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HUMAN PHYSIOLOGY

MACMILLAN AND CO., LIMITED

LONDON BOMBAY CALCUTTA
MELBOURNE

THE MACMILLAN COMPANY

NEW YORK BOSTON CHICAGO
DALLAS SAN FRANCISCO

THE MACMILLAN CO. OF CANADA, LTD.

TORONTO

HUMAN
PHYSIOLOGY

v

BY

PROFESSOR LUIGI LUCIANI

DIRECTOR OF THE PHYSIOLOGICAL INSTITUTE OF THE ROYAL UNIVERSITY OF ROME

TRANSLATED BY

FRANCES A. WELBY

EDITED BY

DE. M. CAMIS

INSTITUTE OF I'll YsIoLui IY, UNIVERSITY OF PISA

WITH A PREFACE BY

J. N. LANGLEY, F.R.S.

PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF CAMBRIDGE

IN FOUR VOLUMES

VOL. II. INTERNAL SECRETION DIGESTION-
EXCRETION THE SKIN

MACMILLAN AND CO., LIMITED
ST. MARTIN'S STREET, LONDON

1913

COPYRIGHT

CONTENTS

CHAPTER I

PAOE

INTERNAL PROTECTIVE SECRETIONS ..... 1

1. Theory of glandular organs and secretory processes. Historical
development (Malpighi, Ruysch, Haller, J. Miiller). 2. Glands with
no excretory ducts ; their importance as organs of internal secretion.

3. Structure and mode of secretion of thyroid and parathyroid glands.

4. Cachcxia thyreopriva after total thyroidectomy in man : analogy with
spontaneous myxoedema and cretinism. 5. " Tetania thyreopriva"
in man. 6. Varying effects of thyroidectomy in various animals.
7. Criticism of hypotheses put forward to explain effects of thyroid-
ectomy. 8. Experimental basis for theory of auto-intoxication resulting
from functional deficiency of thyroids. 9. Thyroid grafts : injection of
thyroid juice and thyroid feeding in therapeutic treatment of cachexia
thyreopriva. 10. Theory of specific functional independence of thyroid
and parathyroids. 11. Specific protective function of pituitary gland
(glandular portion of hypophysis). 12. Structure of suprarenal bodies
(adrenals) and paraganglia. 13. Clinical observations and physio-
logical experiments on protective function of the suprarenal bodies.
14. Double function of medullary (or paragangliar) and cortical part
of suprareuals. 15. Experimental injection of suprarenal extract.
16. Active principles of suprarenal and paragangliar system (adrenaline,
paragangline). Physiological action. Bibliography.

CHAPTER II

EXTERNAL DIGESTIVE SECRETIONS ... .67

1. Structure of salivary glands : cranial and sympathetic inner-
vation. 2. Nervous mechanism of secretion in salivary glands.
3. Cytological changes in secretory epithelium during rest and secre-
tion. 4. Selective activity of salivary glands. 5. Chemical analysis of
salivary glands and the various kinds of saliva. 6. Structure of
pancreas. 7. Innervation and mechanism of its secretion. ' 8. Pan-
creatic juice. 9. Internal function of the pancreas. 10. Factors
concerned in internal pancreatic secretion. 11. Structure of gastric
mucosa and glands. 12. Innervation. 13. Gastric juice and the cells
which secrete it. 14. Zymogens which give rise to the gastric enzymes.

v

vi PHYSIOLOGY

PAGE

15. Intestinal glands. 16. Succus entericus. 17. Mechanism of
intestinal sucretion. 18. Structure of the liver. 19. Secretion of bile
in digestion and fasting. '20. Influence on secretion of changes in
hepatic circulation. 21. .Chemical constituents of bile. 22. Origin
and metabolic activity of hepatic cells. Bibliography.

CHAPTER III

MECHANICS AND CHEMISTRY OF DIGESTION IN THE MOUTH AND

STOMACH ....... 152

1. Historical. 2. Mastication, insalivation, formation of alimentary
bolus, and saccharilication of starch. 3. Mechanism of deglutition.
4. Imiervation. 5. Artificial digestion in vitro to determine action of
gastric juice on different food-stuffs. 6. Influence of spleen on gastric
digestion. 7. Natural digestion in the stomach. 8. Eil'ects of total
gastrotomy. 9. Active movements of stomach in gastric digestion.
10. Mechanism of vomiting. 11. Peripheral and central imiervation
of stomach. Bibliography.

CHAPTER IV

MECHANICS AND CHEMISTRY OF DIGESTION IN THE INTESTINE . 207

1. Artificial digestion with the three intestinal secretions : pan-
creatic juice, bile, succus entericus. 2. Mechanism of bile-excretion
in the intestine, and imiervation of muscles of common bile-duct.
3. Natural digestion of chyme in small intestine. 4. Putrefactive
processes in the intestine. 5. Effects of extensive resection of small
intestine in animals and man. 6. Peristaltic movements of intestine.

7. Central and peripheral imiervation. 8. Post-mortem auto-digestion.
Why it does not occur during life. Bibliography.

CHAPTER V

INTERNAL RESTITUTIVE SECRETIONS . . . 263

1. Gastric absorption. 2. Intestinal absorption. 3. Fate of the
different groups of food-stulfs after absorption. 4. Importance of
living epithelium to absorption of crystalloid substances (salts and
sugars). 5. Absorption of neutral fats in form of soaps ; synthetic
regeneration by epithelium of intestine. 6. Absorption of proteins,
proteoses, " and peptone ; synthetic regeneration. 7. Mechanism of
internal secretion of absorbed and regenerated compensation-products.

8. Formation of glycogen (amylogenesis) and glucose (glycogenesis) by
hepatic cells. 9. Hepatic glycogenesis an internal secretion ; regula-
tion by nervous system. 10. Derivation of hepatic and muscular

CONTENTS vii

PAGE

glycogen from carbohydrate i' food. 11. Derivation of glycogen
from decomposition of proteins and fats (diabetes mellitus from patho-
logical causes, experimental diabetes from phloridzin and removal of
pancreas). 12. Accumulation of alimentary fat ; adipogeuesis. 13. Ac-
cumulation and consumption of alimentary protein. 14. Protective
function of intestinal epithelium and liver. Bibliography.

CHAPTER VI

THE INTESTINE AS AN ORGAN OF EXCRETION . 343

1. Physical characters and chemical composition of faeces and
intestinal gases. 2. Alimentary residues and waste products in faeces,
while taking food and in fasting. 3. Formation of faecal masses a
function almost exclusively confined to small intestine. 4. Theory of
normal human faeces. 5. Toxicity of faeces. 6. Mechanical and
chemical functions of caecum. 7. Mechanism of defaecation. 8. Inner-
vation. Bibliography.

CHAPTER VII

ORIGIN OF KATABOLIC CONSTITUENTS OF URINE . . .377

1. General characteristics and composition of human urine. 2. Forma-
tion of urea. 3. Formation of uric acid and the purine bodies.
4. Formation of creatine and creatinine. 5. Formation of hippuric
acid and aromatic substances (ethereal sulphates). 6. Formation of
pigments and chromogens (urochrome, urobilin, uroerythrin, indican).
7. Formation of non-nitrogenous organic acids (oxalic acids, lactic
acids, volatile fatty acids). 8. Carbohydrates of normal and patho-
logical urine, (glucose, lactose, animal gum, acetone, glycuronic acid).
9. Proteins of normal and pathological urine (serum-albumin, serum-
globulin, h'brinogen, enzymes). 10. Inorganic constituents of urine
(chlorides, sulphates, alkaline and earthy phosphates, carbonates,
ammonium compounds). 11. Toxicity of urine, and uraemia. Biblio-
graphy.

CHAPTER VIII

THE EXCRETION OF URINE . 418

1. Structure of the kidneys. 2. Mechanism of urinary secretion.
Vitalist theory of Bowman ; mechanical theory of Ludwig. 3. Modi-
fication of urinary secretion with variations of normal conditions of circu-
lation in kidneys ; conclusions as to functions of glomeruli. 4. Effect
on renal secretion of alterations caused in the blood by diuretics ;
criticisms of mechanical theory. 5. Experimental data in favour of
vitalist theory ; criticisms. 6. Innervation of kidneys. 7. Modifica-

viii PHYSIOLOGY

PAGE

tions of epithelial cells of renal tulmles during secretory activity and
functional rest. 8. Function of ureters. 9. Mechanism of retention of
urine. 10. Mechanism of micturition. 11. Innervation of bladder.
Bibliography.

CHAPTER IX

THE SKIN AND CUTANEOUS GLANDS . 480

1. Structure of the skin : continuous desquamation of the stratum
corneum. 2. Coiled sweat glands : sensible and insensible cutaneous
secretion. 3. Chemical substances excreted in perspiration. 4. Inner-
vation of sweat glands. 5. Sebaceous glands and specific formation of
sebum. 6. Mammary glands. 7. Chemical composition of milk. 8. In-
Huence of diet on the secretion of milk. Origin of secretory products.
9. Histological and chemical processes of milk formation. 10. Influence
of nervous system on the milk secretion. 11. Absorption by the skin.
Bibliography.

INDEX OF SUBJECTS . . 525

INDEX OF AUTHORS 539

EEEATA

VOL. I

Page 6, bottom line, for "quantitatively'' read "qualitatively."

, , 25, line 25, for "cornea" read "stratum corneum."

,, 35, line 3 from below, for "glycerin" read "glycerol."

., 109, line 27, for "carbon disulphide " read "ammonium sulphide."

,, 127, line 3 from below, for " Connstein " read "Cohnstein."

,, 157, heading 3 should precede "Question."

,, 173, fig. 48, last word, for "distend" read "collapse."

,, 219, bottom line, for "rises" read "falls."

,, 238 is mispaged 328.

,, 239, fig. 90, for " Mosso " read "Marey."

,, 333, line 7 from below, for "afferent" read "efferent."

,, 415, line 13, for " inspiratory " read "expiratory."

VOL. II

Page 28, line 1, and page 52, line 5 from below, for " Christian! " read " Cristiani."
,, 73, line 10 from below, for " haernodrometer " read "haemodromometer."
,, 210, line 6, for " Ch. " read "Cl. " (Bernard).

CHAPTEE I

INTERNAL PROTECTIVE SECRETIONS

CONTENTS. 1. Theory of glandular organs and secretory processes. Historical
development (Malpighi, Ruysch, Haller, J. Miiller). 2. Glands with no excretory
ducts ; their importance as organs of internal secretion. 3. Structure and mode
of secretion of thyroid and parathyroid glands. 4. Cachexia thyreopriva after
total thyroidectomy in man : analogy with spontaneous myxoedema and cretin-
ism. 5. " Tetania thyreopriva " in man. 6. Varying effects of thyroidectomy in
various animals. 7. Criticism of hypotheses put forward to explain effects of
thyroidectomy. 8. Experimental basis for theory of auto-intoxication resulting
from functional deficiency of thyroids. 9. Thyroid grafts : injection of thyroid
juice and thyroid feeding in therapeutic treatment of cachexia thyreopriva.

10. Theory of specific functional independence of thyroid and parathyroids.

11. Specific protective function of pituitary gland (glandular portion of hypo-
physis). 12. Structure of suprarenal bodies (adrenals) and paraganglia.
13. Clinical observations and physiological experiments on protective function of
the suprarenal bodies. 14. Double function of medullary (or paragangliar) and
cortical part of suprarenals. 15. Experimental injection of suprarenal extract.
16. Active principles of suprarenal and paragangliar system (adrenaline, para-
gangliue). Physiological action. Bibliography.

IN the last chapter (Vol. I. xiv.) we discussed the formation of
lymph through the walls of the blood capillaries, and the physiology
of the lymphoid tissues and organs (which continually pour out
new cells, as well as the chemical products of their anabolisrn and
katabolism, into the lymph and blood stream), and referred in
general terms to the physiological concept of the so-called secretory
processes. If secretion means every alteration by the tissue-cells
of the medium in which they live either by the removal from
it of all the materials required for their nutrition, or by the
return to it of all the products of their metabolism we should
obviously have to admit that every living cell, as such, exhibits
secretory activity (Brown-Sequard). But the concept of secretion
must be taken in a more restricted sense. The term secretory
is not applied to the cells which form the nervous and mus-
cular tissues, nor, speaking generally, to the active and passive
mechanisms of sensation and movement, while it is used of the
histological elements that participate actively in the production
and purification of the blood and lymph, particularly the epithelia
VOL. II 1 B

PHYSIOLOGY en A I-.

<if the tissues and glandular organs. This differentiation between
the two kinds of cells arises from the fact that while in the former
the exchange of materials with the medium (blood and lymph)
is the means, or condition, of the development of other forms of
energy, and is subservient to other special functions, in the latter,
which are known as <: secretory," this exchange is the specific
function hence it is more prominent, and assumes a distinctive
character.

From this point of view the physiological concept of secretion
is entirely independent of the morphological concept of the gland.
In so far as the cells of the lymphoid or adenoid tissues and
organs considered in the last chapter have a lymphapoietic and
haemapoietic function, they are true secretory tissues and organs,
though destitute of glandular structure proper. But they are
intercalated along the lymph- and blood-vessels, with which they
communicate directly, and into which they pour their cytological
and chemical products, while gland, in the widest sense, implies a
complex of secreting epithelial cells, which form the walls of cavities
that are quite distinct from the lymph- and blood-vessels, and in
which the secretion, i.e. the product of their secretory activity,
accumulates.

The physiological study of the adenoid tissues and glands is
thus logically succeeded by that of the glandular tissues and
organs proper.

I. Midway in the eighteenth century, Albrecht von Haller,
speaking of the functions of the glandular organs, observed :
tnulta in physiologia obscura ; obscurius hac ipsa functions nihil.
So long as the structure of the glandular organs was imperfectly
known, physiological theories as to the secretory processes were
necessarily vague and confused, and highly speculative in
character. To cite a classical example : the ancients long held
that the pituita, or nasal mucus, was a secretion of the brain,
that flowed through the lamina cribrosa of the ethmoid. The
error was only corrected in 1660, when Schneider described the
mucous membrane which bears his name.

At the same period the anatomy of the glands was more
closely studied by Glisson, Wharton, Wirsung, Stensen, Eivini,
Peyer, and Bruuuer. Malpighi (1665) was the first who
investigated their internal structure. He stated that all the
glandular ducts terminate in acini (grana glandulosa], which
receive their juices from the minute blood-vessels by which they
are surrounded, and that the juices collected within the acini were
then poured out through the excretory ducts.

Ruysch (1696) disputed this theory, and maintained, on the
strength of fallacious arguments derived from his celebrated
artificial injection of the glandular vessels, that the gland
substance proper is also composed of blood-vessels, and that the

i INTEENAL PEOTECTIVE SECEETIONS

finest terminal ramifications of these vessels (where no blood
corpuscles can penetrate) are in direct continuity with the origin
of the excretory ducts.

