCREAS

The pancreas consists mainly of tubular alveoh, which
are the seat of formation of the pancreatic juice. Separat-
ing the alveoh are the Islets of Langerhans, small masses
of polyhedral cells not drained by any duct and having a
more profuse blood supply than the alveoh. The Islets
are beheved to be concerned in carbohydrate metabohsm,
and to have no connection with the formation of the
external secretion.

The Pancreatic Juice

This, the most active of all digestive juices, contains
several ferments, of which the most important are the
following —

Trypsin. — When the pancreatic secretion is collected
from the duct without being allowed to come into contact
with the intestinal epithehum, it has practically no action
on proteins. But on addition of a small amount of intes-
tinal juice it rapidly develops a strong proteolytic activity.
From the fact that the degree of activity is independent
of the amount of intestinal juice added, the action of the
latter is concluded to be due to a ferment, to which the
name enterokinase is given. The proteolytic ferment of
the pancreas is therefore secreted in an inactive form —
trypsinogen, the activated ferment being called trypsin.
Trypsinogen on prolonged standing, even when kept
sterile, becomes slowly active — the process being hastened
by the addition of hme salts.

Trypsin, which acts only in alkaline solution, being, in
fact, killed by acid, continues the gastric digestion of

PANCREATIC JUICE 135

proteins. While capable, like pepsin, of acting upon the
native protein, trypsin differs from pepsin in that its
action is more complete, for within an hour of tryptic
digestion, amino-acids make their appearance. As the
result of the action of this ferment, therefore, superadded
to that of pepsin, proteins are converted into a mixture
of peptones, polypeptides and amino-acids.

Accompanying the proteolytic action of trypsin, and
probably due to the same ferment, there is a transient
clotting of milk.

It appears that trypsin is destroyed in an alkaline fluid
of the same degree of alkalinity as the contents of the
intestine, but that this destruction is prevented by the
products of its own activity. As these are removed by
absorption the ferment is killed.

Amylase. — This enzyme resembles ptyahn in converting
starch through the dextrin stage to maltose.

Lipase. — This ferment in the presence of alkaUes converts
fats into glycerine and soaps. It is indeed the principal
hpolytic ferment in the body. Since its action is materially
influenced by the bile, we shall dicuss it more fully later on.

Maltase. — In neutral solutions pancreatic juice has some
power of converting maltose into dextrose. The degree to
which this occurs in the body will therefore depend upon
the extent to which the juice is neutrahsed by the acid
contents of the stomach.

The Secretion of Pancreatic Juice

Although the pancreas receives fibres, both from the
vagus and the sympathetic, the amount of secretion which
can be obtained by stimulation of either of these nerves
is small and uncertain. Shght secretion begins within two
minutes of the taking of food — evidently a nervous mechan-
ism. But the onset of a full secretion coincides with the
first appearance of food in the duodenum. It was shown
in Pavlov's laboratory that the actual stimulus was the
presence of HCl in that part of the gut, and that the effect

136 DIGESTION

was produced even when the pancreatic nerves were cut.
Bayhss and Starhng showed that it occurred when not
only the pancreas but also the duodenum was separated
from the central nervous system. The mechanism, there-
fore, is entirely chemical. Neither acid alone nor extract
of duodenal mucosa alone on injection into the blood is
effective, but when the extract is first treated with HCl
and the mixture injected a profuse secretion from the
pancreas takes place. The substance thus formed, which
differs from a ferment in being thermostable, Bayhss and
Starhng called secretin, and the substance in the duodenal
mucosa from which it is produced they called prosecretin.
Secretin is the best-known example of a hormone or chemical
substance which, made in one organ, travels in the blood-
stream to stimulate another organ to activity.

Since it is the acid of the gastric contents which causes
the formation of secretin, it would appear improbable that
the composition of the pancreatic juice changes in adapta-
tion to the diet, except in so far as the nature of the food
in the stomach alters the amount of acid secreted.

BILE

Bile, the secretion of the liver, is an alkahne, mucinous
fluid of which the principal constituents are bile-salts,
bile-pigments, cholesterol, lecithin and fats. It is con-
tinually being formed in the liver, from which it is secreted
into the intestine either directly or after a period of storage
in the gall-bladder. While in the gall-bladder it becomes
modified by the abstraction from it of water, and the
addition to it of mucin and nucleo-albumin. The signifi-
cance of the gall-bladder appears to be related to the fact
that bile is both a secretion and an excretion. As an excre-
tion it has to be removed from the liver as soon as formed,
owing to the toxic nature of the waste products which it
contains ; as a secretion it has to be passed into the intestine
at intervals owing to its digestive action.

The bile-salts, which are sodium glycocholate and sodium

BILE 137

taurocholate, exert a profound influence over the digestion
of fat by the pancreatic Upase. When the bile-duct is
occluded nearly all the fat fails to be absorbed and appears
in the faeces. Bile-salts possess the peculiar property of
lowering the surface tension between fat and water. They
therefore break up the fat into an emulsion, thus enormously
increasing the surface upon which the lipase can work.
Moreover, they dissolve the soaps which are formed by
the hpase, and in so doing prevent the premature cessation
of hpolysis which would otherwise occur owing to the
formation of an insoluble coat of soap around each particle
of fat. Further, there is reason to beheve that bile has the
direct effect of stimulating the pancreatic lipase.

The other constituents of the bile — bile-pigment, cho-
lesterol and lecithin — -are excretions, and play no part in
digestion. The bile-pigments are bilirubin and biliverdin.
They are partly excreted in the faeces as stercobilin, partly
reabsorbed and excreted by the kidney as urobihn. Cho-
lesterol and lecithin are products of metabohsm of all tissues.
In dissolving them the bile -salts perform yet another
function.

The bile-salts are largely reabsorbed in the lower part
of the small intestine and are returned to the hver.

The Antiseptic Action of pile

Bile being a most perfect medium for growing intestinal
bacteria, it is obviously the very reverse of an antiseptic,
yet its absence from the intestine, as when the bile-ducts
are obstructed, leads to increased bacterial activity. While
it does not directly prevent the growth of bacteria, it
reduces the quantity of protein pabulum on which they
feed. This is due to its action in assisting in the saponifi-
cation of fats, for the meat-fibres which are commonly
enveloped in fat are thereby exposed to the action of the
proteolytic enzymes. Further, bile by its presence increases
the fluidity of the intestinal contents, and thus favours
drainage.

138 DIGESTION

The Secretion of Bile

The bile which pours upon the digestive mass is produced
partly by contraction of the gall-bladder, partly by increased
secretion from the liver. The unstriated muscle of the
gall-bladder is innervated by the vagus and sympathetic.
It is called into play by a nervous reflex originating in the
duodenum. The exact path of the reflex is unknown.

Increased secretion of the liver has been shown by
BayHss and Starhng to be effected by the same mechanism
as secretion of the pancreas — that is, by secretin.

THE INTESTINAL JUICE

The succus entericus or intestinal juice is secreted from
the whole length of the small intestine, but in amount
diminishing from above downwards.

Alkahne in reaction, it contains the following ferments : —

1. Erepsin. — This ferment forms the third and last in
the series of proteolytic enzymes. Without action upon
proteins, it hydrolyses proteoses, peptones and polypeptides,
converting them into amino-acids. By its means protein
hydrolysis is completed,

2. Enterokinase. — This ferment has no digestive action
of its own, but, as we have seen, activates trypsinogen.

3. Maltase. — -Hydrolyses maltose to dextrose.

4. Lactase. — Present, at any rate, in the young; hydro-
lyses lactose to dextrose and galactose.

5. Invertase. — Hydrolyses cane sugar to dextrose and
Isevulose.

The Secretion of Intestinal Juice

Though some intestinal juice appears within a few
minutes of the taking of food, a profuse flow does not
occur until two hours after. The mechanism of secretion
is not definitely known. Attempts have been made to
assess the part played by the vagus and sympathetic in
isolated loops of intestine, but the results are largely

RHYTHMIC SEGMENTATION 139

vitiated by the drastic operative procedure involved. It
appears that secretin, as it influences the activity of the
liver and the pancreas, influences also that of the upper
part of the intestine. During the course of digestion there
may be produced other hormones which cause secretion
in the lower part of the gut.

A local secretion, produced through the agency of
Meissner's plexus, occurs whenever a sohd object touches
the intestinal mucosa.

Movements of the Small Intestine

The digesting mass does not occupy the whole length of

, (T) (X) CD CD O O (S
3.o<i)CD®CDCD(5i^

Fig. 28. — Segmentation movements (Cannon).

the intestine uniformly, but is grouped in segments of
varying length, the intervening sections of the gut being
practically empty. The food, after it has passed the pylorus,
lies quiescent in the duodenum, where, of course, it receives
the conjoint secretion of hver and pancreas. When by
later additions from the stomach a certain longth of gut is
thus occupied, this part of the intestine undergoes rhythmic
segmentation, the nature of which is best understood by
reference to the diagram. As seen by X-ray examination
after a bismuth meal, the continuous dark shadow suddenly
breaks up into a number of segments separated by clear
areas. After a few seconds, these segments as suddenly

140 DIGESTION

divide, adjacent halves of neighbouring segments uniting
together. The new segments again divide, with a return
to the first. These changes occur in man at the rate of
about seven per minute.

These movements favour both digestion and absorption ;
digestion by effecting a thorough mixture of the food with
the digestive juices, absorption by affording the maximum
exposure of the products of digestion to the intestinal
mucosa. Moreover, the alternate constriction and dilata-
tion of the intestinal blood-vessels facihtate the flow of
blood, while at each constriction of the vilh the material
which has been absorbed is pumped into the portal vein
and thoracic duct.

Accompanying rhythmic segmentation are the pendular
movements, which consist in a lateral swaying without
alteration in the size of the lumen.

The above movements, being unaffected when the local
nerve plexus is paralysed by means of nicotine, are myogenic
in origin.

Neither segmentation nor pendular movement causes
any propulsion of the intestinal contents.

After continuing for a period of a half to two hours
segmentation ceases. A peristaltic wave then moves the
whole mass forward to a fresh section of gut where segmen-
tation is renewed. A peristaltic wave consists of a wave
of contraction preceded by a wave of relaxation. Its
continuation after section of the vagi and splanchnics on
the one hand, and its abolition after the apphcation of
nicotine on the other, prove it to be due to the local nerve
centres — to Auerbach's plexus. When the gut is distended
at any part there occurs contraction above and relaxation
below the point of contact.

Two kinds of peristalsis are recognised — distinguished
by their rapidity and by the length of intestine which
they traverse. The more freqvient is slow peristalsis,
which travels at the rate of about 1 cm. per second, and
after propelling the contents a short way, dies out. Its

ABSORPTION 141

purpose appears to be mainly to change the surface of
absorption. Though propulsion of the food is involved,
this is dependent principally upon the more rarely occur-
ring rush-peristalsis, which, when fully developed, may
sweep along the whole length of the intestine in about a
minute. Peristalsis is more active in the upper than in
the lower part of the intestine. At the approach of a
wave to the lower end of the intestine the ileocsecal valve
opens.

The vagus, while not causing the intestinal movements,
nevertheless influences them in the direction of increased
activity after initial inhibition. The sympathetic, on the
other hand, inhibits all movement and tonus, and at the
same time causes vaso-constriction, but it closes the
ileocaecal valve.

Absorption from the Small Intestine

The small intestine is peculiarly adapted anatomically
and physiologically for absorption ; anatomically by its
great length, by the folding of its internal surface into
the valvulse conniventes and by the projection from its
mucous membrane of the innumerable viUi ; physiologically
by the complex movements which it undergoes.

The food as it reaches the ileocsecal valve, though as
fluid as it was when it entered the duodenum, is greatly
diminished in volume and altered in composition, practically
all the carbohydrates and the greater part o^ the fat and
protein having been absorbed, together with most of the
water.

The Nature of Absorption

How far are physical processes, such as osmosis, respon-
sible for the passage of water and substances in solution?
We may say at once that osmosis alone cannot account
for the process, since not only water but sahne solutions
isotonic with blood and even the animal's own serum are

142 DIGESTION

rapidly absorbed. Further, absorption of water is attended
with increased oxygen consumption. Nevertheless, the
process must be influenced in one direction or the other
by the osmotic conditions. Hypertonic saline is usually
absorbed only after a prehminary dilution, due doubtless
to osmosis, while the absorption of hypotonic solutions is
facihtated by the higher osmotic pressure in the epithehal
cells. It may be mentioned, however, that absorption
of hypertonic solutions may occur without prehminary
dilution.

As to the form in which the three classes of foods are
absorbed, this question is best deferred, since it has an
important bearing upon the metabolic history of these
substances. Suffice it to say at present that carbohydrates
are absorbed only after hydrolysis to monosaccharides,
proteins chiefly, if not entirely, after they have been broken
up into amino -acids, and fats only after saponification
into glycerine and soaps. After absorption, carbohydrates
and proteins enter the blood direct, fats chiefly indirectly
by the lacteals and thoracic duct.

THE LARGE INTESTINE

In different animals the large intestine varies in size
relatively to the whole of the gut, according to the nature
of the food which is habitually taken. Its large size in
certain herbivora is associated with the extensive bacterial
decomposition which takes place within it, and by means
of which the cellulose of the food is converted into a form
which is readily absorbed. But in man and carnivora
this process does not occur, cellulose not being absorbed.

The digesting mass, as it passes through the ileoceecal
valve, is as fluid as it was when it entered the small intes-
tine. It enters the large intestine to a great extent deprived
of nutriment. It consists of waste products, undissolved
substances, bacteria and the digestive juices. In the
large intestine this fluid mass becomes concentrated by

PTOMAINES 143

absorption of water, and the faecal residue stored until
ready for evacuation. The large intestine may be divided
physiologically into two parts : a -proximal part, consisting
of the ascending colon and the neighbouring half of the
transverse colon, whose function it is to provide a maximum
exposure of the contents to the intestinal wall, and a
distal part, consisting of the remainder of the colon, which
is concerned in the storage of faeces and in the process of
defsecation. From the nutritional point of view the
principal function of the large intestine is the absorption
of water. The glands of the intestinal wall give out a
mucous secretion, which has no enzymes. It serves to
lubricate the faeces. The chemical changes which occur
are due to bacteria, with which this part of the gut swarms.
Of these organisms the commonest is the Bacillus Coli.

The organisms feed principally upon proteins, and in
particular upon certain products of protein hydrolysis —
tyrosin and tryptophane. From ty rosin they form carbohc
acid, from tryptophane scatol and indol, the substances
responsible for the characteristic odour of faeces. The
extent to which these compounds are formed depends
first upon the amount of proteolytic products reaching the
large intestine — that is to say, upon the efficiency of the
digestive processes; secondly, upon the degree of stasis
of the intestinal contents in this part of the gut. Phenol,
indol and scatol are hable to be absorbed, and when
absorbed are toxic. Normally, however, they are rendered
less toxic by combination with sulphuric acid and excretion
in the urine.

Besides these substances, there are formed certain nitro-
genous bases usually known as " ptomaines." Of these
the commonest are histamine, cadaverine and putrescine.
They are formed by removal of CO2 from certain amino -
acids — the work, again, of bacteria. If absorbed into the
blood-stream they exert toxic effects.

Intestinal bacteria also act upon carbohydrates, con-
verting them into lactic acid.

144 DIGESTION

Movements of the Large Intestine

Food begins to enter the large intestine within three
hours of ingestion. As a peristaltic wave approaches the
ileocaecal valve the colon in the neighbourhood of the
valve first contracts, then relaxes as the wave disgorges
the food into it. The ileocsecal valve is a true sphincter,
having a nervous mechanism of its own. It appears both
from X-ray observations and from the direct observation
of the intestine exposed in warm sahne solution that the
principal movement in animals consists of antiperistaltic
waves. These begin at about the middle of the transverse
colon, and at the rate of about five per minute (in the
cat), sweep towards the caecum. Prevented by the closing
of the ileocsecal valve from regurgitating into the ileum,
the contents escape distally through the peristaltic ring.
By this means is ensured the maximum exposure to the
absorbing surface. From the fact that enemata introduced
at the rectum appear in csecal fistulse, the same process is
beheved to occur in man, though it has not actually been
observed. The contents fill up the ascending colon, and
as they proceed gradually attain the faecal consistency.
In the transverse colon the advancing column is split up
by waves of contraction, which travel slowly towards the
pelvis.

Normally the contents take about two hours to traverse
the ascending colon, and another two hours to reach the
splenic flexure. The part of the large intestine which hes
between the middle of the transverse colon and the rectum
is in a state of constant tonic contraction, interrupted only
by slow peristaltic waves. These have the effect of filling
this part of the intestine from below upwards. As they
pass along, the faeces become gradually harder by absorption
of water.

Defaecation

Defsecation consists of a train of events partly involuntary
and partly voluntary. The faeces accumulate from the

DEFMCATION 145

lower end of the pelvic colon upwards to the splenic flexure,
the rectum meanwhile being empty. The process of
defsecation is initiated by a peristaltic wave, which pushes
the distal end of the faecal mass into the rectum. In
different individuals various stimuh bring this about—
the taking of food or a cold bath. It is a reflex which is
developed by habit. The rectum is specially sensitive to
distension — this being interpreted subjectively as a desire
to defsecate. The rectal distension causes reflexly a strong
wave of contraction, which travels downwards from the
splenic flexure. This is accompanied by the inhibition of
the internal sphincter ani. The efferent path for both
these actions is by the sacral autonomic. This reflex
action is reinforced by the voluntary act of contracting
the diaphragm, the thoracic and abdominal muscles with
the glottis closed.

If the call to defsecation — that is to say, the sensation
aroused by distension of the rectum — is not obeyed, the
sensation passes away, the result being that the rectum
becomes filled with an accumulation of faeces to which it
is insensitive. The reflex mechanism is thus thrown out
of gear. After normal defsecation the bowel should be
empty from the splenic flexure downward.

CHAPTER IX
GENERAL METABOLISM

Introduction

Life consists physiologically of a transformation of
energy. Animals are dependent for their supply of energy
upon the potential energy present in the food, this being
derived in the first instance from the sun through the
anabohc processes characteristic of plant-hfe. The energy
thus presented to the animal is converted by it into a
form which consists physiologically of cell-activity, and
mechanically of work and heat. The extent of this trans-
formation and its relation to the degree of activity are
capable of estimation. The body, in other w^ords, may be
considered as a machine in which the energy supphed is
balanced by the energy liberated.

But the body itself is not unaffected by the processes
of combustion w^hich take place within it. Cell-life involves
a constant wear and tear which has to be made good.
This process of disintegration and reconstruction, unlike
the transformation of energy, cannot be measured, nor is
its relation to cell-activity known.

The food when it enters the body undergoes one of two
fates. In the first place it may serve merely as a supply
of energy; its destiny is oxidation, and any changes
which it may undergo other than oxidation are either for
the purpose of storage or of the nature of preparation for
combustion. In the second place the food may become a
part of the cell itself, an essential cog in the wheel, its
presence being necessary for the performance and for the

146

CALORIMETRY 147

regulation of the chemical changes occurring in the cell.
It controls the dynamic changes, but the energy which it
itself possesses is not thereby utilised. Any changes which
it undergoes consist in an adaptation to the part which
it has to play. Now certain of the substances which form
essential parts of the cell-structure cannot be synthesised
in the body. Some are minerals, others can only be manu-
factured by plants. It follows that a quantitative con-
sideration of the food, as a source of energy, is only valid
when the adequacy of the food for the maintenance of the
machine is guaranteed. To take an example. Supposing
we wish to determine whether fat is necessary as a source
of energy : were this merely an energy question it could
easily be settled by feeding an animal on a fat-free diet.
But it is known that on such a diet the animal will fail to
hve, not because the energy-supply is inadequate, but
because of the loss of certain substances present in fat,
which are constantly required by the body for effecting
chemical changes within it.

The chemical changes occurring from the time of absorp-
tion to the time of excretion, and the transformation
of energy involved therein constitute what is known as
metabohsm.

THE EXPENDITURE OF ENERGY

In this chapter we shall consider the body as a machine,
and proceed to investigate quantitatively the transformation
of energy involved in the processes of life. For estimating
the amount of energy hberated two methods are employed —
Direct and Indirect Calorimetry .

Direct Calorimetry

In this method the subject is put into a specially con-
structed calorimeter and the amount of energy estimated
as heat is recorded. The most modern apparatus for
experimenting upon man is that invented by Benedict.
It consists of a chamber of the size of a small room in
which the subject can hve for a prolonged period. The

148 GENERAL METABOLISM

walls, ceiling and floor of the chamber are composed
essentially of four layers separated by air-spaces. The
outer two are of wood, the inner two of copper. The
copper walls are connected together in an electric circuit
in which is placed a thermo-electric junction and galvano-
meter. These register any difference of temperature between
the two walls. The temperature of the outer copper wall
can be varied by means of an electric heating apparatus.
When any difference of temperature occurs between the
walls it is annulled by heating or cooling the outer. There
is therefore practically no loss of heat by radiation from
the chamber. All the heat evolved by the subject is
absorbed by a circulation of cold water through the chamber,
and its amount calculated from the volume and rise in tem-
perature of the water. But this does not include all the
heat produced, for a certain amount is dissipated in convert-
ing water into water- vapour in the lungs. This is calcu-
lated by absorbing the water-vapour in the outgoing air
with sulphuric acid and estimating the latent heat of its
formation.

The unit of energy employed is the amount of heat
required to raise one kilogramme of water through 1° C.
This is called the large Calorie (C).

The accuracy of the apparatus, tested by burning a
known amount of some inflammable substance in it, is
found to be of a very high order.

When the individual is at complete rest almost all
the energy is given ofE as heat. If it is desired to investigate
the effect of muscular acti^dty, a measured amount of
work is performed on a pedaUing machine. The work
recorded is reduct'.d to its heat equivalent, 1 Calorie being
equivalent to 425 kilogramme-metres of work.

It is first necfsssary to determine whether the foodstuffs
Uberate the sanic amount of energy when metabohsed in
the body and w len oxidised in vitro. It is obvious at the
outset that acci^rate correspondence is not to be expected
unless the oxidation which occurs within the body is as

CALORIMETRY 149

complete as that which occurs without. In the case of
carbohydrates and fats there is no doubt that this is
so, for these substances, provided that they are really
being metabohsed and not stored, are completely oxidised
in the body to carbonic acid and water. But in the case
of proteins, the excretory products, urea, uric acid, etc.,
are not completely oxidised. The whole of the available
energy of the proteins is not used. For this reason the
energy hberated in the body by proteins will fall shghtly
short of the energy hberated by the same proteins in vitro.
The energy available by complete oxidation of a sub-
stance is determined by means of the Bomb Calorimeter,
which consists of a steel case containing a known amount
of the substance in an atmosphere of oxygen. This is
immersed in a known volume of water. Combustion is
effected electrically, and when completed the amount of
heat evolved is measured. With this apparatus the
following values have been determined—

1 gm. carbohydrate on combustion gives off 4-1 C.
Igm. fat „ „ „ 9-3 C.

1 gm. protem „ „ „ 5-0 C.

We now have all the data for constructing the energy
balance. To take an example —

Heat given out by the subject . . 4833 C.

Work done, calculated as heat . . 602 C.

Total energy hberated, calculated as heat 5435 C.

The total energy obtainable from the amount of food
absorbed during that period, less the energy present in
the excreta, v/as 5459 C. The two figures thus agree to
within 0-5 per cent.

Indirect Calorimetry

Since the energy hberated on oxidation within the body
is practically identical with that hberated on oxidation
outside the body, it follows that if we know the amount

150 GENERAL METABOLISM

of each kind of food which is being metabohsed we can
calculate the energy Hberated without recourse to a calori-
meter. This can be done even without a previous analysis
of the food administered, the only data required being :
(1) TJie total respiratory exchange, (2) the amount of nitrogen
excreted.

The Respiratory Exchange : Respiratory Quotient

The various methods which have been adopted for
estimating the oxygen intake and COg output fall into two
groups : {a) The animal is placed inside a chamber through
which air deprived of COg and water- vapour is pumped.
The total volume of air passing through is measured, and
the oxygen and CO2 passing out of the chamber estimated.
(6) This method, more suitable for experiments upon man,
consists in making the individual breathe through a suit-
able mask into a chamber which is supplied with a constant
stream of oxygen, the oxygen admitted and the CO.
expired and absorbed being estimated.

The relation between the amounts of CO2 expired and
of oxygen absorbed during the same period," expressed as

the former divided by the latter (^ A is termed the

Respiratory Quotient (R.Q.). Its value varies according
to the amount of oxygen already present in the food
molecule undergoing combustion. "This will be seen from
the followng equations —

Carbohydrate :

CcHiaOe -f GO2 = 6CO0 + B^O.

ca_6_

O2 ~ 6 ~ ^•

Fat :

C57H110O6 -f 8IIO2 = 57COo -f 55H2O.

^=^-0.7
O2 81J~"^-

THE RESPIRATORY EXCHANGE 151

In the case of proteins, owing to their varying composi-
tion, the R.Q. is not constant. The average figure is 0-8.
The proportion of nitrogen in protein is sufficiently con-
stant to allow of the nitrogen excreted being a measure
of the protein catabohsed, one gm. of nitrogen corre-
sponding to 6"2 guis. of protein which yields on oxidation
5-9 htres of oxygen, and 4-8 litres of COg.

Knowing then the total respiratory exchange, and deduct-
ing from tliis the exchange which is due to the catabohsm
of protein as estimated from the urine, we are left with the
respiratory exchange which represents the combustion of
non-protein material. It only remains to determine how
much is due to carbohydrates and how much to fats.
This can be estimated from the R.Q. obtained from the
non-protein respiratory exchange. If the figure obtained
is 1-0, carbohydrates only are being metabolised; if 0-7,
fats only, any intervening figure representing a certain
proportion of carbohydrates and fats.

The following example (from Krogh) will make this clear.

Total gaseous exchange = 405 litres O2 and 331 litres CO2

N. excreted, 34-93 gms. cor-
responding to 206-9 ,, „ „ 166 ,, ^

Non-protein gaseous ex-
change 198-1 ,, ,, „ 165 „ „

165
Non-protein R.Q. = ' = 0-833.

The figure 0-833 corresponds to a combustion of —
0-51 gms. carbohydrate 1 ,•<- t

and 0-293 „ fat / P^^ ^^'^^ °^ «^^^S'^-

The subject is therefore catabolising —

Protein . . , 34-93 X. 6-2 = 218 gms.

Carbohydrate. . 0-51 x 198-1 -= 101 '.,

Fat . . . 0-293 x 198-1 =. 5S „

Now, as stated above, 1 gm. protein on combustion gives off
50 C, 1 gm. carbohydrate 4-1 C, and 1 gm. fat 9-3 C.
The total heat- production in this case is therefore —

(218 x 5-0) + (101 X 4-1) + (58 X 9-3)
-= 2043-5 Calories.

152 GENERAL METABOLISM

Here, then, is an indirect means of arriving at the
energy production. Though simpler to work than the
direct method, it is not free from certain fallacies. The
first of these is that the actual production of COg may
not correspond to the ehmination, owing to the capacity
of the tissues for storing this gas. A second fallacy is
that processes other than direct utihsation of the food-
stuffs may conceivably be taking place. Supposing, for
instance, that the body is storing fats after forming them
from carbohydrates. In the conversion of an oxygen-rich
into an oxygen-poor compound a certain amount of oxygen
is hberated, and is presumably available for oxidation of
other molecules. The consequence is that the amount of
atmospheric oxygen needed by the tissues is diminished
to a corresponding extent. In other words there will be
an elevation of the R.Q. The abnormally high respiratory
quotients (1-2 or 1-3) observed in hibernating animals at
the onset of the dormant period, and in geese when
they are fed with large quantities of carbohydrates, have
been taken to prove the conversion of carbohydrate into
fat.

A third fallacy lies in the fact that COg may be produced
by processes other than oxidation in the tissues. In
herbivorous animals a large amount of COg is formed in
the intestine by bacterial decomposition.

Intestinal fermentation, then, and conversion of carbo-
hydrate into fat, will both tend to raise the R.Q. Both
factors are probably concerned in the abnormally high
values found at the onset of hibernation.

Under certain circumstances a respiratory quotient of
abnormally low value has been obtained, particularly at
the end of hibernation. The meaning of this is not clear.
It has been ascribed to a conversion of fat into glycogen,
which is stored preparatory to awakening. It is doubtful,
however, whether the amount of carbohydrate thus formed
is sufficient to account for the retention of so much oxygen.
Further, the low R.Q. may be due to other causes, as, for

SPECIFIC DYNAMIC ENERGY 153

instance, to incomplete oxidation evidenced by the appear-
ance of lactic acid in the urine.

Factors Influencing the Expenditure of Energy

Food.- — An important question has here to be settled.
Does the rate of metaboUsm rest with the initiative of the
cell or with the amount of food supphed? Can the cell
only be made more active through causing a physiological
need for enhanced activity, or can it also be made more
active by feeding it? It was noted by Rubner that when
a large amomit of protein was given there occurred an
increased hberation of heat. The same thing occurred
after ingestion of carbohydrates and fats, but to a much
less extent. The surplus energy thus hberated is called
the specific dynamic energy of the food. The cell on
being flooded with protein, which it is unable to store,
is forced to burn it, quite irrespective of any demands for
heat-production on the part of the body as a whole, and
without any increase in voluntary activity. On the other
hand, it may be that the presence of protein makes the
cell burn carbohydrates and fats more rapidly.

There is clear evidence that the rate at which metabohsm
occurs is dependent upon certain chemical substances in
the blood, particularly those elaborated by the thyroid
gland. When this organ is hyper-active the metabohc
processes are quickened, and when it is deficient or absent
they are retarded.

External Tem'perature. — Metabohsm is profoundly in-
fluenced by changes in the temperature of the atmosphere.
This will be discussed more fully in connection with the
regulation of body temperature.

Muscular activity — Basal Metabolism. — It is clear that
in order to estimate the effect of activity upon metabolism
we must first try to find the energy hberated when no
work is being done. In theory this means when none of
the organs in the body are doing any work — that is, are
merely existing in a healthy state. This has been termed

154 GENERAL METABOLISM

the true basal metabolism. In practice the most complete
rest attainable involves considerable activity of the heart
and lungs. The minimum of activity which can be attained
occurs when the body is at complete mental and physical
rest, when no digestion or absorption of food is going on,
and when loss of heat by radiation is at its minimum.
This is usually taken as the Basal or Standard Metabolism.
It has been estimated as 1 Calorie per kilogramme of body
weight per hour, or about 1700 C. per diem, for a man of
average weight and size. In different individuals it varies,
not with the weight but with the area of body-surface.

The energy output of an average person doing sedentary
work has been found by direct and indirect calorimetry
to be about 2500 C. per diem. AVhen hard manual work
is performed this figure may be doubled. These results
agree fairly well with the energy intake as estimated
statistically from the amount of food supplied to large
communities. From the figures thus obtained it appears
that the average daily consumption of food corresponds
in men to an intake of 2500 C. for sedentary workers,
and 4000 C. for those employed in manual labour.

CHAPTER X

INTERMEDIATE METABOLISM

We shall now take each class of foodstufE in turn, and
after summarising the changes which it undergoes during
digestion, follow the transformation which it undergoes
between absorption and excretion. Such transformation
will be found to involve any of the following —

1. Conversion of molecules not immediately required
for consumption into storage forms.

2. Incorporation into the structure of the living cell.

3. Conversion of one form of foodstuH: into another, as,

for instance, proteins into carbohydrates.

4. Conversion of toxic into non-toxic bodies.

5. Breakdown changes preparatory to oxidation.

6. Oxidation itself.

1.— METHODS OF INVESTIGATION

Among the methods employed for investigating these
intermediate reactions are the following : —

1. The direct estimation of substances in the blood,
tissues and excretions.

2. Administration of Intermediate Substances. — A sub-
stance, A, given to the body is excreted in the form D.
There are two substances, B and C, which might from a
chemical point of view be intermediate stages in the change.
B and C are injected into the animal. If B is excreted
unchanged, and C is converted ijito D, the inference is
drawn that the normal course of metabohsm is A -> C -> D
rather than A -> B -> D.

155

156 INTERMEDIATE METABOLISM

Example : Acetic acid is completely oxidised in the body.
Theoretically, either formic acid or oxahc acid might be an
intermediate compomid. But oxaUc acid on injection is
excreted michanged, whereas formic acid is oxidised. The
oxidation of acetic acid therefore takes place thus — -

CH3COOH -> HCOOH -> CO2 + H2O

rather than thus —

COOH

CH3C00H-> I ->C02 + H.O.

COOH

3. Achninistration in Excess. — When a substance is
injected in excess of the amount which can be completely
oxidised it often appears in the urine in an incompletely
oxidised form.

Example : Xanthine administered in small quantities
to most animals is converted into allantoine. Adminis-
tered in excess it appears partly as allantoine, partly as
uric acid. Uric acid is therefore an intermediate stage.

4. Perfusion ami Digestion with Tissue-Pulps. — By this
means have been proved the conversion of ammonia into
urea by the hver and many other reactions.

5. PatJiological Method. — When an abnormal substance,
A, is excreted owing to a pathological condition, if the
administration of a substance B, leads to increase in the
amount of A, the inference is drawn that B is converted
into A, and that the same change may occur under normal
conditions, but is masked omng to the complete oxidation
of A.

Exam])le : Administration of certain amino-acids leads
in diabetes to an increase in the amount of glucose excreted.
The body therefore possesses the power of converting
protein into carbohydrate.

An interesting instance of this method is found in the
abnormahty known as alcaptonuria. In this condition
homogentisic acid is excreted by the kidney, and the corre-

PROTEINS 157

spondence between the amount of this substance excreted
and the amount of tyrosine ingested shows that these are
related. It is therefore beHeved that tyrosine is, under
normal circumstances, first changed into homogentisic acid,
and that the alcaptonuric cannot oxidise homogentisic
acid.

/\ H0/\

CH2CHNH2COOH CH2COOH

Tyrosine Homogentisic acid

6. Knoop^s Resistant Radical Method. — Substances which
are readily oxidised under normal conditions are incom-
pletely oxidised when they are Unked to another substance
itself resistant to oxidation. By hnking fatty acids to the
benzene ring important deductions can be drawn as to the
normal metabolism of these acids (see p. 202).

The location of these changes in a particular organ can
be made —

1. By the perfusion and digestion methods mentioned
above.

2. By studying the effect of removal of the organ under
investigation from the circulation.

3. By a comparative analysis of the blood entering and
the blood leaving the organ.

2. PROTEINS

The Nature of Proteins

A protein is a substance containing carbon, hydrogen,
oxygen, nitrogen, and sometimes sulphur and phosphorus.
Structurally it consists of a large number of amino-acid
molecules hnked together by condensation. Into these

158 INTERMEDIATE METABOLISM

constituents it can be resolved by boiling with acids or by
the action of certain ferments.

All Amino-acid is an organic acid in which a hydrogen
atom, other than that of the carboxylic group, is replaced
by an NHg group. In all the amino-acids occurring in
nature, such substitution occurs in the a position.

The general formula of an amino-acid is therefore —

I
R— C— COOH

I
• H

An amino-acid can be regarded not only as an acid con-
taining an NH2 group, but as a substituted ammonia. It
is therefore an acid at one point and a base at another.
For this reason the acid group of one amino-acid can,
under certain circumstances, combine with the basic group
of another, thus —

CH3CHNH2COOH + NH2CH2COOH

= CH3CHNH2CONHCH2COOH

It will be observed that in this new compound there are
still a COOH group and an NH2 group intact. This process
of condensation can therefore, theoretically, be continued
indefinitely. The compounds thus formed are called di-
tri- poly-peptides, according to the number of amino-
acid molecules composing them. The most complex poly-
peptide hitherto made artificially contains eighteen amino-
acid molecules.
The following are the principal amino-acids : —

The Principal Amino-acids

I. Aliphatic Series.

Glycine (amino-acetic acid)

CH2NH2COOH

AMINO-ACIDS 159

Alanine (a-amino-propionic acid)
CH3CHNH2CQOH

Serine (a-amino- /3-oxypropionic acid)
CH2OHCHNH2COOH

Cystine (Di-a-amino- /3-thiopropionic acid)
CH2— S— S— CH2

CHNH2 CHNH2

Valine

COOH COOH
'^CHCHNH2C00H

Leucine

T 1

CH3'

>CHCH2CHNH2C00H
Oil/

lsoloiicin(

' '>CHCH2CHNH2COOH

Aspartic

acid

OH2COOH

Glutamic

CHNH2COOH
acid

CH2COOH

CH2

CHNH,COOH

Lysine (containing 2 NH2 groups)

CH2NH2CH2CH2CH2CHNH2COOH

160 INTERMEDIATE METABOLISM

Arginine (containing the guanidine group)

NH=C

NH,

NH = C— NH— CH2CH2CIT2CHNH2COOH

II. Amino-acids containing a Closed Chain.
Phenyl alanine

CH2CHNH2COOH

Tyrosine (oxyphenyl alanine)

CH2CHNH2COOH

Tryptophane (/J-indol alanine)
CH

CHf \^^— CCH2CHNH2COOH

G
CH NH

Histidine (/S-imidazol alanine)

/\
NH N

CH= C— CH,CHNH,COOH

CLASSIFICATION OF PROTEINS ICl

Proline

H^C

C^H

CHCOOH

Oxyproline

HOHC

H^C

CH2

CHCOOH

Classification of Proteins

Proteins are divided into two main groups,

1. Simple Proteins, conforming to the definition of a
protein given above. Such are fibrinogen of blood, myosin
of muscle, casein of cheese. These are classified into sub-
groups, e.g. albumins, globulins, etc., according to their
solubility and precipitabihty by certain reagents.

2. Conjugated Proteins. — In these the protein molecule
is hnked with a non-protein molecule ; with nucleic acid,
for instance, in nucleo-proteins.

Hydrolysis of Proteins

In the breakdown of proteins to amino-acids certain
intermediate stages are recognised. The disruption of the
protein molecule is a gradual process, involving the suc-
cessive subdivision of ever-shortening chains of amino-
acids. The diminution in size of the molecules is accom-
panied by a physical change involving increase in solubihty
and decrease in precipitabihty.

The first recognisable change is that the molecule, if
originally completely insoluble, becomes soluble in dilute
acid or alkah, but the solution is easily precipitated and
is coagulated by heat. In this stage it is called a meta-
protein. It then becomes soluble in water, is not coagulated
by heat, and requires half-saturation with ammonium
11

162 INTERMEDIATE METABOLISM

sulphate to precipitate it. It is now known as a primary
proteose or alburaose.

In the third stage it is precipitated only on full satura-
tion with ammonium sulphate. This is a secondary proteose
or albumose.

In the fourth stage the molecule is sufficiently small to
diffuse through an animal membrane. It cannot be pre-
cipitated. This is a peptone.

In the fifth stage diifusibility has increased. The molecule
is now a polypeptide.

The final stage is the separation into individual amino-
acids.

It must be realised that, notwithstanding these stages,
the process is essentially a continuous one, involving a gradual
disintegration of the protein molecule. Further, the pro-
cess takes place irregularly, so that at any stage molecules
of different sixe are present.

The importance of recognising the above stages Ues in
the light thus thrown upon the action of the different pro-
teolytic ferments.

Pepsin, acting only in presence of free hydrochloric acid,
converts protein into a mixture of proteoses and peptones.
Trypsin, acting in an alkahne medium, converts protein
through all its stages into polypeptides and amino-acids,
but it appears to be incapable of breaking down all poly-
peptides into amino-acids. Erepsin, also alkahne, has no
action upon proteins, but converts peptones and poly-
peptides completely into amino-acids.

The succession of an acid by an alkahne digestion occurs
not only in all animals, including even Amceba, but also
in insectivorous plants. It appears that certain protein
hnkages are more readily sundered by an alkahne ferment
after other linkages have been broken by an acid ferment.

* Absorption of Proteins

The proteins found in the various tissues differ from
one another not in containing different amino-acids, but

ABSORPTION OF PROTEINS 163

in containing the same amino-acids cotnbined in different
proportions and in different ways. The individuality of a
protein is due to the arrangement of the amino-acids of
which it is composed. When animal proteins are being
built from plant proteins the change consists in a re-
arrangement of amino-acids. Assuming that the animal
body cannot to any extent synthesise amino-acids, it
might be expected that such rearrangement must first
involve breakdown of the food protein into its amino-
acids, and the ample provision of the means of effecting this
breakdown in the intestine would seem to confirm this view.

But until recently proof of this was wanting. It was
difficult to detect amino-acids in the intestine owing, as
we now know, to their rapid absorption, and still more
difficult to detect them in the blood.

Four views were held.

1. That breakdown into amino-acids is not a necessary
prehminary to absorption.

2. That amino-acid formation occurs only for the purpose
of absorption, being followed by immediate resynthesis
within the intestinal wall.

3. That amino-acids are absorbed, and after absorption
are deaminised in the intestinal wall, ammonia and a non-
nitrogenous residue being carried into the circulation.

4. That amino-acids are absorbed and circulate in the
blood.

The first three theories may be dismissed, since they
have been disproved by the positive evidence in favour
of the fourth. This evidence is here presented.

1. AbeVs Vividiffusion Method {Artificial Kidaeij)

This is a device for separating amino-acids from circulating
blood. The blood is passed from the blood-vessel through
a tube whose walls are made of collodion. This is immersed
in a sahne solution isotonic with blood. The blood is
then returned to the circulation. The amino-acids readily
difiuse through the collodion, and can be estimated.

164 INTERMEDIATE METABOLISM

2. Estimation of Amino-acids in Blood

Sorensen's method. — This depends upon the fact that
amino-acids on treatment with aldehydes midergo this
change.

R R

NH2— C— COOH + HCHO ~> CH2 : N— C— COOH + H2O.

The NH2 group being thus destroyed, the resulting
product behaves as a true acid and can be estimated by
titration.

By the use of these methods it has been shown that the
blood even in the fasting condition always contains amino-
acids, (3-5 mg. per 100 c.c), and the tissues from five to
ten times as much as the blood. During protein digestion
the amino-acid content rises in the general circulation,
and rises still more in the portal vein. But at the same
time there is no accumulation of amino-acids either in the
hver or in the other tissues. As regards the hver, the
amino-acids are evidently converted into some other form ;
they are either destroyed or synthesised into more complex
bodies.

When a certain quantity of amino-acids is injected into
the blood it rapidly disappears. Part is excreted by the
kidneys either unchanged or as urea, but the remainder is
absorbed by the tissues. In the hver there is a rapid rise,
followed by a fall. In the other tissues the rise is more
gradual and soon reaches a maximum, which is maintained
for a considerable time. Simultaneously there is a rise in
the urea of the blood, setting in before the tissues have
become saturated with amino-acids.

Confirmatory evidence against the absorption of foreign proteins
without preparatory hydrolysis is found in the remarkable reaction
known as anaphylaxis. When a protein is injected into the blood

FATE OF AMINO-ACIDS

165

in two doses separated by an interval of about three weeks, im-
mediately upon administration of the second dose the animal
becomes collapsed and dies.

The Subsequent History of the Amino-Acids

Before considering the significance of the above facts it
is necessary to trace the metabohsm of nitrogen compounds
from the other end — that is, from their ehmination. Much
Ught is thrown by a study of the effects upon nitrogen
ehmination on variations in the amount of protein absorbed.
This is shown in the accompanying table.

(Folin).