Haller (1757) decided the controversy between Malpighi and
Ruysch in favour of the latter, and tried tore-establish the ancient
doctrine, by which the arteries terminate in the form of open
mouths, either in the excretory ducts, or in the so-called cellular
tissue, in the lymphatic sinuses, the skin, etc. The argument on
which he founded this unfortunate theory (which contradicted
Malpighi's discovery of the capillary vessels as a completely closed
system uniting the arteries with the veins) was the passage of
injection masses, as performed by Kuysch, from the blood vascular
system into the excretory ducts of the glands, and the haemorrhages
simultaneously observed in the excretory canals. Haller's
doctrine, based on imperfect morphological data, held its own for
many years, until it was overthrown by the masterly monograph
of Johannes Miiller, De glandularum secernentium structura
penitiori (Lipsiae, 1830). M tiller's wide anatomical and embryo-
logical observations on the various secretory organs found in the
different classes of vertebrates, laid the foundations of modern
glandular morphology, and from this he deduced the physiological
concepts of his classical treatise. Its most characteristic points
are briefly as follows :

(a) Whatever differences of structure exist in the glands of
animals and man, they all obey the same laws, and present an
uninterrupted series from the simplest follicle to the most
complex gland.

(&) All glands present internally a large secreting surface,
obtained in an immense variety of forms. In all, however, the
surface extension is due to development of the excretory ducts in
the form of internal cavities or blind canals, as held by Malpighi.

(c) In all glands, the blood capillaries behave in respect to the
walls of the canals and extremities of the glands as to every other
thin secreting membrane. They do not open by orifices into the
secretory spaces or cavities, but form a close capillary network
round them, which unites the dendritic ramifications of the
arteries and veins, as held by Malpighi.

(d) Secretion is only a particular mode of the metamorphoses
which the blood undergoes in circulating through the organs.
The most complicated gland is but a large surface adapted to
the smallest possible space, through which transformation of the
blood takes place. Secretion does not occur only at the ex-
tremity of the glandular ducts, in the acini, supposed hypo-
thetically to exist in every gland. Acini, in the sense of closed
vesicles, are present only in a very small number of glands.
Secretion takes place throughout the length of the glandular
canals.

4 PHYSIOLOGY CHAP.

(e) The special characteristics and differences in the secretions
depend not on any external and mechanical change, nor upon
the anatomical form of the gland, but solely upon the specific
character of the living organic substance (epithelium) which
invests the internal secreting ducts. The difference in secretions
depends, therefore, upon the same cause which determines differ-
ences of conformation and of life of the organs in general : there
is but one difference, i.e. in the one case the altered blood is
incorporated with the organ, in the other it passes beyond its
limits, and appears externally to it, in the form of secretion.

(/) The chemical processes carried out in the secretory organs
are twofold. On the one hand, they serve the nutrition, develop-
ment, or formation of new cells ; on the other, the formation of a
heterologous product of secretion. The secreting cells differ
chemically from the product secreted, although they may contain
a small amount of the latter. Secretion cannot, therefore, be
explained as a simple liquefaction of the pre-existing molecules of
the secretory elements. We must assume that the products of
secretion are gradually perfected in what may be a long journey
through the canaliculi of the gland.

This conception of the general morphology and physiology, of
the secreting glands as formulated by Johannes Mu'ller still holds
good, and is a fitting introduction to the special study of the
functions of the individual organs and mechanisms of secretion.
Subsequent work has supplied a wealth of details, but all are in
harmony with the general doctrine of the great master, which
may be summed up in the statement that what fundamentally
underlies each secretory process is the specific physiological activity
of the living substance l)y which the secreting surfaces are invested.

After Schwanu had established the Cell Theory in 1839, and
it had been applied by Heule and Ivolliker to the physiology of
secretion, the idea of the living substance, as described by Johannes
Miiller in 1830, was more exactly conceived as the living epithelial
cells which clothe the internal cavities and the secreting surfaces.
Real knowledge of the intimate secretory processes of the gland
cells only became possible, however, after the progress of
histological technique enabled Heidenhain and his School to form
a morphological comparison between glands in the state of rest,
and those functioning actively.

A more palpable advance in regard to the specific nature of
the secreting cells resulted from the chemical analyses of the
various products of their secretory activity, undertaken by a host of
observers. Advance in this direction has gone pari passu with
that of chemical physiology. Much, however, in regard to the
chemical composition of the secretions still remains incomplete
and imperfect, and what we know at present is little in comparison
with what remains to be learned except for certain secretions

i INTEENAL PROTECTIVE SECKETIONS 5

which it is possible to obtain in large quantities (e.g. urine, milk,
bile), and which have accordingly been the subject of numerous
and exhaustive researches.

The progress of physics again (particularly Dutrochet's theory
of the phenomena of diffusion through permeable membranes, the
kindred phenomena of imbibition, capillarity, nitration, the
modern doctrine of osmosis through semi-permeable membranes,
the molecular concentration of solutions, the isotonicity of animal
fluids) has stimulated physiologists in the task of reducing the
phenomena of secretion as far as possible to common mechanical
principles. In this laudable attempt Ludwig is pre-eminent.
As we shall see, he founded a mechanical theory of renal
secretion that still holds its own in physiological text -books,
and accounts for the fundamental phenomena that accompany the
formation of urine. Generally speaking, however, it must be
admitted that in the actual state of science we are very far from
any mechanical concept of the secretory processes taken as a
whole. All the forces brought into play with this object are
confronted by the enigma of the metabolic activity of the living
cell, so that the teaching of Job.. Miiller stands firmer nowadays,
after all the vigorous attempts that have been made to overthrow
it, than in 1830 when it was first formulated.

II. The simplest glands, from both the morphological and the
physiological point of view, are represented by epithelial tissues,
which form alveoli or perfectly closed spaces, i.e. are destitute of
excretory ducts by which the secretion is poured out either to
the cutaneous surface, or to the inverted mucous surfaces (of the
digestive tube, respiratory passages, geuito-urinary apparatus).
Since all external secretion is excluded by the absence of excretory
ducts, it is evident that these closed glands are capable of
internal secretion only. Their secretions collect in the glandular
spaces, and in proportion as they acquire a certain tension pass
through the pores or interepithelial spaces into the peri glandular
lymph spaces, or are directly absorbed by the network of blood
capillaries that surrounds the epithelial layer.

These closed glands have therefore a structure and in all
probability a function highly similar to that of the lyniphoid
tissues and organs discussed in the last chapter. Morphologically,
they differ only in having epithelial cells as their essential
substrate, while they do not communicate directly, and are not
intercalated along the lymph and blood paths, but form quite
distinct glandular spaces : physiologically, they differ because
they do not contribute to the formation of the primary cytological
and chemical elements of the blood and lymph, but represent
special factors which modify the constitution of these two fluids, so
as to adapt them to the normal life of the body as a whole.

The recognition of the vast importance of the secretory function

6

'PHYSIOLOGY

CHAP.

of this group of glandular organs constitutes one of the finest
achievements of modern experimental physiology. It more par-
ticularly includes the physiology of the thyroid gland, the
parathyroids, the hypophysis or pituitary gland, the suprarenal
capsules, the paragauglia ; to the same category belong also the
pineal glnnd, the carotid glands, and the coccygeal gland, of which
the functional significance is still unknown.

III. The Thyroid Gland (more correctly glandula thyrcoidea)
is in man a single organ, in colour dark red shading into yellow,
which lies at the sides and in front of the larynx and the two
first tracheal rings. Two lateral lobes and a median isthmus can
be distinguished, above which rises a slender conical process
(Morgagni's pyramid) which is attached to the thyroid bone by a

* . >v%r~

/
;fc *

Fui. 1. A, Human thyroid gland, showing bifurcation of lower end of pyramidal process, one part
going to each ateral lobe. B, the same, with pyramidal process attached to left lobe of
gland ; isthmus absent. C, the same, with pyramidal process and isthmus absent. (C. F.
Marshall.)

fibrous and muscular band (Fig. 1, A). It varies considerably
in size, the weight seldom exceeding 30-40 grms. It is generally
more developed in females than in males, and often swells at the
periods of menstruation.

In the cat, rabbit, guinea-pig, and rat, the isthmus joining the
two lobes is represented by a very slender band of thyroid tissue ;
in the dog, on the contrary, the two lobes are almost always
separated, as, by a congenital anomaly, may also occur in man
(Fig. 1, B and C). The isthmus is almost always well developed
in the ape, as also in ruminants.

The thyroid is invested by a transparent capsule of dense
areolar tissue which connects it loosely with the adjacent parts,
and penetrates to the interior, separating the substance into small
lobules of unequal form and size. When cut into, a yellow,
sticky fluid escapes from the surface, which had previously been
contained in a multitude of closed vesicles or follicles surrounded

i INTERNAL PEOTECTIVE SECRETIONS 7

by areolar connective tissue, and richly provided with blood and
lymph vessels. The size of the vesicles varies considerably ; the
largest may be one millimetre in diameter, so that they are
visible to the naked eye. They are rounded or oval in form,
with a wall consisting of a single layer of cubical or columnar

O O */

epithelial cells, which are the secreting elements (Fig. 2).
According to Langendorff two kinds of cells can be dis-
tinguished : " Hauptzellen," which have sharp outlines and shin-
ing, finely granulated protoplasm ; " Colloidzellen," which have
indefinite outlines and protoplasm filled with large granules,
shown by their affinity for certain pigments to consist of colloidal
substance. The first are young cells that secrete by exudation ;

p [o . _>. Thyroid gland of infant. Vesicles of various sizes, lined with single layer of cubical

epithelial cells.

the second are older and exhibit a marked secretory activity,
during which they liquefy and break up, so that both protoplasm
and nucleus pass into the secretion. In fact, the colloid
fluid of the alveoli contains both the old disintegrated epithelial
cells, and leucocytes that have emigrated from the blood
capillaries, as well as erythrocytes in process of destruction and
discoloration.

Liibcke (1902) concluded from histological observations, more
particularly of fresh preparations of the gland, that the so-called
"colloid" cells are only artificial products, due to the diffusion of the
contents of the vesicle in and around the atrophied epithelial cells.
In any case they would not represent the secreting cells. Accord-
ing to this author the thyroid vesicles contain a homogeneous fluid,
which is not shiny, and is quite distinct from the protoplasm,
being watery or gelatinous in consistency. It can be washed out

PHYSIOLOGY CHAP.

with water, and coagulates after death, when it resembles the
fixed content of the vesicles.

Lewandowsky (1902) came to the same conclusion from histo-
logical work on the thyroid of dog, cat, rabbit, ape, lamb, and
hedgehog. He found that the secretion from the vesicular
epithelium was quite fluid, and indistinguishable under the
microscope from other protein solutions. According to this, there
are no colloid cells which secrete preformed colloidal substances.
This secretion first assumes the properties of a colloid in the
vesicular lumen.

The blood-vessels, which are numerous and large in proportion
to the size of the organ, penetrate the cavities of the interstitial
connective tissue, where they ramify rapidly, and come into
intimate relations with the walls of the alveoli, round which they
form a capillary network that is in perfect contact with the
epithelium. The lymphatics arise from the spaces of the inter-
lobular and interalveolar connective tissue, forming a number of
large trunks that anastomose into plexuses at the surface of the

organ.

The nerves that supply the thyroid come from the two
laryngeals, superior and inferior, from the vagus, and from the
superior cervical ganglion of the sympathetic. Their mode of
termination in the muscle cells of the vessels and in the epithelial
cells is unknown.

Embryology shows that the thyroid originates from three
epithelial diverticuli of the primitive intestine, two of which form
the lateral lobes, and the third the isthmus and pyramid of
Morgagni. The epithelial cells of the three diverticuli are grouped
into small masses which are then transformed into vesicles or
alveoli. The peripheral cells of each mass constitute the epithelium
of the alveolus ; the central cells become granular, and on breaking
up form the colloidal content of the primitive alveolus.

The primitive epithelial masses are mainly grouped together
to form the principal thyroid gland ; but there are almost invari-
ably certain nodules which do not fuse with it, and which give
rise to small accessory thyroids, these in the successive phases
of embryonic development may wander to a considerable distance
from their origin and enter into relation with various organs
derived from the cephalic end of the foetus. On a careful compu-
tation of the accessory thyroids found in various places, they
exist in the tongue and in the sub-maxillary, retro-pharyngeal,
retro-oesophageal, laryngo-tracheal, hyoid, crico-thyroid, bronchial,
aortic, and mediastinic regions (D'Aiutolo, 1890). The accessory
thyroids are perfectly similar in structure to the principal thyroid
body, and they also exhibit alveoli filled with colloidal substance,
blood-vessels, lymph spaces and vessels, and nerve filaments.

The Parathyroids (jjlandulae paratliyreoideae) differ completely

INTERNAL PEOTECTIVE SECRETIONS

in structure (as well as function, infra) from the accessory thyroids.

They were first described by Sandstrom (1880) in man and certain

other mammals, externally

to the lateral lobes of the

thyroid body. Subsequent

observations confirmed their

constant presence in mam-

malia, adding to the extern"/

parathyroids other similar

little glands situated on the

mesial surface of the lateral
lobes of the thyroid, the i>
internal parathyroids, which,
however, may be absent in
certain species (Fig. 3).

In man the outer (also
called the inferior) para-
thyroids lie in front of the
inferior thyroid artery and
the recurrent nerve. Their
position is not constant.
For the most part they are
situated at the inferior
angle of the thyroid lobes,
towards the lower part of
the postero-external border,

FIG. 3. Transverse section of left lobe of thyroid from

at a greater 01" leSS distance a two-months' kitten. (Kolm.) , thyroid tissue ;
f , nil -j_ i ft, thymic tissue; ;> '. innor and outer iiara-

froui it, and closely united thyroids.

by fine connective tissue.

More rarely they are found at the level of the eighth and tenth

tracheal ring (Fig. 4). It follows that in excising the thyroid body

in man by the subcapsular method, the inferior or outer para-

thyroids are easily left in situ a fact which, as we shall see, is

of great clinical and physiological importance.

The inner (or superior) parathyroids are situated on the internal
surface, towards the upper pole of the thyroid lobes, with which
they are intimately connected, since they are wrapt in a common
sheath of connective capsular tissue, and sometimes lie in the
depth of the thyroid substance. In surgical thyroidectomy these
must obviously be excised along with the thyroid body.

The structure of the parathyroids (both outer and inner)
differs from that of the principal and accessory thyroids. They
consist not of hollow vesicles, but of compact masses or columns
of epithelium cells, which sometimes anastomose into branching
cords. Between the cell masses there are septa of connective
tissue, which convey the blood-vessels and nerves into the gland
substance (Fig. 5).

10

PHYSIOLOGY

CHAP.

The epithelial cells which form the specific substance of the
parathyroids are columnar or polyhedral in shape; they have a

FIG. 4. Human thyroid and parathyroid glands. A, from behind ; B ami <_', from in front.
A 1, Superior "parathyroids ; A 2, inferior parathyroids : B 1 and C I, inferior parathyroids.

small roundish nucleus which may exhibit karyokinesis. Accord-
ing to Vassale and General! the cytoplasm of the cells is sometimes

lJ' 1 I \*>'K' *-" t

FK;. "). Part of i-xternal parathyroid of last figure. (Kohn.) ??2. Shows epithelial cells arranjvd
in columns, with intervening septa of connective tissue ; m, m, cells in mitotic division.

clear or finely granular and does not stain, sometimes it has coarse
stainable granules. In all probability these represent two different
stages of functional secretory activity.

i INTERNAL PROTECTIVE SECRETIONS 11

Livini (1900) showed by histological methods that the para-
thyroids are fundamentally composed of epithelium cells, which
are gland cells proper. These cells elaborate two different
substances ; one, the principal, appears in the form of granules
or masses varying in size, which stain an intense green like
colloid substances with Galeotti's method ; the other, in the
form of minute granules, stains bright red, like the chroniatin of
the nucleus. The parathyroid secretion is poured out into the
pericellular lymph spaces, and reaches the blood by way of the
lymphatics.