It will be seen that while creatinine is almost unaffected
by diet, urea undergoes a very considerable variation, the
other urinary constituents occupying an intermediate posi-
tion. These observations led Fohn to distinguish two
forms of nitrogen metabohsm. In one form the amino-
acids not required for tissue-building are split into ammonia
and a nitrogen-free residue. The ammonia is converted
into urea, and the non-nitrogenous part is burnt up hke
a carbohydrate or fat. This Folin termed " exogenous
metabolism." In the other form the amino-acids are
taken up by the tissues and incorporated into the
structure of the cell. Now since the cell is constantly

166 INTERMEDIATE METABOLISM

undergoing wear and tear, the amount of which must
necessarily be determined by activity and not by diet, the
nitrogen in the urine which originates in cell-breakdown
must be that part which is not influenced by diet — that
is, creatinine. This is " endogenous metabolism."

The other constituents of urine — uric acid, ammonia and
" undetermined nitrogen " (which chiefly consists of amino-
acids and nitrogenous bases) — are partly of exogenous,
partly of endogenous origin.

During starvation the amino-acid content of the blood
is shghtly increased. This is due to a breakdown of
protein in the less essential organs, such as the skeletal
muscles, and a transference of amino-acids to the indis-
pensable organs, such as the heart and brain. Migration
of amino-acid also occurs in fish during the spawning
season. Here the nucleo-protein of the sexual organs is
being built up at the expense of stored muscle protein
(see p. 172).

The Formation of Urea
The amino group which is spht off from the amino-acid
in exogenous metabolism is converted into ammonia. This
is probably effected by a process of hydrolysis : —

NH2

CH2COOH

The ammonia thus hberated combines with any acid
radicles which may be present in the blood. Carbonic
acid being the most abundant of these, loose compounds
are formed — ammonium carbonate and ammonium car-
bamate. The close relation which these two substances
bear to one another and to urea is shown by their
formulae : —

/ONH4 /ONH4 /NH2

o=c< o=c< o=c<

^0NH4 ^NHg ^NHg

Ammonium carbonate. Ammonium carbamate. Urea.

AMMONIA 167

While the process of deaminisation seems to occur in all
hving cells, the formation of urea occurs pre-eminently in the
hver. Ammonium carbonate perfused through the hver
is converted into urea. When in the living animal the
hver is short-circuited by leading blood direct from the
portal to the hepatic vein (Eck fistula) ammonia accumulates
in the blood. But even under these circumstances urea
formation does not cease. The hver, therefore, though the
principal, is not the sole seat of the change.

A small amount of urea may be derived from arginine,
the amino-acid which contains the guanidine group.
Several tissues contain an enzyme, arginase, which has the
power of splitting arginine into urea and ornithine.

NH.— C— NH— CH2— CH2— CH2CHNH2COOH

11 Arginine.

NH
NH2— CO + NHo— CH2— CH2CH2CHNH2COOH

I Ornithine.

Urea.

The Excretion of Ammonia

When ammonia, spht off from amino-acids, combines with
an acid radicle other than CO2 it is excreted as an ammonium
salt. If it combines, for instance, with chlorine it is
excreted as ammonium chloride. When abnormal acids
accumulate in the blood as /3 -hydroxy butyric acid in
diabetes, ammonium salts of these acids are formed and
excreted. The ammonia may be said to be diverted from
its normal metabolic path in order to neutralise the acids.

Synthesis and Inter-conversion of Amino-acids

Can the body synthesise amino-acids from ammonia and
a non-nitrogenous group, and can it transform one amino-
acid into another ? These questions are of fundamental
importance, for upon the answers to them depends the

168 INTERMEDIATE METABOLISM

protein requirement in diet. If the tissues cannot make
amino-acids, but can only utilise for tissue-building pur-
poses such amino-acids as are presented to them, then the
form as well as the quantity of the protein in the food
must be taken into account. But if the body can convert
the nitrogen compounds presented to it into the amino-
acids required for the specific structure of its tissues, then
the quantity of protein is the sole consideration.

There is some indirect evidence that the body has the
power of manufacturing amino-acids.

Synthesis of Alanine. — When the liver is perfused with
pyruvic acid alanine is formed —

CH3

CO ->

CHNH2

COOH

Pyruvic acid.

Alanine,

Alanine is also formed on perfusion of the hver with
ammonia, provided that the Uver is rich in glycogen.
These facts point to a synthesis of alanine from ammonia
and non-nitrogenous compounds.

Fornuition of Glycine. — Herbivorous animals daily excrete
considerable quantities of hippuric acid. This is formed
in the kidney by synthesis of the benzoic acid from the
food with glycine.

CeH^COOH + NH2CH2COOH= C6H5CO.NH.CH2COOH

Hippuric acid.

Now the amount of glycine thus used is far greater than
the amount which exists in the tissues and food. Glycine
is therefore being formed in the body from more complex
amino-acids.

There is also evidence that the body can effect the
interconversion of histidine and arginine, and of tyrosine
and phenylalanine.

But the positive evidence for the synthesis of amino-

PURINES 109

acids ends here. On the other hand, there is considerable
evidence to show that for the more complex amino-acids
animals depend upon plants. We shall consider this more
fully in connection with nutrition, merely noting at this
stage that the capacity of the animal body for synthesising
amino-acids is hmited to the very simplest of these. The
possible conversion of amino-acids into compounds other
than protein is discussed later (see pp. 190 and 201).

3.— PURINES

The purines form a group of closely related substances
found extensively in hving tissues. They may be regarded
as composed of two urea groups united together through
a central chain of three carbon atoms so as to form a
double ring.

Purine, though itself only of theoretical importance, may
be taken as a starting-point. It has the formula C5H4N4, or

N=CH

I I

CH C— NH.

II II >H
N C W

Its principal derivatives may be thus classified :—
1. Amino derivatives (with or without oxygen) : —

Adenine (amino-purine)
C5H3N4NH2 or

N=-C-

CH C-

11 1
C-

-NH^

-NH.

)CH

Guanine (amino-oxypurii
C5H3N4ONH2 or

HgN-

HN-C =

-C C-

1 1

N C-

= 0

>CH

170 INTERMEDIATE METABOLISM

These two substances form an essential constituent of
nuclei.

2. Oxidation 'products : —

Hypoxanthine (oxvpurine) NH CO

CjH.N.Oor " I I

CH C--NH.

N C N^

This occurs in all muscular tissue.

Xanthine (dioxypurine) NH CO

C.H^N.O^ or I I

CO C— NH.

NH — C N^

^CH

Uric acid (trioxypurine) NH CO

C^H.N.Ogor ■ I I

CO C-NH.

I II >co

NH C— NH-^

Uric acid is the form in which in man purines are excreted,
the daily urine containing about 0-75 grm. It is also
found in human blood (1-3 mg. per 100 c.c). In gout
the amount in the blood is considerably increased and
large crystalhne deposits are formed in the joints.

3. Methyl derivatives. — Purine bodies occur combined
with the CH3 group, as caffeine in coffee, as theophylli7ie
in tea, and as theobromine in cocoa.

Pyrimidine Bases

These are single-ring nitrogen bases consisting of a
three-carbon-atom chain with 07ie urea group.

PURINES 171

Three are known : —

NH— CO N— C— NH2 NH— CO

II II II

CO C— CH3 CO CH CO CH

II I II I II

NH— CH NH— CH NH— CH

Thymine. Cytosiue. Uracil.

Of these, thymine and cytosine occur in animal tissues
as components of nuclear material. Little is known of
their metabohsm. They can be synthesised in the body;
they do not appear in the urine.

Nucleic Acid

Nuclear tissue consists of nucleo -protein — a protein
conjugated with nucleic acid.

Nucleic acid as it occurs in animals is composed of four
molecules of phosphoric acid, four of a hexose derivative
and one molecule each of adenine, guanine, thymine
and cytosine. These are beheved to be combined in the
following way : —

Phosphoric acid- -Hexose — Guanine

• Phosphoric acid — Hexose Thymine

Phosphoric acid — Hexose Cytosine

Phosphoric acid— Hexose — Adenine

The combination, hexose + nitrogenous base, is termed
a nucleoside, and the combination, phosphoric acid + hexose
+ nitrogenous base, a mononucleotide. Nucleic acid is
therefore called a tetranucleotide.

Briefly, the problem before us is to correlate the purines
taken in with the food, the amino-purines of nucleic acid,
the hypoxanthine of muscle, and the purines excreted in
the urine.

172 INTERMEDIATE METABOLISM

Physiological Synthesis of Purines

This is abundantly proved.

1, Salmon during the breeding season form large quan-
tities of nucleic acid in the sexual organs, the heads of
spermatozoa consisting almost entirely of this substance.
Since during this period the fish take no food, the nucleic
acid must be formed from the tissue proteins, chiefly the
muscles.

2, Purines, absent from the newly laid egg, develop during
incubation.

3, Mammals, both growing and adult, produce and
excrete purines indefinitely when fed on milk or other
purine-free diet.

Exogenous and Endogenous Purine

The amount of purine excreted depends upon the amount
ingested. In man the urinary uric acid is increased after
feeding with substances such as thymus which are rich
in purine. ^Alien uric acid itself is administered it can be
recovered in the urine, sometimes almost completely. From
hypoxanthine and xanthine there is a yield of uric acid
corresponding to about 50 per cent., and from adenine
and guanine a smaller yield.

When no purines are present in the diet, uric acid con-
tinues to be excreted, being derived evidently from the
purines of the body. The source of the uric acid excreted
is therefore twofold, exogenous and endogenous.

Two questions now have to be considered.

1. How does the body transform the purines, whether
from the food or from the tissues, into uric acid ?

2. What conditions determine the conversion and
excretion of body purines ?

The Formation of Uric Acid from Nucleic Acid

Our knowledge of this subject has been obtained by
studying the chemical changes which occur when nucleic

PURINES 173

acid and purines are administered to the intact animal,
when these -substances are digested with various tissue
extracts, and when tissues are allowed to undergo autolysis.
Using these methods, the conversion of nucleic acid into
uric acid has been ascribed to a series of enzymes. The
change occurs in the following stages : —

1. By a series of ferments termed nucleases, the tetra-
nucleotide is split into mononucleotides, from which are
hberated adenine and guanine either directly or through
the intermediate formation of nucleosides.

2. Deaminising ferments, adenase and guanase, convert
respectively adenine into hypoxanthine and guanine into
xanthine.

3. The ferment xanthoxidase oxidises hypoxanthine to
xanthine and xanthine to uric acid.

These changes may be thus set forth : —

' Tetranucleotide (nucleic acid)

^ .
Mononucleotide (phosphoric a cid + hexose + base)

By
nucleases >

> Nucleoside (hexose + base)

V Adenine Guanine

(by I I (by

adenase) I I guanase)

Hypoxanthine -> Xanthine -> Uric acid

(by Xanthoxidase)

It is not to be imagined that all these ferments exist
in every tissue. Indeed, their distribution appears to bo
hmited to a few organs, such as the hver, pancreas and
spleen, and even in these they are not all present. Wide

174 INTERMEDIATE METABOLISM

variations also occur according to age and species. It is
worthy of notice here that gastric and pancreatic juice
have no action upon nucleic acid, and that intestinal juice
only converts it into the mononucleotide form. Nucleic
acid is therefore absorbed practically unchanged. The
conversion of nucleic acid into uric acid occurs almost
entirely in the Uver and spleen. It does not occur in the
kidney.

The Formation of Uric Acid from Muscle Hypoxanthine

Hypoxanthine exists in muscle combined with hexose
and phosphoric acid, forming inosinic acid. It is not
derived from adenine, for muscle contains no adenase.
The oxidation of muscle hypoxanthine to uric acid, sup-
posing this to occur, must have its seat in the liver, for
this is the only organ which contains xanthoxidase.

Factors Influencing the Formation of Endogenous Uric Acid

1. Muscular Activity: — The relation between the degree
of muscular activity and the amount of uric acid excreted
is not yet understood. An increase in purine excretion
does not always follow muscular exercise. Some have
found it to occur only when the exercise has been severe,
or when the form of the exercise is unusual. It is said
to follow involuntary muscular activity such as shivering
rather than voluntary exercise, and tonic rather than
repeated contraction. It has also been observed that the
increase of uric acid excretion occurs not immediately
but two or three days after exercise. The hypoxanthine
content of muscle is said to be increased after activity.
All we can say definitely is that muscular activity is not
necessarily associated with a contemporaneous liberation
of muscle purine.

2. Fevers. — The increased uric acid excretion which
invariably accompanies fevers is to be ascribed to the
abnormal breakdown of tissue, particularly of muscle.

PURINES 175

3. Diet. — A meal rich in proteins, though free from
purines, leads to an increase in the excretion of uric acid
which precedes the rise in urea excretion. Its causation is
not clear. It may be derived from the digestive glands
owing to their increased activity. It may be due to the
metaboHsm of leucocytes, the numbers of which in the
circulation are increased during digestion. The latter view
is supported by the fact that in leucocythsemia, a patho-
logical condition associated with a high leucocytosis, there
is a considerable rise in purine excretion. On the other
hand there is no quantitative relationship between the
rise in uric acid excretion and the degree of leucocytosis.

Purine Metabolism in Animals other than Man

Man is almost unique among mammals in excreting uric
acid as the principal end-product of purine metaboUsm.
Other mammals, with the curious exception of the Dal-
matian breed of dogs, carry purine metabolism one stage
further — to allantoine : —

HN— CO HN— CO NH,

OC C— NH. OC CO

I il >co I

HN— C— NH^ HN— CH— NH

Uric acid. Allantoine.

or
C^H.N^Oa -f H^O -f 0 = C.HgN.Og -f CO^

the allantoine being excreted by the kidneys.

The conversion of uric acid to allantoine is effected by
the enzyme uricase or uricolytic ferment, which is found
chiefly in the kidney and hver. This ferment is not
present in man.

In birds uric acid forms the chief end-product not only
of purine metabohsm but also of protein metabolism in

176 INTERMEDIATE METABOLISM

general. In these animals it is the most abundant nitro-
genous substance in the urine, urea being present only to
a shght extent. When the hver is short-circuited by an
Eck fistula the amount of uric acid excreted falls consider-
ably, its place being taken both in the blood and in the
urine by ammonium lactate. When an extract of avian
hver is digested with ammonium lactate, uric acid is formed.
In the bird, then, the liver synthesises uric acid, taking
the three-carbon-atom chain from ammonium lactate.

Gout

Our ignorance of the cause of gout arises largely out
of the uncertainty which exists as to the form in which
uric acid and its salts occur in the blood. Fresh blood
contains more uric acid after boiling with acids than
before. This suggests that some of the urates exist in
combination.

It is said that the sodium salts exist in two forms,
the lactam form, or a-urate—

NH— CO

I I

CO C— NH

I It
NH— C— NH

^CO

which is soluble but unstable, being readily converted into
the lactim form, or /3-urate —

N COH

I I

COH C— NH.

I II >co

N C-NH^

which is less soluble. It has been suggested that the
formation of gouty deposits is due to the conversion of
the soluble a- into the insoluble y5- form.

CREATINE AND CREATININE 177

4.— CREATINE AND CREATININE

These two substances contain the guanidine group —

I
HN=C

Creatine is methyl guanidine acetic acid —

NH CH3

II I

C N-CH2-COOH

I
NH2

It occurs in all tissues, but principally in skeletal muscle
(0-4 per cent.). In normal adult urine it occurs only
after a meat diet. It appears during starvation and in
fevers. It is constantl}^ present in the urine of children,
and in the urine of women during pregnancy and men-
struation.

Creatinine —

NH CH3

II I

C N— CH2

NH CO

is a dehydration product of creatine which can be obtained
by boihng creatine with acids. It occurs in normal urine,
1-2 grms. being excreted daily.

Effect of Administration

When creatine is given by the mouth some undergoes
bacterial decomposition in the intestine, some appears in
the urine partly as creatine, partly as creatinine, and some
disappears.
12

178 INTERMEDIATE METABOLISM

When creatine is injected into rabbits the greater part
appears unchanged in the urine, but some is deposited in
the muscles and some is excreted as creatinine.

Creatinine when administered by mouth can be recovered
almost completely in the urine.

Endogenous Creatinine

When an animal is fed on food free from these sub-
stances the daily excretion of creatinine attains a figure
(for men about 0-fi grm., measured as nitrogen) which is
remarkably constant, being influenced neither by diet nor by
work. On this account the source of creatinine is ascribed
to endogenous tissue metabohsm, of the extent of which
it therefore forms a measure. This view is supported by
the greater excretion of creatinine during growth and
during fevers.

Creatine of Muscle and Creatinine of Urine

The amount of endogenous creatinine excreted daily
varies directly with the degree of muscular development —
that is to say, with muscle mass. Muscular work increases
neither the creatine content of muscle nor the creatinine
content of urine. But a direct relationship has been estab-
hshed between creatine metabohsm and muscle tonus.
This is borne out by the following facts. Increased crea-
tinine excretion has been found in soldiers to follow pro-
longed standing at attention, but not marching. Decreased
creatinine excretion occurs during sleep. In artificially
induced convulsions, which involve increase of tonus, there
is an increase in the creatinine excreted and a decrease in
the creatine of the muscles. Finally, the percentage of
creatine in the uterus increases during pregnancy.

The appearance of creatine in adult urine seems to
coincide to some extent with periods of muscle break-
down. It occurs, for instance, in wasting diseases and
during the involution of the uterus following parturition.
The evidence seems to show, therefore, that the creatinine

. SULPHUR 179

of the urine is related to the creatine of muscle, and that
the latter is connected with the nutritional condition and
not with the activity of muscular tissue.

As regards the seat of formation of creatinine, the
diminution in this substance found in most hepatic diseases
points to its occurring in the hver. On the other hand,
creatinine continues to be excreted after the establishment
of an Eck fistula.

Concerning the substances from which creatine is formed
we have no definite knowledge.

It will be seen that the significance of creatine and
creatinine is far from clear. It is impossible in the present
state of knowledge to state what part these substances
play in metabolism.

5.— METABOLISM OF SULPHUR

Sulphur is taken into the body principally as cystine —
CH2- — S — S — CII2

I I
CHNH2 CHNH2

COOH COOH

a constituent of most food proteins.

Sulphur is excreted in the urine in three forms : —

1. Inorganic sulphates.

2. The so-called "neutral sulphur "—an incompletely
oxidised form the exact composition of which is unknown.

3. Ethereal sulphates.

It is also excreted in the bile as taurine, which enters
into the formation of one of the bjle-salts — sodium tauro-
cholate.

Inorganic sulphates resemble urea in their relation to
diet. After a protein meal the excretion of inorganic
sulphates and of urea rise and fall almost simultaneously.
It is therefore concluded that these sulphates, like urea,

180

INTERMEDIATE METABOLISM

originate in the exogenous metabolism of protein. The
cystine which is not required for tissue building, at the
same time as it loses its NHg groups loses also its two
sulphur atoms, which are oxidised and excreted.

The excretion of neutral sulphur, on the other hand, is
hardly influenced by changes in diet. On this account it
is considered to be of endogenous origin. The ethereal
sulphates are salts of phehyl-sulphuric acid and indoxyl-
sulphuric acid. They are formed in the following way :—

By bacterial decomposition in the intestine, and to a
lesser extent in suppurating tissues, tyrosine and phenyl-
alanine lose their side-chains and become converted into
phenol. By the same process tryptophane becomes con-
verted into scatol and indol. Phenol, scatol and indol,
all toxic substances, are then absorbed into the blood.
Within the body, probably in the hver, they become hnked
with sulphuric acid, phenol directly and scatol and indol after
oxidation to indoxyl. The effect of this hnkage is to deprive
these substances of their toxicity prior to their excretion.

The above changes may be expressed thus : —

CHjCHNH.COOH

Tyrosine.

Phenol.

HSO4
Phenyl Sulphuric Acid.

HO
HC

/\C

CO OH

CHNH, HC

CH, TT HC

C
CH"^

CH" NH

Tryptophane.

CH,
CH

'HC
HC

CH WH

Scatol.

/\C

CH
CH

CH NH
Indol.

^HC
HC

COH
CH

HC
HC

/\C

CHSO,

CH NH

Indoxyl.

\/c\/

CH NH

Indoxyl Sulphuric Acid

CARBOHYDRATES 181

The potassium salt of indoxyl sulphuric acid is known
as indican.

It follows from the origin of the ethereal sulphates that
the extent to which they are excreted is a measure of the
amount of intestinal putrefaction.

6.— CARBOHYDRATES

A carbohydrate is a substance containing carbon, hydro-
gen and oxygen, the hydrogen and oxygen being in the
same proportions as in water.

The principal carbohydrates fall into the following
groups : —

A. Monosaccharides or Hexoses (CeH^oOg).

Glucose (dextrose).
Laevulose (fructose).
Galactose.

The relation of these sugars to one another is seen from
their formulse.

CHO

CH2OH

H C OH

HO C H

H C OH

HO C H

H C OH

H C— OH

HO C H

CH2OH

Glucose.

CHgOH

Galactose.

CH2OH

Lsevulose.

B. Disaccharides {Q^^^^O^^).

Cane sugar.

Maltose.

Lactose.

182 INTERMEDIATE METABOLISM

These on hydrolysis yield two molecules of a mono-
saccharide according to the equation — ■

C12H22O11 + HgO = 2C6Hi20g.

Cane sugar yields glucose and Isevulose.

Maltose yields two molecules of glucose.

Lactose yields glucose and galactose.

All the above sugars except laevulose are dextro-rotatory.

C. Polysaccharides (CgHjoOg).

These are substances of very high molecular weight.
They include starch, inuhn, cellulose, glycogen and dextrins.

There exists also another series of sugars built up on a
j&ve-carbon-atom basis : —

Pentoses (CgH^oOg).

Pentosans (C5H8O4) are the corresponding poly-
saccharides. They occur in vegetable foods.

Digestion of Carbohydrates

During digestion polysaccharides and disaccharides are
converted into monosaccharides, the change in the case
of starch occurring in the following stages, recognisable
by the reaction with iodine : — ■

Starch

Soluble starch
(blue colour with Iodine)

Maltose

1
Erythrodextrin

(red colour with Iodine)

1
Maltose

Achroodextrin
(no colour with Iodine)

Maltose

1
Maltose

CARBOH YDRA TES 1 83

The conversion into maltose is effected by two ferments^
Ptyalin, present in saliva, and Amylase, secreted by the
pancreas. The disaccharides are hydrolysed by three fer-
ments present in the succus entericus — maltose by Maltase,
lactose by Lactase, and cane sugar by Invertase (so called
because in the process the optical activity of the solution
is inverted).

Metabolism of Carbohydrates

The only carbohydrates which can be absorbed by the
intestine are the monosaccharides. Of these the most
important is glucose. This sugar is the ultimate hydrolytic
product of starch, cellulose and maltose, and it is a con-
stituent of the disaccharides cane sugar and lactose. The
glucose absorbed is practically all oxidised in the tissues
to carbonic acid and water, the rate of oxidation being
determined by the activity of the tissues.

Glucose, then, is being added to the blood intermittently
from the intestine, and is beiftg destroyed at a rate varying
with the physiological activity of the body. Yet the
amount of glucose in arterial blood remains fairly constant
(0- 10-0- 15 per cent.). These facts indicate on the part of
the body a considerable capacity for carbohydrate storage,
and at the same time a mechanism for regulating a constant
currency of glucose in the blood.

The Excretion of Sugar

Glucose occurs in normal urine to the extent of about
1 part in 1000 — that is to say, in about the same concen-
tration as in the blood. Such an amount, however, is not
recognisable by the ordinary methods. When for any
reason there is an increase in the blood-sugar (Hyper-
glycsemia) glucose appears in the urine (Glycosuria), but
in a far higher concentration than in the blood. Assuming
that the kidneys are acting normally, glycosuria indicates
hyperglycaemia, though the amount of sugar in the urine
is no measure of the amount of sugar in the blood.

184 INTERMEDIATE METABOLISM

Carbohydrate Storage — Glycogen

Our knowledge of this subject dates from the epoch-
making researches of Claude Bernard (1855-1859). Bernard
first showed that the blood in the hepatic vein contained
sugar even after a flesh diet. This proved that the hver
had the power of forming sugar. He then showed that
when the liver was excised from a well-fed animal, the
blood washed out and the organ rapidly plunged into
boihng water so as to prevent any post-mortem change,
there could be extracted from it a carbohydrate to which
he gave the name of glycogen. If, however, he allowed
the excised hver to remain at blood-temperature sugar
began to form within it, and the glycogen at the same
time diminished. Bernard behevecl that the intercon ver-
sion of glycogen and glucose took place in both directions
during life, and he was led to regard glucose as an internal
secretion of the liver.

Glycogen is found, though not to the same extent as in
the liver, in almost every tissue, chiefly in skeletal and
cardiac muscle.

Glycogen is therefore the form in which carbohydrate
storage occurs.

The Regulation of Carbohydrate Metabolism

We now have to consider the mechanism whereby the
constancy of the blood-sugar is maintained although the rate
of absorption and the rate of utilisation are independent of
one another. It is clear that disturbance of this mechanism
in the direction of hyperglycsemia, \vith coincident glycosuria,
can be brought about in one of three possible ways. First,
there may be a failure to convert ingested sugar into
glycogen ; secondly, there may be an abnormal flooding
of the blood with sugar derived from glycogen ; thirdly, the
tissues may have lost the power of metabolising glucose.

We shall now discuss the conditions under wliich hyper-
glycaemia occurs, indicating as far as possible which of
these three metabohc faults is responsible.

CARBOHYDRATES 185

Alimentary Glycosuria

When carbohydrates are being digested and absorbed in
large amounts, glycosuria follows. The maximum amount
of any sugar which can be taken without causing glycosuria
is known as the Assimilation-limit of that particular sugar.
Considering that the rate of absorption must depend largely
upon the degree of motihty of the intestine, the amount
of secretion and other variable factors, it is not surprising
that the assimilation-Hmit should be subject to wide
fluctuations. In spite of this, there are wide differences in
the hmit of different sugars. For glucose, for instance,
it is about 200 grms., for laevulose 100-150 grms., for lactose
100 grms.

Ahmentary glycosuria is in itself no indication of a
profound disturbance of carbohydrate metabohsm. Its
occurrence merely signifies that the filtering capacity of
the Hver, if one may so put it, is overtaxed. But any
material lowering of the assimilation-hmit indicates an
impairment of hepatic function.

Neurogenic Diabetes

In his search for a nervous influence over the secretion
of sugar by the hver, Bernard discovered that glycosuria
could be caused by injury to the calamus scriptorius in
the floor of the fourth ventricle. This operation he called
" diabetic puncture," and the part of the brain so destroyed,
the diabetic centre.

The efferent nervous path is the splanchnic nerve.
Glycosuria can be excited reflexly by stimulation of the
central end of the vagus and other nerves. Though it is
clear from this that the sugar-forming function of the
hver is under the control of the central nervous system, it
is doubtful whether a diabetic centre in Bernard's sense
really exists. Glycosuria can be caused experimentally by
injury to the cerebellum, and it occurs frequently in man
after head injuries. Apart from trauma, glycosuria is

186 INTERMEDIATE METABOLISM

known to occur both in man and in lower animals when
they are in a state of emotional excitement. Concerning
this neurogenic form of glycosuria two points must be
noted. First, that it is only transient; secondly, that it
does not occur when the liver has been previously depleted
of its store of glycogen. The fault therefore hes solely in
an excessive discharge of glucose from the hver.

Before discussing further the manner in which the
excessive production of glucose is brought about it is
necessary to mention that glycosuria can be caused by
injection of adrenalin. This comphcates the problem con-
siderably, for we have to decide whether the diabetes is
due directly to the stimulation of the hepatic cells through
the splanchnic nerve or indirectly to the coincident
stimulation of the suprarenal glands.

Experiments on this point have led to conflicting results.
By some observers it has been found that after removal
of the suprarenals stimulation of the splanclmics fails to
cause glycosuria ; by others this has been denied. If, the
suprarenals being intact, the hepatic branches of the
splanclmics be cut and their peripheral ends stimulated
glycosuria occurs, while the same experiment performed
some time after excision of the glands causes only slight
glycosuria. These experiments indicate that sympathetic
excitation of the liver when the blood contains its normal
amount of adrenahn is adequate to provoke the conversion
of glycogen into glucose. When the splanchnics are stimu-
lated after division of their hepatic branches only a slight
degree of glycosuria occurs. We must therefore conclude
that in this form of glycosuria two factors interplay — the
direct action of the nerves upon the hepatic cells and the
coincident stimulation of the suprarenal glands.

Pancreatic Diabetes

When the whole or nearly the whole of the pancreas is
removed there follows a profound diabetic condition which

CARBOHYDRATES 187

leads rapidly to death. If a part of the pancreas be
grafted subcutaneously before the remainder of the gland
is removed, diabetes does not occur, but it supervenes
immediately upon the removal of the graft. This shows
that the diabetic condition is due not to the nervous
derangement incidental to such a severe operation, but to
some chemical influence exerted by the gland through the
blood-stream. The same fact is shown by the operation
of parabiosis. This consists in making a crossed arterial
connection between two animals so that their blood becomes
mixed. Removal of the pancreas from one then causes
diabetes in neither. When pancreatectomy occurs in
pregnant animals diabetes is delayed until after parturi-
tion, indicating that the foetal pancreas influences the
maternal blood.

The injection of blood from a depancreatised dog does
not cause diabetes in a healthy animal. The pancreas
therefore does not act by removing from the blood some
disturbing element. Analysis of the hver in this condition
shows that this organ has lost its power of forming and
retaining glycogen. But more important than this is that
the tissues have lost the poiver of utilising glucose. This
is proved by the fact that on injecting glucose there is no
rise in the respiratory quotient. The blood is therefore
flooded with sugar, which leaves it only through the
kidneys. Concerning the nature of the pancreatic influence
upon the glycolytic powers of the tissues nothing definite
is known.

So far we have seen that the rate of formation of glucose
by the liver is subject to nervous influences and to the
condition of the suprarenal glands, and that the presence
of the pancreas in the circulation is necessary both to
restrain glucose formation in the hver and to promote
glucose utihsation in the tissues. How far do these facts
furnish a reply to the question from which we started,

188 INTERMEDIATE METABOLISM

namely, how is carbohydrate metabohsm normally regu-
lated ? If the tissues, principally the muscles, require an
amount of sugar which varies with their activity, and if
the output of sugar from the Hver is subject to nervous
and chemical influences, there must be some mechanism
for adjusting the supply to the demand. The hyper-
glycsemia which is caused by emotional conditions may be
regarded as a mobihsation of sugar in anticipation of the
muscular efforts of offence or defence which will be demanded
of the animal by the cause of the emotion. But how is
the carbohydrate supply increased to meet a demand
unaccompanied by any emotional state, as in ordinary
exercise ? There are several ways in which the muscles
may influence the liver to satisfy their needs : — ■

1. The path may be nervous throughout, originating in
the afferent nerve-endings of the muscles and reaching the
hver by the sympathetic. The only evidence suggesting
such a mechanism is the reflex production of hyperglycsemia
above noted.

2. Changes in the composition of the blood may affect
the central nervous system, and this in turn the hver.

3. Changes in the composition of the blood may have
a direct chemical effect upon the hepatic cells.

4. The effect upon the liver may occur only through
an increased output of adrenahn, which may be caused
either reflexly or by changes in the blood.

Experiments, so far as they go, indicate that several of
these factors co-operate. Glycosuria, as we have seen, can
be produced reflexly by stimulation of afferent nerves.
As regards changes in the composition of the blood, these
may be of two kinds — a diminution in the amount of
sugar or an increased H. ion concentration. So far there
is no evidence that diminished sugar content has any
influence upon the hver. On the other hand, increased
sugar output has been observed to follow an increased
H. ion concentration, as after severe haemorrhage. Since

CARBOHYDRATES 189

this is not accompanied by increased adrenalin output it
must be a direct effect upon the Kver. But when the
muscular exertion is sufficiently intense to cause cerebral
anaemia increased output of adrenahn may occur, the
suprarenals thus playing a supplementary part in sugar
mobiUsation.

Phloridzin Diabetes

Phloridzin, a substance obtained from the roots of
certain trees, causes glycosuria on injection. The glyco-
suria, however, differs from those above described in that
it is not accompanied by hyperglycsemia. It is evidently
produced by a change in the permeabihty of the kidneys
to sugar. The renal origin of the condition is easily
proved. When the drug is injected into a renal artery
glucose is excreted from the corresponding kidney earlier
than from the opposite side. In spite of continued drainage
the percentage of sugar in the blood remains normal or
nearly normal. The need for making up in the blood the
amount of sugar lost through the kidneys leads to a dis-
turbance of carbohydrate storage and formation. The
importance of phloridzin diabetes therefore Hes in the hght
which it throws upon the capacity of the organism to
produce sugar.

Human Diabetes

The low respiratory quotient observed in diabetics shows
that this condition is due essentially to a loss of the power
of glycolysis by the tissues generally. Hyperglycsemia is
always present. The association of the disease with
degenerative changes in the pancreas was early noted,
and indeed was the cause of investigations into the influence
of that gland upon carbohydrate metabohsm. Whether
the pancreas is always at fault is not known. It may be
that pathological changes occur not visible on post-mortem
examination. As to the location of the cause of the
disease in the Islets of Langerhans, it has been found that

190 INTERMEDIATE METABOLISM

when the pancreas is incompletely extirpated the islets
show signs of hyperactivity when diabetes does not occur,
and degeneration without corresponding changes in the
other tissue when diabetes supervenes.

The Formation of Glucose and Glycogen

In order to find out what substances are capable of
forming glycogen three methods are employed. The sub-
stance in question may (1) be perfused through the excised
hver, (2) be administered to the animal after the hepatic
glycogen store has been exhausted by strychnine convul-
sions, (3) be administered to an animal rendered diabetic
by extirpation of the pancreas or by administration of
phloridzin. If in the last case the sugar excretion is
increased it is concluded that the substance normallv
undergoes conversion into glycogen.

Using these methods the following information has been
obtained : —

From Carbohydrates. — Glycogen is formed not only from
glucose but also from lajvulose, galactose, the ordinary
disaccharides and from starch and cellulose ; also from
formaldehyde and from lactic acid. It is not formed from
the pentoses or from the six-carbon-atom alcohols and
acids, such as glycuronic acid.

From Proteins. — In the diabetic condition there is a
constant ratio between the amount of glucose and nitrogen
excreted. This is called the D : N ratio. When protein
food is administered the excretion of glucose is increased.
In some cases as much as 58 grms. of glucose can be
obtained after ingestion of 100 grms. of protein. The pro-
duction of carbohydrate from protein is therefore proved.

As to the individual amino-acids which can be converted
into carbohydrate, it might be imagined that glucosamine,
which contains the glucose molecule preformed, would be
the principal source. But this is unhkely, first, because
glucosamine forms only a very small part of the commoner
proteins; secondly, because when given to the diabetic it

CARBOHYDRATES

191

yields less glucose than does casein, from which this amino-
acid is absent. Of the other amino-acids, several, including
glycine, alanine, aspartic acid and glutamic acid, have
been proved to be sources of glucose. The chemical
changes involved are sometimes very comphcated. There
is good reason to beheve that in some cases methyl-glyoxal,-
CH3CO.CHO, is formed as an intermediate compound.
There exist in various tissues ferments, called glyoxylases,
which transform methyl-glyoxal into lactic acid, the re-
action being reversible. Methyl-glyoxal yields glucose in
the diabetic organism, glyceric aldehyde being probably
an intermediate compound, for this also is a source of
glucose under the same conditions. Taking alanine as an
example, it is probable that the change takes place in the
following stages : —

CH2OH

CH,

13 V.Vii3 vyj^ig

II I

2 CHNHo->2 CH0H->2 CO

CH2OH

2 CHOH

CHOH

I
CHOH

COOH

CHO CHO

CHOH

Alanine.

Lactic acid.

Methyl
glyoxal.

Glyceric
aldehyde.

CHO

Glucose.

The conversion of protein into sugar appears to take
place not only in the hver but in the tissues generally, for
it occurs after the hver has been short-circuited by an
Eck fistula.

From Fats. — Either component of a fat, glycerine or the
fatty acid might conceivably form a source of carbohydrate.
Although the conversion of glycerine into glucose is not
difficult to perform in vitro, it has been consistently found
impossible to increase the excretion of glucose by admin-

192 INTERMEDIATE METABOLISM

istration of fats. On the other hand, in some cases of
diabetes when there is no carbohydrate in the diet the
D.N. ratio is higher than can be accounted for by the pro-
duction of sugar from protein alone. This points to sugar
production from fats. Though the evidence is inconclusive,
it seems that sugar is produced from fat to a far less
extent than from protein.

Further Metabolic Changes in Diabetes

Notwithstanding the inabihty of the tissues to burn
glucose, there is in the diabetic no decrease in the total
metabohsm or energy production of the body. The source
of energy must therefore be transferred to the proteins or
the fats. This is further shown by the low respiratory
quotient. In view of the large conversion of protein into
glucose which we have seen to occur it is obvious that the
abihty of the protein to take the place of carbohydrate
as an energy producer is very Hmited, little being left for
direct oxidation. The brunt of the work therefore falls
upon the fats, the exalted part played by them being
shown in the rise in blood fat (diabetic hpsemia). There
soon appear in the urine the so-called acetone bodies,
namely, /5-hydroxy butyric acid, acetoacetic acid and
acetone itself. These are unquestionably derived from
fats. How they are produced will be described later. It
is sufficient here to mention that their presence in the
urine shows that the oxidation of fats is not complete.
The tissues therefore either have a diminished capacity for
fat combustion or are unable to cope with the increased
fat oxidation consequent upon the failure to use proteins
and carbohydrates. The accumulation of acetone bodies
in the blood is indeed the usual cause of death in diabetics,
for these substances have a toxic effect upon the nervous
system. To some extent the body protects itself from
this accumulation of acids in the blood by combining the
acids with ammonia, which is thus deviated from its
normal conversion into urea.

CARBOHYDRATES 193

The Breakdown of Glucose

Though there are several ways in which glucose oxidation can
theoretically take place, it is most probable that the molecule first
splits into two molecules, each containing three carbon atoms.
These eventually become converted into lactic acid. Lactic acid
can be produced by the action of alkalies on glucose ; it is formed in
the body when the oxygen supply is inadequate ; it is formed on per-
fusion of a liver loaded with glycogen; when given to the normal
animal it yields glycogen, and when given to the diabetic animal,
glucose.

The intermediate steps between glucose and lactic acid may
probably be represented in this way : —

(Glucose)

I
CH2OH CHOH CHOH

CHOH CHOH CHO

I
CHaOHCHOHCHC

(Glyceric aldehyde) (Glyceric aldehyde)

I (Glucose) : j

CH2OHCHOHCHO CH2OHCHOHCHO

CH3COCHO

(Methyl glyoxal)

I
CH3 CHOH COOH

(Lactic acid)

Each of the above changes can be produced in vitro. Glycerine
(though not glyceric aldehyde) when perfused through the liver
yields lactic acid.

The further oxidation of lactic acid occurs probably through the
intermediate formation of pyruvic acid, acetaldehyde and acetic acid.

CH3 CHOH COOH

Lactic acid.

I
CH3 CO COOH

Pyruvic acid.

CH.CHO

Acetaldehyde.

CH3COOH

Acetic Acid.

CO2 H^O

It is now known that alcohol is not a usual intermediate compound,
13

194 INTERMEDIATE METABOLISM

7.— FATS

A large class of substances occurring in living matter
are distinguished by having a greasy consistency, by being
insoluble in water but soluble in ether. They are known
as Lipoids, and they include the fats, oils, waxes, sterols,
phosphatides and cerebrosides. The simplest hpoids are
the fats.

A fat is an ester formed by the condensation of one
molecule of glycerine CHgOH . CHOH . CH2OH with three
molecules of a higher acid of the ahphatic series — the
so-called fatty acids. It is therefore called a triglyceride.
Fatty acids are of two kinds : —

(a) Saturated Fatty Acids. — These are homologues of
acetic acid, ha\dng the general formula C„H-2„ + iCOOH.
The most commonly occurring members of this group are
Palmitic Acid —

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2

CH2COOH
or C15H31COOH,

and Stearic Acid —

C17H35COOH.

(6) Unsaturated Fatty Acids. — The commonest member
of this group is Oleic acid, which belongs to the oleic series,
the members of which have one unsaturated hnkage.
General formula —

C'fll' (in - 1)C00H.

Oleic acid is —

CH3(CH2)7CH = CH(CH2)7COOH

or Ci7H33COOH.

Fatty acids also occur having a higher degree of unsatu-

FATS 195

ration, such as those of the Unoleic series, C„H(2„-3)COOH,
and the Unolenic series, C,iH(2«_r))C00H.

As an example of the constitution of a fat we may give
glycerine tripalmitate : —

CH2

I
CH.

OOCC13H31
OOCC15H31
OOCC13H31

On boiling with alkahes {saponification) fats are hydro-
lysed, cleavage occurring, at the dotted Une above, into
glycerine and the sodium or potassium salt of the fatty
acids (soap).

Saturated and unsaturated fatty acids differ from one
another physically and chemically, the most important
differences being — •

1. The Melting-point. — Palmitic and stearic acids are
sohd at 60°, while oleic acid is liquid at 0°. When the
fatty acid is combined with glycerine to form a fat it
impresses upon that fat a melting-point which approaches
its own.

2. Behaviour to the Halogens. — Unsaturated acids readily
combine with the halogens, forming saturated compounds.
Oleic acid, for instance, with iodine forms —

CH3(CH2)7CHI - CHI(CH2),C00H.

Since the iodine can be introduced at every double
hnkage, the amount of iodine thus taken up forms a
measure of the degree of unsaturation of the acid ; and
since the double hnkage remains unaffected in the synthesis
of a fatty acid with glycerine, the resulting fat will absorb
the same amount of iodine as the fatty acid of which it is
composed. The amount of iodine with which a fat can
combine is called its iodine number.

Fats as they occur in the body are mixtures of different

196 INTERMEDIATE METABOLISM

triglycerides, and since the properties of each triglyceride
depend upon its fatty acid constituent, the properties of
a mixed fat depend upon the proportion in which saturated
and unsaturated fatty acids are present. So by estimating
the melting-point and the iodine number of a mixed fat
we have a measure of the degree of saturation of the fatty
acids composing it.

Complex Lipoids

Phosphatides {Phospholijnnes). — These may be regarded
as fats in which one fatty acid molecule is replaced by
phosphoric acid, by means of which it is hnked to the
base Choline —

C2H4OHX /CH3
>N^CH3

OW ^CHg

The most important member of this series is Lecithin — ■
CH2OOC15H31

CHoO. .0

OH^ ^OC2H4. /CH3

>NfCH3

Lecithin and allied substances form a constituent of all
living cells.

Cerehrosides {Galactolipines) are compounds of fatty acids
with nitrogen and galactose. They occur largely in nervous
tissue.

Lipoids may therefore be said to exist in the body in two
forms, as simple triglycerides and as more complex bodies.

FATS 197

Between these forms there is an important histological
difference. The fats which are visible to the naked eye,
or are visible in globular form through the microscope, and
stain with the usual reagents are the triglycerides. They are
the fats of ordinary adipose tissue. The complex fats, such
as lecithin, are not visible microscopically, do not stain
in the usual way, but under certain pathological conditions
glycerides may separate out from the complex fats, and
form globules which stain in the characteristic manner.

It is sometimes necessary to find out in any tissue how
much of the hpoid substance exists as triglyceride and
how much in the complex form. This is done by estimating
the proportion of fatty acid to the total hpoid. Comparison
of the formulae given above for glycerine tripalmitate and
for lecithin shows that the fatty acid constituent accounts
in the former for about 95 per cent, and in the latter for
about 60 per cent, of the whole molecule.

Absorption of Fat

Fat exists in blood in the form of ultra-microscopic
particles — the blood-dust. Its amount is increased after a
fat-rich meal. The greater part of the fat enters the blood
through the lacteals and thoracic duct. When the thoracic
duct is Hgatured, fat continues to leave the intestine,
though no demonstrable increase can be found in the
systemic circulation. The fat is evidently transported
from the intestine and deposited elsewhere with great
rapidity. The site of such deposit appears to be the liver,
for when fat absorption is in progress the fat in the portal
vein exceeds that in the jugular vein.

In spite of the appearance of fat droplets within the
intestinal epithehum, there is overwhelming evidence to
show that fat is only absorbed after saponification into
soaps and glycerine, and that these, after passing through
the epithehum, are resynthesised. The evidence in favour
of this view is as follows : —

198 INTERMEDIATE METABOLISM

1. There would be no reason for the existence of pan-
creatic Hpase if such saponification were not necessary.

2. When a mixed emulsion of fats and hydrocarbon oils,
such as turpentine, is introduced into the intestine fats
only are absorbed. For absorption, therefore, something
more than division into a fine particulate state is necessary.
The substance must go into solution, and this in the case
of fats can only occur by saponification.

3. When fats are introduced into the intestine they
'appear in the chyle as neutral fats. Synthesis with

glycerine from some source unknown has therefore occurred
in the intestinal wall.

4. Certain esters introduced into the intestine appear in
the thoracic duct modified as regards both their basic and
their acid constituents. Such a change could only occur
after saponification.

The strongest evidence for the theory that fats may be
absorbed as such is the fact that when fats are administered
stained they appear stained in the thoracic duct. But
this is due to the stains being soluble in the soaps.

The evidence therefore points to a saponification pre-
ceding and resynthesis succeeding absorption. Whether
the two changes are brought about by different ferments or
by the same ferment acting reversibly according to the
laws of mass action we do not know.

The same problem occurs in the passage of fats between
the blood and the cell for the purpose of storage or com-
bustion. If such a transference necessitates saponification
we must assume the ubiquitous existence of hpolytic and
hpo genie enzymes.

The existence of fat in the body may be discussed under
three headings.

1. The Fat Depots. — These are principally the sub-
cutaneous tissues, omentum and peritoneum. The high
percentage of fatty acid (95 per cent.) indicates that the fat
exists in the form of simple triglycerides. Its low iodine
number shows the high proportion of saturated fatty acids.

FATS 199

The character of the depot fat is easily influenced by the
kind of fat in the diet. In dogs fed on mutton fat, for
instance, the depot fat approaches mutton fat in type.
This would seem to show that transformation of food fat
into a particular kind of body fat within the intestinal
wall does not normally take place to any appreci'able
extent, and that the character of the depot fat is an
average of that of the fats eaten ; there being normally
very little change of diet, the character of the depot fat
remains fairly uniform,

2. The Tissue Fat. — By this is meant the fat which is
built up into the structure of the hving cell, and not that
which is found fiUing up the spaces in every tissue. The
latter is only a form of depot fat. Tissue fat differs from
depot fat in two respects. First, the fatty acids form
only 05 per cent, of the molecule, suggesting that they
are built up into a complex molecule, such as lecithin.
Secondly, it has a high iodine value, indicating a high
percentage of unsaturated fatty acids. The characteristics
of tissue fat do not varv with the diet.

3. The Liver Fat. — -The liver contains a higher propor-
tion of fat than any other organ, in man as much as
70 per cent, of the dry substance being fatty acid. Under
ordinary conditions the liver fat resembles tissue fat in
having a high iodine value and a low percentage of fatty
acid ; the fat is therefore in the form of a lecithin. But
after the ingestion of a considerable amount of fat of low
iodine value, the liver fat assumes a low iodine value,
this change preceding the similar change which occurs in
the depot fat. Fat after absorption, therefore, is first
deposited in the Hver.

In the condition known as fatty itifiltration there is a
deposit of fat in visible triglyceride form in the hepatic
cells. This occurs naturally during pregnancy and lacta-
tion, and pathologically in diabetes and after poisoning with
chloroform or phosphorus. The fat deposited comes not
from the complex hpoids of the liver but from the fat

200 INTERMEDIATE METABOLISM

depots. This is proved by the following experiment. Two
dogs are fed, one of them on an ordinary diet, the other
on hnseed oil. On poisoning them with phosphorus the
hver fat is fomid to be composed, in the former, of ordinary
dep^t fat of the dog; in the latter, of hnseed oil. The
origin of the hver fat is therefore from the intestine and
from the depots. Arrived at the liver, the fat undergoes
two changes : double linkages are introduced {desaturation),
whether the fatty acids were previously saturated or
unsaturated. Thus there are formed fatty acids still more
unsaturated than oleic acid. The other change consists
in the building wp of the fat into lecithin, indicated by the
fall in the proportion of fatty acid.

In other words, the hver converts the fat from the
form in which it exists in the food and in the depots into
the form in which it exists in the living cell. From this
it would appear that the hver prepares the fat for use
in the tissues, fat being more easily burnt after being
desaturated. The process of desaturation also occurs in the
tissues in general, but to a less extent than in the liver.

Formation of Fat from Carbohydrate

Though the conversion of carbohydrate into fat in the
body must have been beheved in for centuries, it was not
until 1852 that it was actually proved. In that year
Laives and Gilbert took two pigs of similar size and weight
from the same htter. One they killed, and estimated the
fat, protein and carbohydrate content of its body. The
other they fed on a diet of known composition. After a
few months this pig was killed and analysed. The amount
of fat present in this animal over and above that which
was present in the animal killed earher was found to be
far in excess of the maximum which could theoretically
have been derived from the fat and protein of the food.

A second proof of the conversion of carbohydrate into fat
is alleged from the study of the respiratory quotient. In
the early stage of hibernation the respiratory quotient

FATS 201

rises to an abnormally high figure (l-2-l'3). Assuming
that there is not an abnormal retention of CO2 in the body,
this can only be explained by supposing that carbohydrates
are being converted into fat, and that in the transformation
a certain amount of oxygen becomes available for oxidation
(p. 152).

The formation of glycerine from carbohydrate must be
a very simple matter, as will be seen by a comparison of
the formula? : —

CH20H

CH2OH

CHOH

-> CHOH

CHOH

CH2OH

CHOH

CH2OH

CHOH

^ CHOH

CHO

CH2OH

But as regards the fatty acids the question is more
difficult. It is probable that the carbohydrate is first
broken down into simpler compounds, such as acetaldehyde,
CH3CHO, and pyruvic acid, CH3COCOOH, and that the
fatty acids are built up from these.

Formation of Fat from Protein

The evidence for the formation of fat from protein based
upon a study of fatty infiltration and degeneration, is now
known to be fallacious. We have already seen that fatty
infiltration is due to mobihsation of fat from the depots.
In fatty degeneration, such as occurs in the heart after
diphtheria or in peripheral nerves after separation from
the nerve-cell, there is a deposit of fat from the tissue
itself. This, however, is not derived from protein, but is
an unmasking of the fat from lecithin.

202 INTERMEDIATE METABOLISM

We have, indeed, no direct evidence of the transforma-
tion of protein into fat, except the fact that some amino-
acids yield /?-oxybutyric acid on administration to the
diabetic animal. But we know that protein can be con-
verted into carbohydrate and that carbohydrate can be
converted into fat. There is therefore no reason why
protein should not indirectly be converted into fat when-
ever fat is being rapidly laid down.

Oxidation of Fats

The first step, as we have seen, appears to be an intro-
duction of double hnkages, forming acids of the unsaturated
series. It is now universally beheved that oxidation of
fatty acids occurs in the /5-position — that is to say, that the
carbon atoms in the chain (and they are always straight
chains) are spUt off two at a time. This is the evidence : —

1. In animal fats only those fatty acids occur which
have an even number of carbon atoms.

2. In butter all the even series are present from those
containing eighteen to those containing four carbon atoms.

3. When fats are burnt incompletely, as in diabetes, we
can detect substances partially oxidised in the /5-position :
/3-hydroxybutyric acid, CHg CHOH CHg COOH, and aceto-
acetic acid, CHg CO CHg COOH.

4. On perfusion of the hver with various fatty acids
the formation of acetoacetic acid occurs only when the
fatty acids have an even number of carbon atoms.

5. Knoojps Experiment.— When benzoic acid is adminis-
tered it is excreted combined with glycine in the form of
hippuric acid —

CeHgCOOH + NH2CH2COOH= CgHsCONHCHaCOOH.

When the next homologue, phenyl-acetic acid, is given,
this, too, is combined with glycine, w^th formation of
phenaceturic acid^ —

CfiH.CHoCOOH + NH0CH2COOH =

C«H.CH,CONHCH,COOH,

THE OXIDATION PROCESS

203

Continuing up the series, phenyl-propionic acid is excreted
as hippuric acid, showing that two atoms of carbon have
first been spht oi! and benzoic acid formed.

The next member of the series, phenyl-butyric acid, is
excreted as phenaceturic acid, showing that it has first
been oxidised to phenyl-acetic acid. And so on alternately.
These facts may be tabulated thus : —

Benzoic .
Phenyl acetic .
Phenyl propionic
Phenyl butyric
Phenyl valeric

Acid fed.

CeH^COOH
CsHsCHjCOOH
OsHsCH/JHaCOOH
, C.HsCH^OHjOHaCGOH
CjHjOHjOHjOHeCHjCOOH

Oxidised to

(not oxidised)
(not oxidised)

C'eUjCOOH

OeH.OHjCOOH

C'dHsCOGU

Excreted as

CeHsCONHOHjCOOH
OeHsCHjCONHOHjOO OU
CsHsCONHCHjCOOH
OeHsCHjCONHCHjGOOU
CeHjCONHCHjCOOH

It will be seen that the number of carbon atoms spht
ofE is always even. Phenyl valeric acid would appear to
be oxidised thus : —

CfiHrCHoCHoCHn

CHoCOOH

CeHsCHaCHaCOOH
CeH^COOH.

As to the oxidation of the two-carbon-atom chain we
have no certain information.

8.— THE OXIDATION PROCESS

The nature of the oxidation of the foodstuffs is not yet
completely elucidated. How are substances such as fats,
which normally are so difficult of oxidation at body tem-
perature, oxidised so easily in the tissues ? Why, under
certain circumstances, can some foods be oxidised and not
others, as in diabetes 1

It is beheved that the oxygen must first be converted
into atomic form through the formation of certain peroxides.
A large number of substances, including aldehydes, carbo-
hydrates, etc., undergo on exposure to oxygen at ordinary
temperature slow oxidation, with intermediate formation of
peroxides. An example is seen in the case of benzaldehyde —

QH.CHO -f 0., - CeH.CO . 0 . OH.

Benzoyl hydrogen peroxide.

204 INTERMEDIATE METABOLISM

Now the peroxide can, in undergoing further oxidation,
impart an atom of oxygen to any substance which is
capable of oxidation. This may be either another molecule
of benzaldehyde —

CgHgCO . 0 . OH + CeHjCHO = 2C6H5COOH,
or any other oxidisable substance present —

CeH.CO . 0 . OH + Indigo = CeH^COOH +

oxidation product of indigo.

It is beheved, therefore, that the cell contains peroxides
which act hke benzaldehyde in the above reaction, taking
up molecular oxygen and imparting it to the food molecules
as atomic oxygen.

This view is borne out by the close similarity which
exists between the oxidation processes which take place
in the body and those which occur in vitro by the action
of the simplest peroxide, hydrogen peroxide. To give an
example. Butyric acid is in the body oxidised to ace to-
acetic acid. The only agent capable of effecting the same
change outside the body is hydrogen peroxide. But it
cannot be hydrogen peroxide itself which is responsible
for oxidation in the tissues : first, because this substance
is toxic ; secondly, because several tissues contain a ferment
catalase, which decomposes it with liberation of oxygen in
molecular and therefore inactive form.

The transference of atomic oxygen from the peroxide to
the substance undergoing oxidation is effected by means
of enzymes called peroxidases. The existence of such
enzymes has been demonstrated in certain vegetable
tissues.

Hydrogen peroxide alone has a very slow oxidising
effect on lactic acid, but in the presence of the hving cells
of the horse-radish oxygen is rapidly transferred from the
H2O2 and oxidises the lactic acid. Now a similar accelera-
tion occurs in the presence of traces of ferrous or manganese
salts. For this reason, and also because either iron or
manganese is nearly always found in the ash of peroxidases,

THE OXIDATION PROCESS 205

the view is held by some that peroxidases consist of these
metals in colloidal form.

Peroxide and peroxidase form together a system known
as an oxygenase. The failure of oxidation of certain sub-
stances which sometimes occurs can only be explained by
supposing that different oxygenases exist for different
substances, the specificity applying to either component
of the system or to both.

CHAPTER XI

NUTRITION

The choice of a diet is primarily a question of instinct.
But instinct, while it can be trusted to provide a sufficiency
in amount, may err in providing too much or in not pro-
viding a sufficiency in kind. In order that the diet may
be adequate for the proper performance of the bodily
functions, it must be sufficient in amount as a source of
energy, and in kind as containing in proper amount all
those substances which are necessary for the maintenance
of the body structure and which cannot be synthesised in
the body. The best diet is that which fulfils these functions
with the most economical working of the digestive apparatus.

THE CARBON BALANCE

Assuming that the food is of such a nature as to provide
adequately for the maintenance of the machine, we can
inquire as to the amount and form in which it is best suited
as a source of energy. As to the amount, this can be
determined by comparing the carbon taken in as food and
the carbon excreted. If these are equal the individual is
in a condition of carbon balance, and the food is sufficient
as a source of energy. If intake is in excess of output the
energy supply is more than sufficient and storage is taking
place. If output is in excess of intake the food is insufficient
and the body is hving upon the stores previously accumu-
lated or upon the tissues themselves.

The following figures may be taken as showing the
amounts of the three main classes of foods habitually eaten,

206

THE CARBON BALANCE 207

the lower figures applying to sedentary, the higher to
manual workers : —

Carbohydrate . . . 370-570 grms.

Fat 50-100 „

Protein .... 120-150 „

Since all three classes serve as a source of energy, the
question arises as to what extent each of these is necessary.
In view of the considerable powers possessed by the body
of converting one form into another, it might be thought
that each could to a large extent be replaced by either of
the others.

The Corbohydrate Itequirement . — We have seen how the
body always maintains a constant sugar content of the
blood ; how when need arises, as in phloridzin diabetes,
it transfers proteins into carbohydrates. When carbo-
hydrates are withheld from the diet there follows a pro-
found disturbance of metabolism, due to incomplete
oxidation of fat. Carbohydrate, as such, is therefore a
necessary component of the diet, but the minimum amount
necessary is not known.

The Fat Requirement. — When fats are absent from the
food, evidence of malnutrition soon appears, due, as we
now know, not to a lack of fat as fuel, but of certain
substances present in fat which act in some way other
than as energy producers. Whether the body can live
without fat as a source of energy is not yet determined.

The contraction of isolated muscle can be carried to
the point of fatigue without any depletion of the fat
present in the muscle. But this may be due to the
absence of the circulation; there may be wanting some
hormone necessary for the preparation of the fat for the
furnace.

The oxidation of fat occurs normally without inter-
mediate conversion into carbohydrate. This indicates that
in the hving cell carbohydrates and fats are being oxidised
together.

208 NUTRITION

THE PROTEIN REQUIREMENT— NITROGEN BALANCE

Protein cannot be considered merely as a source of energy
owing to the important part which it plays in maintaining
the body structure. The adequacy of the protein supply
can be tested by comparing the nitrogen ingested with the
nitrogen excreted — the nitrogen balance. This at once
shows that proteins have a more complex metabolic history
than carbohydrates or fats. In the first place, it is im-
possible in the healthy adult to induce a surplus of intake
over output of nitrogen merely by feeding with excess of
protein. There is no retention of nitrogen except during
growth or convalescence. In the second place, reduction
of nitrogen intake leads to an excess of output over intake,
even though there may be an adequate carbon and there-
fore calorie supply. This adverse nitrogen balance is seen
in its most extreme form in starvation, when the nitrogen
output falls to a low value (about 10 gms.), which is
constant day by day. When to the starving person is
given daily an amount of protein corresponding to the
amomit of nitrogen which he lost daily when starvation
was complete there is still an excess of output over intake.
It is not until the nitrogen intake is two and a half times
the starvation output that equiUbrium is attained. But
when in addition to the protein, carbohydrate or fat is
given, nitrogen equihbrium is reached with a lower protein
intake. This is the protein-sparing action of the non-
nitrogenous foods.

These facts show that of the protein which is absorbed,
part, in virtue of the carbon which it contains, goes to
supplying energy — this is the part which can be replaced
by carbohydrates or fats. The other part has a fate other
than that of supplying energy — it becomes built up into
the hving cell.

From a study of the nitrogen balance we therefore come
to the same conclusion regarding protein metabolism as
we did from a study of the efiect upon nitrogen ehmination

THE PROTEIN REQUIREMENT 209

of variations in the diet (p. 165). The fate of the protein
is twofold : either exogenous or endogenous.

If the place of the exogenous portion of the protein
absorbed can be taken by carbohydrate or fat it should
be possible to reduce the protein intake very considerably —
down to endogenous requirements, provided that non-
nitrogenous food is given in abundance. This considera-
tion led to the Chittenden experiments, in which different
classes of people were fed on a very low protein diet for
a period of several months. Chittenden claimed that
health and working capacity were improved owing to
diminished strain upon the kidneys and diminished intes-
tinal putrefaction. If Chittenden's results are correct they
constitute a severe indictment of human instinct, for man
in almost every race takes a far more hberal protein
supply. The experiments have been subjected to con-
siderable criticism. The period over which they were
performed, long as it was, was not long enough to allow
conclusions to be drawn. Again, nations which for any
reason subsist on a low protein diet are distinguished
by a low degree of virihty and increased susceptibility to
bacterial infection.

The Need for Individual Amino-acids

A more serious criticism of Chittenden's theory is that
for the purpose of maintaining the structure of the tissues
it is the form of the protein that matters. The capacity
of the animal body to manufacture amino-acids is, as we
have seen, limited to very few of these. The majority
have to be obtained from the food. Since the amino-acids
are present in varying quantities in different proteins, and
since in some proteins certain amino-acids may be present
only in minute quantity, it follows that the adequacy of
any given protein for tissue-building depends upon its
content of the amino-acid present in least amount, and
that any protein deficient in an amino-acid which the
animal cannot svnthesise is inadequate even though it may
14

210 NUTRITION

have been given in liberal amount, measured by its nitrogen
content. In other words, the character of the protein is of
more importance than the quantity.

In the diet of civilised communities this question does
not often arise owing to the fact that man has obeyed his
instinct in taking a large and varied protein diet, thus
ensuring that every amino-acid will be present in adequate
amount. But when the protein intake is reduced, as in
Chittenden's experiments, it becomes a question whether
the border-hne is not reached so far as any individual
amino-acid is concerned.

Of recent years many experiments have been performed
to demonstrate the need for individual amino-acids. The
pioneer work was performed by Hopkins in 1906. Hopkins
fed rats on a diet of protein, fat and carbohydrate, in
which the protein took the form of zein — a protein deficient
in tryptophane, lysine and glycine. Though the diet was
abundant as regards its calorie value, the animals lost flesh
and died within one to four weeks. On adding tryptophane
to the diet, they lived some time longer and for a time
maintained their weight. Later experiments have shown
that on adding lysine as well as tryptophane growth and
health are restored. Lysine and tryptophane, therefore,
are needed by the hving tissues.

Maintenance and Growth

Nutrition is adequate in the adult when it maintains
the efficiency of the body, and in the young when in
addition to this it provides for the normal rate of growth.
What is the normal rate of growth? Growth depends
upon two factors — the growth factor and the food factor.
The growth factor is the inherent tendency to grow, which
is subject to individual variations, depending upon the
laws of heredity. It sets the upper limit to growth which
no amount of feeding can overstep. The part which the
food factor plays lies in providing the material upon which
the growth factor can work. The normal rate of growth

V IT AMINES 211

is therefore the rate of growth determined and limited by the
growth factor.

Is there a distinction between the food requirement for
maintenance and the food requirement for growth? This
question has been answered in the affirmative by Osborne
and Mendel. These observers fed young rats on a diet
in which the sole protein was gliadin, which is deficient
in lysine, and found that they remained in good health
but ceased to grow. On the addition of lysine to the diet
the stunted animals resumed their growth. Lysine there-
fore, while not essential for maintenance, is necessary for
growth, while its temporary absence from the diet does not
lead to loss of the capacity to grow. Lysine is necessary
for the full play of the growth factor.

ACCESSORY FOOD FACTORS— VITAMINES

Within the last few years there has been accumulating
chnical and experimental evidence to show that something
more is required in the diet than carbohydrates, fats,
proteins and inorganic salts. There are also necessary
certain substances which the animal cannot manufacture,
and which must therefore be derived in the first instance
from plants. They are termed accessory food factors or
vitamines. For our knowledge of these substances we are
indebted to Hopkins.

Their chemical nature is entirely unknown. As to the
part they play in the animal economy, it is clear from the
minute amounts which are sufficient that they do not
contribute energy. They must therefore either form cer-
tain components of the cell architecture or play a part,
like catalytic agents, in determining or regulating metabohc
changes.

Absence of these substances leads in the young to
failure of growth, and in both young and old to signs of
malnutrition, decreased fertility, and abnormal proneness
to infection, and in extreme cases to the development of
certain specific diseases — " deficiency diseases^

212 NUTRITION

There are three such food factors hitherto recognised : —

1. Fat-soluble A. — ^This substance is contained in most
animal fats and oils. It is present also in the seeds and
green leaves of plants, where its synthesis evidently occurs.
Insoluble in water, it is soluble in anything which dissolves
fats. It is destroyed by heating at 100° C. for four hours.
Though not synthesised, it is evidently stored in the
animal body, probably in the depot fat, for when the
substance is withdrawn from the diet there is a shght delay
before signs of malnutrition set in.

Present-day evidence suggests that deficiency of this
substance is the primary cause of rickets.

2. Water-soluble B. — This substance is present in all
foodstuffs in their natural condition. It is most abundant
in yeast, in the embryo of seeds and in birds' eggs. It is
soluble in water and alcohol, but not ether. It is resistant
to drying and to heat at 100° C, but it is destroyed
at higher temperatures. When it is absent from the diet
pathological effects follow immediately, showing that it
is not stored in the body. Recovery is equally rapid on
its restoration. Deficiency of Water-soluble B causes a
profound disturbance of the cerebral nervous system-
muscular weakness and inco-ordination. Now a similar
disturbance is found in the disease beri-beri, which occurs
in communities where the sole diet consists of maize from
which the embryo has been removed in the process of
mining. An analogous condition produced in birds by
similar feeding is called avian polyneuritis. It is beheved
by some that the " anti-nenriiic " substance whose absence
is responsible for beri-beri and polyneuritis is identical
with Water-soluble B.

3. Anti-scorbutic. — This is the substance the absence of
which causes scurvy. It is present in tissues ujjiich are
metabolically active ; it is absent from dry seeds, for instance,
but appears on germination. It is readily destroyed by
heat. It is present most abundantly in cabbage leaves,
in lemons and in oranges.

SUMMARY 213

What has been said above regarding nutrition may be
thus summarised : —

1. Food is required for two purposes — maintenance and
growth. There is some evidence that certain substances
are necessary for the latter and not for the former.

2. The adequacy of a diet has a quantitative and a
quahtative aspect. Quantitatively, an adequate supply of
calories is required to provide energy for the hfe-processes.
For this purpose proteins, fats and carbohydrates are to
a great extent mutually replaceable. But besides the
calorie supply there is need for certain substances which
cannot be made by the animal body. Some of these are
amino-acids. Others are bodies of unknown composition,
called vitamines. These substances are necessary not as
energy providers but as contributing some essential part of
the cell-machine.

CHAPTER XII
URINE

Constitution of Urine

Total Quantity. — ^The average quantity passed by adults
in twenty-four hours is 1500 c.c. Of this the greater part
is secreted during the day.

Physical Characteristics. — Urine has a clear yellow colour,
except after heavy meals, when it may be turbid, due to
calcium phosphate and carbonate. On standing, these
salts form a precipitate which redissolves on heating.
The average specific gravity is 1018, but it varies between
1002 and 1040, according to the volume of urine passed.

Reaction. — Urine is normally acid to htmus. Its acidity
is greatest after a meat diet, owing to formation of sulphuric
and phosphoric acids. On a vegetable diet and during
secretion of the acid gastric juice it becomes alkahne.
The variabihty in the reaction of the urine is one of the
means whereby the reaction of the blood is kept constant.
\Yhen for any reason the Ph of the blood decreases {i. e.
the blood becomes more acid), the normal reaction is
restored partly by excretion of acid sodium phosphate.

Urinary Pigments.
Urochrome.
Uroerythrine.

Urobilinogen — derived from bile pigment. On stand-
ing it is converted into urobihn.

Inorganic Constituents.

Metals. — Sodium, potassium and traces of Ca, Mg

and Fe.

214

FUNCTIONS OF THE KIDNEY

215

Acids. — Chlorides, phosphates and sulphates. Sulphur
is also excreted in a less oxidised form of unknown
constitution — neutral sulphur.

Average Constitution of a Daily Output of Urine

Total Quantity

1500 grms.

Water .

1440

Total Sohds

Urea .

35-0 ,

Uric Acid .

0-75 ,

Hippuric Acid

1-05 ,

Ammonia .

0-65 ,

Creatinine .

0-9 ,

Sodium

5-5 ,

Potassium .

2-5 ,

Calcium

0-26 ,

Magnesium

0-21 ,

Chloride

9-0 ,

Sulphate

2-7 ,

Phosphate .

3-5 ,

The history of the organic constituents is discussed

under metabohsm.

Functions of the Kidney

The functions of the kidney are three : —

1 . To remove waste products from the blood ;

2. To keep the volume and sahne content of the blood

constant ;

3. To keep the reaction of the blood constant.

In considering the manner in which urine is formed it
must be remembered that although we use the word
secretion in this connection, the kidney difl'ers from a
secreting gland, such as a gastric gland, in the following
fundamental respects.

1. Developmentally it is of mesodermal origin, while
most other glands are formed by invagination from the gut.

216 URINE

2. With the exception of hippuric acid, the kidney does
not elaborate the substances which it secretes. It merely
separates them from the blood and alters their concentration.

3. The kidney being an excretory organ, its activity is
readily influenced by changes in the composition of the
blood with which it is supplied.

To account for the manner in which the kidney performs
its work it is necessary to explain —

1. Why some substances are separated from the blood
while others are not ;

2. How the former came to attain a different degree of
concentration in the urine from that in which they exist
in the blood ;

3. What part is played in the process by the glomerulus
and what part by the tubules ;

4. Whether the process can be explained on physical
grounds or whether it is necessary to invoke the specific
activity of the cells ;

5. How diuretics act.

THE FORMATION OF URINE

Structure of the Kidney

Certain essential features of the renal anatomy must
be borne in mind. The functional unit of the kidney
consists of glomerulus, Bowman's capsule and the tubule.
The capsule is the dilated bhnd end of the tubule inva-
ginated to form a cup. In this cup is situated the glomeru-
lus or tuft of capillaries. The invaginated layer of the
capsule is formed of thin, flattened epithelium, which
embraces the glomerulus. The tubule follows a devious
route towards the pelvis of the kidney. In its first part,
the first convoluted tubule, it is, as its name imphes, much
twisted. Here it hes entirely in the cortex. This leads
into the second part, the descending limb, which pursues
a radial course into the medulla. Arrived there, it doubles
back upon itself at the loop of Henle, and returns to

STRUCT V BE OF THE KIDNEY 217

the cortex as the ascending limb. This leads into the
second convoluted tubule, beyond which it unites with
neighbouring tubules to form one of the junctional tubules
which traverse the medulla radially and open at the apex
of a pyramidal projection into the pelvis of the kidney.

The cells hning the tubule differ in different parts. In
the first and second convoluted tubules and in the upper
half of the descending hmb the cells are high columnar,
with well-marked striations formed of rows of granules
in the outer half and at the inner free border, which is
cihated. Though the tube is wide the lumen is small.
In the rest of the tubule, the lumen is wider ^nd the cells
hning it are flattened.

Blood Suppkj. — ^In the surface of separation between
cortex and medulla, the renal vessels form an arcade.
The artery gives off branches which traverse the cortex
radially. From these branches arise lateral twigs which
lead into the glomeruh'. The venules draining these break
up to form a network surrounding the tubules. From this
network the blood is conveyed to the renal veins.

The blood supplying the kidney, therefore, hke that
supplying the viscera, passes through a double system of
capillaries. It is now estabhshed that the tubules receive
no direct arterial supply.

Nerve Supply. — The renal plexus situated at the hilum
of the kidney receives fibres (1) from the sympathetic,
emerging from the lower thoracic segments of the cord, and
(2) from the vagus.

The action of the sympathetic is to cause diminution of
secretion by vaso-constriction. Though this nerve is said
to contain vaso-dilator fibres, its constrictor influence is
paramount.

The function of the vagus is unknown.

The kidney appears to be supphed with no secretory
fibres. Although it is hberally supplied with nerves, these
are not essential to its activity. The kidney when excised
and immediately replaced soon resumes its functions.

218 URINE

Theories of Renal Function

The first conception of the renal mechanism emanated
from Bowman in 1842. Based on anatomical considera-
tions, it was an attempt to differentiate the functions of
the glomeruh from those of the tubules. Bowman sug-
gested that the glomeruh secreted a saline solution which
in passing down the tubules dissolved and separated urea
and uric acid from the cells of the tubules. The whole
process was a physical one.

Two years later this view was combated by Ludwig,
who believed that from the glomeruli appeared a solution
which consisted of plasma minus the proteins. The
function of the tubules was to concentrate this fluid.
Ludwg was at first emphatic in declaring both processes
to be purely physical, but later, discovering that the con-
stituents of the urine differed quantitatively from those of
the blood, he withdrew from this position and was ready
to admit some power of selection on the part of the cells.

In 1874 Bowman's theory, which had been more or less
echpsed by Ludwig's, was revived in a modified form by
Heidenhain.

Heidenhain, hke Bowman, located the secretion of the
water and salts in the glomeruh, and that of the other
sohds in the tubules. He differed from Bowman in very
definitely attributing both processes to the selective power
of the urinary cells.

It will be seen that the controversy is a double one.
First, is the separation of urine from the blood due to
passive filtration or to active secretion ? Secondly, is
the function of the tubules to secrete urinary constituents
or to absorb water? The one point on which there is
universal agreement is that the urine becomes in some
way concentrated as it passes down the tubules. But it
must be emphasised that the differentiation of the glomer-
ular from the tubular function is based entirely on the
histological appearance of these structures. As long as we
are ignorant of the nature of the glomerular fluid, concentration
in the tubules must remain an assumption.

FORMATION OF URINE

219

THE MECHANISM OF URINE FORMATION

If the separation of fluid in the kidney is due to filtration,
the process must obey the following three laws : —

1. The amount of filtration will vary directly with the
blood-pressure in the glomeruH and inversely with the
pressure in the tubules.

2. The tendency to filtration will be resisted by the
osmotic pressure of those constituents of the blood which
do not pass through the glomeruh ; filtration ceasing when
the filtration pressure is counterbalanced by such osmotic
pressure.

3. Any variation in the amount of urine filtered will not
be accompanied by variation in the oxygen consumption of
the kidney.

Let us now see whether these conditions hold.

1. The Filtration-pressure. — As regards the pressure in
the glomeruh the results are set forth in the accompanying
table.

Experiment.

General

blood
pressure.

Eenal
vessels.

Kidney
volume.

-Urinary
flow.

Division of spinal
cord in neck

Falls
to 40 mm.

Relaxed

Shrinks

Ceases

Stimulation of cord

Rises

Constricted

Shrinks

Diminished

Stimulation of cord
after section of
renal nerves

Rises

Passively
dilated

Swells

Increased

Stimulation of renal

Unaffected

Constricted

Shrinks

Diminished

nerves

Stimulation of
splanchnic nerves

Rises

Constricted

Shrinks

Diminished

Plethora

Rises

Dilated

Swells

Increased

Hsemorrhage

Falls

Constricted

Shrinks

Diminished

220 URINE

Here it will be seen that the amount of secretion is in-
fluenced not by the general blood-pressure but by the
degree of dilatation of the renal arterioles — that is to say,
by the local blood-pressure in the kidney.

When the pressure in the ureter is raised by partially
clamping this vessel the rate of flow falls. This might,
however, be due not to the reduction in the filtration
pressure but to the obstruction of the veins consequent
upon the dilatation of the tubules.

2. The Osjnotic Pressure of the Plasma Colloids. — The
proteins of the plasma exert an osmotic pressure of 25-30
mm. of mercury. AVhen the arterial blood-pressure is
reduced to 40 mm. the flow of urine ceases. Allowing for
a certain difference between the arterial pressure and the
pressure in the renal arterioles, these facts indicate that
the cessation of flow occurs because the filtration pressure
is neutrahsed by the osmotic pressure. In confirmation
of this explanation is the fact that when the ureter is
obstructed the pressure rises within it until it is about
30-40 mm. below arterial pressure.

The protein content of the plasma may be reduced by
partially replacing the blood by a suspension of corpuscles
in Ringer's solution. When this is done there occurs a
copious diuresis which cannot be explained by the change
in the viscosity of the blood. Clearly the proteins by
their osmotic pressure restrain the tendency to filtration.

3. The Consumption of Oxygen.- — This question has been
settled by Barcroft and Straub, who studied the gaseous
metabohsm of the kidney upon the injection of salts. The
result is shown in Fig. 29, from which it will be seen that
when Ringer's solution is injected there is a diuresis un-
accompanied by increased oxygen consumption. Under
these circumstances the energy is derived not from the
kidney but from the heart.

There is therefore convincing evidence that physical
factors play a very important part in the formation of
urine.

THE TUBULES
Function of the Tubules

221

In spite of innumerable experiments made with a view
of deciding whether the tubules secrete substances in
solution or absorb water, the question cannot be said to
have been decided. The chief reasons for this are that
in many experiments conditions are so unrehable that
no conclusion can be drawn from them, while in other

2 4-

RJNGEK.

Na^So^

Tig. 29. — Diuresis and oxj'gen consumption (after Bareroft and Straub).
Dotted line = oxygen consumption ; shaded area = amount of urine
secreted.

experiments the results are equally well or equally badly
explained on either theory.

1. Heiclenhain decided the point to his own satisfaction
by injecting substances into the circulation and afterwards
examining their deposition in the kidney. Using Sodium
Sulphindigotate, he showed that shortly after injection
the stain appeared in the cells of the tubules, while later
on it appeared in the lumen of the tubules. For long
these experiments were regarded as proof of tubular
secretion, but they are now known to be fallacious. The

222 VRINE

fact appears to be that at present we have no histological
method of distinguishing between two opposite processes.

2. Nussbaum's Experiment.— Nnsshaum sought hght on
the subject from the frog's kidney. In the amphibian, it
will be remembered, the renal artery supphes first the
glomerulus, then the tubule, as in the mammal, but the
tubule receives, in addition, blood conveyed from the hmbs
by the renal portal vein. Ligature of the renal artery
causes stoppage of secretion; the tubules alone, therefore,
are unable to secrete urine. But when urea is injected into
the renal portal vein some secretion occurs. Sodium
sulphindigotate on injection is deposited in the lumen of
the tubules. The vahdity of the appUcation of these results
to the mammahan kidney may be questioned, for although
structurally similar, amphibian and mammahan kidney are
developmentally different. As to the results themselves,
they are discordant with results obtained from perfusion
of the frog's kidney.

3. Attempts have been made to decide the question by
noting the effect of partial obstruction of the ureter on the
composition of the urine. This operation causes a well-
marked reduction in water and chloride and a shght
reduction in urea and sulphate. For the followers of
Heidenhain this means decreased secretion at the glomer-
uh. For the followers of Ludwig it means increased
absorption.

Experiments in which the tubules have been removed by
gouging out the medulla may be dismissed as causing too
much injury to the kidneys. Similarly attempts to poison
the tubules by injection of mercuric chloride are open to
the objection that the permeabihty of the glomeruh is
altered by this procedure.

It is clear that the formation of urine can only be
accounted for by filtration when its composition is that of
plasma minus proteins. This is the case in the diuresis
caused by injection of Ringer's solution. When the com-
position of the urine difEers from this the process must be

CUSHNTS THEORY 223

due to the physiological activity of the tubules, whether
this takes the form of absorption or secretion.

In Fig. 29 it is shown that when sodium sulphate is the
cause of diuresis the oxygen intake is greatly increased^
evidence of work being done by the cells. In diuresis thus
caused the concentration of the dissolved substances in the
urine differs materially from their concentration in the
plasma.

Cushny's Theory

The most remarkable feature in the action of the kidney
is that the character of the secretion is influenced by the
composition of the blood. WHien from any cause the latter
is disturbed the kidney reacts in such a way as to restore
it to the normal. The urine is usually more concentrated
than the blood ; but it may be more dilute, as when large
quantities of water have been drunk.

It follows, therefore, that no theory of renal function
is complete unless it takes into account the adaptive
nature of the mechanism. This point of view is upper-
most in the most modern theory of renal secretion — that
due to Cushny. Cushny accepts filtration as sufficient to
account for glomerular activity. He believes the glomer-
ular fluid to consist of plasma minus proteins. He regards
the function of the tubules as one of active absorption of
water and of substances in solution, the cotnposition of the
reabsorbed fluid being practically Ringer s solution, whatever
may be the composition of the blood or the urine.

Cushny has arrived at this conclusion by a comparative
study of the concentration of the principal constituents
in blood and in urine. Some of the blood constituents,
e. g. dextrose, sodium and chlorides, only pass into the
urine when they have attained a certain concentration in
the blood. These he calls Threshold Bodies. Others, e. g.
urea and sulphates, appear in the urine when present only
in traces in the blood. These he calls No-Threshold
Bodies. In between these groups are Intermediate Bodies

224

URINE

such as uric acid and potassium, which have a Threshold,
but the Threshold, unUke that of the Threshold Bodies
proper, is habitually exceeded under normal conditions.
All these substances, to whichever category they belong,
pass through the glomerulus, but they differ greatly in the
degree to which they are reabsorbed.

No-Threshold Bodies hke urea are not absorbed at all.
Threshold Bodies hke dextrose are reabsorbed provided
that they do not exceed the threshold in the blood. When
the threshold is exceeded, the excess fails to be absorbed
and appears in the urine.

Cushny's example will make this clearer.

C7 litres plasma
contain

02 litres

filtrate

contain

61 litres reab-
sorbed fluid
contain

1 litre urine
contains

% Total

Total

%
95

Total
950 cc.

Water . .
Colloids .

Dextrose .
Uric Acid .
Sodium
Potassium
Chloride .
Urea .
Sulphate .

261.

621.

67 gms.

1-3 „

200 „

1.3-3 „

248 „

20 „

1-8 „

611.

1 8

0-1
0-002
0-3
0-02
0-37
•03
0-003

5360 gms. 1

67 gms.

1-3 „

200 „

13-3 „

248 „

20 „

1-8 „

U-11

0-0013

0-32

0-019

0-40

67 gms.
0-8 „
196 „

11-8 „
242 „

0-05
0-35
0-15
0-6
20
; 0-18

0-5 gms.
3-5 „
1-5 „
6-0 „
20 „
1-8 „

One htre of urine contains 2 per cent, of urea. The blood

contains '03 per cent. Therefore the Utre of urine is formed

2
from -__ = 67 litres of plasma. The plasma contains
•Uo

62 htres of water. Therefore 62 htres pass through the

glomerulus. Of this amount 61 htres are reabsorbed. The

DIURETICS 225

colloids, which amount to 8 per cent, of the plasma, are
retained in the blood.

The dextrose, which amounts to 0-1 per cent., filters
through the glomerulus, but, being within its threshold,
it all passes back through the tubules. Were it to exceed
the threshold, as in diabetes, the excess would pass into
the urine, while the previous amount would continue to
be reabsorbed. The same apphes to sodium and chloride.
As regards the uric acid, Cushny reminds us that this (in
mammals, at any rate) is not an end product of metabohsm
in the same sense as urea, but that there is always an
attempt on the part of the body to convert uric acid into
urea. Uric acid therefore possesses a low threshold. It
is incompletely excreted, but any excess' in the blood
affects the urine, not the reabsorbed fluid. Potassium
behaves in a similar manner. As for urea and sulphate,
their fate is simple. They are never reabsorbed.

It will thus be seen that however the composition of the
blood may vary, the substances which pass through the
glomeruh are always returned to the blood in amounts up
to their threshold values, while excess passes over to the
urine. The composition of the reabsorbed fluid is constant.
If, for example, the blood is more dilute, a more dilute
glomerular filtrate is formed. But the composition of the
reabsorbed fluid being unaltered, the result is that the
dilution only affects the urine.

An objection which might at first sight be urged against
this theory is the large amount of reabsorption of water
which is entailed, one litre of urine corresponding to
67 htres of plasma. But when it is remembered that the
daily flow of blood through each kidney is estimated at
900 htres, this objection falls to the ground.

DIURETICS

These may be divided into two groups : —

1. Substances usually present in blood.

2. Foreign substances.
15

226 URINE

1. The first group act as diuretics by being present in
blood in excess. According to Cushny they cause diuresis
in two ways.

(a) By Dilution diuresis. By this is meant the diuresis
brought about by dilution oi the colloid content, and
therefore by diminution of the osmotic pressure of the
blood. Among the substances which act in this manner
are ivater and the Threshold Bodies such as chlorides.

(b) By Osmosis. While all saUne substances cause a
certain degree of dilution diuresis, some, and in particular
the No-Threshold Bodies such as sulphates, act also by
exerting through their osmotic pressure a restraining
influence on the process of reabsorption of water.

2. Foreign Substances. — The principal members of this
class are caffeine, digitalis and pituitary extract. Their,
main diuretic action is probably an indirect one through
their effect upon the circulation. Whether they also
stimulate the renal cells is undecided.

THE EXCRETION OF URINE— MICTURITION

The passage of urine down the ureters is due partly to
gravity, partly to pressure of fluid from the tubules, partly
to waves of contraction. The ureters pass through the
bladder wall obhquely — by this arrangement the pressure
inside the bladder prevents the return of urine into the
ureters.

The orifice of the bladder is guarded by three sphincters.
Of these, one, the most proximal, is the sphincter trigoni,
situated at the neck of the bladder. This is essentially an
involuntary muscle, though there may be some vohtional
control over it. The other two sphincters, the compressor
urethrae and the bulbo-cavernosus, are voluntary.

Nerve Supplyf. — The bladder is innervated (1) by sym-
pathetic fibres emerging from the 11th and 12th dorsal
and 1st and 2nd lumbar segments and reaching it by the
inferior mesenteric ganglion and hypogastric nerves,

MICTURITION 227

(2) by sacral automatic fibres from the 2nd and 3rd sacral
segments. These travel by the pelvic nerves and terminate
by arborising around gangha situated in the bladder wall.
From these gangha fibres pass to the muscles.

Stimulation of the sympathetic causes inhibition of
the body of the bladder and contraction of the sphincter;
that of the sacral autonomic, inhibition of the sphincter
and contraction of the body. Both nerves contain afferent
fibres.

The factors contributing to the act of micturition will
be best understood if we consider (1) the action of the
isolated bladder; (2) the action of the bladder when in
connection with the lumbo-sacral part of the cord ; (3) the
modification of (2) due to connection with the higher
centres. First, however, it is necessary to understand the
relation between the degree of distension of the bladder
and the pressure within the organ.

As the bladder fills, tJie pressure ivithin it at first remains
practically unaltered, the wall simply giving before the
gradual accumulation. When distension has reached a
certain point, further filhng causes a rise of pressure — the
wall is now in a condition of increased tonus. At this
stage slow rhythmic contractions make their appearance.
These become more vigorous until eventually one occurs
which is sufficient to overcome the tonic contraction of the
sphincter. This mechanism occurs in the isolated as well
as in the normal bladder.