In certain animals small nodules of adenoid tissue with the
structural character of the thymus gland (Fig. 3) are associated
with the parathyroids, which suggests a common embryological
origin. Livini, however, demonstrated that the cells of these
masses (known as the tliymic lobules') are epithelial cells for
internal secretion, rather than lymphoid cells. He found, in
fact, that they produce a substance which completely fills the
thymic lobule, and usually increases its size. These modifications
in the cell mass are attended by serious nuclear disturbances,,
which eventually lead to the dissolution of the cells. It is worth
noting that this secretory product gives the same reaction as the
principal product elaborated by the cells of the thyroid and
parathyroid glands.

According to Prenant and Fusari, the external parathyroids
have a common origin with the thymus, the internal with the
lateral lobes of the thyroid. The mode in which this transfor-
mation of the structure and specific character of the epithelial
cells is effected is unknown. In any case, we must exclude
the idea (which in the abstract appears rational enough, and
which was propounded by Gley) that the parathyroid is merely
embryonic thyroid tissue, which in the course of its develop-
ment may be transformed into the latter. The thyroid and
parathyroid are two structures specifically distinct in character,
and they cannot be vicariously substituted for one another
(infra).

That both thyroid and parathyroid are secreting glandular
organs, and that the colloidal substance collected in the vesicles is
destined to be absorbed from the inter follicular lymph channels,
has been established by the histological work of Biondi with
Heidenhain (1889), Langendorff (1889), and a long series of other
observers, among whom are Vassale and Brazza, and Galeotti,
in Italy. As early as 1839 King demonstrated on dead bodies
that it is possible by exerting a certain pressure on the thyroid to
express the colloidal content of the vesicles into the lymphatics
that issue from the gland. Kohlrausch (1853) and Baber (1876)
showed under the microscope the presence in the intervesicular
lymph channels of colloid substances similar to that contained

12

PHYSIOLOGY

CIIAI'.

in llic vesicle. Later workers have tried by various modes of
staining to determine the nature of the epithelial secretions and
the paths by which the secretion penetrates the lymphatics. In
this connection Langendorif's results are very interesting. He holds
that the protoplasm of the colloid cells degenerates, passing into
the secretion along with the nuclei, and leaving stellar interstitial
spaces between the principal cells, through which the secretion
passes freely into the lymphatics (Fig. 6). When the vesicle is
emptied its epithelial cells close up again, and once more present
a complete cavity, which in its turn forms outlets for the secretion
by the above process. In the lymph channels the secretion is
diluted by gradual admixture with the lymph, which carries it
away to the circulation.

B

FIG. 6. A, Segment of thyroid follicle from puppy. (Langciulorff.) Treated with Friedlander-Zeiss
osinic-liaematoxylin method, homogeneous immersion. Numerous cells are seen in colloid
< I' -'-iteration, distinguished from the principal cells by their dark colour. B, same preparation.
Superficial view of principal cells and colloid cells. The colloidal cells adhere together to form
a network ; they are attenuated, with occasional nuclei, which are flattened and stain more
deeply than those of the principal cells.

According to Lewandowsky, as stated above, the secretion of
the vesicular epithelium is not the colloidal substance but a
mother substance, from which the colloid is formed. It is, he
says, the mother substance that passes into the lymph or blood
vessels. But the passage of true colloidal substance from the
vesicle into the lymphatics has never been proved, while on the
other hand it is not uncommon for a colloidal substance to form in
the lymph spaces.

There are no glandular spaces in the parathyroids analogous to
the vesicles of the thyroid. We must therefore conclude that the
secretions from the epithelial cells are absorbed in the lymph
channels as fast as they are formed. The observations of Mazziotti
and Capobiauco (1899), particularly those on the parathyroids of
the cat, give interesting details in this connection. They find that
the blood-vessels which irrigate the epithelial cells contain a

i INTERNAL PROTECTIVE SECRETIONS 13

number of leucocytes in excess of the normal (as compared with
the erythrocytes), and that perivascular lymph spaces exist round
them, which are often wider than the vessels and show a network
of connective filaments coming from the adventitia. They regard
these perivascular spaces as the outflow of the parathyroid secretion,
masses or lumps of a granulated substance being sometimes noted,
which stain like colloidal substance.

IV. The physiology of the thyroid and the modern conception
of it as a glandular organ of internal secretion, indispensable to
normal life, is derived from surgery. After the introduction of
antisepsis, thyroidectomy was attempted in cases of goitre, and the
effects observed. As early as 1856-57, indeed, M. Schiff, in a series
of experiments on total thyroidectomy in animals, noticed that it
was frequently fatal in dogs after the first week, in guinea-pigs
somewhat later, although death could not be referred to the state
of the wound nor to lesions of the recurrent branch of the vagus,
nor of the cervical sympathetic. But he gave no adequate account
of the phenomena by which death is preceded, and abandoned his
researches, owing probably to the inconstancy of the results, since
he found that rabbits, some rats, a dog, and several guinea-pigs
survived the operation. It was not till after the publications of
the two Genevese surgeons, Reverdiu, and Kocher, a surgeon in
Berne (who in 1882-83 described the effects of total excision of
goitre), that these experiments were repeated. The credit of
directing the attention of physiologists to this important subject
is accordingly due to surgery.

We will first review the phenomena of deficiency of the thyroid
gland, starting with all the best-known surgical cases, which may
be regarded as so many physiological experiments performed on

o
man.

Patients who have undergone total thyroidectomy, and have
already been discharged from the hospital as cured, experience the
initial symptoms of glandular deficiency either at once or at
latest some weeks after the operation. They feel weak, complain
of heaviness of the limbs, and more or less diffuse dull pains,
particularly in the legs, which may become acute and assume the
character of pains in the bones.

Other more serious symptoms are gradually associated with the
preceding. After four to five months the face and the extremities
swell and become cold, the muscles are torpid, sometimes rigid,
often exhibiting muscular tremors, and are incapable of carrying
out any delicate manual acts with precision. At first the swelling
is variable ; it is more pronounced in the morning than in the
evening, but steadily increases, until it becomes permanent. It is
not ordinary oedema, in which percussion with the finger leaves
a depression ; it is a hard and elastic swelling. It is specially
localised in the hands, feet, and face, where it produces a

I 1 PHYSIOLOGY CHAP.

characteristic alteration of the countenance. The lower eyelids
are the first to present a sacculated semi-transparent swelling,
which is hard to the touch ; then the infiltration spreads to the
folds of the face, which become smoothed out ; to the nose which
gets rounded ; to the lips which swell, and bulge outwards, saliva
dribbling from them. The features are coarsened and expression-
less like those of a cretin.

The mental functions accord with this appearance, since they
are blunted, so that the patients lose their memory, become deaf,
taciturn, melancholy, self-absorbed, and reply extremely slowly to
questions. They further complain of slight but perpetual head-
ache ; feel an almost constant sensation of cold, which is most
acute at the extremities ; at times they are seized with vertigo,
and may even lose consciousness:

All these symptoms become still further aggravated. The
whole body may grow more bulky from the extension of the
swelling. The skin loses its elasticity, can only be picked up in
large folds, and becomes dry owing to defective capacity for
sweating. The epidermis desquamates in more or less extensive
lamellae, particularly on the hands and feet ; the hair turns grey,
falls out, and gets constantly thinner.

The heart functions weakly, but with ordinary rhythm ; the
pulse is small and thready. Examination of the blood shows
nothing constant ; but there is often a more or less pronounced
and progressive oligocythaemia, which undoubtedly contributes to
the characteristic pallor of the skin, this being of the earthy,
yellow-spotted hue peculiar to cretins.

The respiratory rhythm is almost always normal ; the digestive
apparatus functions well, as also the urinary system. The spleen
is not enlarged.

When thyroidectomy has been performed during adolescence,
one of the most serious effects is the arrest of development. A
boy on whom Sick operated at the age of ten, had at twenty-eight
become a cretin whose height was only l - 27 metres; a similar case
was described by Schmidt ; and the same phenomenon appeared
in a lesser degree on a third person, on whom Julliard operated at
the age of seventeen.

This complex and characteristic syndrome of morbid pheno-
mena, as described by Kocher, is now generally known by the
name of cachexia tliyreo- or strumipriva, i.e. cachexia consequent
on complete ablation of the thyroid gland.

In 1874 Sir William Gull presented to the Clinical Society of
London five cases of a disease which presented a morbid syndrome
closely resembling that of cachexia thyreopriva. In 1878 W. M.
Ord described five other cases of the same disease, to which he
gave the name of myxoedema, derived from the constant symptom
of thickening and swelling of the skin, as manifested especially in

i INTEENAL PEOTECTIVE SECRETIONS 15

the face and limbs, which he proved to be due to a pronounced
accumulation of inuciu in the subcutaneous connective tissue.
He observed that the disease was accompanied by a shrivelling of
the thyroid, and the destruction of its follicles by proliferation of
the connective tissue ; but he did not suspect that this degenera-
tion of the gland was the internal cause of the myxoedenia. He
further noted the numerous analogies between myxoedenia and
cretinism ; but did nut regard the latter as dependent on the
alterations of the thyroid.

It was the cousins Eeverdin who recognised these relations,
more particularly the great resemblance between the phenomena
of spontaneous myxoedema and cachexia thyreopriva, to which they
gave the name of operative myxoedema. Kocher, on the other
hand, particularly emphasised the points of contact between
cretinism and cachexia thyreopriva. In 75 per cent of the cases,
cretins exhibit goitre with thyroid degeneration ; and in cases in
which there is no goitre, absence of this gland has been noted
(Curling). In many non- goitrous cretins Kocher verified its
absence by palpation, or at least such a diminution in its volume
that it was not perceptible to touch. It is not surprising that
the resemblance between cretinism and cachexia thyreopriva
should be incomplete, seeing that cretinism is a congenital disease,
and is almost always hereditary. But they may legitimately be
grouped together, since in both the disease depends on a defective
or insufficient function of the thyroid gland.

V. Following the initiative of the Swiss surgeons, the excision
of the thyroid in cases of goitre was practised by many, notably
by Billroth in the Vienna clinique. The results differed from
those described by the cousins Eeve-rdin and by Kocher, in that
the morbid syndrome of slowly developing cachexia thyreopriva
was frequently replaced or accentuated by acute phenomena of
" tetany" which usually caused the rapid death of those operated on.
Out of 53 cases of total thyroidectorny for goitre, reported on by
von Eiselsberg in 1890, there were 12 cases of tetany, 8 with fatal
results. In 8 cases operated on by Mikulicz 4 were attacked by
tetany. Since the first 13 cases of tetany collected by Weiss were
all very young women, it seemed as if this complication were
peculiar to females. Subsequently this was found to be erroneous,
cases of tetany having also been observed in young males by
Kocher, Mikulicz, Hicquet, -and Walkowitsch. Tetany is more
frequent in women than in men, because cases of goitre are
notoriously more frequent in females, and the majority of indi-
viduals operated on accordingly belong to that sex.

" Tetania thyreopriva " may appear on the day of operation ;
more frequently it commences on the second, the fifth or sixth, or
at latest on the tenth day after the operation (Weiss). It begins
with muscular cramp which is usually localised in the limbs, and

16 PHYSIOLOGY CHAP.

particularly iii the flexor muscles of the hand and forearm; soon,
however, the spasms invade other muscular groups, inducing
lock -jaw, blepharospasm, cramp of the tongue, trachelismus,
opisthotonus.

The tetanic spasms are preceded, accompanied, or followed by
tachypnea and tachycardia, with a concomitant rise of tempera-
ture of '2-'.l C. Sometimes the neuro-niuscular super-excitation
assumes the form of clouic-tonic epileptoid convulsions, conscious-
ness being retained. This is generally the most serious symptom
of tetania thyreopriva, and sets in shortly before death.

Unlike simple cachexia, post-operative tetauy seldom exhibits
sugar or even albumin in the urine.

The course and outcome of tetany varies. It may consist in
one or more severe attacks, leading rapidly to the death of the
patient. In other cases it may be protracted for many days and
even mouths, when less acute attacks are observed from time
to time, which may be followed by the slowly developing pheno-
mena of cachexia thyreopriva. In other cases, again, tetany in a
more or less intense form may appear much later, 3-4 years after
thyroidectomy, when the phenomena of cachexia thyreopriva are
already fully developed.

VI. These grave effects of thyroidectomy in man were the
subject of much discussion and controversy at the Congress of
German surgeons which took place in 1883. The observations of
Keverdin, Kocher, Wolfler, and Bardeleben were confronted with
not a few cases of goitre in which no subsequent morbid symptoms
were apparent. We shall return later to the cause of this
phenomenon. Meantime, experimental confirmation of the great
physiological importance of the thyro- parathyroid system was
not long wanting. The merit of its discovery is due to M. Schiff,
who in 1884 published two Memoirs on the effects of removing
the thyroid bodies in the dog, which indicated the true solution of
this crucial question. Schiff was followed by a host of experi-
menters in Italy, Germany, and France, whose work threw much
light on the subject, though it is still obscure.

Let us first consider the phenomena consequent on total
thyroidectomy in the dog, on which many experiments have been
carried out.

The total extirpation of both thyroid bodies in these animals
produces effects no less complex and variable than in man : usually
they present a combination of the phenomena of tetany and of
cachexia thyreopriva. The operation is almost invariably fatal,
after a period varying from 3-4 days to a month. Death more
often occurs between the sixth and tenth days. The fatal issue
is more rapid when acute symptoms of tetany prevail ; it is
retarded when the depressing and dystrophic symptoms of
cachexia predominate. The phenomena of the first and second

i INTERNAL PROTECTIVE SECRETIONS 17

groups, however, combine and succeed each other so variously in
individual cases, that any separate description of them would be
artificial and arbitrary.

Two to three days after the total ablation of the thyro-
parathyroid apparatus, the dogs begin to exhibit signs of depression,
and are sluggish in their movements, with a decided tendency to
remain crouched. They are unwilling to eat (anorexia), swallow
with difficulty (dysphagia), are inclined to vomit, and end by
absolutely refusing all food. When they try to move, or are
forced to stir themselves, they exhibit characteristic fibrillar
tremors of the muscles of the thighs, shoulders, and buck.

These symptoms gradually become aggravated and complex.
The animals appear uneasy, they whine (as if in pain), rub their
noses on the ground or wall, and shake their bodies as if they
itched all over. At the same time, sensibility to painful and
tactile stimuli seems to be objectively diminished or entirely
abolished, -while the pressure -sense is retained (Schiff). On the
third or fourth day, more often on the fifth or sixth, trophic
disturbances make their appearance in the skin, due in great
measure to rubbing with diminished cutaneous sensibility. Con-
junctivitis and keratitis next set in, and are first catarrhal and
subsequently become purulent (Gley), if precautions are not taken
by treatment with disinfectants (Lusena).