Normally micturition occurs when the pressure is about
160 mm. of water. The degree to which distension occurs
before the pressure begins to rise depends upon the rate
at which the bladder fills. When this is rapid, rise of
pressure occurs early, so that only a small amount of urine
is voided. The same effect is also produced when the
bladder wall is unduly irritable.

In the bladder separated from the cord the forcing open
of the sphincter due to the rhythmic contraction of the
bladder wall results in an evacuation which comes to an

228 URINE

end as soon as the intravesical pressure falls below that
which is required to keep the sphincter open. The bladder
is therefore never completely emptied — a fact of great chnical
importance.

When the connections between the bladder and cord are
intact but the cord transected in the thoracic region,
stretching of the bladder wall not only causes rhythmic
contraction but gives rise to impulses which travel to
the cord when they reflexly produce impulses motor
to the body of the bladder and inhibitory to the
sphincter. By this means the bladder is emptied com-
pletely, and the urethra is emptied by reflex contraction
of the muscles surrounding it. Purely reflex micturition
of this sort can be brought about by stimulation of any
sensory nerve, particularly those arising in the pelvis.

In the intact organism the mechanism is to a great
extent under the control of the will. The sudden rise in
intravesical pressure is recognised subjectively. The
evacuation of the bladder is aided by contraction of the
abdominal muscles. There is evidence, too, that the
sphincter trigoni and even the musculature of the bladder
wall are under voluntary control.

CHAPTER XIII
INTERNAL SECRETION

Internal secretion is the elaboration by an organ of
a specific substance, which passes into the blood-stream
and exerts a stimulating or inhibiting effect upon some
function of the body. In some cases the formation of an
internal secretion is not the sole function of the organ.
The ovary and testes, for instance, in addition to forming
the morphological elements of reproduction, pour into the
blood substances upon the presence of which depend the
development of secondary sexual characteristics. The
duodenal epithehum, besides secreting the gastric juice
externally, secretes secretin internally. The pancreas not
only forms the pancreatic juice, but also secretes into the
blood, probably from the Islets of Langerhans, a substance
which regulates carbohydrate metabolism.

In some organs the formation of an internal secretion
constitutes their only function. Of these there are three
of outstanding importance — the thyroid and parathyroid
apparatus, the suprarenal glands, and the pituitary body.
It is with these that we are mainly concerned in the present
chapter.

The substances secreted are known as hormones. They
are not enzymes, for they are of much simpler constitution ;
they are dialy sable and are not destroyed by heat. Some
have been isolated, and one — ^adrenahn — can be prepared
synthetically.

229

230 INTERNAL SECRETION

Methods of Investigation of tlie Organs of Internal Secretion

Our knowledge of the'se organs has been derived —

1. From their structure, development and comparative
anatomy ;

2. From the efiects of extirpation;

3. From the effects of administration of the glands
intravenously and orally both to normal animals and to
those from which the gland has been extirpated ; from the
action of the extract upon isolated organs and from the
effects of transplantation;

4. From pathological conditions associated with changes
in these organs;

5. From a comparative analysis of the blood entering,
and the blood leaving, the organ.

THE THYROID AND PARATHYROID GLANDS

Structure and Development of the Thyroid

The thyroid consists of closed vesicles bounded by a
single layer of epithelium. There being no basement-
membrane, the vesicles are separated from one another
solely by areolar tissue, in which he the profuse blood-
vessels, lymphatics and nerve-filaments, the last-named
being derived from the superior and inferior laryngeal
branches of the vagus, and from the sympathetic. The
cavity of the vesicles is usually distended with a colloid
substance. In some animals the appearance of the vesicles
can be modified by changing the diet. When rats are fed
with lean meat the epithelium is cortical or even flattened,
and the vesicles loaded with colloid. When the diet
consists of bread and milk the epithelium is columnar, and
shows evidence of active secretion ; at the same time the
lumen, diminished in size by the protrusion of the cells,
contains a serous fluid but httle or no colloid. The colloid
thus appears to represent a store of secretion, which exists
when the gland is relatively inactive (Figs. 31 and 32).

THYROID AND PARATHYROIDS

231

)(

r/7y/n. ///

_ Fost. branch.
rAym./V f)Q(/y

Thyro/cf

Fig. 30. — Origin of thyroid, parathyroids and thymus in the mammahan
■ embryo. I, ii, ill, iv, branchial i>ouches. The post-branchial
body in mammals either disappears or becomes incorporated with
the thyroid (from Schafer, The Endocrine Organs).

232

INTERNAL SECRETION

What is believed to be the active principle of the thyroid
has now been isolated, and is known as thyroxin. It is a
compound of tryptophane and iodine.

The thyroid appears as an outgrowth of the entoderm,
hning the floor of the pharynx between the first and second

Fig. 31. — Thyroid of wild iv.t sliowing tiattoned cells and vesicles
distended with colloid (Chalmers Watson, from Schafer, The
Endocrine Organs).

branchial clefts. At first it forms a sohd column of cells
which, opposite the upper end of the trachea, divides into two
lateral parts. From these, by a process of budding, the
thyroid is formed. The sohd column becomes temporarily
canahsed and serves as a duct. After this it disappears,
its pharyngeal extremity persisting as the foramen caecum
of the tongue (Fig. 30).

THYROID AND PARATHYROIDS 233

Structure and Development of the Parathyroid

The four parathyroids, which are either attached to the
thyroid or embedded in it, are composed of epitheUal
ceils arranged sometimes compactly together, sometimes
in lobules which are separated by connective -tissue

Fig. 32. — Thyroid of another wild rat showing cohininar cells and
absence of colloid (Chalmers Watson, from Schafer, The Endocrine
Organs).

liberally endowed with blood-vessels. The cells are
mostly small, and may be either clear or granular. A
colloid substance is sometimes seen lying between them.
This is said to increase in amount after removal of the
thyroid. The parathyroids receive the same nerves as
the thyroid.

The upper and lower pairs of parathyroids are developed

234 INTERNAL SECRETION

from the 3rd and 4th branchial clefts respectively (see
Fig. 30).

Thyroid Deficiency

In the adult, degeneration of the thyroid causes the
condition known as myxoedema. This is characterised by
a dry and thickened skin which pits on pressure, loss of
hair, subnormal temperature, low blood-pressure, muscular
weakness and hypotonus, and mental dullness. There is
a general diminution of the metabolic processes evidenced
by a lessened oxygen intake and nitrogen excretion.
There is an increase in sugar tolerance and a tendency to
deposit fat. Regeneration of tissue after injury is impaired.

In children, to the above signs • are added failure of
growth and of mental and sexual development. This is
the condition known as cretinism.

In short, deficiency of the thyroid leads to a slowing
down of all the bodily functions.

In animals analogous changes can be induced by removal
of the thyroid, the parathyroids being left intact.

Excess of Thyroid

The activity of the thyroid is increased during pregnancy
and lactation, during puberty and menstruation, in the
sexual act and other emotional states.

Exophthalmic goitre is a pathological enlargement of
the thyroid associated with increased activity. It is
characterised by a rapid pulse, high blood-pressure, mus-
cular tremors, protrusion of the eyeballs, and an excitable,
nervous state. There is a general quickening of the
metabolic processes and a loss of body fat. Sugar-tolerance
is diminished. Histologically the gland shows evidence of
active secretion — irregularity of the vesicle walls indicatijig
an increase of surface from which secretion can occur—
the columnar form of cell and absence of colloid.

THYROID AND PARATHYROIDS

235

Administration of Thyroid Extract

In the normal individual this causes slight lowering of
blood-pressure, tachycardia, restlessness, flushing of the
skin, sweating, increased nitrogen excretion and diminution
of body fat. Sugar tolerance is decreased.

In the cretinous or myxoedematous individual it causes
a rapid cure of the physical and mental condition.

Fig. 33. — Parathyroid of cat (8chafer, The Endocrine Organs).

Parathyroid Deficiency

Removal of all the parathyroids with the thyroid usually
causes the condition known as tetania parathyropriva.
The muscular system undergoes fibrillar twitchings which
develop into well-marked clonic contractions, and cul-
minate in convulsive seizures. Vomiting, diarrhoea and

236 INTERNAL SECRETION

wasting lead to death in a few days. If but one para-
thyroid is left behind this condition does not occur.

It has been observed among Himalayan children that
in certain cretins nervous manifestations are prominent.
In these the parathyroids have been found to be specially
involved.

Recently considerable evidence has accumulated to show
that parathyroid deficiency is associated with disturbance
of guanidine ^ metaboUsm. The evidence is as follows : —

1. Guanidine is formed in the intestine by bacterial
putrefaction.

2. During intestinal putrefaction, symptoms resembhng
tetania parathyropriva make their appearance. In this
condition the guanidine content of the blood and urine is
increased.

3. Guanidine increases in the blood after removal of
the parathyroids.

4. Tetany can be induced by injection of guanidine.

As regards the effect of administration of parathyroid
extracts we have no reliable information.

The evidence above detailed seems to show that thyroid
and parathyroids subserve functions which are entirely
distinct. The thyroid, while not essential to hfe, is neces-
sary for the proper speeding up of all the bodily functions.
To quote McCarrison, " the thyroid gland is to the human
body what the draught is to the fire." The parathyroids
elaborate a substance which neutrahses a toxin, probably
guanidine, which acts upon the neuromuscular system.

THE SUPRARENAL GLANDS

Structure

Each suprarenal gland consists of two parts, the cortex
and the medulla. The cortex is composed of epithehal-

^ See page 177.

THE SUPRARENALS

237

cells, and is differentiated into three layers, by the way in
which these cells are arranged. From without inwards
these layers are —

1. Zona glomerulosa, in which the cells have an alveolar
formation.

Fig. 34. — Suprarenal cells of medulla stained brown with potassium
bichromates. Note the blood sinuses continuous with those of
the zona reticularis (Schafer, The Endocrine Organs).

2. Zona fasciculata, where they form single columns,
running radially.

3. Zona reticularis, in which they form an open mesh-
work.

The cortical cells contain a doubly refracting hpoid
composed of lecithin and cholesterol esters. In the inner-
most layer they contain a pigment.

238 INTERNAL SECRETION

The medulla consists of a mass of cells permeated by
blood-sinuses. The cells are irregular in shape and
contain granules, some of which stain brown with chromates.
On this account they are called ChromafiQn cells.

Of all organs in the body, the suprarenals receive, for
their weight, the most abundant blood supply. The blood
passes through the gland from without inwards. In the
two outer layers of the cortex a network of capillaries runs
in the connective tissue, between the columns of cells but
not penetrating them. In the zona reticularis the blood-
vessels are dilated and occupy the spaces between individual
cells. They run into the blood-sinuses of the medulla.

There is a liberal nerve supply, derived from the sym-
pathetic, filaments passing in through the cortex and
forming a plexus, containing ganghon cells, among the
cells of the medulla.

Development and Morphology

The cortex is of mesodermal origin, being formed from
the Wolffian ridge in conjunction with the primitive kidney
and genital gland. The human foetus is pecuhar in that
the cortex is abnormally large, owing to great development
of the inner layer or " boundary zone." After birth the
boundary zone degenerates, and at the same time the
permanent cortex develops superficially. In the an-
encephalic foetus the boundary zone is absent.

The medulla is of epiblastic origin. At an early stage
of development certain nerve cells migrate out of the
spinal cord. Some of these form the sympathetic gangha ;
others become enclosed by the cortex of the suprarenal,
and form the medulla. .The former, of course, are in
connection with peripheral structures through their
post-ganghonic fibres, and w^th the cord through the
pre-ganghonic fibres. The medullary cells retain their
connection mth the cord, but assume a secretory function.

The cells of the medidki therefore correspond to symjxithetic
ganglion cells.

THE SUPRARENALS 239

In the fish cortex and medulla remain separate ; in
amphibians they adjoin ; in mammals the cortex encloses
the medulla.

Functions of the Suprarenal Glands

Notwithstanding that the blood-supply in the mammal
suggests that cortex and medulla function together, the
wide difference in the origin of the two parts, and the fact
that they remain distinct in many animals, indicate that
the functions of the cortex and medulla are separate.

The Cortex

We have no definite information regarding the function
of the cortex. Two suggestions may be mentioned. The
first, based on the high content of lipoids, is that it is
concerned with the manufacture of lipoids to be used
elsewhere. The second is that the cortex plays a part in
connection with the development and activity of the
sexual organs. Enlargement of the cortex occurs during
pregnancy ; hypertrophy in children is constantly associated
with sexual precocity.

The Medulla — Adrenalin

From the chromaffin cells is secreted adrenalin, which has
the formula —

CH3NHCH2CHOH

Adrenahn is remarkably active physiologically. It acts
upon every organ endowed with sympathetic fibres in a
manner identical with stimulation of these fibres. Its
most striking effect is upon the blood-vessels, especially

240 INTERNAL SECRETION

those of the splanchnic system, in which it induces power-
ful vaso-constriction. In the intact animal the heart may
be slowed — a reflex effect due to the increased blood-
pressure, but after section of the vagi the beat is much
accelerated and augmented. The pupils are dilated and
the eyeballs protruded. The sahvary glands are either
paralysed or secrete a scanty thick saliva. The intestines
are relaxed, but the ileo-csecal sphincter and the sphincter
ani are contracted. The body of the bladder is relaxed
and the neck of the bladder constricted. In the male the
retractor penis is stimulated; in the female the uterus is
sometimes stimulated, sometimes inhibited. The bron-
chioles are relaxed. The sweat glands are stimulated and
the hairs erected.

The hver is stimulated to increased sugar production,
sugar appearing in the urine. It is also said that the
recovery of fatigued muscle is accelerated and that
coagulation of the blood is hastened.

The action of adrenahn is not upon the sympathetic
nerve endings, for the drug is still effective after degenera-
tion of the nerves. Nor is its action upon the peripheral
organ itself, since it has no effect upon structures which
have no sympathetic supply. It is therefore believed to
act upon a receptor substance (neuromuscular junction)
lying between the nerve-ending and the organ.

An increase in the adrenahn content of the suprarenal
veins has been shown to occur on experimental stimulation
of the splanchnic nerves and during violent emotions.

Disease of the Swprareniils (Addison's disease). — Usually
due to tuberculosis of the glands, it is characterised by
low blood-pressure, feeble heart action, abdominal pain,
vomiting, extreme muscular weakness, and pigmentation
of the skin. It is invariably fatal.

The circulatory disturbance is referable to deficiency of
adrenalin in the circulation.

Removal of both glands causes muscular weakness,
lowering of blood-presssure and cardiac failure, death

THE PITUITARY 241

occurring usually within forty-eight hours. When the
animal is moribund, stimulation of vaso-constrictor fibres
is without effect upon the blood-vessels.

Administration of suprarenal extract, whether to patients
suffering from Addison's disease or to animals from which
the glands have been removed, at most only prolongs
hfe slightly.

It is clear that the function of the medulla is to produce
adrenahn. The part which adrenahn plays in the animal
economy, hke the part which the sympathetic nerves play,
is to adapt the animal to efforts of defence or offence in
emergency. The quickened heart-beat, the varied blood-
pressure, the intestinal paralysis, the relaxation of the
branchioles, the secretion of sweat, the mobilisation of
sugar, are all means to this end.

THE PITUITARY BODY

Structure

The pituitary body is composed of three parts, which
are histologically distinct.

The Pars Anterior consists of a mass of epithelial cells,
some of which contain basophile granules, some oxyphile
granules. In others the protoplasm is clear. These cells
abut on large blood-sinuses. The pars anterior is incom-
pletely separated by a narrow cleft from the

Pars Intermedia. — Although continuous with the pars
anterior at the circumference of the cleft, the pars inter-
media differs in certain respects from the pars anterior.
It is less vascular; the cells contain neutrophile granules,
and are here and there disposed in vesicles which contain
colloid. The pars intermedia is closely adherent to the

Pars Posterior {or Nervosa). — This consists of neuroglial
fibres and cells and has only a scanty blood supply. Appear-
ances have been described which suggest that the colloid
material secreted bv the pars intermedia passes into the
16

242

INTERNAL SECRETION

pars nervosa, up into the infundibulum, and enters the
third ventricle. Other observers deny this.

The pituitary receives nerve fibres from the cervical
sympathetic.

Fig. 35. — Mesial sagittal section through the pituitary body of an
adult monkey (semi -diagrammatic) : a, optic chiasma ; b, 3rd ven-
tricle (infundibulum) ; e, pars anterior; /, cleft ; g, pars intermedia ;
h, pars nervosa (Herring).

Development

The anterior and intermediate parts are derived from
an outgrowth of the buccal epitheUum {Rathkes 'potich),
the cleft between them being the remains of the original
lumen of the invagination. The pars nervosa develops
as a hollow downgrowth of the third ventricle. In man
the cavity becomes obliterated.

It will therefore be seen that the pars intermedia, while
morjjhologically related to the pars anterior, becomes

THE PITUITARY

243

associated anatomically with the pars nervosa. Pars
intermedia and pars nervosa together constitute what is
commonly known as the posterior lobe.

Fig. 36. — Pituitary of cat: o, pars anterior; b, cleft; c, pars inter-
media ; d, pars nervosa (Schafer, The Endocrine Organs).

Functions of the Pituitary
Pituitary Extract. — An extract of the posterior lobe (pars
intermedia and pars nervosa) has the following effects : —

244 INTERNAL SECRETION

The heart (with vagi cut) is slowed, but individual beats
are augmented. Blood-pressure is increased by vaso-
constriction, but the effect is not repeated on a second
dose.

All plain muscle is contracted, the most striking effect
being upon the uterus.

The renal cells are stimulated— causing diuresis.

A secretion of milk occurs, due, however, not to activity
of the glands but to squeezing out of the milk already
present by contraction of the muscle fibres.

The assimilation hmit of sugar is lowered.

Extract of the pars nervosa is more effective in pro-
ducing the above effects than extract of the pars intermedia.

Extract of the pars anterior is inactive.

Disorders of the Pituitary. — Two conditions are associated
with affections of the pituitary— acromegaly and dystrophia
adiposo-genitalis.

In acromegaly there is an enlargement of the face, hands
and feet, due chiefly to great hypertrophy of the bones.
There is abnormal muscular development, thickening of
the skin, overgrowth of hair, and sometimes diminished
carbohydrate tolerance. This condition is attributed by
Gushing to superactivity of the pituitary. If the dis-
turbance sets in before ossification is completed, all the
long bones undergo a great increase in length — pituitary
gigantism.

Dystrophia adiposo-genitalis is beheved to be due to
insufiiciency of the pituitary, the signs being the reverse
of those found in acromegaly. Growth and sexual develop-
ment are defective. The mind is lethargic and the tem-
perature subnormal. There is marked adiposity and an
increased sugar tolerance, 200-300 grms. of glucose being
absorbed without glycosuria occurring.

In this condition administration of an extract of the
anterior lobe reheves only the subnormal temperature,
while extract of the posterior lobe only raises the low
blood-pressure and lowers the sugar-tolerance.

THE PINEAL 245

Removal of the Pitituary. — It is now agreed that com-
plete removal of the pituitary is rapidly fatal, the terminal
event being ushered in with lethargy, general weakness,
tremors, cardiac weakness, subnormal temperature, and
coma.

Removal of the pars nervosa alone causes no symptoms.
Removal of a large portion of the anterior lobe is incom-
patible with hfe, but when a small portion only is removed
there develops a condition resembhng dystrophia adiposo-
genitalis^ — atrophy of the genital organs and deposition
of fat. The same condition can be produced experi-
mentally when the pituitary is deprived of its blood
supply by section of the infundibular stalk. When this
is done the cells of the anterior lobe undergo atrophic
changes.

The functions of the pituitary, so far as we know them,
may be thus summarised : —

The anterior lobe is essential for hfe ; the posterior
lobe is not only not essential but its absence causes no
symptoms.

The anterior lobe seems to have a profound influence
upon bodily, and particularly skeletal, growth.

The biological significance of the physiological effect of
posterior lobe extract is not known.

THE PINEAL GLAND

This is a small body situated in the root of the third
ventricle. Morphologically it is related to the median eye
of the reptile. It is composed of epithehal cells with
profuse blood-sinuses. Proportionally larger in youth, it
afterwards undergoes atrophy.

Little is known of its function. Abnormal growth and
sexual precocity have been variously associated with
excision, with disease, and with injection of pineal extract.

246 INTERNAL SECRETION

GENERAL FEATURES OF THE ORGANS OF INTERNAL

SECRETION

It is of interest to note that the three organs which we
have discussed at length — the thyroid and parathyroids,
the suprarenals, and the pituitary — have the following
features in common : —

1. Each is composed of two parts, which are distinct in
their development and structure, and appear to be distinct
in their functions. Whether such duahty is of biological
significance, or is mere fortuitous, we cannot say.

2. The organs in the course of development undergo a
curious transformation in disposition, and sometimes in
their very nature. The medulla of the suprarenal originates
as a mass of migrating nerve cells ; the anterior lobe of the
pituitary is formed from a gland opening to the mouth.

3. Their blood supply is remarkably profuse, indicating
a high degree of activity.

4. In all cases complete extirpation causes death.

5. Extract of one component is more active physio-
logically than extract of the other.

Interaction of the Internal Secretions

A feature of the internal secretions is that they all in-
fluence, in one direction or the other, certain fundamental
biological processes, such as carbohydrate metabohsm,
growth, and sexual development. As regards carbohydrate
metabohsm, sugar tolerance is diminished by injury to the
pancreas, by injection of adrenahn and by over-activity of
the thyroid or pituitary. It is increased by deficiency of
the thyroid or pituitary. Growth is influenced by the
thyroid, pituitary and the suprarenal cortex. Abnormal
sexuaUty is associated with hypertrophy of the cortex of
the suprarenal; arrested sexuaUty is found in cretinism
and subpituitarism.

Furthermore, the glands are not without influence upon

INTERACTION OF INTERNAL SECRETIONS 247

one another. Removal of the thyroid causes hypertrophy
of the pituitary; disease of the pituitary leads to over-
growth of the thyroid. The regulation of the metabohc
processes therefore depends upon a balance between the
activities of all the internal secretions. The disturbance
which follows the absence of one secretion may be due,
not directly to such absence, but to the unchecked activity
of the secretions which remain.

CHAPTER XIV
THE REGULATION OF TEMPERATURE

The energy liberated by the metabolic processes appears
as physiological activity and as heat. Of these the former
is a primary, the latter a secondary or incidental effect.
In cold-blooded animals the heat evolved is immediately
lost by conduction and radiation to the environment.
The temperature of these animals is therefore only shghtly
higher than that of the surroundiag medium. But heat,
while it is the result and not the cause of metabohc changes,
has a considerable influence upon the rate at which such
changes occur; the rate of metabohsm varying in cold-
blooded animals directly with the external temperature.
This is seen in the rise in CO2 output which in the frog
accompanies rise of temperature. In warm-blooded
animals there is developed a mechanism for the conserva-
tion of the heat produced by cell activity, in such a manner
that the temperature of the body is maintained at an
almost uniform level which is independent of and higher
than the usual temperature of the environment. Owing
to the rapidity of the circulation all the internal organs
are practically at the same temperature.

The advantages of this arrangement are obvious. The
constancy of the temperature abohshes any dependence
of functional activity upon the environment, while its
tropical level is suitable for the rapidity of metabohc
changes.

In man the body temperature, as usually taken, in the
mouth or axilla, is 36-9° C. (98-4° F.). A more accurate

248

REGULATION OF TEMPERATURE 249

record of the temperature of the internal organs is ob-
tained from the rectum or from the urine. Normally
there is a daily fluctuation between 37-5° C. (99-5° F.)
in the evening and 36-2° C. (97-2° F.) in the early morning.
This is due to the greater bodily activity which occurs
during the daytime, for it is reversed in those who follow
nocturnal employment.

The constancy of the temperature is due to a balance
between the heat produced and the heat lost.

Heat is produced solely in the metabolic processes,
principally in the voluntary muscles.

Heat is lost —

(1) By radiation to the surrounding atmosphere;

(2) By evaporation of sweat ;

(3) By evaporation of water in the lungs ;

(4) By discharge of warm excreta — carbonic acid, urine

and faeces ;

(5) By warming foods ingested cold.

Heat regulation is seen in its simplest form in muscular
exercise when increase in heat-production is counter-
balanced by an increase in heat-loss brought about by
dilatation of the cutaneous blood-vessels and increased
evaporation of sweat from the skin and of water from the
lungs.

Variations in the external temperature produce a two-
fold reaction — change in the amount of heat lost (physical
regulation) and change in the amount of heat produced
(chemical regulation). These alterations being in a re-
ciprocal direction the temperature remains constant.

Physical Regulation

The action of external cold upon the skin is to con-
strict the blood-vessels and to stop sweating. These
effects are produced reflexly through the central nervous
system, the sensory nerves constituting the afferent and
the sympathetic the efferent path. In the absence of

250 THE REGULATION OF TEMPERATURE

such a mechanism the heat lost would, of course, increase
as the external temperature fell. Now physical regula-
tion only partially compensates for this, for the heat
lost still rises with fall of temperature, but not to the
same extent as would occur were the mechanism absent.
Physical regulation therefore produces a relative, not an
absolute diminution in heat-loss. The amount of heat
lost is further diminished by the instinctive act of putting
on more clothes, these serving as a means of entanghng
a layer of warm air around the body. Radiation of heat
is less in the obese than in the thin, the heat of the body
being preserved in the former by the subcutaneous fat.

Chemical Regulation

The increased heat- production is again a reflex effect.
To its occurrence, which can be demonstrated by calori-
-^letry, several factors contribute :■ —

{a) Increased inclination to voluntary activity ;
(6) Involuntary movements — shivering ;
(c) Increased tonus of the muscles.

In dogs, when the passage of impulses from brain to
muscles is blocked by administration of curare, the animal
loses the power of maintaining a constant temperature
when the temperature of the environment falls.

Increased metabolism leads to increased appetite. Food
is taken in larger quantity, and when absorbed adds the
heat due to its specific dynamic energy (p. 153). Observa-
tions on the respiratory quotient show that this approaches
unity — proving that the increase in metabohsm chiefly
involves the carbohydrates.

As the surrounding temperature rises, heat-loss in-
creases owing to the discarding of clothes, the diminished
vaso-constriction and, later, the secretion of sweat. At
the same time, heat-production is decreased owing to a
progressive disinchnation for activity and a diminished

REGULATION OF TEMPERATURE 251

muscular tone. Heat-production, however, cannot be
diminished below the hasal metabolism which, we have
seen, amounts to about 2500 C. When this hmit is reached
the temperature can only be maintained at a constant
level by increased loss of heat — that is by radiation and
evaporation.

Radiation is facilitated by the constant removal of the
warmed air from the surface of the body; it is therefore
more effective in a wind than in a still atmosphere. As
the surrounding temperature rises, conduction diminishes
and evaporation comes more and more into play, until
when the temperature of the air is as high as or higher
than that of the body evaporation becomes the sole avenue
for heat-loss. The effectiveness of evaporation depends
upon the degree of saturation of the air with water- vapour.
When the air is so hot that radiation cannot occur, and so
humid that evaporation cannot occur, the heat-regulating
mechanism breaks down and the body temperature rises.

A centre for the regulation of temperature is said to
exist in the corpus striatum. Damage to this area leads to
rise of temperature. Stimulation with water colder than
the blood leads to shivering and vaso-constriction, stimu-
lation with, water warmer than blood to diminished muscular
tone and to vaso-dilatation. The rise of temperature which
occurs during fevers (pyrexia) is attributed to the stimu-
lation of the centre by the toxic products of the infective
process.

CHAPTER XV
THE NERVOUS SYSTEM

PART I
THE NEURONE AND THE NERVOUS IMPULSE

The functions of the nervous system are to co-ordinate
the activities of the different organs of the body and to
bring the body into relation with its environment.

The cells of which the nervous system are composed are
distinguished by possessing in an exalted degree two pro-
perties, irritability or the capacity to respond to a stimulus,
and conductivity or the capacity to transmit a disturbance
arising at any point in the cell with great rapidity through-
out the whole cell. Out of these two properties arise
others — the capacity to store impressions and to associate
them together — properties upon which depend the more
complex mental processes.

THE NEURONE

The nervous system is made up of a chain of nerve-cells
or neurones, each of which consists of a cell-body and
one or more processes. These processes are of two kinds,
axons and dendrons (or dendrites). The cell-body is the
enlarged part of the neurone which contains the nucleus.
It is the meeting-place of the processes if more than one
exist, and if only one process exists it is the part at which
the neurone comes into anatomical contact with the

252

NERVE-FIBRES 253

processes of neighbouring neurones. The cell-body is
sometimes known as the nerve-cell. It should be remem-
bered, however, that the whole neurone, processes and all,
is one cell. The cell-body contains a well-marked nucleus,
within which is a nucleolus. In a perfectly fresh cell the
protoplasm surrounding the nucleus contains fine granules
uniformly distributed. Shortly after death these granules
clump together and form the Nissl bodies, which stain
readily with methylene blue. But although entirely a
post-mortem phenomenon, the formation of Nissl bodies
fails to occur {ehroinatolysis) unless the cell was previously
in a healthy state. It fails when the cell has undergone
prolonged disuse or excessive fatigue.

Among the granules, and traversing the cell-body from
dendrites to axon are fine fibrils which join together to
form a plexus.

According to the number of processes arising from the
cell-body the nerve-cell is known as unipolar, bipolar, or
multipolar. However many processes the cell may possess,
only one is termed an axon. Collections of cell-bodies
outside the central nervous system are known as gangha,
and inside are often termed nuclei.

Nerve-fibres

These are the processes of the nerve-cells. They are
of two kinds : white or medullated, and grey or non-
medullated. Medullated fibres consist typically of three
layers. The innermost layer — the axis cylinder — is com-
posed of fine longitudinal fibrils continuous with those of
the cell-body. Surrounding the axis cylinder is the
medullary sheath, composed of a hpoid substance known
as myelin. It is non-nucleated and probably structureless.
It is interrupted at intervals — the nodes of Ranvier. The
medullary sheath probably serves to protect, nourish and
insulate the axis cylinder.

Surrounding the medullary sheath is the neurolemma or
sheath of Schwann. This forms a thin nucleated and un-

254 THE NERVOUS SYSTEM

interrupted investment. At the nodes, when the medullary
sheath is deficient, it is contiguous with the axis cyhnder.
The neurolemma is only found in nerve-fibres outside the
central nervous system.

The above description appUes equally to dendrons and
to axons. These differ in that dendrons branch very
freely, while axons, though they give off minute lateral
branches {axo7i collaterah), do not properly divide until
near their termination.

Under physiological conditions an impulse travels from
the dendrons to the cell-body and from the cell-body to
the axon (axi petal conduction).

Non-medullated fibres, as their name implies, have no
medullary sheath. Upon them he nuclei beheved to belong
to a kind of neurolemma. They ramify more freely than
medullated fibres.

In the nerve -trunk the nerve-fibres are packed together
in bundles, which are separated by connective tissue — the
perineurium. This contains blood-vessels, lymphatics and
sensory nerve-endings (nervi nervorum). Surrounding it
is an outer fibrous layer — the epineurium.

Degeneration and Regeneration of Nerve

When a nerve is cut, the axons which are separated
from their cell-bodies undergo the process of Wallerian
degeneration. The medullary sheath is decomposed into a
mass of fatty globules, and the axis cylinder becomes broken
into fragments. The dMris is absorbed by leucocytes.
Meanwhile the nuclei of the sheath of Schwann undergo
proliferation, forming a chain of cells in which fibres are
deposited. Regeneration — a slow process — occurs by down-
growth of fibres from the central stump. These find their
way into the peripheral part, the newly formed fibres of
which form a kind of scaffolding for the new nerve pro-
cesses to grow down.

When a motor nerve is cut profound changes take place
in the muscle which it supplies. There is a high degree

THE NERVOUS IMPULSE 255

of atrophy and depression of excitability. The muscle
ceases to respond to the alternating current. At make
and break of the constant current it responds with a
sluggish contraction. Further, while a normal muscle
responds better to a closing (make) current when stimulated
by the kathode than when stimulated by the anode
(KCC > ACC), in the degenerated muscle it responds to
kathode and anode indifferently.

THE NERVOUS IMPULSE

We shall now consider the excitability and conductivity
of the nerve-fibre with a view to understanding the nature
of a nervous impulse.

Velocity

The rate at which a nervous impulse travels is estimated
in the nerve-muscle preparation by stimulating the nerve
first at one point, then at another point along its course,
and measuring the difference in the latent period. For
the frog the velocity is twenty-eight metres per second.
For warm-blooded animals it is probably at least five times
as great, the rate of conduction increasing considerably
with rise of temperature.

Reversibility of the Impulse

A disturbance arising at any point in a nerve-fibre is
transmitted throughout the fibre in both directions. This
was proved by the classical experiment of Kiihne. The
frog's gracilis muscle consists of two halves, separated by
a fibrous band ; each axon as it enters the muscle divides,
one branch going to each half of the muscle. Stimulation
of one half of the muscle where it contains nerve-end-
ings causes contraction of the whole muscle, the impulse
having travelled up one set of branches of the axon to the
point of division and down the other set.

An analogous phenomenon is found in connection with

256

THE NERVOUS SYSTEM

the bladder. The innervation of this viscus is shown in
Fig. 37. After section of the nerves going to the inferior
mesenteric gangUon, when the left hypogastric nerve is
cut and its central end stimulated, the right half of the
bladder contracts. This is due, as Langley and Anderson
showed, to the division of each axon going to the inferior

Sp cord

Inf. meig --f
Post -ganglionic fibre

^ 'Pre -ganglionic fibre
-Hypogastric nerves

Fig. 37. — Diagram to show the axon-reflex in the innervation of the
bladder. The axons divide at x (from the Journal of Physiology).

mesenteric ganglia. Such an effect is termed an Axon-
reflex.

The question now arises, if nerve-fibres can conduct
impulses in both directions, do they do so under natural
conditions ? It is usual to regard nerve-fibres as either
exclusively motor or exclusively sensory, but the anti-
dromic impulses (p. 87) seem to indicate that the posterior
root-fibres, in addition to conveying sensory impulses
centrally, convey vaso-dilator impulses peripherally. Again,

EXCITABILITY OF NERVE 257

when the posterior root gangUon is diseased, an eruption
occurs along the cutaneous distribution oi the nerve (herpes
zoster).

The Excitability of the Nerve Fibre

The nerve-fibre, hke any other part of the neurone, is
highly irritable; it responds to various stimuU, such as
heat, or the action of chemicals by an internal disturbance
which is propagated throughout the neurone and cul-
minates in a subjective impression or a motor effect. Of
all the stimuli or exciting agents the most convenient to
employ for experimental purposes is electricity, for although
this is a form of energy which but rarely affects nerves
under normal conditions, yet it is the only one which in
this connection can be measured.

When a constant current is passed through a nerve,
excitation occurs at make and again at break. While the
current is passing no visible result is produced. In nerve,
as in muscle, the state of excitation begins at the kathode
on make and at the anode on break. Change of potential,
then, rather than potential itself, is the stimulating agent.

On inquiring further into the effect of change of
potential upon the development of the excitatory state,
it is found that there are two separate factors concerned —
the intensity of the current and the rate of change of
potential. As to the latter there is for nerve as for every
irritable tissue an optimum rate of change or gradient
which is effective. This is known as the " characteristic."
The high-frequency current, for instance, is harmless to the
body, since the rate of change is too rapid to influence
any of the tissues. The single induction shock, while an
efficient stimulus to nerve, is too rapid for less irritable
tissues, such as intestinal muscle.

Yet though no excitation occurs while the constant

current is passing, duration of 'current is an important

factor. There is between duration and intensity of current

a reciprocal relation ; the smaller the current, the longer

258 THE NERVOUS SYSTEM

must it last in order to be effective. The following figures
by Keith Lucas show this : —

Duration of cvirrent Strength of current

in seconds. in volts.

00 -086

•00087 -179

Here the smallest current which is effective, given unhmited
time, is '086 volt. When the strength of current is doubled
the minimum duration required is -00087 sec. This figure
was called by l/ucas the excitation-time. He found it to
be smaller in nerve-fibre than in muscle, and much smaller,
again, in the nerve-ending.

Factors influencing the Activity of the Nerve-fibre

The two properties possessed by the nerve-fibre —
excitability or the capacity to initiate a disturbance, and
conductivity or the capacity to propagate that disturbance —
are both profoundly modified by various circumstances.

1. Temperature.— The rate of conduction increases con-
siderably with rise of temperature. The change in excit-
abihty depends upon the form of current used. With rise
of temperature nerve becomes more irritable to induction
shocks and less irritable to mechanical stimulation.

2. Previous Activifi/.— 'Piomded that the nerve-fibre is
liberally supplied with oxygen it seems to be completely
immune to fatigue. When, after the motor nerve-endings
have been paralysed with curare, a nerve is subjected to
prolonged stimulation the muscle which it supplies con-
tracts when the effect of the drug has passed away.

But the effect of a stimulus is influenced by an impulse
which has just occurred, the direction in which it is
influenced depending upon the interval between the
stimulus and the previous impulse. The most notable
change is a change in excitabihty. This is shown in
Fig. 38. For a period of about -002 sec. after an impulse
has passed along it a nerve is completely inexcitable. This

REFRACTORY PERIOD

259

is known as the absolute refractory period. Then follows
the relative refractory period, during which the excitability
is steadily rising to the normal. This is succeeded by a
period of heightened excitabihty, the supernormal phase.
It will be noted that the refractory period of nerve differs
from that of muscle in being much shorter.

It is now known that these three phases in the change

ex!
o

o
x:

100-

50-

-^ — i—, — ■ > I
•01 -oz

TIME IN SECONDS AFTER.
FIR5T STIMULUS

■03

Fig. 38. — Diagram (after Adrian and Lucas) to show recovery of excit-
ability after the passage of an impulse : A, absolute refractory
period ; B, relative refractory period ; C, supernormal phase.

in excitabihty are accompanied by corresponding changes
in conductivity.

It follows as a corollary from this that if a nerve is
stimulated while it is in the supernormal phase due to
a previous stimulus, the initiation and propagation of the
second impulse will be facihtated — the disturbance will be
greater and will travel more rapidly than it would had
there been no previous stimulus. If two stimuh, each of
which acting alone would be ineffective, are sent into a
nerve such that the second enters while the nerve is in

260 THE NERVOUS SYSTEM

the stage of exalted excitability due to the first, the second
stimulus becomes effective. This is known as summation.

3. The Passage of a Constant Current — Electrotonus. — •
Though there is no propagated disturbance while a con-
stant current is passing through a nerve there is a change
in excitability, known as electrotonus. This takes the form
of diminished excitabihty at the anode {anelect rot onus) and
increased excitabihty at the kathode {hatelectrotonus).

4. Drugs. — Narcotics, such as alcohol and COg, depress
both conductivity and excitabihty.

The Changes accompanying a Nervous Impulse

1. Current of Actioyi. — When an impulse passes along a
nerve-fibre this shows a current of action resembhng that
found in muscle, the part of the nerve which is in a state
of excitation being negative to the rest of the nerve. On
this is based a method for determining whether a nerve is
active in situ, e. g. the depressor nerve.

2. Evolution of Heat. — By means of the thermopile it has
been found that a very minute though indisputable rise
of temperature accompanies the passage of an impulse.

3. Gaseous Metabolism. — When a nerve-fibre is deprived
of oxygen it loses its excitability more rapidly when it is
stimulated than when it is not. This shows not only that
oxygen is necessary for the maintenance of the fibre in a
healthy condition, but also that oxygen is used up in the
passage of a nervous impulse.

Similarly it has been shown that the CO2 output of a
nerve is increased 2*5 times when it is stimulated. These
facts therefore point to an unmistakable gaseous interchange
accompanying a nervous impulse.

The Nature of the Nervous Impulse

From the fact that a nervous impulse is generated on
make of a constant current at the kathode, and on break
at the anode, and that it depends upon, the rate of
change of current rather than upon the current itself, the

THE ALL-OR-NONE PRINCIPLE 261

hypothesis has been put forward that the initiation of an
impulse depends upon the rate of change of concentration
of ions at the point stimulated. More certain is our
knowledge concerning the nature of the impulse when it
is being propagated. There are two possibilities. Either
the impulse is launched with a certain quantity of energy
which carries it to its destination, or it is dependent for
its conduction upon a renewal of energy by molecular
changes at each successive point in its course. In the
first case we should expect to find that a nerve-fibre is
capable of carrying impulses of different strength accord-
ing to the intensity of the energy with which the impulse
is started. In the second case the intensity of the dis-
turbance would be independent of the strength of stimulus
and dependent Mily upon the nerve-fibre itself. The fibre,
in other words, would obey the all-or-none principle. Proof
that the latter supposition is true comes from Adrian's
experiment. When a given length of nerve is narcotised
for a certain time the impulse is extinguished as it traverses
the narcotised portion. Suppose that a length of nerve
D (Fig. 39, A) is narcotised in such a way that the
impulse started at III is just abolished at the distal
end of D. Now suppose this length to be divided into
two, d and d', separated by a length of healthy nerve I.
When the impulse emerges from d it will be reduced to
half its intensity. If it remains at this mtensity until
it enters d' it will again be completely extinguished at
the distal end of d'. Its intensity will be represented as
shown by the continuous line in Fig. 39, B. If, on the
other hand, the impulse arrives at the muscle with un-
diminished force, it means that every time it enters a healthy
part of the nerve it recovers its initial intensity as shown
in Fig. 39, C. Adrian found the latter to be the case, thus
proving that the nervous impulse rather resembles a train
of gunpowder. If a part of the train is shghtly damp
there is a delay in the rate of conduction, but provided
that the molecular changes arc able to pass through the

262

THE NERVOUS SYSTEM

damp part the conduction in the dry part beyond is in
no way impaired. This experiment shows that the impulse
depends for its conduction upon energy hberated along its
course, and that the nervous impulse obeys the all-or-none
law in that its intensity is independent of the intensity of
the stimulus to which it owes its origin.

To Muscle

'\r^

II d I d'

Fig. 39. — Adrian's experiment (from the Journal of Physiology).

In confirmation of this view is the evidence, already
given, of a definite increase in the metabohsm of a nerve-
fibre when it is active.

Conduction from Nerve to Muscle

The axis cylinder pierces the sarcolemma of the muscle-
fibre and arborises in a mass of protoplasm known as the

THE N EURO-MUSCULAR JUNCTION 263

end-plate. The latter therefore forms an anatomical break
in the neuro-muscular mechanism. This break has a definite
physiological significance, for it possesses certain special
properties on account of which the nature of the impulse
passing along it differs from an impulse passing along a
nerve-fibre. (1) There is evidence to show that the end-
plate is more liable to fatigue than the nerve-trunk;
(2) there is a delay in the transmission of the impulse
across it; (3) impulses traverse it in one direction only —
from nerve to muscle ; (4) it responds to stimuh of extremely
short duration ; (5) it is pecuharly susceptible to the action
of drugs.

It is therefore beheved that between the nerve-ending
and the muscle-fibre a third substance exists differing
physiologically both from nerve and from muscle. This
substance forms a structure called the neuro-muscular
junction.

PART II

THE CENTRAL NERVOUS SYSTEM

By means of the nervous system an animal reacts to
changes in its environment. The physical form which the
reaction takes is the expression of the ability of the
animal to overcome the alteration in the external circum-
stances ; the reaction is purposive and protective. Evolu-
tion from lower to higher forms is distinguished by nothing
so much as by an increase in the variety both in degree
and in kind of the responses which the organism is able
to make.

The earliest formation of cells speciahsed to respond
to stimuh is seen in Hydra (Fig. 40, I), where certain
epithelial cells are endowed with a high degree of irrita-
bihty on their superficial surface and with a high degree of
contractihty on their deep surface — this being expanded
to form a contractile plate. The next stage is the migra-
tion of the contractile element away from the epithelium
so that it may be exposed to the environment. Accompany-
ing this migration is a separation of the single responsive
cell into two, one specially endowed with irritabihty, the
other with an exalted contractihty (Fig. 40, II). The con-
nection between the two cells is by a strand of the irritable
cell — the first appearance of a nerve-fibre. In a third
stage this strand acquires a nucleus of its own and becomes
an independent cell (Fig. 40, III). We now have a con-
tractile cell responding to a stimulus arising in another cell
situated at a distance from it. The fourth stage consists
in the estabhshment of a means of co-ordination between

264

EVOLUTION

265

all the neuro-muscular mechanisms in the organism. This
is effected by free anastomosis of the nerve-fibres — an
arrangement of which the best instance is seen in the jelly-
fish (Fig. 41). Here a plexus of nerve-cells and nerve-
fibres connects all the sensory cells on the outer surface
with all the contractile cells in the interior, the nerve-
fibres being continuous throughout. This has been termed
the diffuse nervous system. Such an arrangemenb has its
advantage and its hmitation. The advantage is that the
whole motor apparatus can be immediately brought into
action as the result of a stimulus arising at any one spot on

.SEMiOICC CELL-.

M'J5CUi-/iR. PK0CE33

NERyE-CElL

^MUSCLE CELL

Fig. 40. — Diagram (after Foster) to show the evolution of the
nervous system.

the epithehum. The hmitation is that the whole muscular
mechanism must be brought into play if at all. Owing to
the freedom of the nervous connections no contraction of
parts of the muscle sheet is possible. But from the nature
of the organism this is not necessary, since locomotion,
which is the only response possible, can only be brought
about by a contraction of the whole swimming-bell. The
response, then, in this stage is always crude and maximal.
It is possible that the nerve-net system is represented in
Auerbach's plexus of the intestine.

The development of the capacity for graded responses
is the fifth and last stage in the evolution of the nervous
system. It is associated with the appearance of the

266

THE NERVOUS SYSTEM

central or synaptic nervous system. Out of the single
continuum of nervous tissue is evolved a system of nerve-
cells or neurones which form a complex chain, adjacent
hnks of which are functionally continuous, but, so far as
is known, histologically discontinuous, the gaps which
separate the neurones being known as si/napses. As an
impulse traverses a synapse it is hable, as we shall see,
to modification both in intensity and in character. It is

EPITHtLIUM

NUCLEUS

MUoCLE FIBRE5

Fig. 41. — Diagram of part of body-wall of Medusa (jelly-fish),

after Bethe.

owing to the special physiological characters of the synapses
that the animal is enabled to grade and to alter in kind
the form of its nervous response.

Synapses or junctions between neurones are collected
together into groups, and in segmented organisms each
segment has its own synaptic centre, the centres of all
the segments being connected together by nervous strands.
In this way is formed the beginning of a spinal cord wliich
serves the purpose of conducting an impulse from one
segment to another, and thus of co-ordinating the activities
of all the segments for the good of the whole organism.

THE TRACTS 267

The animal, being now elongated along one axis, develops
at one end (the front end) epiblastic cells speciaUsed to
receive stimuh from a distance — hght, smell and, later,
sound-waves. In this way it is enabled to explore new
territory before moving into it. The information gained
from these sensory cells largely determines the reaction of
the organism, the rest of the body becoming subservient
to the advancing end. With the greater responsibihty
thrown upon this region, the neurones belonging to it
undergo considerable increase in number and complexity —
in this way the cerebrum is formed.

But in addition to knowledge of the external world, the
animal requires information regarding its own position. In
different parts of the body special cells are developed to
be excited by position and by change of position. These
impulses converge upon masses of nerve-cells lying behind
the cerebrum and forming the cerebellum.

THE TRACTS OF THE CENTRAL NERVOUS SYSTEM

The following methods have been employed for tracing
the course of fibres within the central nervous system :■ — •

1. Fleschig's Myelination Method. — This depends upon
the fact that in different tracts the axis cylinders acquire
their myelin sheaths at different stages of embryonic
development.

2. Wallerian Degeneration. — The histological changes
which follow the separation of a nerve-fibre from its cell-
body have already been noted. In about three weeks
after section, the myehn is converted into a simple fat
which can be stained with osmic acid (Marchi's method).

3. Successive Degeneration. — This is a modification of the
above method. Fig. 42 represents a longitudinal section
of the cord, A, B, C and D being the segments. It is
desired to find out what descending neurones arise in the
segment B. The cord is transected between A and B and
several months allowed to elapse, so that all fibres arising

268

THE NERVOUS SYSTEM

from above B (1, 2 and 3) undergo complete degeneration
and disappear. Section is then made between B and C,
and three weeks later the newly-degenerated fibres (4, 5
and 6) arising from B will be visible lower down on

staining with osmic acid.

4. Retrograde Degeneration. —
When a nerve-fibre is cut, though
the proximal part does not un-
dergo Wallerian degeneration, the
cell-body undergoes a diminution
in size and chromatoly sis or failure
of formation of the Nissl bodies

A — changes which can be readily

{yA made out by staining with methyl-
' ^ ene blue. In this way it is pos-
sible, for example, to find out from
what cells in the cord a motor
nerve arises.

5. Histological Method. — The
tissue is stained in bulk with
methylene blue or silver nitrate.

The main tracts are the follow-
ing:—

Descending Tracts : —

1. Pyramidal Tracts. — These
arise from large cells (Betz cells)
situated in the motor or 2)re-
Rolandic area of the cerebral cortex.
As they pass inwards they form a
converging mass of fibres — corona
radiata. They then form in turn the posterior hmb of the
internal capsule and the middle part of the crus cerebri.
In the pons some of the fibres end by arborising around
the nuclei pontis, the fibres of which pass transversely to
the cerebellum in the middle peduncle. These transverse
fibres break up the main tract into a number of bundles,

% 6

Fig. 42.— To show the
method of successive
degeneration.

THE TRACTS

269

which, however, are collected together again in the medulla,
where they form the ventrally placed 'pyramids. At the
lower end of the medulla the great majority of the fibres
cross over {decussation of the pyramids) and occupy an
area in the lateral columns of the cord (crossed pyramidal
tract) (Fig. 43, 1). They terminate at different levels by
passing into the grey matter and arborising around cells in
the anterior horn and at the roots of the posterior horn.

s/^.L

Fig. 43. — Diagram sho^nng the ascending (right pide) and the de-
scending (left side) tracts in the spinal cord (from Schafer's Essentials
of Histology).

A few fibres {uncrossed lateral pyramidal tract) pass into
the lateral columns of the same side.

Some fibres {direct pyramidal tract) pass into the anterior
columns of the cord on the same side (2).

2. Prepyramidal or Rubrospinal Tract {Bundle of Mona-
how). — This bundle arises in the red nucleus of the mid-
brain, through which it gains connection with the cerebellum.
In the cord the fibres occupy a position anterior to the
pyramidal tract (4) and end in the grey matter, joining
the anterior and posterior horns.

3. Tecto-spinal and Olivo-spinal Tracts {Bundle of

270 THE NERVOUS SYSTEM

Helweg). — These tracts arise from the anterior and posterior
corpora quadrigemina and from the olive. Passing down-
wards they cross over and occupy in the cord a small
area opposite the outermost point of the anterior horn
(3, a).

4. Vestibulo-spinal or Anterolateral Descending Tract. —
Arising in Deiters' nuclens, through which it gains con-
nection with the cerebellum, this tract occupies in the
cord a marginal position in the anterolateral column (3).

Short Descending Tracts : —

5. Comma Tract (5). — The descending branches of
posterior root-fibres.

6. Septo-marginal bundle (5, m). — Mainly proprio-spinal.

Ascending Tracts : —

1, Posterior Columns. — These are formed by fibres from
the posterior roots. Passing inwards, these fibres first
occupy a position adjoining the posterior horn. As they
pass upwards they are gradually pushed towards the
middle line by fibres coming in at higher levels. In the
upper part of the cord the posterior column becomes
divided into two parts — a postero-median part (Column of
Goll), containing fibres from the lower limb, and a postero-
lateral part (Column of Burdach), containing fibres from
the upper hmb. These fibres terminate at different levels
by entering the grey matter, the largest travelhng into
the medulla, w^here the column of Goll arborises around
the nucleus gracilis, and the column of Burdach around the
nucleus cuneatus. From these nuclei a second relay of
fibres takes origin, and decussating in the medulla, forms
the median fillet, which ends in the optic thalamus. From
the thalamus a third neurone travels to the cerebral
cortex.

The fibres of the posterior column are uncrossed in the
cord.

THE TRACTS 271

2. Cerebellar Tracts : —

The Direct or Dorso-lateral Cerebellar Tract {Tract of
Flechsig) arises from the cells of Clarke's column (situated
internally on the posterior horn), occupies a dorsolateral
position in the cord and enters the cerebellum by the
inferior peduncle, ending in the lower part of the vermis.
This tract is uncrossed.

The Indirect or Anterolateral Cerebellar Tract {Tract of
Gowers). — These fibres arise from Clarke's Column, form
a ventrolateral tract and enter the cerebellum by the
superior peduncle, ending in the superior part of the
vermis. They are mainly uncrossed.

3. Spino-thalamic and Spino-tectal Tracts. — Intermingled
with the Tract of Gowers are a few fibres travelling upwards
to the thalamus and corpora quadrigemina. They are
partly crossed, partly uncrossed.

PART III

REFLEX ACTION

With the exception of the axon-reflexes, already described,
all reactions to stimuli in the higher animals occur through
the central nervous system. Such reactions are called
reflex actions. In order to study them it is necessary to
transect the spinal cord in its upper part in order to
eliminate influences due to cerebral processes, such as
wifled movements. An animal so prepared is known as
the spinal animal. For our knowledge of reflex action
we are indebted to the researches of Sherrington.

Examples of Reflex Action : —

1. The Flexion Reflex. — When the skin of the foot in the
spinal animal is pricked, burnt or stimulated electrically
the foot is drawn up.

2. The Extensor Thrust. — When pressure is apphed to
the pad of the foot the leg is fully extended.

3. The Scratch Reflex. — When any point over a wide
area of the back and flank is stimulated the hind leg per-
forms a rhythmic scratching movement directed to the
point stimulated.

In reflex paths three component parts can be made
out : —

1. A receptor organ, situated peripherally. This struc-
ture is endowed not only with a high degree of irritability,
but also with the power of responding to stimuU of a
particular kind.

2. An effector organ — muscle or gland,

272

REFLEX ACTION 273

3. A conductor mechanism, composed of the afferent
neurone, the motor or efferent neurone, any neurone or
neurones which connect them centrally, and the inter-
neuronic synapses.

From every segment of the cord there emerges on each
side two nerve-roots, which soon unite to form a spinal
root. Of these roots, one, the posterior, normally conveys
impulses towards the cord, the other, the anterior, away
from it (Bell's law).

Posterior root fibres, when they enter the cord, ramify
and connect with other cells as follows (Fig. 45, p. 286) ; —

1. They arborise around posterior horn cells as soon as
they enter.

2. They pass to the opposite side of the cord.

3. They arborise around anterior horn cells at the same
level.

4. They arborise around cells of Clarke's column.

5. They form a tract running up and down the cord
for a short distance and terminating in the substantia
gelatinosa, a mass of grey matter which caps the posterior
horns.

6. They enter the white matter to form the posterior
columns. Here each fibre divides into an ascending and
descending branch. The latter group pass a short distance
down the cord and end by arborising around posterior
horn-cells. The ascending branches pass upwards, ter-
minating at various levels, the largest of them reaching
the medulla, where they arborise around cells of the nucleus
gracilis and nucleus cuneatus.

The anterior root fibres, with the exception of those
destined to supply the visceral system, all arise from
nerve-cells in the anterior horns.

It will thus be seen that the path of conduction from
the receptor to the effector organ must involve at least
two neurones, with the synpase between them. In point
of fact, in most reflexes more than two are involved, since
one or more neurones are intercalated between the posterior
18

274 THE NERVOUS SYSTEM

iibre and the anterior fibre. Such intermediary fibres, since
they are situated entirely within the cord, are known as
proprio-spinal. They serve especially to connect the
posterior fibre of one segment with the anterior fibre of
another.

Conduction in the Reflex Arc

Conduction in a reflex arc differs from conduction along
a nerve-fibre in the following respects : — ■

1. In its slower speed. Frog's nerve at 15° C. conducts
at the rate of 3 cm. per o {o ^ -001 sec). The flexion
reflexion in the frog occupies 30 a. Moreover, the rate of
transmission varies with the intensity of the stimulus and
differs in different reflexes.

2. In the tendency to after-discharge. In the reflex the
effect often continues long after the cessation of the
stimulus, this period of after-discharge increasing with
intensity of stimulus.

3. In its irreversibility. Conduction occurs only from
receptor to effector.

4. In its liability to fatigue.

5. In its greater dependence upon oxygen.

6. In its greater susceptibihty to the action of ancesthetics.

7. (When the reflex response is rhythmic), in the want of
correspondence between the rhythm of stimulation and the
rhythm of effect. The rhythm of the scratch-reflex, for
instance, is the same whatever the mode of stimulation.

8. In its greater habihty to summation. Summation we
have already seen in nerve-fibre — it is the effectiveness of
frequently repeated stimuh each of which is ineffective
singly.

9. In the greater length of the refractory period.

Tendon or Deep Reflexes

The question arises here whether the contraction of a
muscle which occurs when its tendon is struck — the knee-
jerk, for instance— is reflex or not. Clearly the spinal

TENDON REFLEXES 275

cord is involved, since the jerk is abolished when the
motor nerve has been cut. But it might be that the cord
sends out a constant succession of impulses which keep
the quadriceps muscle in a state of tonus, and that the
jerk is the expression of a local irritabihty only present
when the muscle is in tonic contraction. Against this
view is the fact that while the cut peripheral end of the
motor nerve to the quadriceps is being stimulated so as
to keep the muscle in tetanic contraction, the knee-jerk
cannot be ehcitated. In favour of the view that the
knee-jerk is a true reflex is the fact that contraction of the
quadriceps is accompanied by relaxation of the hamstrings.
It was once alleged that the knee-jerk could not be a
true reflex, since its latent period was too short. But
recent and more accurate estimations have shown that the
time elapsing between the moment of stimulation and the
moment of contraction is of the same order as in the case
of actions known to be of a reflex nature. We are therefore
justified in regarding tendon-reflexes as true reflexes.

Such being in general the nature of reflex action, it now
remains to find out which of the morphological components
is responsible for those characteristics of the reflex arc which
distinguish it functionally from the nerve-fibre. It cannot
be the nerve-cell (so-called), since we have no evidence of
any alteration in character of a nervous impulse as it
travels through the spinal gangha. The functions of the
cell-body have always been regarded as being to control
the nutrition of the whole cell, including the fibres, and
to serve as a junction or meeting-place of dendrites and
axons.

Many of the features of reflex conduction resemble
those of conduction from nerve to muscle : the irrever-
sibility, the delay in transmission, the liabihty to fatigue,
and the susceptibihty to drugs. For this reason, as
well as by a process of exclusion, we are driven to the

276 THE NERVOUS SYSTEM

conclusion that just as the junction between nerve and
muscle confers certain characteristics upon conduction, so
the synapse or junction between the neurones exerts, but
to a greater degree, its influence upon impulses passing
through it. As to the physical nature of the synapse we
have no definite information. Even if it be that the
synapse is composed of fibrils uniting neighbouring neurones,
conduction along these must be profoundly difierent from
conduction along the nerve-fibre. Moreover, it is only by
ascribing such an influence to the synapse that we can
explain how reflexes are, singly and in combination,
adapted so as to become purposive acts. This we shall
now consider.

Inhibition — Reciprocal Innervation. — Among the visceral
nerves there are some, stimulation of which causes a
depression or even cessation of a pre-existing state of
activity. Stimulation of the peripheral end of the cut
vagus, for example, slows and even stops the heart.
Increased activity in a nerve leads to diminished activity
in the organ which the nerve supphes. Inhibition
is seated peripherally. Throughout the skeletal system
there is no instance of a peripheral nerve which, when
artificially stimulated, causes relaxation of a contracted
state previously existing. But when a muscle is made to
contract reflexly the act is always accompanied by active
relaxation of the antagonistic muscle. This is easily proved.
If an extensor muscle is severed from its distal bony con-
nection it undergoes lengthening when the flexion reflex
is stimulated. The relaxation of the one muscle is as
essential a part of the reflex as contraction of the other.
It has the same time relations, the same tendency to
after-discharge, and generally observes the same rules.

Instances of reciprocal innervation are also seen, at any
rate in a crude form, in the visceral system. In the
intestine, stimulation at a certain point causes contraction
above and relaxation below. Here, as in the case of the
vagus nerve, the mechanism is purely peripheral.

RECIPROCAL INNERVATION ,

277

In the skeletal system the mechanism of inhibition and
of reciprocal innervation is situated centrally. An active
state in an afferent nerve is converted centrally into a

Fig. 44. — Diagram indicating connections and actions of two affei'ent
spinal root cells a and «' in rcgai'd to their reflex influence on the
extensor and flexor muscles of the two knees. The i-ign + indi-
cates an excitatory and the sign — an inhibitory effect (Sherrington).

double effect — a positive effect upon one group of neurones
and a negative effect upon another. Central inhibition is,
however, not confined to the skeletal system. The
depressor nerve arising in the heart and aorta inhibits a

278 THE NERVOUS SYSTEM

pre-existing state of tonus of the blood-vessels. Respiratory
movements are inhibited during the act of swallowing. In
all these cases the conversion of a positive into a negative
effect must be ascribed to the synapses.

Another degree in this transformation of a positive into
a negative effect is seen in the scratch reflex. The nervous
impulse resulting from the stimulus, which may be a
constant stimulus, causes at one moment contraction of
flexors and relaxation of extensors. At the next moment
this effect is transformed into relaxation of flexors and
contraction of extensors. , This repeated gives the rhythm
of the scratch. Such a reflex is termed by Sherrington
a reflex of successive double sign.

The Final Common Path. — A given group of muscles can
be brought into action by the stimulation of any of a
large number of receptors. The flexion reflex is induced
from any point on a large surface of the hind Umb, the
scratch reflex from a large surface on the back. There is,
then, centrally a convergence of paths upon every group
of motor nerves. The motor neurone upon which so many
neurones impinge is therefore called the final common
path.

Spread of Reflex. — When the flexion reflex is induced
with stimuh of increasing intensity the movement involves
more and more of the musculature of the hind limb. With
very weak stimuh only the foot is involved, with strong
stimuli the whole limb and even the other parts of the
body. In addition, therefore, to there being centrally a
convergence of paths there is also a divergence — a radiation
from a central focus on the motor side. The spread of
the reflex effect from the focus can only be explained by
assuming that each afferent fibre comes into connection,
directly or indirectly, with several motor cells, and that
the synapses between the afferent fibres and the several
anterior horn cells present to the afferent impulse varying
resistances. Some of these resistances are forced easily,
others only with difiiculty.

REINF0RCE3IENT 279

Reinforcement and Combination of Reflexes. — When the

scratch reflex is induced from two points situated close
together on the skin the motor efiect is more intense than
if either stimulus acted singly. The two stimuli sum in
their efiect upon the final common path.

Antagonistic Reflexes — Interference.^ — Some reflexes are
incompatible — the scratch and the flexion reflex, for
example. If the flexion reflex is induced by a strong
stimulus while the scratch reflex is in progress, the latter
may be inhibited, the former taking its place. This is
known as interference. Whether or no interference occurs,
depends upon the relative strength of the stimuli causing
the two reflexes. The cessation of one reflex and its replace-
ment by another always occurs without delay and without
confusion. One begins immediately the other stops.
There is no intermediate period during which a composite,
purposeless reflex occurs.

The Functions of the Cord

The grey matter of the cord forms the lowest member
of the hierarchy of the central nervous system. Each
segment governs the nervous reactions performed by that
segment ; in addition, the anterior horn cells govern the
nutrition of the muscles which they supply. The segments
of the cord are bound together functionally by tracts.
On this account no reflex is confined to any one segment
of the body. When an anterior root-fibre is stimulated
the resulting movement is purposeless and inco-ordinate.
The motor impulses which form a co-ordinated movement
emerge by several roots. In this way certain segments of the
cord are bound closely together — those for the upper limb
form one group, those for the lower hmb another. These
sections of the cord have control over certain complex
acts — not only skeletal movements but visceral functions — ■
micturition, defaecation and parturition, all of which can,
at any rate in lower animals, be performed when the cord
is severed from the higher centres.

280 THE NERVOUS SYSTEM

There remain certain functions which the cord alone
cannot perform— willed movements and the psychical
appreciation of sensory impressions. It is the f miction
of the cord to convey these impulses between the higher
centres and the periphery.

Lesions of the Spinal Cord in Man

After complete transverse lesions of the dorsal region, when the
effects of shock have passed away a flexion reflex gradually develops.
This becomes more and more easily elicitablc, until a stage"^ is reached
when stimiilation of any point causes strong flexion of both legs
and contraction of the abdominal muscles. This is known as the
mass -reflex.

Reflex micturition and defecation are performed, the stimuli
being distension of the bladder and rectum respectivelj'.

Lesions of the dorsal region involving one-half of the cord lead
to a condition known as Brown-Sequard Paralysis. It is char-
acterised by —

1. Motor paralysis of the same side.

2. Slight vaso-motor paralysis of the same side.

3. Loss of sense of position and of passive movement on the

same side.

4. Loss of touch, pain and temperature sensation on the opposite

side.

PAET IV

THE EXTEROCEPTIVE SYSTEM

The following description of the higher centres is based
upon Sherrington's division of the sensations into three
main classes — exteroceptive, proprioceptive and interoceptive.
We shall first consider the exteroceptive sensations — that
is, those arising from changes in the outside world — and
the manner in which the animal reacts to them. Secondly,
we shall consider the proprioceptive sensations, or those
which give impressions of bodily position, and the reactions
which they induce. Finally, we shall deal with the intero-
ceptive system, which relates to the gut and the structures
derived from it.

The exteroceptive sensations are those changes in its
surroundings to which the animal responds, which rise
into its consciousness, and to which, if it is in a normal
condition, it pays attention. They may be classified as
follows : — ■

1. Those due to direct contact of a body with the skin
{cutaneous and deep sensation).

2. Light.

3. Sound-waves.

4. Chemical stimuli produced by vapours of substances
situated at a distance {smell), and by substances actually
in contact with the mouth {taste).

These disturbances are appreciated because they stimulate
certain nerves specially adapted to receive them. Each
kind of sensory nerve conveys to the brain only one kind

281

282 THE NERVOUS SYSTEM

of subjective sensation, in whatever way that nerve is
stimulated. This apphes not only to the nerve-ending but
to the nerve-fibre. The optic nerve, however stimulated,
only conveys a sensation of light ; the auditory nerve only
one of hearing. This is the law of specific irritability, first
enunciated by Miiller. The reason why normally a par-
ticular nerve only responds to a particular stimulus is
partly because it is so situated in the body that only the
appropriate stimulus can excite it, and partly because it
is endowed with a higher susceptibility to that mode of
stimulation than to all others.

Certain conditions materially affect the subjective sensa-
tion arising from a stimulus. One of these is the duration
of the stimulus. The sense organs on prolonged stimula-
tion become fatigued, and the resulting sensation becomes
fainter. Another is the action of a previous stimulus.
Hot water, for instance, feels hotter to the hand after
cold. For these and other reasons sensations are never
an accurate judge of stimuh. Attempts have been made
to relate the intensity of the stimulus with the intensity
of sensation, but the only law which is to any degree
estabhshed is that of Weber, according to which the least
increase in stimulus which can be appreciated bears a
constant relation to the whole stimulus. If, for instance,
a person can only just appreciate the difference between
10 grms. and 11 grms., he can only just appreciate the
difference between 100 ^rms. and 110 grms.

1.— CUTANEOUS AND DEEP SENSATION

The three sensations which may be aroused by contact
of the skin with an object are touch, pain and temperature.
When an area of skin is carefully examined it is found that
the appreciation of these sensations is confined to certain
spots. There are spots for touch, for pain, for heat and
for cold. These spots are bizarre in shape and distribu-
tion. Some overlap one another ; others are separated by

CUTANEOUS AND DEEP SENSATION 283

patches of skin which seem to be totally insensitive. Each
of these spots when stimulated causes but one kind of
sensation, however stimulated ; a cold spot touched with
a hot object feels cold.

Touch. — -The touch-spots are arranged especially aromid
the roots of the hairs. Hairs considerably increase the
sensitiveness of the skin to touch, by their leverage stimu-
lating the nerve-endings which are in intimate association
with their roots.

The number of touch-spots per unit area varies in
different parts of the body, and with this is associated a
corresponding variation in the power of accurately locahsing
the point stimulated and of discriminating between one
stimulus and two stimuh apphed at the same time. The
power of discrimination is greatest at the tip of the tongue,
where two stimuli about 1 mm. apart are distinguished,
least on the back, where two spots touched are not
recognised as two unless they are about 70 mm. apart.

A rough estimation of the degree of sensitiveness to
touch can be measured by means of Von Frey's hairs.
These are hairs of different thickness mounted on handles.
Knowing the pressure which just bends the hairs we can
tell the pressure required to evoke a sensation.

Pain. — Pain is the affective aspect of a stimulus which
is harmful and which therefore tends to evoke a pro-
tective motor response. The different kinds of pain are
probably due to the coincident stimulation of other sense-
organs. A tingling pain, for instance, would be caused by
the coincident stimulation of pain- and touch-spots. Loss
of sense of pain without loss of other forms of sensation
is known as analgesia.

Temperature. — The sense of temperature is more acute
in some parts of the body than in others. In general it
may be said to be less acute on the exposed parts and in
the mouth.

Several forms of nerve-endings are present in the skin.

284 THE NERVOUS SYSTEM

There are the Pacinian corpuscles, Meissner's corpuscles,
the encl-bulbs, the nerve-plexus surrounding the hairs, and
the free nerve-endings which ramify in the epitheUum.
Attempts have been made to identify each of these with
some particular sensation. It is beUeved by some authorities
that the corpuscles of Pacini and of Meissner are receptive
to touch and the end-bulbs to temperature. It is natural
to regard the nerve-plexus of the hairs as sensitive to
touch. Pain is commonly held to be evoked by the free
nerve-endings, the chief ground for this belief being that
the cornea, in which these are the only nerve-endings
present, is sensitive only to pain.

Deep sensation. — When an object is pressed against the
skin with sufficient force to cause deformation of the skin,
there is set up a complex of sensations, arising partly
from the skin and partly from the deep structures, such
as the muscles and their tendons. Our estimation of the
texture, hardness and shape of objects is derived from an
analysis of the combination of superficial and deep
sensations.

Head, partly as the result of an experiment performed
upon himself, showed that after section of a cutaneous
sensory nerve recovery took place in two well-marked
stages. In the first stage, which is usually fully estab-
Mshed six months after section, pain of a burning, dis-
agreeable character is felt, touch feels rough, and there
is a crude form of temperature sense. Heat is only felt
when above 38° C, and cold only when below 24° C. All
the sensations are poorly localised and tend to radiate
widely. This form of sensation Head terms protopathic.

In the second stage pain becomes more bearable and
more definitely locahsed, the sense of touch becomes more
delicate, while fine grades of temperature are appreciated.
This form of sensation is known as epicritic. Deep sensi-
bility, in which two elements are recognised, deep pressure
and pressure pain, is not lost unless the motor nerves are

SENSORY PATHS 285

cut. Head therefore believes that in the nerve-trunks
three forms of sensation are carried^protopathic, epicritic
and deep.

For the investigation of the Central Paths taken by
afferent impulses two methods have been used. The first
is the examination of patients suffering from partial injury
to the spinal cord. For touch and pressure this is, indeed,
the only method, but for pain there is in addition a second
method, based upon Sherrington's Pseudoaffeetive Reflexes.
An animal is deprived of its cerebrum and a sensory nerve
stimulated. It cannot, of course, feel pain, but the reflex
arcs subserving the bodily expression of the emotions are
intact. There are snarhng movements of the face, move-
ments of the limbs and an elevation of blood-pressure.
The occurrence of these changes when a nerve is stimulated
denotes that pain would have been felt had the cerebrum
been present. Different columns of the cord are divided,
and the effect upon the transmission of the sensory impulse
noted.

Within the cord there is a complete regrouping of sensa-
tions. There is no longer a distinction between protopathic
and epicritic, nor between superficial and deep sensations.

Sensations of light touch and dee.]) pressure pass upwards
on the same side for a variable distance, then cross over
gradually and continue their upward course in the anterior
columns. Arriving at the optic thalanii, they are con-
tinued in a fresh relay of fibres to the cortex. The part
of the cortex concerned is the pre-central (motor) area,
and probably the adjacent post-central area. When these
areas are irritated, tinghng sensations are felt. Conscious
sensations of passive movement are located in the motor
area.

Sensations of 'pain and of temperature of all kinds are
beheved to decussate immediately on entering the cord
and to pass up in the anterolateral region, eventually
reaching the optic thalamus.

286

THE NERVOUS SYSTEM

There appears to be no area in the cortex devoted to
the reception of pain impulses. Irritation of the cortex
in man never gives rise to pain, nor does stimulation in
animals. According to Head, the optic thalamus is the
centre for the reception of crude sensations of pain, and
the cortex exercises over this centre an inhibitory effect.
When the fibres between the cortex and the thalamus are

CONSCIOUS IMPULSES
OF POSITION AND
PASSIVE MOVEMENT

UNCONSCIOUS

IMPULSES

(RESPONSIBLE.

FOR.
C0-OR.DINATION|

UNCONSCIOUS

IMPULSES

RESPONSIBLE

FOR.

iCO-ORDINATION

TOUCH AND PRESSURE

Fig. 45. — Diagram to illustrate the main conucctions of a posterior root
and the transmission of sensations up the cord (after Page May).

destroyed there follows a condition, known as thalamic
over-reaction, in which pain is felt to be abnormally
intense and to have a disagreeable character. On this
view the function of the cortex is to modify this crude
sensation and to give it a discriminating and intellectual
stamp.

2. VISION

The eyeball has three coats — from without inwards, the
sclerotic (protective layer), choroid (vascular layer) and

STRUCTURE OF THE EYE 287

retina (sensitive layer). The sclerotic is a firm membrane
composed of white fibrous tissue lined externally and
internally with a layer of endotheUum. The internal
endothelial layer contains a network of pigment cells
[lamina fusca).

At the front of the eye the fibrous tissue of the sclerotic
becomes modified to form the transparent cornea. The
cornea has a smaller radius than the rest of the eye, and
therefore forms a projection upon what is otherwise an
almost perfect sphere.

In the cornea five layers are recognised : (a) stratified
epithehum, continuous with the conjunctiva; (6) the
anterior elastic layer of Bowman; (c) the substantia
propria^this consists of laminse of connective tissue fibres
arranged parallel to the surface and separated by cell-
spaces or lacunae, in which he corpuscles ; [d) the posterior
elastic layer of Descemet; (e) endothehum.

The cornea has no blood-vessels, its cells Ijeing nourished
by a flow of lymph from peripheral blood-vessels. The
surface of the cornea is kept clean by the tear-fluid secreted
from the lachrymal gland.

The choroid is composed of three layers : (a) externally
the lamina suprachoroidea, which contains pigment-cells;
(6) the vascular layer, in which the blood-vessels form a
rich anastomosis ; (c) the membrane of Bruch.

In the anterior part of the eye the choroid is modified
to form the ciliary glands and muscles and the iris.

At the cihary glands the surface of the choroid is thrown
into folds (ciliary processes), which afford attachment to
the suspensory ligament of the lens. The cihary glands
secrete aqueous humour.

The cihary muscles will be described later in connection
with accommodation.

The iris forms a diaphragm having a central aperture.
It is composed of three layers : (a) an anterior layer of
endothehum, continuous with the posterior layer of the
cornea; (6) a layer of fibrous connective tissue; (c) a

288

THE NERVOUS SYSTEM

pigmented layer behind, continuous with the retina. In
the middle layer are two muscles — sphincter pupillse, whose
fibres are arranged circularly, and the dilator, whose fibres

Fig. 4r). — Transverse section through equator of left eye seen from
above (from Starling's Principles of Physiology).

are arranged radially. Immediately behind the iris is the
lens, biconvex in shape and having a high refractive index.
It is supported by and enclosed in the suspensory ligaments.
It divides the eyeball into two compartments, anterior and
posterior. The anterior chamber is occupied by the fluid

STRUCTURE OF THE EYE

289

aqueous humour, and the posterior by the semi-gelatinous
vitreous humour.

The greater part of the aqueous humour, after being
secreted by the cihary glands, passes into the anterior
chamber between the lens and the free margin of the iris.
It leaves the anterior chamber by the sinuses of Fontana,
situated near the attached border of the iris, and enters
the canal of Schlemm (Fig. 47). The aqueous humour

FILTRATION ANOLE

CANAL OF SCmlIMM

CtLIAI^r
OLAHD3

Fig. 47. — Diagram showing origin and fate of aqueous humour
(Hartridgc, from Starling's Princifles of Physiology).

exerts a pressure of from 25-40 mm. of mercury (intra-
ocular pressure).

The retina is composed essentially of the rods and cones
and their nervous connections, these being supported by
a scaffolding of connective tissue. It should be realised
that the rods and cones are directed into the substance
of the eyeball — that is to say, away from the source of
light, not towards it, as might be supposed. The layers
of the retina from without inwards are shown in the
accompanying figure. It will be seen that the rods and
cones abut distally against a layer of pigm^ted epithelium,
19

290

THE NERVOUS SYSTEM

and centrally come into contact at the outer molecular layer
with the first order of neurones — bipolar cells, which in

TTTT . 1 »l7m PIGMENTED EPITHELIUM

receptor; \ / \

CELLS \ II \

FIRST

RODS AND CONE5

OUTER NUCLEAR. LAYER.

> ii ■>*• 1^ A OUTER MOLECULAR LAYER.

NEURPNE5*\ (m O 0 "^^^"^ NUCLEAR LAYER

SECOND
NEURONES

11^ 0^. ^ INNER MOLECULAR U^YER

' t" '" ""

OPTIC NERVE FIBRES

Fig. 48. — Diagram showing layers of retina.

turn are connected at the inner molecular layer with the

dendrites of the optic nerve. Internal to this comes a

layer of optic nerve-cells, and then the optic nerve-fibres.

Certain parts of the retina require special mention.

STRUCTURE OF THE EYE 291

Opposite the pupil is the macula lutea, or yellow spot
which surrounds a depression known as the fovea centralis.
Here only cones are present, and each fibre of the optic
nerve is connected only with one cone. This area is
further distinguished by the fact that there are no optic
nerve-cells or nerve-fibres directly beneath it, and that it
is devoid of blood-vessels. At the periphery of the retina
rods predominate. The fibres of the optic nerve converge
upon a point (the blind spot) just internal to the yellow
spot, where they pierce the choroid and sclerotic and form
the trunk of the nerve. Here too there is a depression — •
the optic cup, from the bottom of which enter and leave
the central artery and vein. At the optic cup there are
neither rods nor cones.

Movements of the eyeballs are effected by the six ocular
muscles. These are the superior, inferior, external and
internal recti, which draw the eyeball upwards, downwards,
outwards and inwards respectively; the superior oblique,
which rotates the eyeball so that the eye looks outwards
and shghtly downwards ; and the inferior oblique, by which
the pupil is directed outwards and upwards. The lower
motor nerve-centres for these muscles are situated in the
grey matter surrounding the Sylvian aqueduct. Move-
ments of the eye muscles can be induced by stimulation
of several of the higher centres — notably the frontal lobe
and angular gyrus of the cerebrum and the deep nuclei
of the cerebellum. The movements thus induced always
involve both eyes in such a manner that the axes of
the eyes are parallel (conjugate deviation). This is owing
to the intimate connection which exists between the mid-
brain centres. Like the muscles of the hmbs, the ocular
muscles show reciprocal innervation, contraction of one
muscle being associated with relaxation of its antagonist.
Contraction of the left external rectus is accom])anied by
contraction of the right internal rectus and inhibition of
the left internal and right external recti.

Voluntary movements of normal eyes are always con-

292 THE NERVOUS SYSTEM

jugate when the eyes are focussed on distant objects.
When near objects are looked at a certain amount of
convergence takes place.

The muscles of the iris are controlled by two sets of
nerves, the ciliary branches of the third cranial nerve
which supply the sphincter pupillse, and the sympathetic
which supplies the dilator. These muscles are related to
one another reciprocally, contraction of one being accom-
panied by active relaxation of the other.

Under normal conditions the pupil is contracted : —

1. When the eye is exposed to light. This is the light
reflex, the afferent path being the optic nerve, the efferent
being the third nerve. When any part of this arc is
destroyed, e.g. by atrophy of the optic nerve, the light reflex
fails. The purpose of this reflex appears to be to protect
the retina from sudden changes in brightness.

2. During accommodation for near objects. In this way
a sharper definition is obtained, owing to the cutting out
of the rays from the periphery of the lens {see later).

3. During sleep.

The pupil is dilated (1) in the dark; (2) on focussing
upon distant objects; (3) on sympathetic stimulation,
whether due to a sensory stimulus or to an emotional state.

When the eye ceases to respond to hght but can stiU
accommodate the condition is known as the Argyll-
Robertson pupil.

Action of Drugs

The following drugs contract the pupil : —

Opium and morphia, by stimulating the third nerve

centrally ;
Pilocarpine and physostigmine, by stimulating the

third nerve peripherally;

while the following dilate it : —

Atropine, by paralysing the third nerve peripherally ;
Adrenalin, by stimulating the sympathetic peripherally.

REFRACTION 293

REFRACTION

The refractive power of the eye, by which rays of hght
are brought to a focus on the retina, is attributable to the
cornea, aqueous humour, lens and vitreous humour. Of
these the most important is the cornea.

Errors of Refraction.— Hypermetropia, or long-sight, is due
in children to the eyeball being too small, owing to its
having prematurely ceased to grow. Rays of light come
to focus behind the retina. This error is corrected by the
use of convex glasses. Hypermetropia also occurs in old
age owing to failure of accommodation.

In Myopia, or short-sight, hght comes to a focus in front
of the retina. It is due either to the eyeball being too
long or to the lens being too highly refractive. The former
defect is due to deficient nutrition during the growing
period and over-strain, the weakened eyeball being unable
to withstand the intraocular pressure. It is for this reason
that treatment should not only include the provision of
concave glasses, but should also be directed to relieving
the general condition.

Another error of refraction is astigmatism. This is due
to the lens not having the same curvature in its horizontal
and vertical axes. The consequence is that horizontal and
vertical lines cannot be simultaneously focussed. For this
defect cyhndrical glasses are used.

ACCOMMODATION

When the eye is looking at a distant object the rays
of hght coming from that object are practically parallel.
These in a normal eye come to a focus on the retina without
any accommodation. Rays from a near object, however,
diverge as they approach the pupil, and if no change took
place in the eye would come to a focus behind the retina.
To correct for this the eye undergoes the process of
accommodation, which takes place in the following way.

294

THE NERVOUS SYSTEM

The lens, being enclosed in an elastic capsule, always tends
to assume a spherical form, but is prevented from doing so
by the tension of the suspensory ligaments (due to the intra-
ocular pressure), which attach it to the cihary processes. The

imus venosus

,cniuni

Corpus Zonula
ciliare cillaris

Retina

Fig. 49. — Anterior part of eyeball showing relation of iris, lens, ciliary
bodies and corneosclerotic junction (from Starling's Principles of
Physiology).

cihary muscle consists of two parts : circular fibres which
run round the eye at the corneosclerotic angle, and meri-
dional fibres which pass backwards to be inserted into
the cihary processes. When this muscle contracts the
circular fibres draw the cihary processes as a whole into

ACCOMMODATION 295

a smaller circle, while the meridional fibres cause the
cihary processes to be drawn towards the pupil and sUghtly
forward. The effect of contraction of this muscle is there-
fore to release the tension of the suspensory Ugament
and to allow the lens to become more spherical. The
refractive power of the lens is in this way increased and
divergent rays are focussed on the retina. The ciliary
muscles are supplied by the third nerve.

Accommodation is always accompanied by contraction
of the pupil. This results in a clearer definition of the
image, owing to the cutting off of the rays which strike
the periphery of the lens, and to the increased depth of
focus.

The clearness of the image formed upon the retina is
limited by diffraction — that is to say, the tendency of the
edges of the wave of light to spread and form patterns.
Diffraction is a physical process, and is therefore inevitable.
There remain to be considered two other optical errors
and the means taken by the eye to overcome them.

Chromatic Aberration. — The waves of short length (those
at the blue end of the spectrum) are deflected by the
refracting media more than the long red waves. The
normal eye is so shaped that yellow — that is, the most
intense^rays focus on the retina, red rays behind and
green and blue rays in front. Around a central spot of
yellow there are therefore formed a small halo of red, a
small halo of green and a large halo of blue. The red
and green halos combine to form yellow, while the blue is
too diffuse to stimulate the retina.

Spherical Aberration. — If the refracting media were of
miiform density and their surfaces of uniform curvature,
rays striking the cornea peripherally would come to a focus
in front of those passing centrally. This is obviated in
two ways : (1) the centre of the lens is more highly refractive
than the periphery ; (2) the curvature of the anterior
surface of the cornea is less peripherally than it is centrally.

296 THE NERVOUS SYSTEM

PHYSIOLOGY OF THE RETINA

When light falls upon the retina certain changes take
p!ace which may be summarised as follows : —

Structural Change. — The cones shorten and the processes
of pigment emerge from the epithehal layer to envelop the
ends of the rods.

Electrical Change. — This occurs on darkening as well as
on exposure to light.

Chemical Change. — In the ends of the rods is a purple
pigment, rhodopsin or visual purple. It is bleached by
exposure to light. The whole retina, too, takes on an acid
reaction. The restitution of the rhodopsin is performed by
the pigment cells.

It is believed that the cones respond to dayUght and
the rods to twihght vision, and that only the cones
respond to colour. The evidence for such a distinction
between the two elements is — (1) twihght vision is most
acute at the periphery of the retina where rods are most
abundant, and deficient at the fovea where only cones are
present ; (2) green rays, which are seen best of all colours at
twihght, are those which are most effective in bleaching
rhodopsin. Foveal vision further differs from peripheral
in being more sharply defined.

The peripheral hmit of retinal sensitiveness is determined
by means of the perimeter. It is found that the extent
of the visual field varies for different colours,

COLOUR VISION

Of the theories which have been put forward to explain
colour vision, the following are the most important.

Young's Hypothesis. — On this view there are three
different substances present in the retina, one responding
to red, another to green, a third to blue. When these are
stimulated simultaneously fusion in the brain leads to a
sensation of white. Different colour sensations are due

, PERCEPTION 297

to different combinations of the stimulated substances.
Colour blindness on this view is due to the absence of one
or more of these substances, or to abnormality in their
absorption of light.

Bering's Hypothesis. — There are three substances present
in the retina called red-green, yellow-blue and white-
black. These are capable of being cataboHsed or ana-
bohsed. When, for instance, the red-green substance is
stimulated by red rays it is built up into a more complex
compound, while under the influence of green rays it is
broken down. On this view colour bhndness to red and
green or to blue and yellow is due to the absence of the
corresponding substance.