The muscular tremor becomes continuous ; it is complicated by
rigidity of the extremities, particularly the hind-limbs, in the form
of tonic extension ; twitches or clonic contractions of certain groups
of muscles, particularly in the temporal muscle and the masseters,
tonic contraction of the masticator muscles (lock-jaw), extending
sometimes to the muscles of the back and limbs (opisthotonus),
and assuming the form of true spasms of tetanic convulsions.

The convulsive spasms are not infrequently complicated by
attacks of tachypnea of no long duration, during which there is a
proportionate increase of temperature (Murchesi). Sometimes the
tachypnea is so intense that the respirations can only be counted
by the graphic method (G-ley). Not infrequently, at the close of
life, the respiratory rhythm becomes periodic (Cheyne- Stokes
phenomenon), but this does not last long, and is irregular in form.
Along with tachypnea and hyperthermia there is regularly
tachycardia, which may reach maximal intensity (150 beats to the
minute). On the other hand, in the long intervals (sometimes
whole days) in which there are no convulsive phenomena nor
tachypnea, and the animal is in a drowsy, stupid state or in coma,
the temperature may fall gradually to two degrees below normal
(Ughetti), while the cardiac beats also become less frequent than
the normal (Lusena). Investigation of the respiratory gas ex-
changes agrees with this fact, as they are found to be diminished
after thyroidectorny (Baldoni).

VOL. II C

18 PHYSIOLOGY CHAP.

Much work has been done with the object of determining the
changes iii the blood after thyroidectomy, but has led to no
concordant results. The number of the erythrocytes and the
amount of haemoglobin diminishes according to some authorities,
according to others it remains approximately invariable. The .
quantity of oxygen fixed by the haemoglobin of dethyroidised
dogs may diminish, or remain approximately unaltered, according
to the nature of the pathological phenomena at the moment of
investigation. The isotouic coefficient of the erythrocytes is
somewhat reduced, owing probably to the altered metabolism
(Bottazzi). The proteins of the plasma alter in their qualitative
relations : at first there is a relative diminution of globulins and
increase of serin ; later, on the contrary, the serin diminishes,
while the globulins relatively increase (Ducceschi). This fact
depends probably on the state of almost complete inanition in
which the dethyroidised dog exists, also on the albuminuria
frequently observed in these animals (Herzen), owing to which
a predominating amount of serin passes into the urine.

Coronedi's recent and systematic researches on this albumiuuria
have shown it to be a constant phenomenon, although it varies
in intensity. It sometimes precedes the onset of characteristic
symptoms of thyro-parathyroid deficiency, more particularly the
convulsions. It is curious that this albuminuria can as a rule
be detected most certainly by means of Esbach's citro- picric
reagent.

In addition to albuminuria, glycosuria is often seen in
dethyroidised dogs. It usually sets in two days after the opera-
tion (so that it is not the effect of post-operative traumatism),
and lasts, sometimes intermittently, till death (Falkenberg, Gley).
According, however, to the later and more accurate work of
Coronedi, the reducing power of the urine is seldom due to
dextrose. Coronedi and Luzzato further noted in dogs that the
reaction of the urine became alkaline after parathyroidectomy,
owing to the presence of free ammonia.

Such are the principal pathological features exhibited in dogs
after complete ablation of the thyro-parathyroid apparatus. They
present a less acute course than the typical cases of tetany in man,
and a much more rapid course than Kocher's cachexia. This
greater rapidity doubtless accounts for the absence of myxoedeina
in dethyroidised dogs, i.e. swelling owing to infiltration with
mucin. In the dogs which, as a rare exception, lived for some
time after thyroidectomy, Tizzoni and Centanni (1890) saw that
trophic phenomena similar to myxoedenia did make a tardy
appearance. Coronedi and Marchetti have recently described
two typical cases of experimental myxoedeina in such animals,
the psychical decadence being also particularly pronounced.

In thyroidectomy practised on monkeys (which by their greater

i INTERNAL PROTECTIVE SECRETIONS 19

affinity to the human race might a priori be expected to show
a greater likeness in pathological phenomena), Horsley (1885-86)
reproduced and described the psychical decadence, the alterations
in general nutrition, the special oedemas that were described for
man by Reverdiu, and which constituted the syndrome of operative
mijxoedema. Tetany was occasionally observed in apes as in man,
and rapidly produced the death of the animal.

Fatal effects with phenomena similar to those in dogs were
observed on cats (Schiff, Vassale, and Sacchi) and foxes (Sanquirico
and Orecchia). In some of the herbivora, on the contrary, especially
the rabbit, on which many experiments have been made, no
particular effects were observed (Schiff, Colzi, Tizzoni and Fileti,
Sanquirico and Orecchia, etc.) Later on we shall examine the
reason for these negative results, as also for the rare survival of
dethyroidised dogs, as noted by Albertoni and Tizzoni, H. Munk,
and others. Thyroidectoniy in birds yielded varying results to
Moussu, negative results to Allara and Ewald. In reptiles and
amphibia, on the contrary, the physiological importance of the
thyroid apparatus was evident. The salamander usually died
after a week (Gley, Phisalix, Nicolas). Lizards and snakes
perished in 3-4 weeks (Cristiani).

VII. After this description of the phenomena, the first question
to determine is whether the complex pathological effects observed
after ablation of the thyroid bodies are really the direct con-
sequence of loss of function in the glandular organ, or the indirect
effects of the operation performed on man and other animals. We
will shortly review the principal opinions in regard to this
subject.

Prior to the observations of the cousins Reverdin and of
Kocher on man, which were confirmed by Schiff for other animals,
there was no really scientific theory of the specific function of the
thyroid body. The current hypotheses were more or less gratuitous,
or founded upon superficial observations. Among many such
(which need not be recorded) was that formulated by Schreger
(1*791), which had a certain objective foundation. In view of the
situation of the gland between the heart and brain, of the large
arterial vessels with which it is provided, and of their origin in
the arteries that carry the blood to the brain, he opined that the
thyroid functioned as an organ for regulating the circulation in
the upper part of the body, particularly in the brain : Haec
ylandida. sanguinis immodicos appulsus a cerebro aderceat et
moderetur. Rush (1806) supported this hypothesis, and explained
the greater development of the thyroid in women by their greater
predisposition to emotion, which is associated with cardiac ex-
citement. The same doctrine was taken up more vigorously
by Liebermeister (1864), who attempted to bring out the great
importance of the regulatory mechanism represented by the

20 PHYSIOLOGY CHAP.

thyroid, in all cases in which there is danger of plethora or
cerebral anaemia. In the first case, by dilatation of its vessels,
the thyroid receives the excess of blood which would otherwise
reach the brain ; in the second, by contraction of its arteries, it
determines a greater flow of blood to the cerebrum. Guyon (1868)
adopted a more complicated, but analogous point of view, affirm-
ing that every increase in cerebral blood-pressure produces an
augmentation in the volume of the thyroid (probably by passive
vascular dilatation) which causes compression of the carotids,
and prevents the blood from flowing in large quantities to the
brain. Finally, Meuli (1884) attempted to give an experimental
basis to the Schreger-Liebermeister theory, demonstrating by a
series of measurements upon himself that the circumference of
the neck varies considerably with the position of the body, these
variations being maximal at the level of the thyroid region.

Without denying whatever may be true in this theory, as put
forward by Liebermeister, its importance must not be exaggerated.

It is obvious that any regulatory or compensatory influence on
the cerebral circulation which may be attributable to the thyroid
arteries can have nothing to do with the specific function of the
thyroid as a glandular organ of internal secretion.

The cousins Eeverdin and Kocher (1883), who, as we have seen,
were the pioneers of research into the physiology of the thyroid
as a glandular organ, were not happy in their first attempt to
explain tetany and cachexia thyreopriva in man. According to
Reverdin, this characteristic syndrome depended on disturbances of
innervation caused by lesions of the nerve trunks in the course
of extirpating the thyroid organ. According to Kocher, on the
contrary, the ligation of the great thyroid vessels in excision of
this body produced on the one hand a considerable diminution
in the lumen of the trachea, owing to deficient irrigation by the
blood stream, on the other, a disturbance of the cerebral circulation
by suppression of the thyroid system. The constriction of the
trachea diminished the respiratory gas-exchanges, and indirectly
produced anaemia, leucocytosis, cretinism, coma ; the disturbance
of the cerebral circulation (according to Liebermeister's theory)
caused the convulsions, tachypnea, and tachycardia.

After Schiff's publications (1884) these hypotheses, which, as
we shall see, were reared on an unstable basis, were abandoned
even by their authors. According to Schiff the grave symptoms
consequent on thyroidectomy are the direct consequences of
deficiency of thyroid function, i.e. of the internal secretion of
substances of unknown nature, which are of great importance in
the normal nutrition of the nervous system. When deprived of
these substances of thyroid origin the nervous system becomes
disordered in its functions, and gives rise to the phenomena of
tetany and cachexia thyreopriva. Schiff proved that the extirpa-

i INTERNAL PROTECTIVE SECRETIONS 21

tion of one thyroid only was innocuous in the dog. On the other
hand, he found that if the thyroid of one dog were grafted into
the peritoneal cavity of another, and the two thyroids of the latter
extirpated after a considerable period, the pathological phenomena
were delayed, and the animal survived the operation longer. He
observed that, generally speaking, the grafted thyroid did not take
root, but was absorbed after a certain time. He explained the
protracted survival of the animals on the assumption that during
the disintegration of the thyroid introduced into the peritoneum,
the substances necessary to the normal nutrition of the nervous
system are absorbed and carried to the circulation. 'He con-
jectured that the same effect could be obtained by the periodic
injection of thyroid juice into a dethyroidised animal, as was
subsequently demonstrated by other experimenters.

Another important fact stands out in Schiff's memoir. He
states that if both thyroids in a dog are excised in two successive
operations, at about a month's interval, no pathological symptoms
appear in the animal. With a less interval between the two
operations, the fatal symptoms are delayed ; if the interval is
reduced to one w r eek they invariably set in. This suggested to
Schiff the hypothesis that in the interval between the first and
second thyroidectomy the activity of another organ, similar to or
identical in function with the thyroid, might be progressively
exaggerated, so as to act vicariously for the excised thyroid. The
presumptive existence of another organ functioning vicariously for
the thyroid, explains, he says, why total thyroidectomy in certain
animals, e.y. rabbits and rats, and on rare occasions dogs also, may
be innocuous. Later on \VQ shall examine the value of this
hypothesis. Meantime it may be stated that the fundamental
fact on which it is based was immediately contradicted by the
experiments of Sanquirico and Canalis (1884-85), who constantly
obtained fatal results from the removal in two operations of both
thyroids in dogs, whatever the period between the first and second
operation. They also observed another enigmatical fact, the
importance of which will appear below. Removal of the upper half
of both thyroids is fatal in the dog, while removal of the two
lower halves is innocuous.

Immediately after Schiff's publication, Colzi proposed that
these experiments upon the thyroid should be repeated in our
laboratory in Florence, in order to see, from an exclusively
surgical standpoint, which minimal portion of the organ it was
necessary to preserve in dogs in order to avoid the phenomena of
"tetania thyreopriva." The results of his experiments, published in
1884, showed that if half the thyroid, or even half of one lobe
were retained, the animal escaped death. In this case transitory
phenomena of functional insufficiency were often apparent.

The rapid course and violence of the phenomena of tetany as

1'IEYSIOLOGY CHAP.

observed in the most robust dogs, after Colzi had excised both
thyroids with a perfect surgical technique, led us to suspect that
the whole pathological syndrome depended on an auto-intoxication.
To prove this hypothesis we suggested that Colzi should perform
direct reciprocal transfusion of blood between two dogs, one that
had been operated on and was in the most acute period of tetany,
the other perfectly normal. On joining a carotid artery of the
first dog with a jugular vein of the second by glass caunulae
united with rubber tubes, the vascular systems of the two animals
completely exchanged their blood content, so that after a few
moments the blood of each animal was perfectly mixed with that of
the other. Previous experiment had shown that reciprocal trans-
fusion can be borne for over half an hour, a period more than
sufficient for the total mass of the blood of the two animals to be
physiologically affected by the thyroids of the healthy dog, since
we know that half a thyroid suffices for each dog.

The effects obtained by this experiment, as frequently repeated
by Colzi, were what we had predicted. On suspending the trans-
fusion after 20-30 minutes, the dethyroidised dog no longer showed
symptoms of tetany, and seemed to have reverted to the condition
it was in on the day of the operation. This more or less complete
disappearance of pathological symptoms lasted only for two or
three days, after which they set in with their former violence, and
rapidly induced the death of the animal. The dog with intact
thyroids appeared depressed for some hours after the transfusion,
but soon recovered and became perfectly normal.

These results, as obtained for the first time in our laboratory,
were the initial demonstration of the theory that the thyroid
apparatus has an antitoxic function, a theory essentially different
from that of Schiff, and confirmed, as we shall see, by subsequent
researches. At the Session of the Medico-Physical Academy of
Florence, July 13, 1884, we formulated our fundamental theory as
follows, on the strength of Colzi's experiments. " The function of
the thyroid secretion is to withdraw from the blood, and probably
to destroy, a product of tissue katabolism that tends to accumulate
slowly, and is capable, when accumulated, of producing a species
of auto -intoxication analogous to the uraemia consequent on
bilateral extirpation of the kidneys. The presence of the entire
thyroid is not indispensable for this cleansing function, a half or
quarter of it will suffice."

Although Schiffs experiments had established the fundamental
fact that the pathological symptoms consequent on thyroid-
ectomy were essentially phenomena of glandular deficiency, other
authorities referred these phenomena to the operative lesions,
more particularly of the nerves, adopting the hypothesis of
Eeverdin. H. Munk, in repeated publications (1887-88, 1897),
and contrary to the observations of other experimenters, maintained

i INTEENAL PKOTECTIVE SECEETIONS 23

that dogs often bear up well against the effects of bilateral thyroid-
ectomy, provided there are no lesions of the sensory nerves of the
region, and that the total occlusion of the thyroid vessels was
equally without effect.

The direct confutation of Muuk's opinion is given more
particularly by the experiments on dogs of Fuhr (1886), Fano
(1893), and Vassale (1893), which prove that lesions of the nerves
and vessels of the neck, translocation of the thyroids and the
grafting of them subcutaiieously, have no sequelae, and that
suppression or complete ablation of the gland are alone capable of
producing the symptoms described by Schiff. Vassale proposed
an experimentum crucis: if the thyroid lobe be excised from a dog
on one side, and the sympathetic nerves divided on the other, this
double operation is not followed by phenomena of cachexia and
tetania thyreopriva.

At a later time E. Cyon (1897-98) formulated a new hypo-
thesis to explain the effects of thyroidectomy. His theory at first
seemed highly suggestive, but it proved fallacious in face of
many facts that have received experimental confirmation. Cyon
attempted to fuse the old theory of Schreger-Liebermeister with
that which attributes a secretory antitoxic function to the thyroid,
directed, i.e., to the removal of some toxic matter from the body
as a whole, and more particularly from the nervous system.