Edridge-Green's Hypothesis.— As in Young's view, three
substances are present, responding to red, green and blue,
but these are located in the brain.

THE PERCEPTION OF SIZE, SHAPE AND DISTANCE

When we look at an object with one eye we are dependent
for our idea of its size, shape and distance upon our past
experience. Into this several factors enter : (1) from our
knowledge of the true size of the object we can gauge its
distance ; (2) from the intensity of hght upon its diflerent
surfaces we can tell its shape ; (3) from the apparent con-
vergence of hues which we know by experience to be
parallel we can judge how far the lines recede ; (4) finally,
from parallex — that is, the relative movement of distant
and near objects as we move — we can estimate distance.
It is not possible that the muscular movements concerned
in accommodation give us a sensation of depth and
distance.

With uniocular vision this power of judgment would
fail us if we were faced with conditions of which we had
no past experience. Even when we look at familiar
objects and scenes these always seem flatter to one eye
than to both eyes.

298 THE NERVOUS SYSTEM

Binocular perception adds a further method of judging
distance. In animals such as man which have parallel
optical axes the visual fields of the two eyes overlap to
a considerable extent. Rays of hght coming from any
point in the common field of vision stimulate corresponding
points on the two retinas, so that the two stimuli are fused
centrally to form one visual impression. For instance, an
object situated in front of another forms an image on the
temporal side of the other on the left retina and an image
on the nasal side on the right retina, yet these corresponding
images cause but one image to be formed in consciousness.
The images formed on the two retinae are thus not exactly
the same, and it is the fusion of these shghtly different
images in the brain which gives us stereoscopic vision.

CENTRAL CONNECTIONS OF THE OPTIC NERVES

The two optic nerves join together at the optic chiasma,
where a partial decussation takes place. The fibres from
the nasal half of the retinae cross over, while those
from the temporal half remain on the same side ; fibres
from each fovea being partly crossed, partly uncrossed.
The regrouped fibres are conveyed by the optic tracts to
the brain-stem, where thev terminate in three nuclei, the
anterior corpora quadrigemina, the Oftic thalamus and the
external geniculate bodies. In the anterior corpora quadri-
gemina some fibres arborise round nuclei of the third and
fourth cranial nerves; others arborise around cells which
pass down the brain-stem in the posterior longitudinal
bundle and thus bring the optic nerves into functional con-
nection with the other cranial and the spinal nerves. This
connection provides a means of co-ordination between
visual impressions and the muscles of the Umbs.

From the optic thalamus and external geniculate bodies
there starts a fresh relay of fibres which pass through the
posterior hmb of the internal capsule to end in the occipital
lobe in the anterior part of the calcarine fissure. Destruc-

CONNECTIONS OF THE OPTIC NERVES 299

tion of this area in man causes blindness to objects situated
on the opposite side of the body — that is to say, there is

eORP.GEN.lNT.

Fig. 50. — Diagram of connections of oiitic nerve (Cunningham).

an inabihty to appreciate objects whose images are formed
on the temporal half of the retina of the same side and
on the nasal half of the retina of the opposite side.

300 THE NERVOUS SYSTEM

Stimulation over a wide area on the occipital lobe in the
monkey causes movement of the eyes to the opposite side.
It is probable that the visual area is more restricted in
man than in the monkey. The view is also held that a
small (visuo-sensory) area devoted to the reception of visual
impressions is surrounded by a wider (visuo-psychic) area
concerned in the higher psychical processes associated with
vision.

3.— HEARING
STRUCTURE OF THE EAR

The External Ear

This consists of the pinna and external auditory meatus.
The pinna in lower animals by its tubular shape serves the
purpose of collecting sound-waves, and by its mobility
enables the animal to detect the direction from which the
sound is coming.

The meatus is a slightly curved passage, about one inch
in length, directed into the skull forwards, inwards and
shghtly upwards. Internally it is closed by the tympanum
or membrana tympani. The walls of the meatus are hned
with skin, which is continued as a thin layer over the
tympanum. The meatus by its depth and curvature serves
to protect the membrane from damage and cold, and the
cerumen secreted by the glands keeps it moist and protects
it from insects and bacteria.

The middle ear is a cavity in the petrous bone. The
membrana tympani separates it from the external ear, and
two small foramina, the fenestra ovalis oxi^ fenestra rotunda,
covered with membranes, separate it from the internal ear.
By the Eustachian tube, directed downwards and backwards,
it is in communication with the cavity of the pharynx.
The opening of the Eustachian tube is normally closed
except during the act of swallowing, when it opens. In
this way the pressure on the two sides of the membrane is
kept equal. When the tube is blocked by disease the air

STRUCTURE OF THE EAR

301

within the middle is absorbed and the inequality of pressure
thus produced causes deafness.

The tympanum is a thin elastic membrane covered

Fig. 51.— Auditory organ (diagrammatic, after Schafer) ; 1. Auditory
nerve ; 2. internal auditory meatus ; 3. vitricle ; 5. saccule ;
fi. canalis media of cochlea ; 9. vestibule containing perilymph ;
12. stapes; 13. fenestra rotunda; 14. pinna; 16. external
auditory meatus; 17. membrane tympani; 18. malleup ; 19.
incus ; 23. Eustachian tube.

externally by skin and internally by mucous membrane.
The fibres composing it are arranged circularly and radially.
Along part of its inner surface is attached the handle of
the malleus, the outermost of the three ossicles.

302 THE NERVOUS SYSTEM

The function of tlie tympanum is to transform the
vibrations of the atmosphere into mechanical movements.
To perform this function adequately it must be aperiodic —
that is to say, it must itself have no period of vibration.
Owing to the pull of the tensor tympani on the malleus
the tympanum is bell-shaped, its apex inwards. It is
composed of a series of superimposed and gradually narrow-
ing rings. Each ring has its own periodicity, but the
bell cannot vibrate as a whole.

The ossicles form a chain of bones crossing the middle
ear. The malleus consists of a head and two processes,
the handle attached to the tympanum and the processus
gracihs to the wall of the middle ear. The head of the
malleus engages with a hollow surface on the next ossicle,
the incus. The incus has a long process, directed down-
wards, articulating with the third ossicle, the stapes, a
stirrup-shaped bone, the base of which is adherent to the
fenestra ovahs. The function of the ossicles is to transmit
the vibrations of the tympanum to the fenestra ovalis,
and so to the fluid perilymph of the internal ear.

The malleus rotates through a horizontal axis which
passes just below the heads of the malleus and incus.
When, therefore, the handle of the malleus moves inwards
the upper part of the malleus and incus move outwards and
the process of the incus moves inwards. The inward move-
ment is transmitted through the stapes to the fenestra ovalis.

It is beheved by some authorities that in the ossicles
a magnification of effect is produced owing (1) to the
handle of the malleus being larger than the process of
the incus, and (2) to the fenestra ovahs being only one-
twentieth the size of the tympanum. It is probable that
any effect of this kind is to a great extent discounted by
the friction and inertia of the system.

Of the two muscles of the tympanic cavity the tensor
tympani exerts a constant pull, as already stated, upon
the membrane, and therefore keeps it taut. It is also said
to influence by alterations in its tension the receptivity of

STRUCTURE OF THE EAR 303

the membrane for high and low notes. When the mem-
brane is stimulated the muscle undergoes reflex contrac-
tion. The view is also held that the tensor tympani
protects the drum from over-stretching by allowing it to
slacken when no sounds fall upon it.

The function of the stapedius is not known with certainty.

The Internal Ear

Embedded in the temporal bone is a system of canals,
the bony labyrinth, part of which forms a spiral tube, the
cochlea. Within the bony labyrinth is an inner system,
the membranous- labyrinth, composed of the saccule,
utricle, semicircular canals, and a part within the cochlea
known as the scala media. Both labyrinths are filled with
fluid, that filhng the bony labyrinth being called perilymph,
that filhng the membranous labyrinth, endolymph. The
cochlea is the only part of the labyrinth with which we
are now concerned. About 25 mm. in length, it is wound
around a central pillar, the modiolus. From the modiolus
a ledge projects into the canal of the cochlea throughout
its course. This ledge is therefore known as the spiral
lamina. From the outer edge of the spiral lamina two
membranes stretch across the canal of the cochlea, dividing
this into three parallel compartments, the scala vestibuli
uppermost, the scala tympani lowest, and the scala media
between. The scala vestibuli is separated from the scala
media by the thin membrane of Reissner, and the scala
media from the scala tympani by the basilar membrane
and the structures situated upon it. At the bhnd end of
the canal of the cochlea the basilar membrane is deficient,
and scala vestibuh and scala tympani communicate. Both
the scala vestibuli and scala tympani form part of the
bony labyrinth and contain perilymph, and both are in
connection through membranes with the middle ear, the
former at the fenestra ovahs, the latter at the fenestra
rotunda. The scala media, on the other hand, is, as stated

304

THE NERVOUS SYSTEM

above, part of the membranous labyrinth and is filled with
endolymph.

Upon the basilar membrane are the two rods of Corti,
which lean together, so that with the part of the basilar
membrane between them they form a tunnel extending
all the way up the cochlea. Leaning against the inner
rod is a row of hair-cells, and external to the outer rod

LAMINA
SPIRALIS

ME.MBIV1NEOF
R.EI55NEFL

MEMBRANA-j
TECTORIA

5CALA TYMPANI

SCALA MEDIA

SCf\\J\
VLSTIBULI

SPIRAL GANGLION

AUDITORY NERVE
'ORGAN OF CORTI
Fig. 52. — Diagrammatic vertical section through cochlea.

BASEMENT
MEMBRANE

are several rows of the same, separated by sustentacular
cells. The hair-cells are the peripheral end-organs of the
auditory nerve, filaments of which reach them by passmg
up the modiolus and along the base of the spiral lamina.
From the spiral lamina a projection known as the mem-
brana tectoria overhangs the hair-cells so that its under
surface either just touches or just fails to touch the ends
of the hairs.

When the stapes drives the fenestra ovahs inwards the
increase in pressure is communicated to the perilymph in

MECHANISM OF HEABING

305

the scala vestibuli. This movement is transmitted through
the membrane of Reissner to the endolymph and to the
basilar membrane, and from these to the scala tympani,
the result being a bulging outwards of the fenestra rotunda.
It is usually beheved that the auditory nerve is stimu-
lated by vibrations of the basilar membrane, which cause
the hairs of the hair-cells to move and possibly to touch
the membrana tectoria.

As to the way in which sounds of different pitch are
recognised, the most satisfactory hypothesis is that put

B.M

Fig. 53.— End-organ of the auditory nerve (from Starling's Principles
of Physiology) : B.M., basilar membrane ; C, canal of Corti ; R.C.,
rods of Corti; I.H., O.H., inner and outer hair-cells; S.C.,
sustentacular cells ; Au., auditory nerve ; m.t., membrana tectoria.

forward by Helmholtz, who regarded the basilar membrane
as a series of resonators each responding to a certain
periodicity of vibration. In favour of this view is the
fact that when the short fibres of the membrane are de-
generated, as in boilermakers' disease, there is inability to
hear high notes. In other conditions there may be deaf-
ness to some notes, not to others. Further, the ear can
be fatigued to one note, leaving its appreciation of other
notes unaffected.

CENTRAL CONNECTIONS OF THE AUDITORY NERVE

The cochlear division of the eighth nerve has its cell-
body in the spiral ganglion of the cochlea. The axons of
"20

306

THE NERVOUS SYSTEM

these cells enter the medulla at the level of the restiform
body (Fig. 54). Here they divide into two branches, and
end by arborising around groups of cells in close relation to
the restiform body. These are the accessory nucleus and
the tuberculum acusticum. Here connections are also made
with the superior olive. The second neurones starting

FIBRES TO NUCL.LEMNISCI
&CORPORA QUAORICEMINA

.SA

FIBRES OF
COCHLEAR
ROOT

NERVE-ENDINGS

IN ORGAN OF CORTI

,."•, PYRAMID

Fig. 54. — Connections of the cochlear division of the eighth nerve
(from Schafer's Essentials of Histology) : r, restiform body ; V, de-
scending root of fifth nerve; tvb. oc, tuberculum acusticum ; n.acc,
accessory nucleus ; s.o., superior olive; n.tr., nucleus of trapezium ;
n.VI, nucleus of sixth nerve ; VI, issuing root-fibre of sixth nerve.

from these nuclei cross to the opposite side, superficially
by the strise acusticse and deeply by the trapezium. Having
crossed, they turn upwards in the lateral fillet and end in
the posterior corpora quadrigemina and internal geniculate
bodies. From these centres a third group of neurones
travels to the superior temporal convolution (Fig. 56, p. 315).
Stimulation of this area in the monkey causes the animal
to prick up the opposite ear and generally to behave as

8MELL 307

though it were listening to a sound from the opposite
side. Lesions of this area in man are usually found to
be associated with deafness. In the monkey, however,
both superior temporal lobes may be removed without
causing any objective signs of deafness. It is beheved,
chiefly on histological grounds, that around this area of
the brain, which forms a receiving station for stimuh
(audito-sensory area), there is a large area, involving
probably the whole of the temporal lobe, concerned with
the higher psychical processes, such as the memory of
sounds. This is the audito-psychic area. It is connected
with the audito-sensory area by association fibres.

4.— SMELL AND TASTE

THE SENSE OF SMELL

Compared with some of the lower animals, man has
but a poor sense of smell. Nevertheless his olfactory
nerves are remarkably sensitive. The olfactory sense-
organs are situated in the mucous membrane covering
the superior turbinate bone and the part of the septum
opposite. They take the form of bipolar cells, of which
the free distal processes project slightly below the general
level of the mucous membrane. Among these processes
are the columnar sustentacular cells and the serous glands
of Bowman, the latter serving to keep the sensitive nerve-
endings moist. The proximal processes of the olfactory
cells take the form of non-medullated nerve-fibres, which
pierce the cribriform plate of the ethmoid and enter the
olfactory lobe.

Here they terminate in a rich arborisation in close con-
nection with the dendrites of the mitral cells, the arborisa-
tion of these two neurones forming the " glomeruli." The
mitral cells, whose cell-bodies are also situated in the
olfactory lobe, send axons into the fore part of the brain,
where they make extensive and ill-defined connections with

308 THE NERVOUS SYSTEM

the hippocampus, the posterior and inferior parts of the
frontal lobe, and the gyri in relation to the anterior part
of the corpus callosum. In animals in which the sense
of smell is more acute these parts of the brain and the
olfactory lobe itself are much better developed.

The olfactory epithehum is situated out of the direct
hue of the respiratory current. Air is diverted towards
it in the act of sniffing.

The failure of some persons to recognise certain smells,
and the fact that the nose may be fatigued to one kind
of smell though retaining its sensitiveness to others, indicate
that the sense of smell is complex, but no clear analysis
of smells has yet been made. The sense of smell must
be distinguished from other sensations arising in the nose,
e.g. pungent sensations due to stimulation of the fifth
nerve.

As regards the central locaHsation of olfactory sensation,
the only experimental observations of positive value are
those of Ferrier, who by stimulating the hippocampus
induced movements of the nostril on the same side.

THE SENSE OF TASTE

Lying in the epithehum of the mouth are small bodies
known as taste-buds. They are most plentiful around the
circum vallate papilte and upon the fungiform papillse. A
few are also found on the wall of the pharynx and cheek.
The taste-buds contain the sensory nerve-endings of taste.
These are spindle-shaped cells with free processes which
project through the small orifice of the taste-bud. Among
them are the columnar sustentacular cells. The taste-cells
on the anterior part of the tongue are connected with the
hngual branch of the fifth nerve and the chorda tympani,
those on the back of the tongue with the glossopharyngeal.
These nerves make widespread connections in the brain
stem. The cerebral locahsation of taste is not known.

THE CORTEX 309

Certain well-defined qualities of taste are recognised —
salt, bitter, sweet, sour, alkaline, metallic. Some so-called
tastes are in reality a combination of true taste sensation
with smell and common sensation.

5.— MOTOR FUNCTIONS OF THE COKTEX

Having described the different sensations which play upon
the cerebrum, we may now consider the motor aspect of this
part of the central nervous system. Although the relation-
ship between the cerebrum and the skeletal muscles had
long been known from clinical experience and histological
investigation and particularly from the work of Hugh-
hngs Jackson, it remained to Fritsch and Hitzig, in
1870, to demonstrate the connection experimentally. This
pioneer work was afterwards amphfied by many workers,
particularly those of this country, Ferrier, Horsley, Schafer,
Bastian, Sherrington and 'others. The principal part of
the brain concerned in movement is the strip which hes
immediately anterior to the Rolandic or central fissure (the
precentral or motor area). Here all parts of the body are
represented in order, from the toes near the middle line
to the face laterally. An area on the third frontal con-
volution is concerned in conjugate movement of the eyes
to the opposite side (Fig. 55).

The movements which are evoked by stimulation of any
part of this area are confined to the opposite side of the
body, except in the case of those movements in which
muscles of both sides of the body normally take part,
such as movement of the eyes, jaw and trunk. The move-
ments are always co-ordinated and involve reciprocal action
of antagonistic muscles.

When the motor area of one side is removed in the
monkey the resulting paralysis is followed by a certain
degree of recovery, but there is a permanent loss of finer
accurate movements. The recovery is not due to education

310

THE NERVOUS SYSTEM

of the opposite hemisphere, since no relapse occurs when
the opposite side is subsequently ablated. Motor control
appears to be taken over by the lower centres.

Irritative lesions of the motor area cause a peculiar kind
of fit, known as Jacksonian epilepsy. The movement of

Toes
Ank/e^\
Knee

Anus & Vagina

.■ Sulcus , .
. centra I IS

Abdomen
,Chest

Shoulder
Elbow
Wrist^'

Finders
& thumb

Ear--" .^ .

Eyelid, -'Closure ,

Nose °^ j^^ Opening \

of jaw \/ocal

cords MasticdTiop

Sulcus centralis

Fig. 55. — Outer surface of brain of chimpanzee, showing movements
obtained by electrical stimulation (Sherrington).

the limbs is at first tonic, then clonic or rhythmic. The
disturbance spreads from a focus to adjacent areas in the
order of their proximity (the march of the fit), and in
severe cases involves the whole side of the body and even
the opposite side. Unhke ordinary epilepsy, the cause of
which is unknown, Jacksonian epilepsy is usually not
accompanied by loss of consciousness.

SPEECH 311

6.— SPEECH

A sound has three quahties : pitch, which depends upon
the frequency of vibration ; intensity, which depends upon
the ampUtude of vibration ; and timbre or quahty, which
depends upon the relative proportions of the overtones.

The voice is produced by the vibration of the true vocal cords
caused by the blast of air which is driven against them in expira-
tion. The vocal cords are two parallel elastic membranes covered
with mucous membrane and forming ridges which stretch between
the thyroid cartilages in front and the anterior end of the arytajnoid
cartilages behind, the two cartilages being separated by a cleft, the
rinia glottidis. Tiie arytsenoid cartilages are capable of rotation on a
vertical axis.

The size of the rima can be varied by approximating or drawing
apart the posterior ends of the vocal cords. These movements are
effected by adductor and abductor muscles respectively.

The principal abductors are the posterior crico-arytanioids,
which, arising from the posterior siu-face of the cricoid cartilage,
pass upwards and outwards to be inserted into the outer angle of
the arytsenoid cartilages.

The chief adductors are the arytsenoid muscles which pass from
one arytsenoid cartilage to the other, and the lateral cricoarytsenoid
which pass from the upper border of the cricoid to the outer angle
of the arytajnoid.

The cords are put on the stretch by the cricothyroid muscle
which passes from the cricoid cartilage to the inferior border of
the thyroid cartilage. When it contracts the anterior part of the
cricoid is drawn up and the posterior part drawn down.

The cords are relaxed by the thyi-o-arytasnoid muscles which run
from the thyroid cartilage to the outer border of the arytsenoids,
drawing the latter cartilages forward and also approximating the
cords. Some of the fibres, forming a separate portion {musculus
vocalis), are inserted into the cord itself. This has the effect of
shortening the cords, and probably allows a part only of the cords
to vibrate.

The fundamental note of a vocal sound depends upon the tension
of the vocal cords. The quality of the sound depends upon the
combination of overtones imposed upon the fundamental note by
the resonance of the air passages. These include the pharynx,
nasal cavity, laryngeal cavity, the cranial air-sinuses, and the
trachea. The variations in quality are produced by alterations in

312 THE NERVOUS SYSTEM

the shape of the resonator through movements of the cheeks, lips

and tongue.

Consonants are produced by resisting the passage of au- after it
has passed the vocal cords. This may take place at the tip of the
tongue and lips (dentals), between the tongue and the hard palate
(labials), and at the fauces (gutturals). Explosives (?j, t, k, b, cl, g)
are formed by the sudden release of resistance; aspirates (/, s, I,
sh, V and z) by passing the air through a small slit; m and n by
nasal breathing. _

In whispering, the vocal cords do not vibrate, the sounds being
produced entirely in the mouth.

The Central Mechanism of Speech

It is probable that the development of the power of
speech in the human race occurs, as in each civihsed child,
in three stages. (1) The cry. This is used to express the
emotions, and in lower animals to make signs of warning.
The cry is probably represented centrally in the lower
part of the brain, since Goltz's dog, which had been
deprived of both cerebral hemispheres, was able to snarl,
bark and growl. Its doing this to friend and enemy ahke
showed that it was ignorant of the significance of the
sounds it made. (2) Vocalisation. This is the production
of simple vowel sounds. It is beheved to be represented
bilaterally in the cortex. (3) Articulation. This develops
with the growth of intelUgence.

The power of speech is closely associated with the use
of the hands, in gestures among primitive and in gestures
and writing among civilised races.

Speech is a means of forming auditory symbols, and
graphic records are a means of forming visual symbols
for objects and ideas. The child learns to talk through
hearing sounds. It then acquires the habit of imitating
these sounds, and finally it learns to associate with
certain visual images the sounds which others make and
which it copies. When the name of an object is pronounced
to an adult a complex mental process is set going— an audi-
tory image, the corresponding visual image, and memories
and associations connected with his past experience of the

SPEECH 313

object. The same processes must be working when he
himself speaks or \vrites the name of the object. In such
a comphcated process as this it is clear that the brain
must act as a whole. Nevertheless there appear to be
certain regions of the brain which seem to be specially
concerned in the production of the spoken and written
word.

In 1863, Broca showed that loss of speech was produced
by lesion of the third frontal convolution on the left
side in right-handed and on the right side in left-handed
people. These patients have lost the power of articulation.
They can express themselves in writing and can hear a,nd
understand what is said to them and what they read.
This condition is known as motor aphasia, and the centre
which is diseased is known as the glosso-kinsesthetic centre,
for it is the area supposed to be concerned in the sensation
of the position and movement of the tongue. It was
pointed out, however, by Marie that aphasia may occur
without demonstrable lesion of this area. He beheves
that in the cases quoted by Broca the lesion was not
hmited, as was supposed, but involved subcortical fibres
in such a way as to interrupt impulses coming from other
parts of the cortex. Marie beheves that there is no
locahsation of speech. In a sense this is true, but it might
be expected that the power of speech would be more
intimately associated with those areas of the brain con-
cerned in the reception of images. Of these there are
two — the auditory and the visual. The former is the
centre concerned in the reception and storage of auditory
words ; it is situated in the temporal lobe. The latter is
concerned similarly with visual words, and is situated in
the occipital lobe. Above Broca's area, too, is an area
in which the sense of movement of writing is said to be
located. This area is adjacent to the part of the motor
area devoted to the hand. It is therefore to be ex-
pected that a disturbance of any of these centres may
cause loss of speech, and there is a certain amount of

314 THE NERVOUS SYSTEM

clinical evidence to support this view. Cases have been
described in which the spoken word is not understood
(word-deafness). In these cases reading may not be
impaired; the motor functions of speech may not be
seriously disturbed. The loss of speech is due to an
inabihty to hear and to form mental (auditory) images
of words. This is one form of sensory aphasia. It is
associated with a lesion of the temporal lobes. Cases of
word-blindness also occur, but these are not associated
with aphasia to the same extent, since auditory images
are more important than visual images for speech.

The inabihty to write when it is unaccompanied by
paralysis of other hand movements is known as agraphia.

The close connection which exists between speech and
the more complex mental processes is shown by the fine
distinctions in the disabihty found among different sufferers
from aphasia. Some cannot state the names of objects,
others cannot describe what the objects are for ; in others
there are certain particular words which have dropped out
of their vocabulary. Others, again, are capable of emotional
but not of intellectual expression.

LOCATION OF THE HIGHER PSYCHICAL PROCESSES

In its higher psychical function the cerebrum seems to
act as a whole, the claims of the phrenologist being without
scientific foundation.' The only suggestion that any kind
of locahsation prevails comes from the examination of
people suffering from injuries to the frontal lobes. Such
patients often show a curiously facile behaviour, and seem
to have lost the capacity for taking things seriously.

7.— THE FUNCTIONS OF THE CEREBRUM

The dominance of the cerebrum over the rest of the
nervous system increases as we rise in the animal scale.

THE CEREBRUM 315

Goltz's dog, from which the cerebral hemispheres had been
removed, was able to perform all movements, though in
a clumsy manner. Its sensations were not impaired. It
snarled and growled, but did so to friend and foe ahke.
It had no memory, and was only induced to eat when
food was pushed up close to its nose. In the dog, then,
the functions of the cerebrum are principally psychical.

The higher in the scale the animal is the more do motor
and sensory functions come to be located in the hemispheres.

FI5SUK£ OF RX)LflNDO Z™^'^''' ""^ESSUI^E ANO

PASSIVE MOVEMENT

.vAUDITO-
P5YCHIC

AUDITO-SENSORY VI3U0-5EN50Ry

Fig. 56. — Principal sensory centres of the brain.

These functions have already been described, and their
location will be readily understood from Figs. 55, p. 310,
and 56, p. 315. One further word is necessary. We have
seen that the reflex arc, as it travels through the cord,
involves at least two and probably three neurones. It
enters the cord as a sensory impulse and leaves it as a
motor impulse. Where centrally the change from sensory
to motor occurs it is impossible to say. Now sensori-
motor reactions involving the brain also form a reflex
arc, distinguished from a simple spinal arc only by the
greater length of its path and the greater complexity of
its connections. When, therefore, a motor reaction follows

316 THE NERVOUS SYSTEM

artificial stimulation of the cortex it is not always possible
to say whether the part stimulated is sensory or motor.
The latent period of the reaction gives us some clue, a
long latent period indicating that the part stimulated is
sensory, the stimulus calling up a sensation which evokes
a response. In other words, the cortex forms, as it were,
a rounded summit to the arc.

When the cerebrum is disconnected from the remainder
of the nervous system by section through the mid-brain
the whole skeletal system goes into decerebrate rigidity, a
condition characterised by increased tonus involving all
, the muscles, but. some to a greater degree than others.
This tonus is produced reflexly by the proprioceptive
system, soon to be described. The cerebrum must there-
fore send down a constant stream of unconscious impulses,
inhibitory in character.

The functions of the cerebrum may be summarised in
this way. The cerebrum contains the receiving centres for
those impulses aroused by external stimuh and for the con-
scious sensations of the relative positions of parts of the
body. Ally impression arriving at the cerebrum causes, on
account of the free interconnection of different parts of the
cortex, a more varied and more diffuse, and therefore more
complete, response than can occur in the spinal animal. In
addition, impressions which reach it tend to stamp upon
it a more or less permanent record in the form of memory,
and the animal is able to modify his reaction to an
external stimulus according to his past experience — that
is, according to the accumulation and association of his
previous impressions.

Stimuli of a painful character tend to be more indehbly
stamped upon the brain than those which are indifferent,
owing to the fact that the former are accompanied by a
subjective state known as an emotion. The human
cerebrum is the seat of emotional feehngs, of intellectual
processes and of consciousness itself. The cerebrum, in

THE CEREBRUM 317

Sherrington's words, is the head-centre of the entero-
ceptive system. It presides over the reactions of the body
to its environment, restrains the lower centres and forms
out of the primitive reflexes a co-ordinated response which
past experience shows to be the most efficient under the
circumstances.

PART V
THE PROPRIOCEPTIVE SYSTEM

By the proprioceptive system is meant the mechanism
which is concerned in the transmission and reception of
impressions which arise in the organism as the result of
changes in its relation to the environment and of changes
in the relative positions of parts of the body. The de-
cerebrate animal, when suspended, adopts a certain posture,
the hmbs being partly flexed, difierent muscles being in
a different state of tension or tonus. When the posterior
roots are cut this state of tonus is at once abohshed, the
position of the limbs being now determined by gravity
alone. As this effect is not produced when the cutaneous
sensory nerves are cut, the afferent impressions which give
rise reflexly to tonus must arise in the deeper structures —
in the joints and in the muscles themselves. The intact
animal is aware of the position of his hmbs and of any
changes in position which his hmbs undergo.

The afferent nerves arise as extensive arborisations
surrounding the tendons and bundles, and as branches
which are entwined around certain of the muscle-fibres.
The latter structures are known as muscle-spindles. Con-
scious sensations of position and of passive movement
pass, as already described, to the motor area of the
cerebrum. Unconscious impressions, as we shall see, pass
up to the cerebellum.

THE LABYRINTH

While the afferent impulses from muscles and joints give
us information regarding the position of our hmbs, by other

318

THE LABYRINTH 319

impressions we are made aware of the position of the
body as a whole and of the head in particular, in relation
to the outside world. These impressions arise partly in
the labyrinth, the end-organ of the vestibular branch of
the eighth nerve. The labyrinth consists of a system of
passages within the temporal bone (osseous labyrinth).
Within the osseous labyrinth, and separated from it by a
membrane, is an inner system, the membranous labyrinth.
The osseous labyrinth is filled with perilymph and the
membranous with endolymph. The labyrinth contains, in
addition, the cochlea, but we are here concerned only with
that part of the membranous labyrinth from which the ves-
tibular branch of the eighth nerve arises. This part con-
sists of two sacs, the utricle and saccule, which are connected
together by a tube, the saccus endolymphaticus, and the
three semicircular canals. The utricle and saccule are two
small sacs, into which open, from a projection on its wall,
a number of hairs which are the terminations of some of
the fibres of the eighth nerve (Fig. 51, p. 301). Among the
hairs are a few calcareous nodules, the otoliths.

In lower animals, notably the crayfish, the otohth organ
is cup-shaped, the hairs pointing inwards. In these animals
the otohth can be removed and a small piece of iron
inserted in its place. When a magnet is then brought near
the head the equihbrium of the animal is disturbed. This
experiment suggests that the otohth organ in the crayfish
and, by analogy, the saccule and utricle in higher animals
serve to give the individual information regarding the
position of the head in relation to gravity. For any
position of the head the weight of the otohth falls in a
particular manner on the hairs, and this is interpreted
centrally as a sensation of position.

The three semicircular canals, which are continuous with
the cavity of the utricle, are disposed in three planes at
right angles to one another, one horizontal and two
vertical. Of the two vertical canals, the anterior canal
of the one side hes in the same plane as the posterior

320

THE NERVOUS SYSTEM

canal of the other. At one end of each canal is a dilata-
tion, where is situated a hair-structure resembUng those
of the utricle and saccule, but without otoUths.

When the horizontal canals are destroyed on both sides
there follow continual movements of the head in the
horizontal plane, a condition which lasts a considerable

Fig. 57. — End-organ in ampulla of semicircular canal (from Starling's
Principles of Physiology): sec, semicircular canal; h., hairs;
amp., ampulla.

time. When the canals on one side are destroyed there
follows, in addition to disorders of equihbrium, considerable
loss of tone on the same side of the body.

When in the bird the canals are destroyed on both
sides the animal loses all sense of equihbrium, and per-
forms violent and perpetual somersaults. After a pro-
longed period it recovers in some degree. This is owing
to the education of other senses, chiefly the eyes, for when
the partially recovered bird is bhndfolded it reverts to

THE VESTIBULAR NERVE 321

the condition which existed immediately after the opera-
tion. In the re-education of the sense of equiUbrium the
central region concerned is the cerebral cortex, for when
this is removed from the animal which has to some extent
recovered its equihbrium a permanent relapse ensues. No
disturbance of equihbrium follows excision of the cerebrum
when the labyrinth is intact.

How the canals act is shown by the classical experiment
of Ewald. Ewald bored two holes into one of the canals
and induced movements of the fluid by blowing into one
or other of the holes. The head was always moved in
the plane of the canal and in the direction of the current.
The terminations of the eighth nerve in the hairs of the
ampullae are therefore stimulated by movement of the
endolymph relative to the canal, such relative movement
being due to the inertia of the fluid. This is why giddi-
ness occurs, particularly wheiV"otation is suddenly stopped.
Some deaf mutes in whom the semicircular canals are
imperfectly formed do not feel giddiness when rotated.

CENTRAL CONNECTIONS OF THE VESTIBULAR

NERVE

The cell-bodies of the vestibular nerve are situated
peripherally and form the ganglion of Scarpa. The axons
entering the brain-stem deep to the restiform body
(Fig. 58) divide into ascending and descending branches.
The descending branches pass downwards into the medulla.
The ascending, which are the more important, arborise
around (1) the principal vestibular nucleus, (2) the nucleus
of Deiters and nucleus of Bechterew, large cells situated
in the outer part of the floor of the fourth ventricle,
and (3) the nucleus fastigii of the cerebellum. By the
nuclei of Deiters and of Bechterew they come into
contact (a) with the cranial nerves by the posterior longi-
tudinal bundle, and (6) with the spinal nerves by the
vestibulo-spinal tract.
21

322

THE NERVOUS SYSTEM

The chief connections of the nerve are, however^ with
the cerebellum.

VISUAL SENSATIONS

Among the sensations by which the animal is made

TO VERMrS

FIBRES O
VESTIBULA
ROOT

NERVE -V/7%(GANGLION OF
ENDINGS -Vy/ SCARPA
IN MACUL/E
8. AMPULL/E

Fig. 58. — Connections of the vestibular division of the eighth nerve
(from Schafer's Essentials of Histology): c.r., rcstifonn body;
V, descending root of fifth nerve; p., principal nucleus of vesti-
bular root; cZ., descending vestibular root; D, nucleus of Deiters ;
B, nucleus of Bechterew; n.t., nucleus fastigii of cerebellum ; p.l.b.,
posterior longitudinal bundle.

aware of its own movement are those arising in the eyes.-
The optic nerve at the anterior corpora quadrigemina
comes into connection with the cerebellum by the superior
peduncles, and with the spinal nerves by the posterior
longitudinal bundle.

THE CEREBELLUM 323

THE CEREBELLUM

The cerebellum consists of a middle lobe, called the
vermis, and two lateral lobes. The grey matter upon its
surface is divided into two layers, an outer molecular
layer composed of interlacing fibres, and an inner granular
layer of small nerve-cells. At the junction of these layers
are situated the cells of Purkinje, large cells whose axons
pierce the subjacent white matter to terminate in the deep
nuclei of the cerebellum. The latter are four masses of
nerve-cells, the nucleus dentatus, nucleus emholiformis,
nucleus globosus and nucleus fastigii. By its three
peduncles the cerebellum makes the following connec-
tions : —

Afferent Tracts : —

1. With the spinal cord, by uncrossed fibres arising in
the cells of Clarke's column travelling up {a) in the direct
cerebellar tract, inferior peduncle, and terminating in the
vermis; (6) in the indirect cerebellar tract, reaching the
vermis by the superior peduncle.

2. With the medulla, and thus indirectly with the spinal
cord, by fibres arising (a) in the nucleus gracihs and
nucleus cuneatus; (6) in the ohve. These fibres pass up
by the inferior peduncle and are chiefly crossed,

3. With the vestibular nerve.

4. With the pons, by fibres arising in the nucleus pontis,
crossing the mid-line, and terminating in the cerebellar
cortex. Through these the cerebellum comes into con-
nection with the cerebral cortex of the opposite side.

5. With the mid-brain, by fibres from the anterior cor-
pora quadrigemina. This tract gives connection with the
optic nerves.

Efferent Tracts. — ^These arise in the deep nuclei.

1. Fibres from the nucleus dentatus passhig by the
superior peduncle to the red nucleus and optic thalamus
of the opposite side.

2. A few fibres to the nuclei pontis of the opposite side.

324 THE NERVOUS SYSTEM

3. Fibres from the nucleus dentatus to Deiters' nucleus,
from which arises the vestibulospinal tract of the same
side.

Removal of the Cerebellum. — When one half of the
cerebellum is removed and sufficient time has elapsed to
allow the efiects of irritation to pass away, the following
condition occurs :—

1. Shght weakness on the same side {asthenia).

2. Loss of muscular tone on the same side (atonia).

3. Tremors on performing voluntary movements on the
same side (astasia).

The animal is at first unable to walk, and hes down
curled towards the side of the lesion, with the eyes directed
to the opposite side. After several months it learns to
stand, first by buttressing itself up against a wall. Later,
it gains the power of walking in a modified way (drunken
gait), the legs being abducted so as to overcome the
tendency to fall over on the affected side. The recovery
is due to the re-education of the motor area of the cerebrum,
for when this is subsequently removed on the side opposite
to the cerebellar lesion, the animal reverts permanently to
its former condition.

When the cerebellum is completely removed the con-
dition is in reahty intensified, though owing to the sym-
metrical nature of the disorder it may be apparently less
severe.

Cerebellar Lesions in Man. — In unilateral lesions the
same symptoms are produced as after removal in animals^
asthenia, atonia and astasia. Disturbance of equihbrium
is shown in the gait, which is reefing, as that of a drunken
man. Movements are slow, executed inaccurately, with
a tendency to over-action. In walking, for instance, the
feet are raised unnecessarily high (hen-gait). Speech is
often affected, becoming slurred. On looking to one side,
particularly to the side of the lesion, the eyes, owing to
the muscular weakness, do not remain steady but tend to

THE CEREBELLUM 325

return to the normal position. There result clonic move-
ments, in which both eyes take part synchronously. This
condition is known as nystagmus. There is no conscious
loss of muscle sense — that is, sensation of position or of
passive movement. Whatever impressions pass into the
cerebellum are therefore unconscious.

Stimulation of the Cerebellum. — When the cortex of the
cerebellum is stimulated, movements are only induced
when strong currents are used. It is therefore beheved
that the cortex is inexcitable, the effects produced on
strong stimulation being due to spread of the current.
When the deep nuclei are stimulated, movements con-
cerned in preserving equihbrium follow, particularly those
of the head and eyes.

It will be seen that the afferent nerves from the muscles
and joints and the vestibular nerve have this in common —
that the impressions arising in them contribute reflexly to
the maintenance of tonus, upon which posture depends.
There is, again, a close similarity between the effect of
destruction of the labyrinth and of removal of one lobe
of the cerebellum. In both cases there is a loss of tonus
on the same side of the body; in both cases a certain
degree of recovery foUows, owng to education of the
cerebrum.

From the receptor organs of the muscles arise conscious
sensations which give us information regarding the position
of the hmbs. From the labyrinth arise conscious sensa-
tions as to the relation of the body to its environment.
These conscious sensations are located in the cerebrum.
Unconscious impressions from the afferent spinal nerves
play upon the centres of the cord and those from the laby-
rinth upon the cells of the medulla, in particular the nuclei
of Deiters and Bechterew. It is the function of the cere-
bellum to analyse these impressions and to originate from
them impulses which have for their object the main-
tenance of a condition of equihbrium and stabihty. By

326 THE NERVOUS SYSTEM

its connection with the cerebrum of the opposite side and
with the vestibulo-spinal tract of the same side it steadies
the vohmtary impulses from the cerebral cortex.

In any reaction of the body the part which the proprio-
ceptive system plays is always secondary. An external
stimulus causes a certain motor response. This motor
response stimulates the proprioceptive nerve-endings.
It is the proprioceptive system which the cerebellum
dominates.

Summary of Functions of the Lower Centres

The corpus striatum, composed of the lenticular and caudate
nuclei, is said to contain a centre for heat- regulation (p. 251).

The optic thalamus is believed to be the centre for the reception
of crude afferent sensations. It is in contact with nearly all sensory
nerves, especially with those from the eye, and with the cortex
cerebri.

The red nucleus in the mid-brain is the head of the rubro-
spinal system. It is connected also with the cerebellum.

The pons is a junction between one cerebral hemisphere and the
opjOTsite lobe of the cerebellum.

In the medulla are the vaso-motor and respiratory centres. It
contains the nuclei of the vagus and hypoglossal nerves. Here
enters also the eighth nerve. The nucleus of Deiters comiects the
cerebellum, the vestibular nerve and the spinal cord.

The function of the olive is unknown.

PART VI
THE AUTONOMIC SYSTEM

The autonomic system is that part of the nervous
system which supphes organs which are not under the
control of the will. If we regard the primitive animal as
being composed of two tubes lying one within the other,
the autonomic system is that which is supphed to the
inner tube (the gut) and its diverticula.

The disposition of the autonomic system will be more
readily understood if the following points be borne in
mind : —

1, The fibres of this system issue from the central
nervous system in three situations —

a. From the brain stem, accompanying certain of the
cranial nerves. This is the cranial autonomic.

6. From the region of the cord which hes between the
cervical and lumbar swelhngs {thoracico-lumbar outflow).
The fibres issuing here, and these only, are the sympathetic.

c. From the sacral region of the cord (sacral autonomic).

These three regions are therefore separated by two
regions of the cord from which no autonomic fibres issue.
These are the cervical and lumbar swelhngs, which are
devoted entirely to the skeletal innervation of the hmbs.

2. The general distribution of the autonomic system is
as follows —

The cranial autonomic supphes the pupils, the sahvary
glands and their blood-vessels, the heart and lungs, the
ahmentary canal and its diverticula down to the lower end
of the small intestine. Also the kidney and spleen.

327

328 THE NERVOUS SYSTEM

The sacral autonomic supplies the lower end of the gut
and the organs of reproduction, with the exception of the
uterus.

The sympathetic supphes (a) the gut, with its diver-
ticula, from the cardiac orifice of the stomach to the
rectum; (6) all the arterioles of the body, except those
of the brain and heart ; (c) the hairs and sweat glands of
the skin ; {d) the pupil and sahvary glands ; (e) the urino-
genital organs.

3. As a general rule, to which, however, there are some
exceptions, an involuntary organ is supphed by nerves
from two sources : (a) the sympathetic ; (6) the cranial or
sacral autonomic. The organ is usually capable of activity
independently of both these nerves. The two nerves serve,
the one to increase its activity, the other to decrease it.
The cranial and sacral autonomic have the effect of exalt-
ing digestive and reproductive functions ; the sympathetic,
while it depresses these functions, adjusts the animal to
a condition of defence or offence.

4. Between its exit from the central nervous system and
its destination the nervous impulse passes through one
cell-station, and one only. This rule, to which no excep-
tion has yet been found, is known as Langley's law. A
fibre which issues from the central nervous system {pre-
ganglionic fibre) is invariably medullated, and in the case
of the sympathetic is known as a white ramus commu-
nicans. The distal fibre with which this communicates
(post-ganglionic fibre) is invariably non -medullated. The
arborisation between the terminal filaments of the pre-
ganghonic fibre and the nerve-cell of the post-ganglionic
fibre can be identified by nicotine, which blocks conduc-
tion at the synapses. It takes place in one of three
situations : (a) in the gangha of the sympathetic (lateral)
chain ; (b) in the great gangha situated upon the ab-
dominal aorta and its branches [collateral chain), and
(c) peripherally in the organ itself {terminal ganglia).