His hypothesis may be summed up as follows :

(a) The function of the thyroid gland is to form and pour
into the blood a special substance designed to stimulate or keep
up the functional tonus of the nerve centres which regulate the
beats of the heart. This substance is thyro-iodine (discovered, as
we shall see, by Baurnann among the active substances of the
thyroid, infra, p. 30).

(&) In proportion as thyro-iodine is formed by the activity of
the glandular epithelia, the iodine salts circulating in the blood
which have a paralysing action upon the regulatory apparatus of
the beats of the heart (Barbera and Cyon), are withdrawn from the
circulation and remain innocuous, forming organic combinations.

(c) By means of the depressor nerves and cardiac branches of
the recurrent nerve, the heart exerts a direct control over the
thyroid function, determining the formation of the amount of
thyro-iodine that is necessary for its normal activity.

(cT) The thyroid, which lies at the entrance of the carotids into
the cranium, is a protection against an excessive flow of blood to
the brain, since it can carry off a great quantity of blood through
its vessels in a very short time. It therefore acts as a secondary
circulation of low resistance.

(e) This regulatory function of the cerebral circulation attri-
buted to the thyroid is also controlled by the heart, since the
depressors are able to determine the active dilatation of the

24 PHYSIOLOGY CHAP.

thyroid arteries, by reducing the quantity of blood that flows to
the brain.

The fallacy of Cyon's theory becomes obvious when we
remember, on the one hand, that the effects of thyroidectomy are
totally avoided in dogs by preserving the two upper halves of the
two thyroid lobes (Sanquirico and Canalis), or even one upper half
of one lobe (Colzi) ; on the other, the double clinical syndrome of
cachexia and tetany exhibited in man after extirpation of the
thyroid, with the various associations and successions of the two
categories of phenomena consequent on thyroidectomy in dogs.
The most direct and convincing refutation of Cyon's hypothesis,
however, lies in other important experimental facts which must
now be examined.

VIII. We have seen that the first generic proof of the theory
which regards the sequelae of thyroidectomy as phenomena of
auto-intoxication from accumulation in the blood of the katabolic
products of the various tissues, resulted from the direct reciprocal
transfusion between two dogs, one dethyroidised and the other
normal, as performed under our directions by Colzi in our
laboratory. The conclusion we arrived at of the protective
antitoxic function of the thyroid gland, was too important for the
work not to be taken up and repeated by many investigators and
with various methods.

Eogowitsch (1886-88) was the first to verify these results.
Next in order, with more variation in detail, came the experiments
of Fano and Zander (1889), and of Lusena (1889).

Starting from these fundamental notions, Gley (1895) con-
ceived the happy idea of comparing the degree of toxicity of blood
serum from a healthy dog with that of a dog suffering from tetany
and cachexia thyreopriva, by injecting these sera into frogs,
guinea-pigs, and rabbits. He came to the conclusion that the
toxicity of the serum of dethyroidised dogs, as compared with that
of the normal dog, is exhibited in these animals by different and
more acute symptoms, i.e., by severe convulsions.

The toxicity of the urine in dethyroidised animals also increases
relatively to that of the urine of healthy animals. This fact,
which was at first denied by Alonzo (1890), was clearly established
by Gley (1894), and was subsequently confirmed by Laulanie and
by Maison (1894).

Reasoning from this fact, which shows that the toxic substances
that accumulate in the blood after thyroidectomy are eliminated
by the organism through the renal excretory system, Dutto and
Lo Monaco (1895) were led to suspect that the intoxication
consequent on thyroidectomy occurred by a process analogous to
that which produces uraemia, more particularly as the symptom-
atology of the latter is no less varied, and presents not a few points
of resemblance with cachexia thyreopriva. This suggestion was

i INTERNAL PROTECTIVE SECRETIONS 25

tested in our laboratory by the so-called washing of the Uood in
dethyroidised dogs, i.e. the repeated injection into the veins of an
isotonic solution of sodium chloride in quantities large enough to
increase the urinary secretion and accelerate the elimination of
all the toxic products accumulated in the blood. Our results
were approximately identical with those obtained by Fauo ; after
each injection the morbid symptoms were alleviated or entirely
disappeared for some time.

This temporary cessation of all the symptoms is strictly
associated with the increased diuresis, and thus with the normal
functions of the kidneys. When the latter are affected and do
not expel the excess of injected fluid fast enough, the symptoms of
cachexia are not suspended.

Another important fact appears from the researches of Dutto
and Lo Monaco. These authors found on methodical analysis of
the urine that elimination of nitrogenous waste products diminishes
in dethyroidised dogs, so that they accumulate in the body : the
washing of the blood abolishes the symptoms of cachexia thyreo-
priva because it determines the elimination by way of the kidneys
of these nitrogenous products, which had been retained and
accumulated in the body.

These experimental results as a whole reinforce the hypothesis
formulated by ourselves, to the effect that the toxic substances
which determine tetany and cachexia thyreopriva are katabolic or
waste products from the tissues, i.e., they have the same origin,
and, in part at least, consist of the same urinary materials. It
appears from certain experiments of Vassale and Rossi (1893) that
these toxic substances are largely derived from the muscles, which
represent the tissue that predominates considerably over any other
in the body. These authors studied the degree of toxicity of the
juice prepared from the muscles of normal dogs, compared with
that of the muscles of dogs killed when suffering from tetany and
cachexia thyreopriva. The muscular extract of healthy dogs
yielded negative results : the muscular extract of dogs in tetany,
on the contrary, when injected into the veins of dogs that were
normal or recently deprived of the thyroid, induced the gravest
symptoms, anorexia, vomiting, fibrillar contractions, and event-
ually convulsions.

If (as appears highly probable from what we have been stating)
the phenomena of tetany and cachexia thyreopriva really depend
on auto-intoxication ; if the toxic substances by which this is
determined are the waste products from the various tissues, notably
from the muscles which form the predominating tissue ; if these
toxic katabolites are normally eliminated by the renal system as
fast as they are formed, then the protective, antitoxic action of the
thyroid secretion may validly be conceived as the direct or indirect
effect of a physiological excitation of the renal epithelia. The

i'0 PHYSIOLOGY CHAP.

phenomena of thyroid insufficiency will thus consist mainly in the
el'l'eets of the progressive accumulation in the blood and tissues of
these products, owing to the altered or retarded secretory function
of the rpit, helium.

That the kidneys do not function normally in dethyroidised
animals may be argued from the albuminuria that accompanies
tetania thyreopriva, as also from the lesions which are invariably
found in the kidneys of dethyroidised animals, ranging from a
simple albuminoid degeneration of the epithelia of the canaliculi
to severe parenchymatous nephritis (Alonzo, Hofuieister, etc.).

Blum (1901) found nephritic alterations of greater or less
gravity in dogs that had survived thyroidectomy for at least eight
days. He, too, attributed the origin of these to auto-intoxication,
which according to him is of an en terogeneous nature, due, i.e., to
the suppression of the antitoxic activity of the thyroid, which
normally has the task of destroying the enterotoxins.

Bensen (1902), again, who particularly devoted himself to the
histology of the lesions of various organs in the rabbit incident
on thyroidectomy, arrived at a conclusion that coincides with the
above. He admitted that, " after thyroidectomy, owing to the
suppression of the thyroid gland, a poison is produced or retained
in the body, which determines a characteristic degeneration of the
cell protoplasm, especially in the kidneys, liver, and myocardium,
leading eventually to the destruction of the cells. The products
of protoplasmic degeneration appear in the form of colloidal
spherules or cylinders in the renal canaliculi. When the morbid
state is protracted an interstitial nephritis is readily set up, leading
to the formation of scars, similar to those which Blum describes
in dogs."

The theory of the intimate functional relations between the
thyro-parathyroid apparatus and the kidneys, however, finds its
fullest experimental confirmation in the studies of Coronedi (1907)
and his pupils. In the first place, this author observed that the
alterations of the kidney (consisting in inflammatory and de-
generative processes) in animals exhibiting symptoms of a defective
thyro-parathyroid system is a constant fact, certain to appear,
and, at least within certain limits, proportional to the intensity
and gravity of the pathological symptoms. It is worth noting that
the lesions may be present even when the syndrome of symptoms
has scarcely been initiated.

While the amount of katabolites increases after excision of the
thyroid and parathyroids, and the elaboration of these products is
never fully accomplished, the functional capacity of the kidneys
diminishes pari passu. Hence a true intoxication of retention
ensues, which, if not identical with, is at any rate highly similar
to, uraemia.

Coronedi believes that among its other functions the internal

i INTEKNAL PEOTECTIVE SECEETIONS 27

secretion of the thyro-parathyroid apparatus serves mainly as
a physiological <l.i.uretic (stimulating the nutrition and specific
activity of the renal epithelium). He arrives at this conclusion
from studying the action of the gland-extract upon the kidney,
and noticed that the salutary effects of thyro-parathyroid organo-
therapy and of the halogenated fats which are its equivalent, are
entirely wanting or become less, with experimental alteration of
the kidney.

IX. Schiff's ingenious idea of transplanting and grafting the
thyroid to avert the fatal effects of thyroidectomy opened up a
wide field of research, which is interesting both from the
physiological and from the therapeutic point of view. After he
had demonstrated that preventive intraperitoneal grafts of fresh
thyroid are capable of prolonging the life of dogs that were sub-
sequently deprived of their thyroids, it was natural to conclude
that the same treatment might obviate the serious consequences
of total thyroidectomy in man, and be a cure for spontaneous
myxoedema.

Bircher (1889) was the first to graft a piece of human thyroid
into the abdomen of a dethyroidised patient, who exhibited
symptoms of cachexia. He obtained a temporary improvement
which was repeated after a few mouths on renewing the graft.

Horsley (1890) attempted the cure of spontaneous myxoedema
by grafting under the skin or in the peritoneum, the thyroids of
sheep or monkeys (which are histologically very like those of man),
after proving that thyroidectomy in these animals produces a
syndrome which closely resembles human myxoedema. The results
were so encouraging that this method of cure was repeated in a
short time by many others, among them Lannelongue, Kocher,
Bettencourt and Serrano, Merlen, etc.

The most interesting results were, however, obtained by
Eiselsberg (1892), who repeated Schiff's experiments on cats, trans-
planting an excised lobe not to the peritoneum, but to the thick-
ness of the abdominal wall, and then a month later when the
graft might be supposed to have taken excising the other lobe.
Of the many cats thus operated on, four long survived and
exhibited no morbid symptoms. Three months after grafting,
Eiselsberg exposed the transplanted gland, and found that it was
attached by vascular adhesions ; he then excised it again, and
found normal glandular structure under the microscope. Two
days after this second operation the animals developed acute
tetany, and soon died. It is thus possible, even if exceptional,
for the transplanted thyroid to become rooted in other than
its normal surroundings. This is an experimentum crucis, by
which the too - ingenious theory which Cyon founded entirely
upon the peculiar nervous and vascular relations of the thyroid
is invalidated.

PHYSIOLOGY CHAP.

These experiments have recently been confirmed by Christinni
(1901) on a large number of animals.

He gives certain important details in regard to the method of
performing the thyroid graft so that it shall take well.

X<> arbitrary quantity of thyroid can be grafted, but only such
an amount as is required by the body in each individual case. If,
e.g., a whole thyroid is grafted on a completely dethyroidised rat, it
may become attached as a whole, but if a whole thyroid, or several
thyroids, are grafted^ on a partially dethyroidised rat, a part only
takes root, corresponding, to a certain degree, with the deficit.

This shows that the action of the thyroid is, generally speaking,
more useful to the body in proportion as the maximal intensity of
its function is contained within physiological limits.

Graves or Bascdow's disease, which is characterised by a
well-known complex of symptoms (tachycardia, oesophthalmia,
increase of general katabolic processes, etc.) is now attributed by
the majority of clinicians to exaggerated activity of the thyroid,
whatever the conditions which initiated it. The same syndrome
is also exhibited when thyroid preparations are administered to
persons whose thyroid is normal, as, e.g., with the therapeutic object
of reducing obesity.

However efficacious in this direction, the cure is so dangerous
owing to its tendency to produce the symptoms of Graves' disease,
that it has now been generally abandoned (Strlimpell).

Eiselsberg, having failed with other clinicians in the radical
cure of spontaneous or operative niyxoedema by thyroid grafting,
owing to the difficulty of regeneration, put in practice SchitT's
suggestion by preparing a thyroid extract, and injecting it beneath
the skin of dethyroidised animals. His results, however, were not
encouraging, either from the position of the injection, or from the
amount of juice injected. Vassale was more fortunate. At the
end of 1890, independent of Eiselsberg, seeing the therapeutic
efficacy of certain drugs injected directly into the veins (Baccelli),
he injected large quantities of thyroid juice into dethyroidised
dogs, and obtained a beneficial, though transitory, action from such
injections. These results were amply confirmed by Gley (1891),
and applied very successfully by Murray (1893), both in a case
of spontaneous myxoedema and in a monkey deprived of its
thyroids.

A year after Murray's first cure of myxoedema Howitz,
Mackenzie, and Fox substituted the administration of thyroid by
the mouth for venous injections. This method is very simple, and
within the grasp of all ; and it gives surprising therapeutic
results in cases of myxoedema which have gone on for years, and
proved refractory to all kinds of treatment. This shows that the
active principles of the thyroid juices are not decomposed by the
action of the digestive secretions.

i INTEENAL PEOTECTIVE SECEETIONS 29

The salutary effect, both of injection of thyroid juice and of
thyroid ingestion by the mouth, is probably owing to the fact that
it facilitates the elimination of the toxic products accumulated in
the blood. In this connection the following observation of Yassale
is interesting : " After the injection of thyroid juice," he wrote in
1892, " the animal as a rule drinks water, sometimes in very large
quantities ; it subsequently excretes an excessive amount of urine,
after which it returns to its normal condition, and remains well
for at least twenty-four hours. It seems as though the animal
drinks much water in order, with the large amount of urine it
then evacuates, to wash the body free of a toxin that had previously
accumulated in the blood and tissues." This gives weight to our
hypothesis that the thyroid secretion normally has the function of
directly or indirectly exciting renal secretion.

The work of Godard and Slosse, carried out under Heger's
direction, also supports this point of view. According to these
experiments, the thyroid juice has a lyrnphagogic action, analogous
to that exhibited by the lymphagogues of Heidenhain's second
category (Vol. I. p. 523 et seq.\ which indirectly promote diuresis
by transporting water and the products of katabolism into the
lymphatic sinuses and vessels and the blood.

From the physiological point of view these results show that
the protective action of the thyroid depends on the specific
character of the chemical substances which it contains, and which
normally pass into the blood by continual internal secretion.
Many workers have therefore devoted themselves to research in
this direction by chemical analysis of the thyroid juice. Their
results are interesting, though inadequate for the solution of this
difficult problem.

Notkin (1895) prepared a special substance from calf's thyroid
which he termed thy r eo - protein ; this on injection into a dog
recently deprived of its thyroid induced phenomena of tetany
that subsequently ceased, to reappear at each fresh injection. He
concluded that it was this substance (normally retained by the
thyroid and rendered innocuous) which causes the auto-intoxica-
tion consequent on thyroidectorny. In addition to thyreo-protein
Notkin isolated another indefinite substance from thyroid extract
which he termed tliyreo-gummin ; this acts upon the former and
transforms it into an innocuous substance, necessary to the nutrition
of the body. He was in fact able to neutralise the noxious effects
of thyreo-protein by simultaneous injection of thyreo-gumniin.
These very suggestive results have not, so far as we know, been
repeated or confirmed by other workers.