It follows from what has been said that certain fibres
may pass through a ganghon without interruption. The

■.GREY RAMI

^ 1 ■■5WHITE RflHI

HYP06rtSTRIC PLEXUS

Fig. 59. — Autonomic system (diagrammatic). On the right are shown
the white rami and the grey rami which join the spinal (somatic)
nerves. On the left are shown the fibres which supply the viscera :
P., pupil; C.G., ciliary ganglion; SM.G., submaxillary ganglion;
O.G., otic ganglion ; SM.GL., submaxillary gland ; SL.GL., sublingual
gland ; PAR.GL., parotid gland ; S.C.G., suj)erior cervical ganglion ;
I.C.G., inferior cervical ganglion; S.G., stellate ganglion; G.S.N.,
great splanchnic nerve ; S.G., semilunar ganglion ; S.M.G., superior
mesenteric ganglion ; I.M.G., inferior mesenteric ganglion.

330

THE NERVOUS SYSTEM

fibres which form a white ramus usually terminate at
different ganglia, as shown in Fig. 60. Stimulation of a
pre-ganglionic fibre always produces an effect over a wider
area than does stimulation of a post-ganghonic fibre. The
gangha therefore serve as distributing centres.

-0

■PREGANGLIONIC FIBRf.

~^<?

POSTGANGLIONIC FlBR£3
Fig. 60. — Diagram to show distributing function of sympathetic ganglia.

Sympathetic System

The fibres arise in the lateral horns of the cord from the
first dorsal to the third or fourth lumbar segment. Emerging
from the cord in company with the anterior root, they
soon leave this root and enter one of the sympathetic
gangha. These are joined together to form the sympa-
thetic or lateral chain which runs through the whole length
of the trunk and is continued upwards into the neck.
Some of the fibres, after passing for a variable distance
up and down the chain, end in one of these gangha. Those
destined for the abdominal and pelvic viscera pass through

THE AUTONOMIC SYSTEM 331

the sympathetic chain by the splanchnic nerves to termi-

A CERVICAL 5E6KIENT

T-POSTERIOR. ROOT

AN UPPER DORSAL SEGMENT \

SYMPATHETIC,
GANGLION

Fig. 61. — Diagram to show how a dor.sal segment of the cord has both
a white and a grey ramus, while a cervical segment has a grey
ramus only.

nate in the collateral gangha — the semilunar ganghon, the
superior and inferior mesenteric gangha.

332 THE NERVOUS SYSTEM

All the fibres which convey impulses to the skin end
in the ganglia of the lateral chain. Here post-gangUonic
fibres (grey rami communicantes) arise and join the seg
mental somatic nerves. It follows, therefore, that in the
thoracico-lumbar region each spinal nerve has a white
ramus leaving it and a grey ramus joining it. In seg-
ments of the body from which the sympathetic does not
arise only a grey ramus, derived from another segment,
is present (Fig. 61).

The detailed distribution and action of the sympathetic
is shown in the Table given on p. 333.

Cranial Autonomic

Third Nerve. — The visceral fibres have their cell-station
in the cihary ganglia. They are motor to the sphincter
pupillse and cihary muscles.

Seventh Nerve.— The visceral branch is the chorda
tympani which supphes secretory and vaso-dilator fibres
to the submaxillary and subhngual glands. The cell-
stations for the subungual gland are in the submaxillary
ganglia, and those for the submaxillary gland in the gland
itself.

Ninth Nerve. — ^A small branch of this nerve is secretory
and vaso-dilator to the parotid gland. Its cell-station is
the otic ganghon.

Vagus. — The fibres are motor to the bronchial muscles,
the oesophagus, stomach and small intestine, secretory to
the glands of the stomach, and inhibitory to the heart.
The cell-stations are situated peripherally, e. g. in the heart,
at the sino-auricular node. In the intestine they are
probably represented by the cells of Auerbach's plexus.

Sacral Autonomic

The pre-ganglionic fibres form the pelvic nerve or nervus
erigens. The cell-stations are in the hypogastric plexus
situated at the neck of the bladder. Stimulation causes
vaso-dilatation of the penis (erection), contraction of the

THE AUTONOMIC SYSTEM

333

Distribution and Action.

Vaso-consti'iction except to vessels of brain.

Secretion of sweat.

Erection of hairs.

Dilatation of pupil and protrusion of eyeball.

Secretion of saliva.

Vaso-constriction.
Secretion of sweat.
Erection of hairs.

Accelerates and augments heart- beat.
? Relaxes bronchioles.

Vaso-constriction of abdominal viscera.
Inhibition of muscular coats of small intestine.
Constricts the ileo-colic sphincter.
Discharge of sugar from iver.

Vaso-constriction to pelvic viscera.
Inhibition of muscular coats of colon and rectum.
Constriction of internal sphincter of anus.
Inhibition of body of bladder.
Constriction of sphincters of bladder.
Stimulation and inhibition of uterus and vagina.

Vaso-constriction.
Secretion of sweat.
Erection of hairs.

Superior cervical
ganglion

"Si

1
02

-»^

r— H

ia2

Semilunar and su-
perior mesenteric
ganglia

Inferior mesenteric
ganglia

6th and 7th lumbar
and 1st sacral
ganglia

O
H

I-H

Th. 7-12
I-. 1-4

Th. 7-12
L. 1-4

Th. 11, 12 .
L. 1-4

Head
and
neck

Oh
Oh

tx!

Abdomen

1
2

334 THE NERVOUS SYSTEM

rectum, colon and bladder, and inhibition of the neck of
the bladder and internal sphincter ani.

INTEROCEPTIVE OR VISCERAL SENSATION

Compared with the exteroceptive field the interoceptive
field possesses very few afferent nerves, and there are no
sensory endings, free nerve-endings, or touch-spots such
as are found in the skin.

Touch. — The whole of the mucous membrane of the
alimentary canal, from the upper end of the oesophagus
to the lower end of the rectum, is insensitive to touch.

Temperature. — The oesophagus and anal canal are sen-
sitive to temperature, the former, hke the mouth, being
■able to withstand a higher temperature than the skin.
The stomach is usually insensitive to temperature, sensa-
tions of temperature commonly regarded as arising in
the stomach being in reahty felt at the lower end of the
oesophagus. If two concentric tubes, one within the
other, be passed into the stomach and water poured down
the inner one, the subject is usually unable to tell whether
the water is hot or cold. The intestine similarly is
insensitive to temperature, and the colon and rectum
usually so.

Chemicals. — Both the oesophagus and stomach are insen-
sitive to dilute acids. Alcohol of 50 per cent, and glycerine
cause in the stomach a burning sensation.

Pain. — The stomach and intestines, gall bladder, bile
ducts and ureter are completely insensitive to pin-pricks,
cuts and pinching. Sensation of pain only arises as the
result of abnormal tension of the muscle-fibres. This
occurs when a part of the viscus goes into spasmodic
contraction, e.g. upon an obstruction such as a gall-stone
or renal calculus, or when there is obstruction to the
normal peristaltic wave of the stomach or intestine.

The sensation of fullness is caused by a mild degree of
muscular tension.

REFERRED PAIN 335

Hunger. — This may be analysed into three sensations :
(1) general bodily weakness; (2) a feehng of emptiness
referred to the abdomen ; and (3) hunger pains. The last
come on at intervals, and are due, as Cannon has shown,
to periodic contraction of the stomach wall.

From the oesophagus the afferent fibres pass up by the
vagus ; from the rest of the ahmentary canal, first by
the sympathetic, then entering the cord by the posterior
roots.

Localisation of Interoceptive Sensation. Referred Pain

Compared with sensations arising in the skin, visceral
sensations are very poorly localised. Intestinal pain is
felt vaguely in some region of the abdomen. But the
locahsation of pain is not always confined to the viscera.
It is often accompanied by pain and tenderness of a
certain area of skin, to which the visceral pain is said to
be referred. Referred pain is felt approximately in the
part of the skin which belongs to the same primitive body
segment as the part of the gut from which the visceral
pain arises. It is due apparently to the overflow of
impulses as they enter the cord, and to the inability of
the higher centres to distinguish from wdiich part of the
segment the pain arises. Pain from the stomach, for
instance, is referred to the epigastrium ; pain from the
ureter to the flank and groin.

CHAPTER XVI
MUSCULAR ACTIVITY AND FATIGUE

MUSCULAR ACTIVITY

We are now in a position to piece together the changes
which occur in the different organs when the body passes
from a state of rest to a state of muscular activity. Upon
the proper co-ordination of these changes depends the
efficiency of the animal as a machine.

The repeated contraction of the muscles produces three
changes in the blood flowing through them : (1) a
mechanical effect, the pumping of the blood at a greater
rate through the capillaries ; (2) the production of meta-
bohtes, such as CO2 and lactic acid, which have a direct
vaso-dilator action upon the arterioles and capillaries ; (3)
a rise in the temperature of the blood.

The increase in the venous flow and the raised tem-
perature of the blood have a direct effect upon the output
of the heart, the former increasing the diastohc filhng and
therefore the output per beat, the latter increasing the
rate of the beat. Further, the increased venous pressure
causes a quickening of the beat reflexly through the vagus.
The combined result is therefore a greatly increased cardiac
output.

The increased hydrogen ion concentration of the arterial

blood stimulates the medullary nuclei — the respiratory

and vaso-motor centres. By the enhanced activity of the

.former the pulmonary ventilation is increased. In this

way the increase in ventilation of the lungs keeps pace

336

MUSCULAR ACTIVITY 337

with the increase in the velocity of the blood passing through
the pulmonary circulation, a direct linear relationship
being estabhshed between them. Incidentally the in-
creased pulmonary movement, and especially the ascent
and descent of the diaphragm, reinforce the pumping action
of the muscles in driving blood to the heart.

By the stimulating action of the increased hydrogen ion
concentration of the blood upon the vaso-motor centre,
impulses passing along the sympathetic fibres cause vaso-
constriction of the visceral organs, whereby the general
blood-pressure is raised and blood is diverted in greater
quantity to the organs which require it — the brain, the
heart and the skeletal muscles.

These several factors combine greatly to increase the
oxygen supply to the active tissues. The increased H. ion
concentration of the blood facihtates the dissociation of
oxyhgemoglobin, and therefore causes the blood to part
the more readily ^vith its oxygen as it passes more quickly
through the capillaries.

So far we have considered the adaptation in the circu-
latory and respiratory mechanism only in so far as they
are produced by the increased muscular activity. Were
this the only causative factor, such adaptation would
take some time to establish itself. Experience shows,
however, that the increased blood-pressure, the deeper
respiration and the quickened pulse-rate occur within a
second of the beginning of exercise. In the mental pro-
cesses of concentration, therefore, impulses pass from the
cerebral cortex influencing directly the medullary centres.
When in an animal the lower hmbs are tetanised this
initial adaptation does not occur.

As the temperature of the body is raised, changes occur
in the skin — dilatation of blood-vessels and secretion of
sweat — which have the effect of preventing the body
temperature from rising excessively.

It is well known that the maximum physical effect of
which the body is capable depends upon the degree of
22

338 MUSCULAR ACTIVITY AND FATIGUE

excitement or emotion which is the accompaniment of the
exertion. Two factors seem to be responsible for this.
First, the greater intensity of the mental processes means
a greater outflow of impulses to the medulla — further
quickening of the heart, rise of blood-pressure and depth
of respiration. Secondly, it is beheved that owing to
sympathetic stimulation of the suprarenal glands, adrenalin
is discharged into the blood. This has the effect of in-
tensifying and prolonging the effect already produced by
the sympathetic impulses to the organs themselves. By
the quickened heart-beat and visceral vaso-constriction
the maximum diversion of blood to the active tissues
is established; by the erection of hairs and secretion of
sweat there is an increase in the amount of heat lost. The
metabohc needs of the active muscles are met by a dis-
charge of glucose from the hver. It is stated, also, that
adrenahn accelerates the recovery of the muscles from
fatigue. In tliis way adrenahn completes the transforma-
tion of the resting into the fighting animal. At the end of
exercise, in normal individuals the pulse and respiration
rapidly subside and should reach their normal rate within
five minutes.

FATIGUE

Fatigue is distinguished objectively by a diminished
functional capacity, and subjectively by a general feehng
of lassitude, tiredness referred to the muscles, and desire
for sleep. The two problems which we have to consider
are the location and the cause of the diminished capacity
for work.

As to the location, this may be in any of the following
structures : (1) muscles; (2) nerve endings; (3) peri-
pheral nerve-fibres ; (4) spinal nerve-cells ; (5) synapses ;
(6) cerebral cells.

When the excised muscle is stimulated repeatedly its
contraction undergoes a progressive alteration — lengthen-
ing of the latent period, slowing of the contraction, diminu-

FATIGUE 339

tion in the height of contraction, and a very considerable
prolongation of the period of relaxation. In fact, the
muscle fails to recover its original length and undergoes
gradual and permanent shortening. Eventually it fails
to respond altogether : the muscle has lost its capacity for
contraction.

When a muscle is made to undergo repeated volimta/nj
contractions, these diminish to extinction ; but when it is in
this state the muscle has not lost its capacity to contract,
for it responds briskly to electrical stimulation appUed
to the muscle itself or to its nerve. Under physiological
conditions, then, loss of functional capacity is not to be
entirely or even primarily located in the muscle, nor in
the nerve-ending, nor, again, in the nerve-trunk. As regards
the last, nerve-fibres are beUeved to be almost immune to
fatigue. ^,

We have seen that the reflex arc is more Uable to fatigue
than the nerve-fibre. This greater susceptibility of the
arc must be attributable to the nerve-cell, or to the synapse,
or to the receptor organ.

It is not the nerve-cell, for the final common path (p. 278),
when stimulated to fatigue by one receptor, responds with
undiminished vigour to another. Nor is there any evidence
that the receptor is specially prone to fatigue. Fatigue
must therefore be located in the synapses between the
neurones. As to the cells of the brain, histological changes
have been described in them as the result of prolonged
activity. The diminished capacity to function seems,
therefore, to occur in the synapses and in the higher nerve-
cells.

The Cause of Fatigue. — The signs of fatigue in the nerve-
muscle preparation are associated with the accumulation
of lactic acid, and are, indeed, in large measure due to it,
for if the muscle is perfused with a fluid not containing
any food substances or oxygen, recovery ensues. If, on
the other hand, fresh muscle is perfused with lactic acid, it
becomes more prone to fatigue. This accumulation of

340 MUSCULAR ACTIVITY AND FATIGUE

acid is, however, not the cause of fatigue, for there is a
Hmit to which recovery can be obtained by mere removal
of the acid. Under these conditions recovery can only
be induced when the perfusing fluid contains food substances
such as carbohydrates.

Two factors, then, are concerned in fatigue of the isolated
muscle — accumulation of lactic acid and deficiency of food
material. As a necessary consequence of the absence of
circulating fluid, the former is the more important. To
what extent is lactic acid a cause of fatigue in the muscle
in situ?

Now lactic acid, as we have seen, is not an abnormal
product of muscular metabohsm but a normal inter-
mediate product, its ultimate oxidation providing the
necessary energy for subsequent activity. What is ab-
normal is not the formation of the acid but its accumulation
due to failure of oxidation. We may therefore look to
deficiency of oyxgen as a cause of this accumulation. This
is borne out by experimental findings in cases of muscular
exercise. The appearance of lactic acid in the urine de-
pends not upon the duration of exercise nor upon the
amount of mechanical work involved, but upon the coinci-
dent respiratory distress — that is to say, owing to the call
for oxygen by the tissues not being satisfied.

Provided, then, that the supply of oxygen is sufiicient,
there is no accumulation of lactic acid, at any rate in
sufiicient amount to cause overflow into the general circu-
lation. But in the measure that oxygen fails, acid accumu-
lates. In so far, then, as fatigue can be located in muscle,
we may attribute its occurrence to accumulation of lactic
acid.

As regards fatigue of the nervous system, this may be
induced in the frog by depriving the spinal cord of oxygen,
recovery ensuing when the cord is perfused, still in the
absence of the gas. Fatigue, then, would seem to be the
same process essentially, whether in the central nervous
system or in the muscles.

FATIGUE 341

"Whether the lactic acid (or any other metabohte) afEects
the nerve-centres directly or whether it directly stimulates
the nerve-endings is unknown.

The view is also held that fatigue is due to the mechanical
stimulation of the nerve-endings consequent upon the
prolonged movement.

CHAPTER XVII
KEPRODUCTION

Introduction

The capacity for reproduction is one of the principal
characteristics of hving matter. In the simplest forms
of hfe it occurs in two ways. One consists merely in the
division of the single-celled organism into two and the
subsequent growth of these until they resemble the parent.
By the repetition of this process several times a large
number of individuals is formed. But sooner or later
this process comes to an end, the capacity for division
undergoing decay. Further propagation can only occur
by a second method which consists in the fusion of two
cells. By this process the reproductive function is re-
stored, the new cell undergoing division with great vigour.

In higher animals reproduction is effected by essentially
the same two processes. The repeated division which the
fertihsed ovum undergoes are exactly comparable with the
division of protozoa, the only difference being that in
the former the cells formed, instead of becoming inde-
pendent, remain bound together to form the multicellular
animal, the process culminating in the formation of a new
individual.

The capacity for division comes to an end at different
periods according to the nature of the tissue. In nerve-
cells new-formation probably never occurs after birth,
while in other tissues it persists throughout hfe. In the
latter case it may be continually occurring, as in the cells

342

REPRODUCTION 343

of the epidermis which are constantly being formed to
make up for those shed, or it may be a fmiction called
into play only for the purpose of filHng up the ranks in
tissues which have been destroyed by disease. Such a
process happens in the lung epithehum after pneumonia.

Death of the individual in the higher animals corresponds
to the cessation of the capacity to divide in protozoa ;
and, as in the latter, the continuation of the race depends
upon a periodic fusion of cells. But fusion as it occurs
in the protozoa differs from :^usion in higher forms in two
important respects. First, in protozoa all the cells pro-,
duced by division seem to be capable of pairing and fusing,
while in the higher animals this capacity becomes the
special property of a small group of cells which exist for
no other purpose. As we ascend in the animal scale
these cells become fewer relatively to the whole body.
Secondly, while in the protozoa the two cells which fuse to-
gether appear to have identical structure, in higher forms
a difference arises between them. This is associated mth
anatomical differences in the two individuals in which
they are formed. Of these individuals one plays but a
momentary part in the process of reproduction, while the
other protects and nourishes the offspring until the latter
is capable of an independent existence. The higher the
animal the more prolonged is the period of its helpless-
ness. The changes which take place in the reproductive
process during evolution may therefore be summarised
as a speciahsation in certain cells of the capacity for fusion,
differentiation of sex and increasing dependence of the
young upon the mother.

Yet though in higher animals the sexual organs have
sunk to form but a small part of the body, they exert a
profound influence upon the growth and metabohsm of the
whole organism. We shall see how the ovary and testis
pour into the blood substances the presence of which is
necessary for the orderly succession of events which make
up the reproductive process, beginning in the desire for

344 REPRODUCTION

copulation and ending only when the offspring can fend
for itself.

Division of Cells

Division of cells occurs by a process known as mitosis
or karyokinesis. It involves the nucleus as well as the
cytoplasm.

In the resting cell the nucleus is surrounded by an irregular
mass of a basophile material — chromatin. In the cyto-
plasm is a small star-shaped body — the centrosome.
Division takes place in the following stages : —

1. The chromatin is arranged in one long skein or
spireme.

2. The skein divides into a number of segments which
are sometimes V-shaped. These are now known as chro-
mosomes. The number of chromosomes is constant for
each species, the number in man being twenty-four. Mean-
while the centrosome has divided, one division migrating
to the opposite side of the nucleus. The stellate appear-
ance of the centrosomes becomes accentuated and the
two become joined together by fine lines in the form of a
spindle — the achromatic spindle {Diaster stage).

3. The chromosomes dispose themselves radially at the
equator of the spindle.

4. Each chromosome divides longitudinally, the halves
separating and passing to the two centrosomes. Here they
join up into a skein, eventually resuming the form of the
resting nucleus.

5. The spindle disappears, and at its equator the cyto-
plasm is modified to form a partition. In this way the
division of the cells is completed.

This, the usual form, is known as homotype mitosis.

A modified form of mitosis, known as heterotype, occurs
at one stage in the course of formation of the mature
male and female sexual cells. The number of chromosomes
into which the skein divides is only half the normal. These
divide transversely instead of longitudinally. In the male,

THE MALE ORGANS 345

heterotype mitosis occurs at the formation of the spermatids,
and in the female at the casting off of the second polar
body. The spermatozoon and mature ovum therefore
contain each of them half the amount of chromatin. At
the fusion of the nuclei in fertihsation the normal amount
of chromatin is restored. The reduction of chromatin
is therefore a device for the prevention of the doubhng of
the chromosomes at each new generation.

Fig. 62. — Plan of arrangement of tubules and ducts of testicle (from
Schafer's Essentials of Histology, after Quain) : a, seminiferous
tubules ; 6, straight tubules ; c, rete testis ; d, vasa efierentia ;
e, f, g, epididymis ; h, vas deferens ; t, tunica albuginea with
trabecular.

THE MALE ORGANS OF REPRODUCTION

The Testis and Vas Deferens

The testis consists of a number of seminiferous tubules
grouped into lobules by strands of fibrous tissue. These
strands arise from a fibrous mass called the mediastinum
testis, which is situated posteriorly and is continuous with
the tunica albuginea or sheath which invests the testis.
In the connective-tissue between the tubules are cells of
epithelioid form — the interstitial cells. The seminiferous

346 REPRODUCTION

tubules are united posteriorly in groups to form the straight
tubules which lead into the rete testis — a network of canals
situated in the mediastinum. From the rete about twenty
vessels known as the vasa efferentia lead into the canal of
the epididymis. For part of their course the vasa effer-
entia are convoluted — tfie coni vasculosi. The epididymis,
a tube much coiled and of great length, serves as a store
for spermatozoa, and its cells contribute to the seminal
fluid. It leads into the vas deferens. The vasa efferentia
and epididymis are cihated internally and their walls
contain unstriated muscle fibres. The wall of the vas
contains three muscular layers; its epithelium is not
ciliated. The vas opens into the prostatic portion of the
urethra. Shortly before its termination the seminal vesicle
opens into it.

The Formation of Spermatozoa

Each seminiferous tubule is composed of several layers
of cells enclosed in a basement-membrane. The layer
next to the basement-membrane consists of cubical epi-
thehal cells — the spermatogonia. These by division are
continually giving rise to the next layer of much larger
cells — the spermatocytes. Each spermatocyte divides into
two daughter-cells, and each of these again into two sperma-
tids. In this last division there is a reduction of the
number of chromosomes {heterotype mitosis). The sperma-
tids elongate, the nucleus passes to one end and a tail
develops at the other. The spermatozoa as they are thus
being formed he in groups on the inner part of the tubules,
their tails occupying the lumen. Accompanying each
group is a cell of Sertoh, an elongated cell derived from the
epithehum at the periphery of the tubule. The cells of
Sertoh are beheved to take part in the nutrition of the
spermatozoa. The last stage is the hberation of the
spermatozoa in the seminal fluid.

The various stages in the formation of the spermatozoa
are represented in Fig. 64, p. 348.

REPRODUCTION

347

1^ ^i^.0^^:-% sie-i^ .

?5^= ./ ^- '^5 ^■" :^;L

Fig. G3. — Portion of two seminiferous tubules in testis of rat : a, base-
ment membrane ; b, spermatogonium ; c, spermatocyte ; d, sper-
matozoa in cavity of tubule ; e, interstitial tissue containing vessels
(Marshall).

348

REPRODUCTION

These changes constitute the maturation of the sperma-
tozoa and have their counterpart in similar changes
undergone by the ovum.

Structure of Spermatozoa

The human spermatozoon consists of three parts, a
flattened ovoid head, a small cyhndrical body, and a long
tail which consists of a filament embedded in protoplasm.
The head constitutes the nucleus and contains chromatin.

SPER.MAT060NIUM

SPERMATOCYTE

HETER.OTYPE.\
Dl VISION I

SECONDARY
SPERMATOCYTES

SPERMATIDS

* d d # 3PERJ<ATOZ.O^

Fig. 64. — Scheme of spermatogenesis (after Boveri).

The tail runs through the middle of the body, arising from
the base of the head. At the anterior part of the head is
an apical projection known as the achrosome. The
motiUty of a spermatozoon is due to a lashing movement
of its tail.

Accessory Sexual Glands

The seminal vesicles consist of convoluted tubes opening
into the termination of the vas. They secrete a fluid
which nourishes and stimulates the spermatozoa.

THE MALE ORGANS 349

The prostate consists of alveoli lined with cubical
epithelium and separated by connective tissue and plain
muscular fibres. The secretion of the prostate probably
serves to dilute the semen, to prolong the activity of the
spermatozoa by affording them nourishment and to
wash out traces of urine from the urethra preparatory
to ejaculation.

Concerning the function of Cowper's glands, which open
into the urethra about two inches below the prostate, httle
is known. From the fact that their secretion pjpcedes
ejaculation it is suggested that they, like the prostate, serve
to clean the urethra of urine.

The Internal Secretion of the Testis

It is well known that castration in the young prevents
the development of the secondary sexual characteristics
which normally occurs at puberty — -the voice remains high-
pitched ; hair fails to grow on the face ; there is an absence
of bodily and mental vigour. The presence of the testis,
therefore, exerts a profound influence upon the bodily
metabolism. That this influence is brought about by
chemical means is abundantly proved. The acquirement
of the secondary sexual characteristics is not prevented
by Ugaturing the vas, nor when the testes are removed
and transplanted elsewhere in the body.

Removal of the testes in the adult leads to atrophy of
the seminal vesicles, prostate and Cowper's glands.

A substance having the formula C5H14N2 — known as
spermine — -has been isolated and is alleged, but on uncon-
firmed evidence, to be the active principle.

There is some evidence that the formation of the internal
secretion is the function not of the tubules but of the
interstitial cells. After occlusion of the vas, the former
atrophy, but the latter undergo no change.

350 REPRODUCTION

The Penis

The penis consists essentially of three columns of erectile
tissue — the two corpora cavernosa which lie side by side,
and the corpus spongiosum which hes inferiorly and sur-
rounds the urethra. The three corpora are surrounded
by a sheath which contains white, elastic, and plain muscle
fibres. Proximally, the corpora are enlarged and are sur-
roundod by muscles, the corpora cavernosa by the ischio-
cavernosus muscles or erectores penis, and the corpus
spongiosum by the bulbo-cavernosus or ejaculator urinse.
At the distal end of the penis the corpus spongiosum is
dilated to form the glans penis. The erectile tissue of the
three corpora consists of a network of trabeculse enclosing
venous spaces.

Erection consists in an engorgement of the venous spaces
of the corpora. It is brought about by two factors. There
is an active vaso-dilatation of the arterioles, and a compression
of the veins by the ischio-cavernosus and bulbo-cavernosus
muscles. Erection is essentially a reflex action, for it
occurs after section of the spinal cord above the lumbar
region. The centre lies in the lumbo-sacral region. The
afferent nerves are those arising in the glans penis. The
vaso-dilator fibres {nervi erigenies) arise in the first and
second sacral nerves. The lumbar nerves, derived from
the sympathetic, which also supply the penis, are vaso-
constrictor and therefore inhibit erection.

Erection has been produced by electrical stimulation of
the crura cerebri and cord.

The ejaculation of semen is a reflex induced by the
friction of the glans penis against the vulva. Waves of
contraction pass along the epididymis and vas. At
the same time there occur contractions of the seminal
vesicles and prostate. The combined fluid is thus driven
into the urethra. It is prevented from entering the bladder
by the contraction of the sphincter. The discharge of the

THE FEMALE ORGANS 351

semen into the vagina is due to the ischio-cavernosus
and bulbo-cavernosus muscles, which undergo rhythmic
contraction.

The centre controlhng ejaculation hes in the lumbo-
sacral region of the cord. The efferent fibres for the con-
traction of the vasa deferentia leave the cord by the second,
third and fourth lumbar roots. Passing through the in-
ferior mesenteric gangha, they form the hypogastric nerves.
The motor fibres to the ischio-cavernosus and bulbo-
cavernosus muscles lie in the nervi erigentes.

THE FEMALE ORGANS OF REPRODUCTION

Between puberty, when the sexual organs first be-
come active, and the menopause or climacteric (at about
the forty-sixth year), when they cease to function, the
ovary and uterus undergo a parallel series of cyclical
changes, which are only interrupted by the more profound
modifications which occur during pregnancy.

The cycle of changes, which is fundamentally the same
in all mammals, is known as the OGstrous cycle. lif consists
of the following phases : — -

Pro-oestrum. — This is the period of uterine congestion,
culminating in a discharge of blood and mucus.

CEstrus or Period of Desire.— This follows immediately
upon pro-cestrum. In many mammals it is the only
period during which the female evinces sexual desire and
during which copulation leads to fertilisation. O^^strus
corresponds in point of time to ovulation, to be described
later.

Metoestrum. — During this period the activity of the
sexual organs diminishes.

Ancestrum or Period of Rest.— The sexual organs are now
relatively quiescent.

Some animals— e. 5^. rabbit, bitch — may, after coitus,
undergo a condition known as pseudo-pregnancy — the
uterus, mammary gland and corpora lutea (see below)

352 REPRODUCTION

hypertrophy until the fifteenth day and then atrophy, the
animals not being pregnant.

When pregnancy or pseudo-pregnancy happen metosstrum
does not occur. The cycle which takes place under these
conditions may therefore be represented thus —

Pro-oestrum

CEstrus

Pregnancy Pseudo-pregnancy
Anoestrum

Changes in the Human Non-pregnant Uterus

The Menstrual Cycle. — The complete cycle usually
occupies twenty-eight days. It is divided into four stages^ —

1. Stage of Quiescence. — This lasts about twelve days.

2. The Constructive Stage. — This begins with an increase
in the glands and stroma of the mucous coat, accompanied
by dilatation of the blood-vessels. Exudation of blood
and serum occurs into the tissue-spaces. These changes
are associated with a general thickening of the mucosa.
The constructive stage lasts about five days.

3. The Destructive Stage — Menstruation. — This begins
with free extravasation of blood into the stroma, due
partly to diapedesis, partly to rupture of the capillaries.
The blood accumulating under the epithehum breaks
through into the lumen, blood and epithehal cells being
discharged from the vagina mixed with mucus from the
enlarged glands. The average duration of the menstrual
flow is four days. This period is accompanied by a general
bodily disturbance — lassitude and pains in the back.

THE MENSTRUAL CYCLE 353

4. Stage of Repair. — Lasting about seven days, this stage
consists iu a regeneration of the mucosa, contraction of
blood-vessels and reabsorption of blood which has not
been discharged.

It is clear from what has been said above that the
menstrual cycle is but a form of the oestrous cycle. We
may thus synchronise the process as it occurs in women
with the general type appertaining to all mammals.

Stage of Quiescence Anoestrum.

Constructive Stage \ ppn-oestrum

Destructive Stage {Menstruation) J

Stage of Repair | Metoestrum

In civihsed mankind oestrus has practically disappeared,
but it still persists in primitive races.

The significance of menstruation and its correlation
with the changes which occur in the ovary will be discussed
later.

The Ovary

The ovary consists of a stroma of fibrous tissue with
unstriped muscle-fibres and blood-vessels. It is covered
by a single layer of epithehal cells — the germinal epithe-
lium. Lying in the stroma are a large number of vesicles
of varying size — these are the Graafian follicles in different
stages of development. Each follicle contains an ovum.
There occur also the corpora lutea, or discharged follicles.

Ovulation and Maturation

During sexual hfe the ovary undergoes a cycle of changes
concurrent with those occurring in the uterus. Those
consist in the hypertrophy of one or more folHcles. At
an early stage the folhcle consists of the ovum surrounded
by a single layer of epithehal cells. Immediately around
it the stroma is condensed to form a sheath. The growth
23

354

REPRODUCTION

of the follicle is due to the prohferation of the epithelial
cells. These eventually form two layers — the memhrana
granulosa hning the cavity and the discus proligerus cover-
ing the ovum. These two layers become partly separated
by the gradual accumulation of fluid — liquor folliculi.
Hypertrophic changes simultaneously occur in the fibrous
sheath, in which two layers become recognisable — theca
externa and theca interna.

Fig. 65. — Section of cat's ovary (Schron), from Schafer's Essentials of
Histology, after Quain : 1, gemiinal epithelium ; 5, Graafian
follicles in their earliest stages ; 6, 7, 8, more advanced follicles ;
9, almost mature follicle; 10, corpus luteum.

The ripe folhcle has a diameter of 15 mm. and protrudes
from the surface of the ovary.

The ovum consists of a single cell containing nucleus and
nucleolus. It is surrounded by a thin membrane — the
vitelline membrane, around which is the zona radiata, a
radially striated structure which is supposed to contain
fine canals through which the ovum is nourished.

The growth of the follicle culminates in its rupture, the
ovum, surrounded by the discus proUgerus, being dis-
charged into the peritoneal cavity. This process, which
is known as ovulation, occurs regularly at oestrus in most

MATURATION 355

mammals, but in some — e. g. the rabbit, cat — only as the
result of copulation. Failing copulation in these animals
the follicle undergoes atrophic changes. Upon the discharge
of the ovum the fimbriae of the Fallopian tube are erected
around the ovary, and by their muscular and cihary action
sweep the ovum into the tube.

While these changes are taking place the ovum undergoes
the process of maturation. The ovum divides by karyo-
kinesis, the cleavage being very unequal. The smaller
product is extruded upon the surface of the ovum and is
known as the first 'polar body. This may later divide into
two. The ovum then forms a second polar body, but in
this division the number of chromosomes is reduced by
a half. The nucleus of the matured ovum is known as
the female jjronucleus.

The process of maturation may be thus represented : —

OOaONIUM %

PRJMARy OOCYTE
OR OV^UM

SECONDARY __^ _.

OOCYTE. ^H^ ^ F/RjST POLi^R. BODY

[HETEROTYPL
\ DIVISION

M/9 TUR.E
OVUM

-POLAR. BODIES
Fig. 06. — Maturation. Compare with Fig. 64, p. 348.

In the male all four products of division become
functional reproductive cells ; in the female this happens
only to one, the others playing a subsidiary role.

356

REPRODUCTION

The Corpus Luteum

When the ovum has been discharged the epithehal cells
which remain in the Graafian folhcle hypertrophy and
form a sohd mass of large cells containing a yellow pig-
ment— lutein — and separated by connective tissue which,

Fig. G7. — Fully formed corpus luteum of moute(from Sobotta). The
luteal tissue is vascularised and the central cavity filled in with
connective-tissue (from Marshall, The Physiology of Reproduction).

together with vessels, grows inwards from the outside
wall. This structure is called the corpus luteum. In
the centre there may be a clot of blood caused by the
rupture of the blood-vessels during ovulation. If preg-
nancy does not occur the corpus luteum in some animals
grows only for a short period, then atrophies. But if
conception takes place its growth continues until the middle

THE CORPUS LUTEUM 357

of pregnancy, when it attains a diameter of about half an
inch. This size is maintained — at any rate in the rabbit —
mitil a late period of gestation or even into lactation.
It then undergoes degeneration and becomes transformed
into interstitial tissue. The persistence of the corpus luteum
is dependent upon the presence of the foetus in the uterus
in all those animals such as Man which do not experience
pseudo-pregnancy.

In animals which do experience pseudo-pregnancy (p. 351)
the corpus luteum persists for a period as long, or almost
as long, as in true pregnancy.

Internal Secretion of the Ovary

WTicn both ovaries are excised in early hfe the changes
characteristic of puberty do not occur. There are no
oestrous cycles, the uterus remaining in an infantile con-
dition. Secondary sexual characteristics fail to appear,
there being in some animals an approach to the male
physical form.

On removal of the ovaries after puberty, menstruation
ceases, while the uterus, and sometimes the breast, undergo
atrophic changes.

In some animals the ovaries have been removed and
other ovaries grafted. Under these conditions folUcle-
formation occurs in the graft and the oestrous cycle is
resumed.

Any reflex connection between the ovarian and uterine
changes is out of the question. This is proved not only
by the transplantation experiments mentioned above, but
also by the fact that the changes in the uterus occur when
all nervous connection with the ovary is destroyed by
removal of the lumbo-sacral part of the cord.

The ovary therefore produces a hormone which is neces-
sary for the nutrition of the uterus. As the ovary under-
goes its cycle of changes it is probable that the secretion
varies in amomit, and that this variation determines the
parallel cycle of changes in the uterus.

358 REPRODUCTION

The hormone responsible seems to be produced either
in the epitheUal or in the interstitial cells. There is some
positive evidence that it is independent of the corpus
luteum.

Function of the Corpus Luteum

The corpus luteum is beUeved to furnish a hormone
which is responsible for the changes in the uterine wall
which occur during the early stages of pregnancy and
which are necessary for the proper nutrition and fixation
of the embryo. When the ovaries are removed early in
pregnancy abortion occurs, but when the operation is
performed at a later period there is no interruption of the
normal course of events.

In pseudo-pregnancy the uterus undergoes very pro-
nounced hypertrophy, congestion and great glandular
development under the influence of the corpus luteum in
just the same way as happens during true pregnancy.
Moreover, after a mechanical stimulus (introduction of a
foreign body or incision of the wall), decidua cells are
formed, but only if corpora lutea ate present in the ovary.

The corpus luteum is also considered responsible for a
hormone which initiates the hypertrophy of the mam-
mary gland. This is discussed more fully later.

Correlation of the Ovarian and Uterine Cycles

There is no certain cUnical evidence to show whether
in women the process of ovulation precedes, succeeds or
is coincident with menstruation. But the identification
of menstruation with the period of pro-oestrum, and the
known synchronisation of the subsequent period of oestrus
in lower animals with the ripening of the folhcle, are strong
arguments in favour of menstruation preceding ovulation.
On this view the purpose of menstruation is a kind of
freshening up of the uterine mucosa preparatory to the
reception of the fertihsed ovum. In some animals rupture
of the ripened folhcle occurs only as a reflex effect of

FERTILISATION 359

copulation. It is probable that in women the period
immediately following menstruation, corresponding to
oestrus in lower animals, is the only period during which
fertihsation can occur. The descent of the ovum down the
Fallopian tube coincides with the ascent of the spermatozoa.

Fertilisation

During coitus the spermatozoa deposited in the vagina
are sucked into the uterus by peristaltic contraction of
this organ initiated reflexly by contact with the male,
the efferent path being the sympathetic. They travel up
into the Fallopian tubes, overcoming by the propulsive
action of their tails the downward current produced by
the ciha of the female passages. In the tube they meet
the matured ovum on its way down from the ovary.

Of the many million spermatozoa which enter the
female organs only one enters the ovum.

After impregnation, the tail is absorbed and the head,
now known as the male 'pro-mwleus, fuses with the female
pro-nucleus. In this process the number of chromosomes,
which in each element has been reduced by a half during
maturation, is restored to the number characteristic of
the species. The nucleus thus formed is called the seg-
mentation-nucleus. From the fertihsed cell or oosperm
arises the new generation.

CHANGES IN THE PREGNANT UTERUS

As the fertihsed ovum passes down the Fallopian tubes
changes occur in the mucous membrane of the uterus,
preparatory to the embedding of the ovum within it.
The stroma becomes transformed into a mass of decidual
cells — large cells with small nuclei. The glands enlarge,
the epithehum prohferates, and the blood-vessels are
dilated. In this way the mucous membrane becomes
greatly thickened.

By the time it reaches the uterus the ovum has developed

360

REPRODUCTION

as far as the blastocyst stage (see Fig. 68). It is a mass
of cells containing a vesicle. In this form the ovum
buries itself in the decidua. As the embryo increases in
size it projects into the cavity of the uterus. In the
decidua three parts are now distinguished : (1) the decidua

enveloping epiblast

enclosed epiblast

hypoblast
enveloping epiblast

Fig. 08. — Bilaminar blastocyst (Keith, after Van Eeneden).

serotina or basalis, where the embryo is attached to the
uterus ; (2) the decidua reflexa, which covers the embryo ;
and (3) the decidua vera, which hues the remainder of the
uterine cavity. With further growth the decidua reflexa
and the decidua vera come into direct contact (Fig. 69).
At an early stage the nutrition of the embryo is prob-

DEVELOPMENT OF THE FCETUS

361

ably derived directly from the decidual cells and uterine
glands.

Soon, however, the outermost layer of the embryo
becomes speciahsed for the provision of nutrition — ^for
this reason it is called the trophoblast. The trophoblast,

.OEClDUA VERA

-DECIDUA REFLECTA

,DE.CIDUA BASAUS

BLASTODERMIC
VESICLE.

DE.CIOUA VERA

CERVIX

DECIDUA VERA

VAQiNa

Fig. 69. — Diagrammatic section of the pregmint uterus to show the
three parts of tlio decidua (Keith).

and a layer of mesoblast which surrounds the embryo
together form the chorion. This becomes divided into
two layers : (a) the Basal or Langhan's layer on the
inner side, and (6) the Syncytium, a mass of proto-
plasm containing nuclei but no proper cell divisions.
The syncytium is powerfully phagocytic. It invades the
decidua, eroding not only the decidual cells but also the
walls of the capillaries. The maternal blood oozes into the

362

REPRODUCTION

eroded spaces, where it comes to lie in contact with the
syncytium.

Internal to the basal layer is a layer of mesoblast.
These two layers send out processes which ramify in the
syncytium to form the chorionic villi. In the mesoblast
are laid down blood-vessels which become connected with
the foetal circulation by the umbihcal vessels.

The above changes involve both the decidua serotina

uterine vessel-

SiWmuc. layeK^
of uterus

decidua —
syncytium

syncytium.

basal layer,

mesoblast
of chorion

blood space

Fig. 70. — Diagrammatic section of the decidua serotina and chorion
to show how the placental blood spaces are formed (Keith).

and the decidua reflexa. In the third month the hyper-
trophy of the chorionic vilh in the former and their atrophy
in the latter lead to the formation of the placenta.

In the fifth month the growth of the villi ceases and in
place of the basal layer and syncytium there appears a single
layer of flattened cells. On one side of this membrane is the
foetal blood circulating in the chorionic villi, on the other
side is the maternal blood circulating in the lacunae eroded
out of the decidua by the syncytium. Across the mem-
brane the food material and oxygen are transferred from

PARTURITION 363

the mother to the offspring, and the waste products from
the offspring to the mother. It is important to reahse
that there is no mixing of the maternal and foetal blood.

The growth in size of the uterus as pregnancy proceeds
is due largely to the elongation and thickening of the
muscle fibres.

PARTURITION

Pregnancy lasts about 280 days and is terminated by
the expulsion of the foetus. Throughout pregnancy the
uterus undergoes shght contractions which are not felt
by the mother. As the uterus reaches its maximum growth
these contractions become gradually stronger and more
frequent. At the onset of labour they increase further
in intensity and frequency, and are accompanied by pain
which eventually becomes extreme. Labour is technically
divided into three stages. The first is the dilatation of
the OS uteri, due to contraction of the longitudinal uterine
muscles. The second is the expulsion of the foetus. The
tliird is the detachment of the placenta from the uterine
wall and its expulsion. The second and third stages are
brought about by the combined contraction of the longi-
tudinal and circular muscles of the uterus and of the muscles
of the abdominal wall. As the contents of the uterus become
smaller the uterine muscles after each contraction remain
at their shortened length.

Parturition can occur in animals after section of the
thoracic region of the cord, and in women suffering from
complete paralysis of the lower limbs. For its proper
performance the integrity of the lumbar part of the cord
appears to be essentia], but in some animals it occurs, though
often imperfectly, after complete destruction of the lower
part of the cord. Under these circumstances parturition
occurs through the uterine contractions only, the abdominal
muscles play no part. Normal parturition is therefore
due partly to the inherent rhythmicity of the uterus and
partly to reflex contraction. The function of the spinal

364 REPRODUCTION

centre is to co-ordinate the contractions of the abdominal
muscles with those of the uterus.