Frankel simultaneously affirmed that the active principle of
the colloid substance, or secretion, which the thyroid pours into
the lymph and blood system, is a rnucin, which he obtained from
the watery extract of boiled and filtered thyroid. He called it

30 PHYSIOLOGY CHAP.

thyroid-antitdxin, and maintained that it was capable of inhibiting
the appearance of cachexia when injected into dogs deprived of
the thyroid.

These experiments of Notkin and Fraukel were abandoned as
soon as the work of Baumanu (1895-96) appeared. He proclaimed
the discovery of iodine in the thyroid, and raised hopes that the
active principle of the thyroid had been found in an organic
compound of iodine, to which the name of thyro-iodine was given.
Baumann, with Ross and with Goldmaun, Hofineister, Hildebrand
and Irsai, maintained that the injection of thyro-iodine into the
veins was able to compensate for the functions of the thyroid
when that organ had been excised. The experiments of Gottlieb
(1896), Wormser (1897), and Pugliese (1898) contradicted this
vicarious action of thyro-iodine. According to Wormser, thyro-
iodine is " neither capable of impeding the onset of an attack
of tetany nor of arresting an attack that is already running
its course."

On the other hand, by injection of the gland, as a whole,
whether administered by the mouth or injected into the veins in
the form of an extract, in sufficient quantity, it is possible to
check the paroxysms of tetany, and to keep the dethyroidised
animals alive for a long time, as was first demonstrated by Vassale.

Other facts tell against Baumann's theory. According to his
own researches, the thyroid of dogs after a flesh meal contains
either no iodine or the merest traces of it. Iodine is rarely found
in the pig's thyroid ; hardly any, or merely a trace, in the thyroid
of sheep and horse (Topfer). The human thyroid does not contain
it constantly (Baumann). The subsequent researches of Neu-
meister and Malthes (1897) showed that iodine is frequently
absent in the thyroid of adults and infants, and that while that
of the ram and pig contains 50'9 mgrms. of iodine per gramme of
dry gland, that of the dog, horse, and calf contains either none or
merely traces of it. Thyro-iodine cannot therefore be the active
principle required, although it is probable that the iodine, intro-
duced in minute doses with vegetable aliments, is retained and
fixed in organic form by the thyroid gland. It has been observed
that the iodine of the thyroid increases after the medicinal use of
iodides and iodoform.

On the other hand, the experiments of Coronedi and Marchetti
on the biological importance of halogens to the function of the
thyro - parathyroid apparatus have thrown new light on the
subject. They actually succeeded in rendering animals (dogs and
rabbits) perfectly immune against cachexia and tetany, and
were able to cure them easily, when already attacked, by the
administration of iodine or bromine in an alimentary form
(halogenated fats), which can easily be stored in the adipose
tissue of these animals, since, in comparison with normal animals,

i INTERNAL PEOTECTIVE SECRETIONS 31

they have a decided tendency to retain such halogens in the
body. When the organic supply of halogen conies to an end, as
may occur after months or even years, the characteristic symptoms
of thyro-parn thyroid deficiency reappear.

Bunge (1898), on the simple ground of analogy, propounded
the hypothesis that the protective antitoxic substance secreted
by the thyroid consists in an unstable protein compound, belonging
to the enzyme group, with the property of producing large effects
by infinitesimal doses. When poured into the blood along with
the colloidal substances, this enzyme would influence the metabo-
lism of the body and accelerate the elimination by the renal outlets
of the katabolic products as fast as these are formed. But as
yet no experiments are to hand in direct evidence of this
hypothesis.

X. In order to explain the fact that some animals (rabbits
constantly, and dogs in certain rare cases) can bear the complete
ablation of the thyroid without injury, Schiff (suprct) proposed
the hypothesis that the body contains another organ capable of
supplementing the functions of the thyroid. This hypothesis led
to a number of ineffective researches, with the object of determining
which this vicarious organ could be.

Fano (1893) showed that the removal of one suprarenal
capsule, of the salivary glands, the ovaries, and a large portion of
the pancreas, produced no modification in the sequelae of subsequent
'total thyroidectomy.

That no functional relation exists between the thyroid and
the spleen was plainly shown by the experiments of Tizzoni and
Fileti (1883-84), of Sanquirico and Canalis (1884), of Ughetti and
Mattel (1885), and others. In 1893 Zanda revived the subject,
and stated that thyroidectomy was not fatal in dogs, if performed
about a month after spleuectorny. Had these results been con-
firmed, they would have been of great importance, justifying the
hypothesis put forward by Zanda, that the spleen pours toxic
products into the blood, which the thyroid renders innocuous.
Unfortunately, the later experiments of Fano, Vassale, and Di
Brazza proved that dogs and cats, deprived of their spleen, w*ere
liable more than a month afterwards to the effects of thyroid-
ectomy, like normal animals.

The principal argument against the existence of any functional
relation between spleen and thyroid rests on the recent histological
work of Massenti and Coronedi on the first of these organs in the
dethyroidised dog. The spleen undergoes a process of sclerosis
and atrophy, which is the more advanced in proportion as the
survival power of the animal to thyro-parathyroidectomy is
greater.

Nor was the work of Marie and Mobius, of Cadeac and Gurnard
(1894), who sought to establish a functional relation between the

PHYSIOLOGY CHAP.

thyroid and the thymus, more successful. Gley (1894) demon-
strated the fallacy of this theory.

Attempts to demonstrate a functional relation between the
thyroid and the glandular portion of the cerebral hypophysis or
pituitary gland succeeded better. These results will be referred
to below, in their proper connection.

It is to Gley (1892) that we must ascribe the merit of having
pointed out the importance of the parathyroid glands, previously
discovered by Sandstrom. Along with the thyroids, he excised
the two little glands of Sandstrom in rabbits, which died, under
these circumstances, with symptoms of tetany, even when the
removal of the parathyroids was effected a month later than that
of the thyroids. But when the parathyroids alone were excised
in rabbits, no pathological symptoms appeared. He concluded
that the parathyroids acquire great importance only after the
extirpation of the thyroids probably because they have the
function of vicariously replacing them. In confirmation of his
hypothesis, Gley observed that the parathyroids become hyper-
trophic a month after the excision of the thyroids, and exhibit
modifications by which their structure approximates to that of
the thyroids, as if they were embryonic thyroids intended to
supplement any functional insufficiency of the adult gland.

Subsequently, in collaboration with Phisalix (1893), he per-
formed the same experiment on dogs, and came to the conclusion
that these animals also survived the complete extirpation of the
thyroids, when precautions were taken to spare the parathyroids
and leave them in situ; while symptoms of tetany inevitably
supervened, when the latter were also extirpated. Ablation of
the parathyroids alone did not, according to Gley, produce morbid
sequelae. This confirmed his theory of the supplementary function
of the parathyroids.

His conclusions were, however, contested by Moussu (1893),
Hofmeister (1894), and particularly by Vassale and Generali
(1896). These authors disputed Gley's observations as to the
structural modifications of the parathyroids after removal of
the thyroids. But as Rouxeau (1896) confirmed the fact of the
conspicuous increase of the parathyroids after thyroidectomy, and
the innocuous effects of simple parathyroidectomy, many people
adopted Gley's view of the functional interchanges between the
thyroid and parathyroid glands.

Gley's hypothesis was first shaken by the accurate work of
Vassale and Generali (1896), which showed that a specific
functional importance distinct from, and even greater than that
of the thyroids must be granted to the parathyroid glands. These
authors excised the parathyroids only on numerous dogs and cats,
and found that they succumbed rapidly, the cats usually in 5, the
dogs in 3 to 4 days after the operation, i.e. the more rapidly in

i INTEENAL PEOTECTIVE SECRETIONS

proportion as the thyro-parathyroid excision was more complete.
Sometimes the animals succumbed after incomplete ablation of
the parathyroid glands, i.e. when one parathyroid only was left
in situ, as usually occurs in the case of dogs that have more than
four parathyroids. As a rule, however, the animals that survive
partial thyroidectomy exhibit slight and transitory pathological
symptoms. These are analogous to the effects of thyro-parathy-
roidectomy acute phenomena of " tetania thyreopriva," which is
speedily fatal, or slight and transient, according as the para-
thyroidectomy was complete or partial. When partial para-
thyroidectomy is associated with total thyroidectomy, the chronic
phenomena of cachexia thyreopriva set in, with or without slight
convulsions.

In view of their significance, the experiments of Vassale and
Generali were at once repeated and confirmed in France by
Moussu (1897). Of four dogs on which he performed total
thyroidectomy, three died of tetauy on the 2nd and 7th day,
and the fourth survived because (as shown at the post mortem) it
had a fifth supernumerary parathyroid.

Edmunds and Welsh (1898) independently repeated and con-
firmed the results of Yassale in England.

The same work was continued in Italy by Capobianco and
Mazziotti (1899), and more extensively by Lusena (1899). The
latter, in a fine series of comparative experiments on dogs,
shows

(a) That the (chief) characteristic symptom of thy ro- para -
thyroidectomy is coma, the period from the operation till death
being on an average 1 days ;

(I) That the characteristic symptom of parathyroidectorny is
tetany, the interval between the operation and death being usually
3 days ;

(c-) That the excision of the thyroid, including the two internal
parathyroids (which, as we shall see, are included with them) is
not fatal if perfect nutrition is maintained in the two external
parathyroids which are left in site.

Lusena, in order to confirm the fact that the presence of
the thyroids aggravates the pathological syndrome of total
parathyroidectorny, conceived the idea of excising the thyroids
iu dogs already deprived of their parathyroids, which were on
the point of dying from tetany, and saw that the convulsive
phenomena were gradually attenuated, and a state of comparative
amelioration introduced, so that the fatal issue was postponed.

The effects of parathyroidectorny can also be attenuated by
the so-called sulstitutive therapeutics, i.e. by hypodermic, or better
intravenous, injections of aqueous extract of the parathyroids
alone. These experiments were performed almost simultaneously
by Moussu and by Lusena (1898). Moussu showed that such

VOL. II D

34 PHYSIOLOGY CHAP.

injections, besides suspending the phenomena of tetauy, effected
a sensible prolongation of the life of the animal. Luseua added
the further fact that injections of pure thyroid juice exerted no
beneficial influence on the syndrome of parathyroidectomy or
thyro-parathyroidectouiy, and that the injection of the juice
prepared from the thyroids of dogs that had tetany from para-
thyroidectomy, aggravated the symptoms of thyro-parathyroid-
ectomy. This last result rests on a single experiment only, and
deserves to be confirmed by further research.

Lastly, Lusena has established by the method of reciprocal
transfusion, or that of the partial substitution of the blood by an
isotonic solution of sodium chloride, that the phenomena of tetany
in parathyroidectomy can be suspended or attenuated like those
of thyro-parathyroidectorny. In the first as in the second case,
accordingly, there must be toxic substances in the blood of the
animals that have been operated on.

All these interesting data as to the functional importance of
the parathyroids throw new light upon many obscure points, and
subtract not a little from the value of the earlier conclusions as
to the physiology of the thyro-parathyroid system.

We can now see why rabbits and other animals frequently
survive complete extirpation of the thyroids, and why even dogs,
on which the greatest number of experiments have been carried
out with positive results, may also survive. This is evidently
due to the fact that the external parathyroids are constantly in
rabbits, and occasionally in dogs, distinct from the thyroid lobes,
and are therefore left in situ when those lobes are excised.

So, too, we can explain why, after excision of goitre, the patient
may only exhibit symptoms of a slowly progressing cachexia
thyreopriva or operative myxoedema, while in other less frequent
cases acute phenomena of tetany supervene. Previous to the
investigation of the parathyroids, these two essentially distinct
pathological forms were regarded as different steps of one identical
process, due to the abolition of the function of a single gland,
the thyroid. Cachexia thyreopriva is now held to be the effect of
functional deficiency of the thyroid gland alone, and tetany the
effect of inhibited function of the parathyroids. In excision of
goitre by the subcapsular method, the surgeon in the majority of
cases leaves the inferior parathyroids, which are distinct from
the thyroid lobes ; but in certain cases the inferior parathyroids
are included in the ablation of the thyroid, being joined to the
body of it. In the first case cachexia ensues, in the second tetany.
Sometimes there may be transitory or intermittent tetany, in
consequence of functional insufficiency of the parathyroids. This
occurs, according to Yassale, when a single inferior parathyroid
is left in situ during the operation. In order to avert this
pathological consequence, it is necessary for the operator to spare

i INTERNAL PROTECTIVE SECRETIONS

the lowest portion of the thyroid body, as well as the inferior
parathyroids.

Opinions differ at present as to the functional relation between
the thyroid and the parathyroids. Cley (1898) was inclined to
admit the existence of such an association between them, and
to think that the parathyroids prepared a substance which is
subsequently taken up and poured into the circulation by the
thyroids. According to Moussu, Vassale, and Generali, on the
other hand, the two glandular functions are independent and differ
specifically from one another. The thyroids have an essentially
trophic function, i.e. they secrete substances indispensable to
good general nutrition, particularly to the nervous and skeletal
systems ; the parathyroids, on the contrary, have an antitoxic
function, i.e. they neutralise or facilitate the elimination by the
kidneys of the toxic substances formed during metabolism.

How, then, are we to explain the fact suspected by Vassale and
established by Lusena, to the effect that after simple parathyroid-
ectomy the convulsive nervous symptoms are more grave, and
lead more rapidly to a fatal issue, while after thyro-para-
thyroidectomy they are less serious and run a more protracted
course ? In order to account for this difference Lusena assumes
that in dogs deprived of the parathyroids only, the quantity of
toxic substances circulating in the blood is greater than that
circulating after complete thyro-parathyroidectomy. He believes
that the thyroids normally have the property of subtracting from
the blood the materia peccans of unknown character, to return it
transformed and innocuous ; and he holds this antitoxic function
of the thyroids to be dependent on the normal function of the
parathyroids, so that when the latter are removed a larger amount
of poison circulates in the blood.

This bold hypothesis does not --it seems to us explain
the fact that the subsequent excision of the thyroids con-
spicuously attenuates the symptoms of tetany consequent on
parathyroidectomy. If, after removal of the parathyroids, the
thyroids are no longer capable of abstracting and transforming
the materia peccans in the blood, it is difficult to see why their
extirpation should diminish the symptoms of auto-intoxication.

Vassale's theory is simpler, and suggests a better interpretation.
He holds the specific function of the thyroid gland to be that of
pouring into the circulation a secretion that excites and promotes
general metabolism. The myxoedenia consequent on functional
deficiency of the thyroid exhibits a complex of symptoms which
clearly indicate a reduction or perversion of the metabolic
exchanges, and the therapeutic action of thyroid juice or of
ingestion of thyroid in spontaneous or post-operative myxoedema
is characterised by phenomena of quickened metabolism. The
parathyroids, on the contrary, have a specific antitoxic function.

D l

36 1'IIYSIOLOGY CHAP.

'Hi is may l>r because they throw into the circulation a secretion
that accelerates the renal elimination <>f the products of tissue
consumption; and these in all probability constitute the materia
peccans. The tetany consequent on parathyroidectomy is a neces-
sary consequence of the accumulation of katabolites owing to the
defective function of the parathyroids, and the therapeutic action
df parathyroid juice is the proof that the parathyroids contain
protective antitoxic substances.

On this assumption it is easy to understand why parathyroid-
ectomy alone determines an acute auto-intoxication, and thyro-
parathyroidectomy a less acute auto-intoxication, which runs a
slower course. In the first case, where general metabolism is
active, owing to the presence of the thyroid, the amount of
toxic matters accumulating in the blood is larger ; in the second
it is, on the contrary, smaller, because metabolism is reduced
owing to absence of the thyroid. This is the reason why the
de-parathyroidised animal is attacked by morbid symptoms, when
subjected at a later period to thyroidectomy.

In support of his views Vassale adduces the following experi-
mental data :

(a) The phenomena of " tetania parathyreopriva " are more
serious in young than in very old animals.

(&) The said phenomena are more acute and more rapidly fatal
to the animal, if it eats much, especially meat, after the operation.

(c) Fasting reduces the pathological syndrome consequent on
thyro-para thyroidectomy.

(d~) In animals deprived of the parathyroids alone, when
metabolism is normal, cicatrisation of the wound in the neck
occurs regularly by first intention ; in animals deprived of the
whole thyroid body it is on the contrary difficult in spite of
every antiseptic precaution - - to obtain healing of the wound
per primam, owing to the sluggish metabolism.

In conclusion, we must add that, according to the latest
researches of Alquier and Theuveny (1907), and of Vassale's pupil
Massaglia (1908), the renal lesions which are, as we have seen,
inevitable on the extirpation of the entire thy ro- parathyroid
system, are in reality due solely to the suppression of the para-
thyroids, their secretion no longer being able to neutralise the
toxic products of metabolism, which therefore injure the renal
system, producing albuminuria and tetanic convulsions.

The pathological anatomy of man confirms the experimental
data from other animals, i.e. it teaches us that the tetany of
thyroid excision, the so-called "tetania thyreopriva," is only a
"tetania parathyreopriva." We owe to Erdheini some careful notes
on serial sections of the organs of the neck in three persons who
died from tetany after excision of the thyroid. In two of these
the parathyroids were entirely wanting, in the third, one only

i INTERNAL PEOTECTIVE SECRETIONS 37

remained, and that was necrosed. These three cases, therefore,
verified what experiments on animals had indicated. To-day
every surgeon agrees with Vassale's conclusions that in thyroid
excisions it is essential, in order to avoid a fatal tetany, to spare
at least one or possibly two of the parathyroids (the two inferior
parathyroids).

Another form of human disease which is also characterised by
violent convulsions, and which is known as eclampsia yravidica,
has recently been attributed by Vassale and his pupils to
functional insufficiency of the parathyroid apparatus. To support
this theory Vassale invokes the following facts :

In the first place, he observed and described a case of tetany of
lactation and pregnancy in a partially parathyroidectomised bitch,
in which after some five years of apparently normal life after the
operation, suckling and pregnancy provoked violent convulsive
epileptiform fits, which were cured by specific organo-therapy.

Other authors had already observed independently that the
female of dogs or cats, in which the thyroid apparatus had been
partially extirpated, are attacked during pregnancy and parturition
\\-ith acute convulsions (Verstraeten and Vanderlingen, Lange).
According to Vassale, the convulsions in this experiment also, in
which thyroidectorny involved parathyroidectomy in the dog or
cat, were due to parathyroid insufficiency.

Another no less valid argument in favour of the parathyroid
theory of the pathogenesis of eclampsia gravidica is seen, according
to Vassale, in the beneficial effects observed in certain cases of
spontaneous eclampsia gravidica with specific organo-therapy, on
administration of parathyroidine.

More recently, Vassale has found further evidence for
the parathyroid theory of eclampsia in the following observa-
tions :

(a) Pathological, the post mortem showing alterations or con-
genital loss of one or two parathyroids in the bodies of eclamptics
(Pepere, Zanfrognini).

(6) Clinical, since it has been found possible to prevent and
even overcome the spasm by the administration of parathyro-
iodine (Zanfrognini, Stradiviri, Brim, Vicarelli, Kaiser).

(c) Experiments on cats, on female rats, and gravid bitches,
which show that in latent parathyroid insufficiency convulsive
phenomena regularly break out in the final stage of pregnancy
(experimental eclampsia of Zanfrogniui, Erdheim, Thaler, and
Adler, Vassale, Massaglia and Sparapani).

Lastly, it should be added that certain workers (Pineles,
Chvostek and Yanase) express the opinion, on clinical and ana-
tomical grounds, that all the varied pathological forms of tetany
in man are in pathogenic relation with insufficiency of the
parathyroid glands.

D 2

38

PHYSIOLOGY

CHAP.

XI. The Pituitary Body (hypophysis cerebri) consists of t\\<>
distinct parts or lobes (Fig. 7). The posterior lobe, which is
greyish-yellow, is an outgrowth from the third ventricle of the
brain ; it has no glandular structure and is probably a rudimentary
organ of no importance in vertebrates at any rate. The anterior
lobe, on the contrary, which is reddish in colour, and is much
more highly developed than the posterior lobe, has quite a distinct
function, and is derived from the primitive pharynx. At a certain
point in embryonic development it appears as a pouch, which is
empty at first, and subsequently fills by the development of

FIG. 7. Hypophysis or pituitary body. A, lateral aspect, showing relations with .sella tmcica.
B, posterior aspect. C, sagittal .section, a, anterior lobe <>f hypophysis (pituitary body
proper) ; ?, posterior or nervous lobe ; c, pineal peduncle ; <l, optic chiasina ; e, infundibulum ;
/, optic foramen ; <j, quadrilateral plate of sphenoid ; 7i, sulcus occipitalis.

epithelial cells disposed in groups or columns, which recall the
structure of the parathyroids. Two kinds of cells can be distin-
guished, the chief cells and the chromaphile (Fig. 8).

The latter have a special affinity for stains, and react like
" colloid " substances ; they are probably more developed than the
chief cells, and serve for the secretion of a hyaline substance,
in analogy with the epithelia of the thyro- parathyroid system
(Lothringer). The secretion passes into the lymphatic spaces of
the surrounding connective tissue, and also in part to the blood-
vessels, in which it may for short distances replace the blood
entirely (Pisenti and Viola).

Experiment on the functions of the pituitary body has led to

INTEKNAL PROTECTIVE SECRETIONS

39

divergent, often indeed contradictory, results. Hypophysectomy,
initiated with little success by Horsley, Dastre, Gley, Marinesco,
was pursued with a better technique by some of the Italian
workers.

Vassale and Sacchi (1892-94), in a considerable number of
experiments on cats and dogs, obtained the survival of a few
individuals, in which the hypophysis had been totally or partly
destroyed by cauterising with chromic acid, a method that is
certainly not free from objection.

The first symptoms observed in these animals is that of great
depression and complete apathy, making them indifferent alike to
caresses or ill-treatment.
Motor disturbances, at
first slight and afterwards
more intense, set in. These
consist of fibrillary move-
ments, muscular contrac-
tions, rigidity of posterior
limbs, curvature of back,
unsteady gait,lastlyclonic-
uonic spasms of varying
intensity, in the course of
which the animal sue -
ciimbs without the slight-
est trace of infective or
other complications being
discovered at the post
mortem. With these
symptoms are associated
anorexia, tachypnea, polyuria, growing density of highly alkaline
urine (without either albuniinuria or glycosuria), hypothermia,
rapid and progressive emaciation, coma not infrequently preceding
death, which occurs in 2-11 days after the operation.

Gatta (1896) and Kreidl and Biedl (1897) repeated these
experiments, and obtained results which agreed approximately
with those of Vassale and Sacchi.

The syndrome obtained by Caselli (1900) in his many experi-
ments on hypophysectomy in both dogs and cats was somewhat
different: depression of mental powers, motor disturbances,
curvature of back, spastic gait without convulsions, progressive
cachexia, rapid loss of weight, coma, death.

This syndrome has undeniable resemblances with that which
appears after excision of the thyro-parathyroid organs, justifying
the surmise of Rogowitsch (1888) that the pituitary and the
thyroid glands are homologous, and are therefore able to function
vicariously. In order to discover why rabbits always support
thyroidectomy without injury, he made a microscopic examination

pil

Weigert's method. (Lothringer.) The lighter, ]>rinci)jul
cells can be distinguished from the darker, chromaphile
cells.

40 PHYSIOLOGY CHAP.

of the various organs of these animals in search of possible
modifications. The glandular part of the hypophysis proved to
be considerably larger in volume, with bigger follicles, and more
colloidal substance in the interfollicular spaces. This led him to
conclude that in rabbits the hypophysis might supplement thyroid
deficiency.

The experiments of Eogowitsch were repeated and confirmed
by Stieda (1890), Hofmeister (1882), Gley (1892), and others.

Tizzoni and Centanni (1890) observed the same facts in three
dogs that long survived total thyroidectomy as Eogowitsch had
noted on rabbits, and came to a similar conclusion. Schdueiuann
(1892) adduced the results of clinical observation in support of
the same thesis, and demonstrated a hypertrophy of the pituitary
body in cases of goitre, when a great part of the parenchyma of
the thyroid gland does not function. These observations, although
contradicted by Schwarz, have recently been confirmed by Conite.

This theory of a close relation and functional substitution
between the thyroid and the hypophysis was shaken by the work
of Vassale and Sacchi, and of Caselli, while the later observations
of Gaglio on amphibia (1900), and of Lo Monaco and Van Eyn-
berk in our laboratory (1901) on dogs, proved that the syndromes
brought forward to support it are not the necessary and direct
consequences of loss of the pituitary body.

Moreover, Luzzatto, working in Coronedi's laboratory on the
hypophyses of animals that long survived the total ablation of
the thyro-parathyroid apparatus, never succeeded in finding any
morphological indication of hypertrophy of the pituitary body
from exaggerated function.

The same negative results were obtained by Friedemann and
Maass in Germany, and more recently by Dalla Vedova (1903) in
the Institute of Surgery in Eome. Thus, whatever may be the
function of the pituitary body, we now know that it is not of
sufficient importance for its complete ablation necessarily to
bring about the death of the animal, provided the technique
is satisfactory.

Nor did Cyon's experiments (1898-1902) lead to more
positive results. Starting from his work on the thyroid he
assumed that the hypophysis co-operated with this organ in
maintaining equilibrium of endocranial pressure, founding his
theory upon the alterations of pressure consequent 011 injections
of pituitary extract obtained by various methods. It may be
remarked that the results of various experimenters as to the
role of the supposed active principles of the pituitary gland
differ widely. According to Szynionowicz (1898) pituitary
extract diminishes blood pressure and accelerates the pulse ;
Schafer and Swale Vincent (1899) say that it raises blood pressure ;
Mairet and Bosch (189G), that it excites the nervous system ;

i INTEENAL PEOTECTIVE SECEETIONS 41

Osborne and Vincent, on the contrary, that it has a depressing
action ; Howell (1897), that it retards and reinforces the pulse ;
according to Cyon, lastly, it contains two active substances, the
one retarding, and the other accelerating, the pulse.

Cyon thought he had demonstrated that the hypophysis
regulates eudocranial pressure, slowing and strengthening the
pulse, and reducing blood pressure, by the fact that its direct
stimulation by gentle mechanical compression and weak electrical
currents, produced these effects. It is difficult to determine
exactly how much of this interpretation can be accepted. The
situation of the pituitary body justifies the assumption that its
excitatory impulses are transmitted by the lobule of the infundi-
buluin to the cardiac centres of the vagus. If this be so, it plays
no part in the production of the phenomena described.

Gaglio, moreover, found that in frogs operated on by hypo-
physectorny, the bulbar centres of the vagus are as excitable to
increased blood pressure, not only days and weeks, but also a few
hours, after the operation, as in normal frogs. This does not agree
with Cyon's observations on rabbits.

Nor has clinical observation thrown more light on the functions
of the hypophysis. Since Marie and Marinesco (1891) suggested
that acromegaly was the expression of a systematic dystrophy,
consequent on functional disturbance of the pituitary body, many
new facts have militated against their theory. Collina (1898)
diligently collected all cases of this disease in which there had
been a post mortem. He found that in a large majority the tumour
was represented by adenomata and sarcomata. On the other hand,
as was observed by Striirnpell (1897), hypophysal tumour is not
invariably present in acromegaly, while such a tumour often
occurs without acromegaly. As regards organo-therapy, Mendel
and Marinesco (1895) noticed improvement with pituitary ex-
tract ; Schultze, on the contrary (1897), denied that it had any
beneficial action.

The function of the hypophysis is therefore wholly un-
determined, and it may be stated in conclusion that of the
various far-fetched and improbable theories, that proposed by
Eogowitsch as above appears least hazardous, although it has
not been demonstrated.

Among the more recently acquired experimental data the
following should be noted.

<_3

Guerrini (1904) found, by a series of microscopic researches
on various animals, that the pituitary body, in every alteration
of metabolism due to endogenous or exogenous intoxication,
exhibits phenomena of functional irritation analogous to those
shown in other glandular organs ; if protracted, these may lead
to hypertrophy and hyperplasia of the parenchyma of the gland.

Fichera (1905) in a first series of experiments (macroscopic

42 PHYSIOLOGY CHAP.

and microscopic) on fowls, buffaloes, oxen, rabbits and guinea-
pigs, concluded that there is an intimate relation between the
hypophysis and the sexual glands (testicles, ovary), which, as we
shall see elsewhere, are also the seat of an important internal
secretion.

He found in castrated animals that removal of the testicles or
ovaries led rapidly to hypertrophy and hyperplasia of the pituitary
body, which showed histological modifications indicative of func-
tional hypertrophy. If the castrated animals are treated by
organo-therapy with the sexual glands, the irritative phenomena

of the parenchyma of the hypophysis are
reduced and eventually disappear.

In a second series of experiments, Fichera
(1905) destroyed the hypophysis in fowls by
a new method of operating. He found in a
number of experiments, confirmed by micro-
scopic examination, that this organ was not
indispensable to life. Animals that survived
its total destruction merely exhibited an arrest
of development, particularly as regards the
skeleton.

Gernelli has recently obtained almost
identical results.

Cerletti (1 906 - 8), studying in young
guinea-pigs, rabbits, dogs, and lambs the effect
on somatic growth of continuous injection of

Fir.. 9. Right kidney and , , . , J

suprarenal body of a full- extract of lamb s hypophysis, showed that
view." (Au!n US Thonfs r ono this substance particularly affects the de-
>, suprarenal capsule ; v velopmeut of the skeletal system, although

vein issuing from it; r, J.

foetal kidney ; a, renal in ail Opposite 861186 to what might 1)6 expected

artery and vein emerging P _r, - TT

from hiiium ; n, ureter, iroiii the preceding experiments. He con-
cluded from his observations that persistent
dosage with pituitary extract retards the growth of the body in
general, as shown most deleteriously for the skeletal system, where
the activity of the connecting cartilages (delay in lengthening of
long bones) is conspicuously diminished, while the activity of the
periosteal ostogenic function (increased development of depth of
epiphyses and diaphyses) is, on the contrary, augmented. Control
animals treated with extracts of other organs (thyroid, muscle) did
not exhibit similar changes.