THE FCETAL CIRCULATION

The oxygenated blood from the placenta travels by the
umbilical veins and reaches the inferior vena cava either
through the hver or directly through the ductus venosus.
In the inferior vena cava it becomes mixed with the venous
blood returning from the lower hmbs. Entering the right
auricle, it is directed across that chamber through the
foramen ovale into the left auricle — ^from there into the
left ventricle and aorta. This blood supphes chiefly the
head, neck, and upper hmbs. The venous blood from
these parts is collected in the superior vena cava. It
passes through the right auricle into the right ventricle.
From this chamber it passes by the pulmonary artery and
ductus arteriosus into the descending aorta, by which it
reaches the abdomen, lower hmbs and placenta (by the
umbihcal arteries). The special features to note are : —
(1) Very httle blood traverses the Imigs. (2) In the right
auricle there are two independent currents of blood, one
from the inferior vena cava to the left auricle, the other
from the superior vena cava to the right ventricle. The
two streams are kept apart by the Eustachian valve.
(3) Blood leaves the heart in two degrees of purity — the
more oxygenated blood from the left ventricle which
supphes the upper part of the body, and the venous blood
from the right ventricle which supplies the abdomen and
lower hmbs. (4) No part of the foetus receives fully-
oxygenated blood, since the blood which leaves the placenta
is mixed with that which is returning from the lower part
of the body of the foetus.

The expansion of the lungs which occurs at the first in-
spiration determines a flow of blood from the right ventricle
into the lungs and from the lungs into the left auricle.
The foramen ovale between the auricles is a valvular arrange-

LACTATION 365

ment which permits the flow of blood only from right to
left. The increased pressure in the left auricle closes the
valve, which is soon sealed. The placental circulation
ceases owing to the Ugature of the umbiUcus. Finally, the
lumina of the ductus arteriosus and ductus venosus become
obUterated.

LACTATION

The Mammary Glands

These consist of a number of lobes subdivided into
lobules. The lobules are composed of alveoh, separated
by connective tissue. From the alveoH run ducts which
join together to form the lactiferous ducts, of which about
fifteen or twenty open on the nipple. At their proximal
ends the lactiferous ducts are dilated so as to allow of
the accumulation of milk in the intervals between suckhng.
Some unstriped muscle fibres are found in the walls of
the ducts. The gland owes its rounded appearance to a
layer of fat which hes between it and the skin. It is
plentifully supphed with blood-vessels and nerves.

The nipple is an erectile organ containing unstriated
muscle fibres. On its surface are papillae connected with
sensory nerves.

The secretory cells hning the alveoh form a single
layer. Their appearance varies according to the physio-
logical condition of the gland. When the gland is at rest
they are flattened, when it is active they are columnar.
They contain protein granules and fatty globules. The
latter are found also in the lumen of the alveoh, together
with free granular cells.

The act of secretion is provoked directly by the negative
pressure produced in suckling, aided probably by reflex
contraction of the unstriped muscle. The lactiferous
ducts are kept patent in face of the pressure of the suck-
hng's hps owing to the nipple becoming erectile. During
suckhng the vessels of the gland are reflexly dilated.

366 REPRODUCTION

Growth of the Mammary Glands

The glands undergo a slight increase in size at puberty,
and a further temporary increase coincides with the
menstrual periods.

The enlargement at pregnancy begins (in multiparse,
or those who have been previously pregnant) soon
after the second month, in virgins immediately after
conception ; the nipples at the same time become pig-
mented. During the latter stages of pregnancy a clear
fluid known as colostrum can be squeezed out.

The growth of the gland at puberty is due to an internal
secretion elaborated by the ovary, for it does not occur
when the ovaries are removed. The congestion which occurs
with menstruation also appears to be of ovarian origin.

The hypertrophy of pregnancy, similarly, is not due to
a nervous influence, for it occurs when all nervous con-
nection between the pelvic organs and breasts have been
severed by transection of the spinal cord.

In the first half of pregnancy mammary growth is due
to a hormone poured into the blood by the corpus luteum.
The continued development of the glands in the second
half of pregnancy is also due to the corpus luteum, the
persistence of which probably depends upon the presence
of the foetus.

Since no secretion occurs until after parturition, it is
held that the responsible hormone, at the same time as it
stimulates the growth of the gland, inhibits its activity.
On the removal of this inhibiting agent secretion occurs.
However that may be, the secretion, when once started,
depends for its continuance upon the act of suckhng. It
is also readily influenced by nervous agencies. The flow
of milk ceases at the onset of a new pregnancy.

Composition of Milk

Milk is amphoteric in reaction and has a specific gravity
lying between 1-028 and 1-034. From the following Table

MILK 367

it will be seen that human milk contains less protein but
more lactose than cow's milk.

Cow's.

Human.

Water ,

88-3

88-8

Proteins

1-0

Fats .

3-5

Lactose

4-5

6-5

Salts . . . ,

0-7

0-2

100-0

1000

The proteins are three in number — caseinogen, lactal-
bumin and lactoglobulin. It is the first which is precipi-
tated by rennet-ferment, being converted into casein and
leaving whey.

Of inorganic salts, milk is rich in calcium and phosphorus
but is almost completely deficient in iron, the infant
apparently relying during suckUng upon the iron which is
present in high percentage in the liver.

Immediately after parturition the gland secretes colos-
trum. This differs from milk in being a clear fluid con-
taining very little caseinogen. It coagulates on boiling,
and contains characteristic granular corpuscles which stain
with osmic acid. These are probably leucocytes.

Interaction of the Female Sexual Organs

The interaction between the uterus, ovary and mammary
gland may be thus summarised : — -

In the first half of pregnancy the presence of the corpus
luteum determines, on the one hand, the hypertrophy of
the mammary gland, and on the other, the fixation and
early nutrition of the foetus through the formation of the
decidual cells.

In the second half of pregnancy the foetus influences
the corpus luteum, and this in turn causes the further
development of the mammary gland.

CHAPTER XVIII

DEFENCE

Most of the diseases to which animals are liable are due
to the invasion of the body by micro-organisms. It is
famihar to every one that when an epidemic occurs, of the
many who are exposed to the infection, not all take the
disease ; some are naturally or innately immune. Of those
who take the disease a number, in most cases the greater
number, recover; those who recover are for a certain
period or for ever insusceptible to the disease. They have
acquired immunity.

The micro-organisms owe their effects to the toxins or
poisons which they produce. Immunity, whether natural
or acquired, consists in the prevention of the propagation
of the organisms, the neutrahsation and excretion of their
toxins, and the repair of damaged tissue.

The methods by which the animal overcomes the action
of bacteria are seen at their simplest in lower forms of hfe.
Unicellular organisms, such as Amoeba and Paramoecium,
hve upon bacteria. They ingest them and subject them to
the hydrolysing action of their proteolytic enzymes. On
this account Amoeba and Paramoecium are practically
immune to bacteria.

If we now pass to the simpler multicellular animals we
find a reaction of a shghtly more complicated kind. Let
us take the developing starfish in the Gastrula stage.
The body consists of an invaginated cup, the outer layer
being the ectoderm, the inner the endoderm. Between
them is the body-cavity in which float free mesoblastic

368

CHEMIOTAXIS 369

cells. When a foreign body is introduced into this cavity
there is a new formation of mesoblastic cells. These cells
are attracted to the foreign body ; they surround it, and if
it is of protein nature they digest it. The attraction of the
cells towards the foreign body is known as Chemiotaxis.
It corresponds to the movement of amoeba towards its
food. It will be seen that the gastrula has in this respect
advanced beyond amoeba in two ways, in the specialisation
of certain cells for the purpose of defence, and in the
reproduction (prohferation) of the cellular defending
agents.

The response to invasion is essentially the same in higher
animals. Certain cells, the phagocytes, are the defending
agents, and they destroy the bacteria by intracellular diges-
tion. The greater complexity of the process in the higher
animals is due to the more comphcated manner in which the
phagocytes are mobihsed in large numbers to the site of
infection. There is also a further difference. In the course
of evolution host and parasite have, as it were, developed
together. Each has become in some degree immune to
the other. In some cases they may live in symbiosis, each
deriving some benefit from the other. The bacilli which
inhabit the large intestine of the horse live upon the
cellulose which the horse eats. Owing to the bacterial
hquefaction of the cellulose the horse is enabled to absorb
nutriment from the grasses. But there is not always this
mutual advantage. The host may tolerate the presence
within it of certain bacteria. Yet under certain conditions
these same bacteria may cause fatal illness. The respira-
tory passages of human beings are the normal habitat of
the pneumococcus. It is only when the natural resistance
to this organism is lowered, as by exposure to cold, that
the pneumococcus produces an acute inflammation of the
lungs.

When pathogenic organisms are introduced into the
body the phagocytes acquire an adaptation to them. At
first the cells are repelled (Negative Chemiotaxis) ; then
24

370 DEFENCE

they are attracted towards the bacteria (Positive Chemio-
taxis). They attempt to ingest them, but the reproductive
and toxic powers of the latter prove too strong for them
and they succumb. Phagocytes arriving later upon the
scene of action are endowed with stronger properties and
succeed in destropng the bacteria. While the capacity for
defence is thus being gradually acquired, the infected
individual runs through the course of the disease, and it is
owing to the development of the mechanism of defence
that he recovers.

The changes which result from infection may be readily
followed in a thin vascular tissue. The first change is a
dilatation of capillaries, accompanied, however, by retar-
dation of the blood-stream. Leucocytes pass by diapedesis
through the capillary walls, accompanied by an excessive
flow of lymph which distends the intercellular spaces.
This reaction is known as inflammation. It was recognised
by the ancients by its four signs — rubor, tumor, dolor and
calor; rubor, the redness due to the capillary dilatation;
tumor, the distension and puffiness of the tissue due to the
exudation ; dolor, the pain produced by irritation of the
nerve-endings ; calor, the increased warmth of the part due
to the dilatation of the vessels.

The essential features of the inflammatory process are
the effusion of lymph whereby the toxins are diluted, and
the mobihsation of leucocytes whereby the bacteria are
ingested. The infected region becomes a mass of bacteria
and cells floating in lymph. Of the cells, some are the
proper cells of the part in different stages of degeneration.
Some are the leucocytes, those in the centre of the mass
being dead, while those situated peripherally are ingesting
the bacteria. If the diseased area is small in extent all
the dead cells and bacteria will be absorbed by leucocytes.
If it is large, absorption will take place only to a hmited
degree, there remaining a central dead mass cut off from
the supply of blood and surrounded by a capsule of newly
formed fibrous tissue laid down by cells known as fibro-

INFLAMMATION 371

blasts. This is an abscess, and the dead material which
it contains is known as pus. An abscess usually ruptures
on the surface of the body and its contents thus discharged.
Its walls collapse, further development of fibrous tissue
leading to the formation of a scar. Finally, the rent in
the skin heals by new growth of epithehum.

The cells which are actively engaged in the inflammatory
process may be divided into two groups : (1) those normally
present in the blood in considerable number; (2) those
formed from connective-tissue in general and relatively
scanty in the blood. Of the first group the most important
are the polymorphonuclear leucocytes. These are the
Microphages of MetchnikofE. They are present in great
numbers in all acute infections, and are at the same time
greatly increased in number in the blood. They are
actively amoeboid and digest the bacteria. In certain
infections the coarsely granular eosinophiles are increased,
but the function of this type of leucocyte is not properly
understood. The lymjjJiocytes appear to play no part in
acute infections, but they are increased in chronic con-
ditions such as tuberculosis. What part they play is not
known ; their phagocytic powers are very feeble.

The cells of the second group are of three kinds : —

(a) Endothelial (hyahne, mononuclear) cells present in
very small numbers in the blood. They arise from the
endothehum of serous cavities and of blood-vessels when
these are infected. Metchnikoff called them Macrophages,
and beheved that they devour especially the microphages
which have succumbed to the bacteria.

(6) Fibroblasts. — These are spindle-shaped cells arising
in and forming fibrous tissue.

We have said that bacteria owe their deleterious effects
to the chemical action of the toxins which they form.
Bacteria may be divided into two classes. In the first class

372 DEFENCE

are those which remain locahsed in one part of the body
and secrete a great quantity of powerful toxin which
circulates in the blood. It is through the generaUsed effect
of their toxins that they kill. Such are the bacilh of
diphtheria and tetanus. In the other class are those which
have a greater capacity for reproduction and become dis-
seminated through the body. Their capacity to form dif-
fusible toxin is much smaller than in members of the first
class. The toxins are therefore not found in any quantity
away from the bacteria themselves. The greater number of
bacteria belong to this class : Bacillus Typhosus, Bacillus
Coh, Pneumococcus and many others. It is sometimes
stated that the first class form ectotoxins, the second endo-
toxins. Probably both classes produce ectotoxins, the
difference being one of degree of diffusion of the toxin.

In order that we may understand how the body protects
itself against the harmful effects of toxins, let us first con-
sider how it behaves towards poisonous substances of simple
and known constitution. In the chapters on Metabohsm
we have come across several instances where the absorption
or injection of a substance leads to the excretion of that
substance by the kidney in a combined form which is not
toxic. When phenol, scatol or indol enter the blood-stream
they are excreted as the non-toxic sulphates. Organic
acids, such as aceto-acetic acid are excreted as the ammo-
nium salt. Such a mechanism is known as Protective
Synthesis. The most instructive example for our present
purpose is the excretion of benzoic acid combined with
glycine to form hippuric acid. Benzoic acid is toxic be-
cause it has an affinity for some essential chemical grouping
of the hving cell. By combination with glycine this
affinity can be satisfied. Now when a certain dose of
benzoic acid is administered, glycine is produced far in
excess of the amount required to combine with the benzoic
acid. Here, then, the body produces a protective sub-
stance and produces this substance in excess. Let us
now compare wdth this simple instance the behaviour of

EHRLICH'S THEORY 373

the body towards a toxin of complex and unknown struc-
ture. When an animal is repeatedly injected with a non-
lethal dose of diphtheria toxin it becomes immune to a
dose of the toxin many hundred times the strength of what
would have been originally a fatal dose. Further, the serum
of the animal thus artificially immunised, when injected
into a normal animal, confers upon the latter an immunity.
This is the basis of the modern treatment of diphtheria and
of tetanus. As when hippuric acid is administered, the
body has produced a protective substance — an antitoxin — •
and has produced this antitoxin in excess. The difference
between the two cases is that no toxin or combination of
toxin with antitoxin can be detected in the urine. It
therefore appears that in the two cases the mechanism of
defence is essentially the same, the apparent difference
between them being explained by the fact that in one case
the molecules concerned, being small, diffuse through the
kidney, while in the other case the molecules, being large,
remain in the blood and accumulate there.

Ehrlich has given a graphic representation of the forma-
tion of antitoxin. He conceives the cell protoplasm as
having a number of different unsatisfied aflfinities which he
calls receptors. To one of these receptors a particular
toxin fits as a lock fits a key, and when it is thus fixed it
kills the cell. It is quite clear that a toxin can only kill a
tissue by entering into chemical combination with some
component of its structure. Tetanus toxin attacks the
nervous system. When an animal has died of tetanus the
toxin can be recovered from every tissue except nervous
tissue. It has combined with the nervous tissue to form a
permanent compound. According to Ehrhch, when a
non-lethal dose of toxin is administered, the tissue which
is susceptible to that toxin is stimulated to produce the
corresponding receptor in great numbers and to cast them
off into the body-fluids. The result is that when a second
dose of toxin is given, the molecules combine with the free
receptors and the cell protoplasm is unaffected (Fig. 71).

374 DEFENCE

When a toxin is heated to 60° it loses its toxic power
but still retains the capacity to form an antitoxin when
injected. Thus modified it is known as a toxoid. It is
therefore beheved that a toxin contains two molecular
groups, one the haptophore which unites with the receptor
of the protoplasm, the other the toxophore group which
can only exert its action when the haptophore group is
hnked to the cell. In the toxoid the toxophore group only

Fig. 71.

is destroyed, the haptophore group being still capable of
stimulating the production and hberation of receptors
(Fig. 72).

From the fact that the capacity to induce the formation
of neutrahsing substances is found in such widely differing
substances as benzoic acid and bacterial toxins, it is not
surprising to find this property widely possessed by many
other classes of substances. Any substance which has this
property is called an antigen, and the substance produced
in the body, an antibody. Any foreign protein, for instance,

ANTIBODIES

375

when injected into the blood causes the appearance in the
blood of a substance known as a precipitin, which precipi-
tates that protein. This reaction is highly specific. When
the serum of an animal of species A is injected into an animal
of species B, the latter develops a precipitin for the serum
of species A only. Upon this fact is based an important
medico-legal test for human blood. There are also agglu-
tinins which cause a clumping together of bacteria. Further,
when foreign cells are introduced there are developed anti-

T0XOPHOR.E GROUP

HrtPTOPHORJi GROUP

RECEPTOR.

PRDTOFL/iSMlC
MOLECULE .

Fig. 72.

bodies — cytolysins — which destroy those cells. The most
important of these are the hsemolysins which are produced
on the injection of foreign red blood corpuscles. The
mechanism in this case is rather comphcated. Let us take
a specific example.

The red blood corpuscles of the rabbit added to the normal
serum of the goat are hsemolysed, but if the serum has
been previously heated to 60° ha3molysis does not occur.
If, however, the red blood corpuscles of the rabbit be added
to the heated serum of the goat together with normal
(unheated) rabbit's serum, haemolysis results. Ehrhch be-
lieves, therefore, that there are two substances responsible,

376

DEFENCE

COMPLEMENT

AMBOCEPTOR

to which he has given the names amboceptor and comple-
ment. The amboceptor (immune or intermediate body)
is a specific substance not destroyed by heat. The comple-
ment (or alexin) is a specific substance destroyed by heat.
It is present in nearly all sera. It is the complement which
has the hsemolytic action. The amboceptor has two afiuii-
ties, one for the red blood corpuscle, the other for the
complement. The complement combines with the proto-
plasm only through the ambo-
ceptor. This is shown graphically
in Fig. 73. It will be seen that
in a sense complement corre-
sponds to the toxophore and
amboceptor to the haptophore
group.

When an emulsion of dead
bacteria is introduced into the
body antibodies are formed which
protect against any Hving bacteria
of the same kind which may
gain entrance later. This is the
basis of vaccine treatment. But
the immunity thus conferred is
not always entirely due to the
formation of antibodies. Another
class of substances is developed.
These are the Opsonins, the
action of which is to stimulate the leucocytes to devour
the bacteria.

To conclude this brief account of the reaction of the
body to the invasion by foreign substances, we may
mention a reaction of a different kind — Anaphylaxis. If
5 c.c. of egg-albumen be injected into a guinea pig, no
ill effects follow, but on giving a second dose the animal
becomes violently ill and usually dies within a minute or
two. This curious reaction has the following character-
istics : (1) The first dose may be very minute, as httle

CELL

Fig. 73.

ANAPHYLAXIS 377

as -^^1^^^ c.c, being sufficient; (2) exactly the same
protein must be given on the two occasions ; (3) a certain
interval (two or three weeks) must elapse between the
two injections. If the protein be given daily, anaphylaxis
does not occur. (4) If the animal, as sometimes happen,
does not die it may have recovered completely within ten
minutes of the second injection ; (5) the mode of death
varies in different animals. Guinea pigs and rabbits
experience extreme respiratory distress; dogs undergo a
violent diarrhoea, with the passage of blood per rectum, a
condition resembling cholera. No satisfactory theory has
as yet been advanced to explain the nature of anaphylaxis
or to show its relationship to immunity.

From what has been said it will be seen how compUcated
is the mechanism by which the body protects itself from
bacteria and their chemical products. For further details
the reader is referred to works on Pathology and Immunity.
The subject is introduced here only to show in a general
way how the body adapts itself to its environment.

INDEX

Abscess, 371

Absorption, nature of, 141
Accessory food factors, 211
Accommodation, 293
Acetone bodies, 192
Achroodextrin, 182
Acidosis, 20
Acromegaly, 244
Addison's disease, 240
Adenase, 173
Adenine, 169
Adenoids, 16
Adrenalin :

action of, 240

constitution of, 239
Adrian's experiment, 261
Agglutinins, 375
Agraphia, 314
Alanine, 159, 168
Albumose, 162
Alcaptonuria, 156
Alkaline reserve, 20
AUantoine, 175
AU-or-none principle :

in muscle, 39

in nerve, 261
Alveolar air, 105
Amboceptor, 374
Amino-acids, 158

estimation of, in blood, 164

fate of, 165

intercon version of, 167
Ammonia, excretion of, 167
Ammonium carbamate, 166
Ammonium carbonate, 166
Amoeboid movement, 32
Amylase, 135, 183

Anabolism, 1
. Anacrotic pulse, 77
Anaphylaxis, 164, 376
Anrestrum, 351
Antibodies, 374
Antidromic impulses, 87
Antigen, 374

Anti-neuritic substance, 212
Anti-peristalsis, 144
Anti-scorbutic, 212
Anti-thrombin, 25
Antitoxin, 373
Aortic valve, 58
Aphasia, 313
Aqueous humour, 289
Arginine, 160, 167
Argyll-Kobertson pupil, 292
Artificial kidney, 163
Aspartic acid, 159
Assimilation, 1
Assimilation-limit, 185
Astasia, 324
Asthenia, 324
Asthma, 114
Astigmatism, 293
Atonia, 324

Audito -psychic area, 307
Audito -sensory area, 307
Auditory nerve, connections of,

305
Auerbach's plexus, 140
Auricular canal, 52
Auriculo-ventricular node, 53

,, ,, bundle, 53

Autonomic system, 327
Axon, 252
Axon-reflex, 87, 256

379

380

INDEX

Barcroft's experiment, 108
Basilar membrane, 303
Basophile cells, 15
Bell's Law, 86, 273
Beriberi, 212
Bidder's ganglion, 49
Bile, 136

antiseptic action of, 137

secretion of, 138
Bile-pigments, 137
Bile-salts, 136
Bilirubin, 137
Biliverdin, 137
Binocular vision, 298
Bladder, 226
Blastocyst stage, 300
Blood, 1 1 et seq.

coagulation of, 23

reaction of, 17

specific gravity of, 17

total volume of, 20
Blood-dust, 197
Blood-platelets, 16
Blood-pressure :

measurement of, 77

regulation of, 80
Blood-vessels :

chemical control of, 91

nervous control of, 84
Boilermaker's disease, 305
Bowman's capsule, 216
Brown -Sequard paralysis, 280
Buffer action, 18
Bundle of Helweg, 270
Bundle of His, 53
Bundle of Monakow, 269
Butter, 202

Cadaverine, 143
Caffeine, 170
Calcium, 24
Calorie, 148
Calorimeter :

Benedict's, 147

bomb, 149
Calorimetry, 147
Cane sugar, 181
Capillaries, circulation in, 92
Capillary electrometer, 44

Capillary pressure, 79

Carbohydrates, ISl et seq.

amount of, in diet, 207

digestion of, 182

formation of, from fats, 191

formation of, from proteins, 190

metabolism of, 183

storage of, 184
Carbon balance, 206
Carbonic acid :

excretion of, 109

transport of, 102
Carbon Monoxide Method :

(absorption of oxygen), 107

(volume of blood), 21
Carboxyhsemoglobin, 13
Cardiac cycle, 57
,, reflexes, 71
,, sphincter, 125
Cardiometer, 66
Caseinogen, 367
Catabolism, 1
Catacrotic pulse, 77
Catalase, 204
Catalysts, 6
Cellulose, 182
Cerebellum, 323
Cerebral cortex, 309
Cerebrosides, 194, 196
Cerebrospinal fluid, 30
Cerebrum, functions of, 314
Chauveau's hsemadromograph, 75
Chemiotaxis, 369
ChejTie-Stokes respiration, 117
Chittenden's experiment, 209
Choline, 19G

Chorda tympani nerve, 85
Chorion, 361
Choroid, 287
Chromaffin cells, 238
Chromatic aberration, 295
Chromatolysis, 253
Chyle, 28
Ciliary glands, 287

muscles, 287

processes, 287
Clarke's column, 271
Climacteric, 351
Coarsely-granular cells, 1 5

INDEX

381

Cochlea, 303
Colour vision, 296
Column of Burdach, 270

of Goll, 270
Complement, 376
Complemental air, 115
Cones, functions of, 296
Conjugate deviation, 291
Conjugated proteins, 161
Constant current, 40
Contractility, 32 et seq.
Contraction :

chemical changes in, 41

efficiency of, 48

electrical changes in, 42

nature of, 46

thermal effects of, 45
Convoluted tubules, 216
Cornea, 287
Corpus luteum, 356

„ striatum, 326
Cowper's glands, 349
Cranial autonomic, 332
Creatine, 177
Creatinine, 177
Cretinism, 234
Curare, 37
Current of action, 44

„ rest, 43
Cushny's theory, 223
Cystine, 159, 179
Cytolysins, 375
Cytosine, 171

Decerebrate rigidity, 316
Decidual cells, 359
Defaecation, 144
Defence, 368
Deficiency diseases, 211
Deglutition, 124
Dendrons, 252
Depressor effect, 89
,, nerve, 72
„ reflexes, 90
Desaturation of fats, 200
Dextrose, 181 ,
Diabetes :

adrenalin, 186

human, 189

Diabetes (contd.) :

metabolic changes in, 192

neurogenic, 185

pancreatic, 186

phloridzin, 189
Diabetic centre, 185

„ puncture, 185
Diaphragm, action of, 110
Diastolic pressure, 78
Dicrotic notch, 76
,, wave, 76
Diet, 206
Diffraction, 295
Digestion, 120
Digitalis, 226
Dilator pupillse, 288
Dilution diuresis, 226
Disaccharides, 181
Discrimination, 283
D : N ratio, 190
Distance, perception of, 297
Diphasic variation, 44
Diuretics, 225
Division of cells, 344
„ „ labour, 2
Dystrophia adiposogenitalis, 244

Ear, structure of, 300

„ mechanism of, 304
Eck fistula, 167, 176
Edridge-Green's hypothesis, 297
Electrocardiograph, 60
Electrotonus, 260
Endogenous metabolism, 106
Endolymph, 303
Endothelial cells, 371
Energy, expenditure of, 147
Enterokinase, 134, 138
Enzymes, 6 et seq.
Eosinophile cells, 15
Epididymis, 346
Erepsin, 138
Ergotoxine, 86
Erythrodextrin, 182
Euglobulin, 11
Eustachian tube, 300
Ewald's experiment, 321
Exogenous metabolism, 165
Exophthalmic goitre, 234

382

INDEX

Extensor thrust, 272
Exteroceptive system, 281
Eye, structure of, 286
Eyeballs, movements of, 291

Fat, 194 et seq.

absorption of, 197

formation of, from carbohydrate,
200

formation of, from protein, 201

iodine -number of, 195

liver, 199

melting-point of, 195

nature of, 194

oxidation of, 202

saponification of, 195

tissue, 199
Fat depots, 198
Fat requirements, 207
Fat-soluble A, 212
Fatigue, 338

of reflex, 274
Fatty degeneration, 201
Fatty infiltration, ] 99
Fenestra ovalis, 300

„ rotunda, 300
Fertilisation, 359
Fever, 251
Fibrin, 23
Fibrinogen, 11, 24
Fibroblasts, 371
Fillet, lateral, 300

„ median, 270
Final Common Path, 278
Flechsig's method, 267
Flexion reflex, 272
Fcetal circulation, 304
Fovea centralis, 291
Fructose, 181

Galactolipines, 19G
Galactose, 181
Gall-bladder, 136
Gaskell's experiments, 49
Gastric juice, 127, 129

„ lipase, 129

,, secretion, 129
Gigantism, 244
Gliadin, 211
Glomeruli, 216

Glucosamine, 190

Gluscose, 181 et seq.

breakdown of, 193

excretion of, 183

formation of, 190

in blood, 183
Glutamic acid, 159 .
Glycerine, 194
Glycine, 158, 168
Glycogen, 184, 190
Glycosuria, 183

alimentary, 185
Glyoxylases, 191
Goltz's dog, 315
Gout, 176

Graafian follicle, 353
Grey rami, 332
Growth, 210
Guanase, 173
Guanidine, 236
Guanine, 169

Hajmatocrit, 17

Hemoglobin, 13, 98

HcTmoglobinometer, 17

Haemolymph glands, 31

Hsemolysins, 375

Haemorrhage, 23

Hair-cells of cochlea, 304

Haldane's method :

for analysing alveolar air, 105
for estimating blood- volume, 21
for investigating oxygen ab-
sorption, 107

Haptophore, 374

Head's experiment, 284

Hearing, 300 et seq.
cortical centre for, 306

Heart :

action of sympathetic on, 71

,, of vagus on, 71
adaptation of, 64 et seq.
efferent nerves of, 71
electrical changes in, 60
influence of higher centres on, 72
junctional tissues^of, 53
output of, 62
volume of, 66
work of, 62

INDEX

383

Heart-beat :

conduction of, 50

myogenic theory of, 50

nature of, 49 et seq.

origin of, 50
Heart-block, 56
Heart-lung preparation, 64
Heart-muscle, 34
Heart-sounds, 60
Heat, loss of, 249

,, production of, 249
Helmholtz's theory of hearing, 305
Bering's hypothesis, 297
Herpes zoster, 257
Hexoses, 181
High altitudes, 23
Hippuric acid, 168
Histamine, 93, 94, 143
Histidine, 160
Homogentisic acid, 156
Hormones, 229
Hunger, 335
Hyaline cells, 15
Hydrochloric acid, action of, 133
Hydrogen ion concentration, 17

determination of, 20
Hyperglycemia, 183
Hypermetropia, 293
Hypoxanthine, 170, 174

Ileo-csccal valve, 144

Immunity, 368

Incisura angularis, 127

Incus, 302

Indican, 181

Indol, 143, 180

Indoxyl-sulphuric acid, 180

Inflammation, 370

Inhibition, reflex, 276

Inosite, 35

Intercostal muscles, action of, 111

Intracardiac pressure, 57

Interference, 279

Intermediate bodies, 223

Internal secretion :

definition of, 229

general features of, 246

interaction of, 246

investigation of, 230

Intestinal juice, 138

Inulin, 182

Invertase, 138, 183

Iris, 287

Islets of Langerhans, 134, 189

Iso-leucine, 159

Isometric contraction, 40

Isotonic contraction, 40

Jaeksonian epilepsy, 310
Jelly-fish, nervous system of, 265
Jugular pulse, 59
Junctional tubules, 217

Karyokinesis, 344
Kidney :

Blood supply of, 217

functions of, 215

mechanism of, 219

nerve supply of, 217

oxygen-consumption of, 220

structure of, 216
Knee-jerk, 274
Knoop's experiment, 202
Krause's membrane, 35
Krogh and Lindhard's method

(alveolar air), 105
Krogh's method (output of heart),

64
Kiihne's experiment, 255

Labour, 316
Labyrinth, 303, 318
Lactalbumin, 367
Lactase, 138, 183
Lactation, 365
Lacteals, 27
Lactoglobulin, 367
Lactose, 181
La;vulose, 181
Langley's law, 328
Large intestine, 142

bacterial decomposition in, 143

movements of, 144
Larynx, structure of, 311
Law of the heart, 70
Lecithin, 196
Lens, 288
Leucine, 159

384

INDEX

Leucocytes :

classification of, 15

enumeration of, 17

functions of, 16

number of, 14

origin of, 15
Leucocythsemia, 175
Linolenic series, 195
Lipase, 135
Lipoids, 194, 196
Lung, expansion of, 113

ventilation of, 110
Lutein, 356
Lymph, 26
Lymph capillaries, 26
Lymphatics, 26
Lymphatic glands, 16, 27

„ system, 26

Lymphocytes, 15
Lymphoid tissue, 16
Lysine, 159

Macrophages, 371

Maintenance, 210

Malleus, 302

Malpighian corpuscles, 16

Maltase, 135, 138, 183

Maltose, 181

Mammary gland, 365

Marchi's method, 267

Marey's law, 72, 82

Mass reflex, 280

Mast cells, 15

Maturation, 355

Mean arterial pressure, 79

Medulla, 326

Membrana tectoria, 304

Membrane of Reissner, 303

Menopause, 351

Menstrual cycle, 352

Metabolism, 146 et seq.
„ basal, 154

„ standard, 154

Meta-proteins, 161

Methajmoglobin, 13

Methyl-glyoxal, 191

Metoestrum, 351

Microphages, 371

Microtonometer, Krogh's, 106

Micturition, 226
Milk, 366

coagulation of, 129
Mitosis, 344
Mitral valve, 58
Modiolus, 303
Mononuclear cells, 15
Mononucleotide, 171
Monosaccharides, 181
Mliller's law, 282
Murmurs, 60
Muscle :

composition of, 54

contraction of, 37 el xeq.

degeneration of, 255

irritability of, 37

latent period of, 38

structure of, 35
Muscle-spindles, 318
Muscular activity, 336
Myohsematin, 34
Myopia, 293
Myosinogen, 34
Myxoedema, 234

Narcotics, 260

Negative ventilation, 118

Nerve -fibres :

action of drugs on, 260

activity of, 258

cliaracteristic of, 257

degeneration of, 254

excitability of, 257

refractor}^ period of, 259

regeneration of, 254

summation in, 260

supernormal phase in, 259
Nervi erigentes, 350
Nervous impulse :

changes accompanying, 260

nature of, 260

reversibility of, 255

velocity of, 255
Nervous svstem :

diffuse, 265

evolution of, 264

synaptic, 266

tracts of, 267
Neuromuscular junction, 263

INDEX

385

Neurone, 252

Nissl bodies, 253

Nitrogen balance, 208

No -threshold bodies, 223

Nucleases, 173

Nucleic acid, ll\ et seq.

Nucleosides, 171

Nucleus cuheatus, 270
,, gracilis, 270
„ of Bechterew, 321
,, of Deiters, 321

Nucleus, red, 326

Nussbauni's experiment, 222

Nutrition, 206 et seq.

Nystagmus, 325

(Edema, 29

(Esophagus, 124

CEstrous cycle, 351

Oils, 194

Oleic acid, 194

Olfactory nerves, 307

Olive, 326

Oncometer, 83

Opsonins, 376

Optic nerve, connections of, 298

Optic thalamus, 270, 326

Organ of Corti, 304

Ornithine, 167

Ossicles, 302

Otoliths, 319

Ovary :

internal secretion of, 357

structure of, 353
Ovulation, 353
Oxidation-process, 203
Oxygen :

passage of, into blood, 103

passage of, into tissues, 109

tension of, 104, 106

transport of, 98
Oxygenase, 205
Oxyhsemoglobin, 13

dissociation of, 99
Oxyntic cells, 126
Oxyproline, 161

Pacemaker of heart, 51, 55
Pain, 283, 335
25

Palmitic acid, 194
Pancreas, 134
Pancreatic juice, 134

secretion of, 135
Parabiosis, 187
Paramyosinogen, 314
Parathyroids :

deficiency of, 235

development of, 233

functions of, 236

structure of, 233
Parturition, 363
Pavlov's experiment, 123, 128
Pendular movement, 140
Penis, 350
Pepsin, 129
Peptones, 162
Perilymph, 303
Peripheral resistance, 83
Peristaltic waves :

of small intestine, 140

of stomach, 130
Peroxidases, 204
Peroxides, 203
Peyer's patches, 16
Ph, 18

Phagocytes, 16
Phenaceturic acid, 202
Phenyl alanine, 160
Phenyl sulphuric acid, 180
Phosphatides, 194, 196
Phospholipines, 196
Pineal gland, 245
Piper's manometer, 57
Pituitary :

development of, 242
disorders of, 244
functions of, 243
removal of, 245
structure of, 241
Placenta, 362
Plasma, 11
Plasma cells, 371
Plethysmograph, 83
Polymorphonuclear cells, 15, 371
Polyneuritis, 212
Polypeptides, 162
Polysaccharides, 182
Pons, 326

386

INDEX

Positive ventilation, 118
Posterior root fibres, connecti(»ns

of, 273
Post-ganglionic fibres, 328
Preciptins, 375
Pre-ganglionic fibres, 328
Pressor effect, 89

,, substances, 91
Primitive vertebrate heart, 52
Proline, 161
Pro-cestrum, 351
Proprioceptive system, 318
Prosecretin, 136
Prostate, 349
Protective synthesis, 372
Proteins :

absorption of, 162

amount required in diet, 208

classification of, 161

hydrolysis of, 161

nature of, 157
Protein-sparing action, 208
Proteoses, 162

Pseudoaffective reflexes, 285
Pseudoglobulin, 11
Pseudo -pregnancy, 351
Psychical processes, location of,

314
Psychical secretion, 123, 128
Ptomaines, 143
Ptyalin, 123, 183
Puberty, 351

Pulmonary circulation, 95
Pulse, 76

tension of, 79

volume of, 79
Pulse -pressure, 79
Pupil, 292
Purines, 169 et seq.

origin of, 1 72

synthesis of, 172
Purkinje fibres, 53
Putrescine, 143
Pyloric sphincter, 131
Pyrexia, 251
Pyrimidine bases, 170
Pyruvic acid, 168

Reciprocal innervation, 89, 276

Red fibres, 36

Red blood corpuscles, 11 et seq.

composition of, 12

enumeration of, 17

haemolysis of, 12, 375

life history of, 14
Red nucleus, 326
Referred pain, 335
Reflex action, 272
Refraction, errors of, 293
Refractory period :

of muscle, 41

of nerve, 259

of the reflex, 274
Reinforcement, 279
Remak's ganglion, 49
Rennin, 129
Reproduction, 342
Residual air, 115
Respiration, 97 et seq.

action of vagus on, 117

regulation of, 115
Respiratory centre, 19

exchange, 150

quotient, 150
Retina :

physiology of, 296

structure of, 289
Retrograde degeneration, 268
Rhodopsin, 296
Rhythmic segmentation, 139
Rickets, 212

Right lymphatic duct, 27
Rigor mortis, 35
Rods, functions of, 296
Rods of Corti, 304
Rush-peristalsis, 141

Saccule, 319
Sacral autonomic, 332
Saliva, 123
Saponification, 195
Sarcolactic acid, 34
Sarcolemma, 35
Sarcomere, 35
Sarcoplasm, 32, 36
Sarcostyles, 32, 36
Saturated fatty acids, 194
Scala media, 303

INDEX

387

Scala tympani, 303

,, vestibuli, 303
Scatol, 143, 180
Sclerotic, 286
Scratch reflex, 272
Scurvy, 212
Secretin, 136
Secretion, nature of, 120
Secretory fibres, 122
Semen, ejaculation of, 350
Semicircular canals, 319
Seminal vesicles, 348
Sensation :

cutaneous, 282

deep, 284

epicritic, 284

interoceptive, 334

paths of, 285

protopathic, 284

visceral, 334
Septo-marginal bundle, 270
Serine, 159
Serum, 23
Serum albumin, 11
Serum globulin, 1 1
Shape, perception of, 297
Shock, 93

Sino-auricular canal, 53
Sino-auricular node, 53
Sinus, 52

Sinus arrhythmia, 72
Size, perception of, 297
Soap, 195

Sodium sulphindigotate, 221
Sorensen's method :

(amino-acids in blood), 164

(H-ion concentration), 18
Small intestine, 134

absorption from, 141

movements of, 139
Smell, 307

Specific dynamic energy, 153
Specific irritability, law of, 282
Speech, 311, 312

Broca's area of, 313

Marie's theory of, 313
Spermatozoa :

formation of, 346

structure of, 348

Spherical aberration, 295
Sphincter pupillse, 288
Sphincters of anus, 145

of bladder, 226
Sphygmograph, 76
Sphj'gmomanometer, Riva-Rocci,

78
Spinal cord :

functions of, 279
lesions of, 28®
Spiral ganglion, 305
Spiral lamina, 303
Spleen, 30

Stannius's ligature, 49
Stapes, 302
Starch, 182
Starvation, 208
Stearic acid, 194
Stercobilin, 137
Stereoscopic vision, 298
Sterols, 194

Stokes-Adams' disease, 56
Stomach, 126 el seq.

absorption from, 132

digestion in, 132

movements of, 130
Striated muscle, 32
String galvanometer, 44
Successive degeneration, 267
Successive double sign, reflex of,

278
Succus entericus, 138
Sulphates, ethereal, excretion of,

180
Sulphur :

metabolism of, 179

neutral, 180
Summation :

in muscle, 39

in nerve, 260
Supernormal phase, 259
Supplemental air, 115
Suprarenal glands :

boundary zone of, 240

cortex of, 239

development of, 238

disease of, 240

lipoids and, 239

medulla of, 239

388

INDEX

Suprarenal glands (contd) ;

morphology of, 238

removal of, 240

structure of, 236
Sweat, 249

Swim-bladder of fish, 105
Symbiosis, 369
Sympathetic system, 330
Synapse, nature of, 276
Systemic circulation, 74
Systolic pressure, 78

Taste, 308
Taurine, 179
Temperature :

regulation of, 248

sensation of, 283
Tendon reflexes, 274
Tensor tympani muscle, 302
Tension, development of, 40
Testis, internal secretion of, 349
Tetania parathyropriva, 235
Tetanus, 39
Tetranucleotide, 171
Thalamic over-reaction, 286
Theobromine, 170
Theophylline, 170
Thermopile, 45
Thoracic duct, 27
Threshold bodies, 223
Thrombin, 24
Thrombogen, 24
Thrombokinase, 25
Thymine, 171
Thymus, 16
Thyroid :

administration of, 235

deficiency of, 234

development of, 232

excess of, 234

function of, 236

structure of, 230
Thyroxin, 232
Tidal air, 114
Tonsils, 16
Tonus, 33
Touch, 283
Toxins, 371
Toxoids, 374

Tracts :

ascendmg, 270

comma, 270

crossed pyramidal, 269

descending, 268

direct cerebellar, 271

direct pyramidal, 269

indirect cerebellar, 271

of Flechsig, 271

of Gowers, 271

olivo-spinal, 269

prepyramidal, 269

rubrospinal, 269

spino-tectal, 271

spino -thalamic, 271

tecto-sjDinal, 269

vestibulo -spinal, 270
Transport system, 2
Transverse band, 127
Triglycerides, 194
Trophic fibres, 122
Trophoblast, 361
Trypsin, 134
Trypsinogen, 134
Tryptophane, 160, 180
Tubules, 221
Tympanum, 302
Tyrosme, 160

Unsaturated fatty acids, 194
Unstriated muscle, 32
Uracil, 171
Urea, 166
Ureter :

flow along, 226

obstruction of, 220, 222
Uricase, 175
Uric acid, 170, 172

endogenous, 172

exogenous, 174
Uricolytic ferment, 178
Urine, 214

excretion of, 226

formation of, 216
Urobilin, 137, 214
Utricle, 319

Vagus nerve, 332
Valine, 159

INDEX

389

Van Slyke's method (alkaline re-
serve), 20

Vas deferens, 346

Vaso -dilator nerves, 85

Vasomotor centre, 84
,, reflexes, 88

Veins, circulation in, 94

Venous pressure, 79

Venous pulse, 59

Vestibular nerve, connections of,
321

Vision, 286

Visual purple, 296

Visuo -psychic area, 300

Visuo -sensory area, 300

Vital capacity, 115

Vital-red method, 22

Vit amines, 211

Vitreous humour, 289

Vividiffusion, 163

Voluntary contraction, 40

Vomiting, 133

Von Frey's hairs, 283
Von Kriess's method, 80

Wallerian degeneration, 254, 267
Water soluble B, 212
Waxes, 194
Weber's law, 282
White muscle-fibres, 36
White rami, 328
Word- blindness, 314
„ -deafness, 314

Xanthine, 170
Xanthoxidase, 173

Yellow spot, 291
Young's hypothesis, 296

Zein, 210

Zuntz's method, output of heart,
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