The results of these new experiments indicate that the hypo-
physis is a gland of internal secretion, serving in some way to
excite or regulate the metabolism of the body and the development
of its various organs, particularly of the skeletal system. While
too indefinite to represent an exact theory of the function of the
hypophysis, this view is, on the other hand, supported by clinical
observations on acromegaly and gigantism, which are often, if not

INTERNAL PEOTECTIVE SECRETIONS

43

always, accompanied by hypertrophy and hyperplasia of the
pituitary body.

XII. The Suprarenal Capsules or Adrenals are two epithelial
flattened bodies of a yellowish- brown colour, situated above the

'. ?;* / F

<

- -'. -.-:, - -..

fi_ /
J

FIG. 10. A, Human suprarenal body; vertical section. (Eberth). 1, cortical substance; 2,
medullary substance ; a, capsule ; '/, zona glomerulosa ; <, zona fasciculata ; d, zona reticularis,
e, groups of medullary cells ; /, section of a large vein. B, cortex of dog's suprarenal ; vertical
section. (Br.hm and v. Davidoff.) a, fibrous covering; 6, zona glomerulosa; c, zona fasci-
culata ; (/, zona reticularis.

kidneys, each weighing about four grammes. They reach their
maximal development during in tra- uterine life. Their size
is considerable in proportion to that of the kidneys in the
foetus at term (Fig. 9). This fact, discovered by Meckel, was
confirmed for man by A. Ecker and H. Frey. It does not, how-
ever, signify (as Bischoff maintained) that the functions of the
suprarenals are in relation with embryonic life, since they would

II

PHYSIOLOGY

CHAP.

X

- . ' f

; Wi-

X ' *I * ' . w

in that case atrophy after birth, wliereas their growtli continues,
though very slowly, till the adult age (Brown-Sequard).

In section, the fibrous sheath is succeeded by a broad cortical
layer, hard, striated in appearance, and dark yellow, which forms
the principal mass of the gland, and an inner, medullary part,
soft and brownish in colour: the older anatomists took this to be
a dense secretion collected in a cavity, from which they incorrectly
designated the whole organ a capsule (Fig. 10, A).

From the fibrous sheath, which often contains plain-muscle
cells (Fusari), fine septa or trabeculae are given off into the
organ, and serve as a framework which supports the columns

of polyhedral epithelium
cells.

Three zones can be dis-
tinguished in the cortex,
better in some other animals
than in man, which are differ-
entiated by the arrangement
of the epithelium cells : these
are known as the zona
glomerulosa, the zoua fasci-
culata, and the zona reticu-
laris (Fig. 10, B).

The medulla is separated
from the cortex by a sheet of
loose connective tissue. It
is composed of a network,
the meshes of which enclose

FIG. ll.-Medullary substance of suprarenal body of cell - Columns, which differ
ox, stained haematoxylm. (Vassale.) o, resting '

cells ; h, cells in active function, filled with trOUl those 01 the COl'tCX in

chromattine substance which is discharged directly i i t ^

into the blood capillaries. being larger, less granular,

more irregular in form, and

vacuolated, and they stain a brown colour with solutions of
chromic acid and its salts, while the cortical cells give hardly
any such reaction. Owing to this specific property the medullary
cells have been termed cliromaffine or cliromaphile (Kohn), a term
now frequently used to distinguish the medullary from the
cortical substance (Fig. 11).

The difference between the two parts of the adrenal glands
is not confined to this histological peculiarity. According to
recent work in embryology and comparative anatomy, the
medullary and the cortical substance represent two perfectly
distinct and independent organs, which in the majority of verte-
brates fuse together during foetal development, and apparently
form only one single organ. In the Elasmobranchs, on the
contrary, the two organs remain separate during the whole of the
animal's life. Balfour (1877) showed that these fishes have no

INTERNAL PROTECTIVE SECRETIONS

45

"suprarenal capsules" analogous to those described in mammals, but
possess two sets of perfectly distinct organs :

(a) The inter -renal body, an unpaired glandular structure,
homologous with the cortical substance of the adrenal gland in
mammals.

(&) The suprarenal bodies, arranged in pairs, in close relation
to the ganglia of the sympathetic chain, homologous with the
medullary or chrornath'ne substance of the adrenal glands.

These results have been confirmed and amplified by recent
workers, among them being
Diamare and Giacomiui in
Italy. '

'The work of embryologists
(of Kohn, in particular) on
mammals, including man, has
fully confirmed the double nature
of the suprarenals. In fact,
while the cortical substance is
mesoblastic in origin (Wolffian
body), the medullary substance
is derived from the phaeo-
chronioblast, one of the two
groups of embryonic cells into
which the primary sympathetic
(ectoderrnic) cells become differ-
entiated. All such chrornamne
or chromaphile cells derived
from sympathetic ganglion rudi-
ments were classified by Kohn
as parayanglia. At a later
period of development the bulk
of the chromafhne or (as Poll

termed it) pliaeOChrOme tissue Fl(; . io._ Scl i e , nat j c reconstruction of paragang-

lion in new-born rabbit. (.A. Kohn.) A, aorta;
' ', suprarenal body ; P, abdominal paragang-
lion, which, with "its prolongations, joins the
niedull.-iry substance of the suprarenal cap-
sides ; p,p, p, small nodular paraganglia.

enters into relation with the
epithelial substance of the
cortex, in which it is englobed,
and thus forms the medulla of
the gland or "suprarenal paraganglion " (Fig. 12). The whole
of the chromaffme tissue derived from the mother-cells of the
sympathetic ganglia is not, however, enclosed in the capsule :
some of the smaller masses remain in various regions more
or less adherent to the sympathetic ganglia or the blood-vessels.
These nodules of chromaffine substance constitute the carotid
and sacral glands, Zuckerkandl's parasympathetic lody or abdo-
minal aortic, paraganglion, etc., which have long been observed
without definite knowledge as to their origin and significance
(Fig. 13). They are now shown by recent work in embryology,

40

PHYSIOLOGY

CHAP.

histology, and experimental physiology, to be organs entirely
similar to the medullary substance of the suprarenal bodies.

Chromaffine or " paragangliar " tissue is thus closely related to
the nerve cells of the sympathetic system, being in fact differ-
entiated from the same embryonic group of cells. In adult
animals it is still intimately connected with the sympathetic

c.

Fn.. 13. (Left.) Parasympathetic bodies of Zuckerkandl (human). From an anatomical pre-
paration of Sperinn and Balli. A, aorta; I", vena cava ; r, left renal artery; vr, left renal
vein ; ')]>, parasympathetic bodies, or paraganglia ; a' r', artery and vein of right paraganglion ;
a"c", artery and vein of left paragangliun ; mi, inferior mesenteric artery; v.sp, spermatic
or ovarian vein ; filn, aortic plexus of sympathetic.

. 14. (Right.) Paraganglion of adult cat. (A. Kohn.) A, aorta ; B, vena cava ; r, suprarenal
capsule ; D, caeliac ganglion ; .V, sympathetic ; P, abdominal aortic, filiform paraganglion ;
p, punctiform paraganglia.

FIG

system, many ganglion cells being mixed with the cells of
the medullary substance of the suprarenal bodies, while nodules
of chromaffine tissue adhere to the sympathetic chain in various
regions (Fig. 14). Chromaffine tissue has accordingly been defined
as " an epithelial tissue of neural origin " (Diamare).

Functionally, too, we shall find an intimate relation between
the sympathetic system and the product of the internal secretion
of chromaffine tissue.

The arteries that supply the suprarenals penetrate the cap-

i INTERNAL PROTECTIVE SECRETIONS 47

sular sheath at various points, after subdividing into small
branches. The veins in the medullary substance form a plexus,
and usually converge into one large vein for each organ, which
leaves by the hiluin. That on the right opens directly into the
inferior cava ; that on f;he left, after a longer course, into the left
renal vein.

According to Pfaundler, the internal vessels of the suprarenals
have no proper tunica externa and media, only a thin wall consist-
ing solely of intinia.

The lymphatics course through the trabeculae of the cortical
substance, and are connected with the lacunae or fissures lying
between the trabeculae and the columns of cells, and between the
cells themselves (Klein). In the medullary substance the lymph-
atics, which are provided with valves, form a plexus that interlaces
with the venous plexus, and surrounds the central vein.

Both suprarenal bodies and paraganglia contain an enormous
number of nerves deriving from the solar and the renal plexuses
(Fig. 15). They are mainly medullated fibres of different sizes,
interspersed before entering the capsule with a number of small
ganglia. They ramify between the cells of the cortex, and are
most abundant in the zona glomerulosa. In the medulla there
are many ganglion cells united in groups, and nerve fibres,
which are distributed to the vessels and also perhaps to the
gland-cells.

In rare cases one or both suprarenal bodies are absent. More
frequently there are accessory adrenals, which vary in size from a
pin's head to that of a pea. The smallest have no medullary
substance (Rolleston). These accessory capsules are usually found
in the neighbourhood of the capsule itself ; but they are sometimes
partially embedded in the kidney or liver, the broad ligament of
the uterus, and along the spermatic vessels.

In 1789 Cassan observed that the suprarenal capsules are
larger in the negro than in Europeans, which led him. to suspect
that these organs are in some relation with the formation of
cutaneous pigment. Meckel subsequently confirmed Cassan's
observations, but held the greater development of the capsules
in negroes to be in relation with that of the genital organs.
These anatomical observations of Cassan and Meckel are in line
with the work of Addison, published in 1855, which promoted
experimental investigation of the suprarenal bodies, and may be
said to have initiated the physiological study of these glandular

organs.

XIII. Addison was the first to describe a form of disease
which is nearly always fatal, and is characterised by a state of
progressive anaemia, pronounced weakness of cardiac beat,
great irritability of stomach, and general atony of nervous and
muscular system, with abnormal brown or bronzed patches on

48 PHYSIOLOGY CHAP.

the skin. From this last very apparent symptom, he named the
new form of disease " bronzed skin." Addisou believed it to
depend on deficiency or functional insufficiency of the suprarenals,
of which he recognised the great physiological importance. He
further held that there was a relation between the absence or
diminished function of the suprarenals, and the amount of pig-
ment deposited in the skin. By diligent research into the

/f :', -^ I

' ''I-

s&v v!iii ffiit^

'^sr^i^SS

V- O- .',-', ,v

li m H :

'i^jpS r.:'^*/"'* v v' BY
NV^ v .. S^fyJ i L \

l-'n.. lo. Transverse section of abdominal aortic paraganglion of adult cat. (Vassale.) , sym-
pathetic ganglion ; b, b, b, nerves ; c, paragangliar or chroinattine tissue.

pathological anatomy of almost every one who had died of
" bronzed skin," he discovered profound alterations in the capsules
of various kinds, more particularly of a tuberculous nature.

Starting from Addison's researches, Brown-Sequard (1856)
performed a series of experiments on animals, and came to the
same conclusion as the English pathologist, viz. : that the supra-
renal capsules were organs indispensable to life.

On destroying the capsules, Brown-Sequard found that they

i INTERNAL PEOTECTIVE SECEETIONS 49

are peculiarly sensitive in rabbits, which give cries of pain when
one of these bodies is crushed in the forceps. Those of dogs, cats,
and particularly guinea-pigs are less sensitive.

When one capsule only was excised or destroyed by crushing,
Brown-Sequard invariably noted the death of the animal (rabbits,
guinea-pigs, dogs, cats) in less than three days. But he sub-
sequently found that destruction of the right capsule alone was
not fatal. Immediately after the operation the animals rotated
upon their own axis, now in one, now in the other direction, and
the pupils of the side operated on were found to be more con-
tracted. These are inconstant phenomena of stimulation, due
probably to the method of crushing adopted by Brown-Sequard,
in which the many ganglion cells contained in the organ are
violently excited.

The suppression of both capsules invariably kills the animal,
rabbits in 9-10 hours, dogs and cats after 49 hours at most. As a
rule young animals survive longer than adults.

In consequence of the suppression of the capsules, the animals
fall into a state of profound lassitude, which differs from that con-
sequent on any other severe and painful operation by its sudden
onset after 10-15 minutes. The weakness increases, and 15-20
minutes before death assumes the form of regular paralysis, attack-
ing first the hind - limbs, then the fore - limbs, and lastly the
respiratory muscles. Sensibility persists to the last hour, and may
even be exaggerated. Convulsions are frequent in the hours
previous to death. The respiratory and cardiac movements are
usually accelerated at first, and then become progressively weaker.
Appetite disappears : digestion is suspended : urinary secretion, on
the contrary, continues normal. The temperature falls consider-
ably (from 4 -5 C. in winter).

Brown-Sequard, by special experiments, demonstrated that the
excision of both capsules usually involves the death of the animal
more rapidly than ablation of the kidneys. Hence he regarded
them as organs indispensable to life, the death which follows
their removal being due to the lapsed function of the suprarenals.

These data at once aroused opposition. Gratiolet and
Philippeaux (1856-57-58) in France,Berruti and Perosino (1857-63)
in Italy, denied the inevitable death of the animals operated on,
and referred it either to operative traumatism, or to peritonitis
or other secondary effects. Brown - Sequard did not reply
exhaustively to all the criticisms, and the question of the func-
tional importance of the suprarenals remained for a long time a
matter of controversy. The subject has been revived of late, with
strictly aseptic methods, by a number of workers who have con-
firmed, developed, and extended to other glandular organs the
conclusions of Brown Sequard, to whom therefore belongs the
honour of having founded the doctrine of internal secretion.

VOL. II E

50 PHYSIOLOGY CHAP.

Cases of survival of the animal after the excision of both
capsules are rare, and must be explained either by incomplete
extirpation or by the existence of accessory suprarenals
(Szymonowicz). The most important points in the rich modern
literature of the 'plt,ysiolo<jy of the capsules may be briefly
summarised.

The methodical research undertaken by Abelous and Langlois
(1891-92) on the frog showed that-

(a) Complete destruction of the capsule by the method of
cauterisation inevitably causes death (after 12-13 days in winter,
after 48 hours in summer) with symptoms of progressive paralysis,
which commences in the lower limbs (24-30 hours after the
operation) and subsequently becomes general and produces death.

(&) General paralysis follows more rapidly if the frog is
frequently excited after the operation, so as to provoke muscular
movements.

(c) Destruction of one capsule alone produces no morbid effects
in the frog : complete destruction of one capsule and of the greater
part of the other determines death in most cases, but after a
longer time. Deatli is then invariably preceded by convulsions
and dyspnoea.

(d) On grafting the capsules of a normal frog into the dorsal
sac of the decapsulated frog, the survival period of the latter is
doubled. On dissection, the graft is found not to have taken, the
capsules being reduced in volume and decolorised. Injection of a
watery suprarenal extract results in a less marked prolongation
of life.

(e) Intravenous or subcutaneous injection of the blood of a
moribund, decapsulated frog into a frog that has been recently
operated on, causes rapid paralysis and death. The same injec-
tion into a normal frog produces only slight and transitory
disturbances.

(/) If immediately after destroying the capsules in a frog the
sciatic is exposed, and a thread tied round the leg at a lower
point, by Bernard's method, while the blood from a moribund
decapsulated frog is injected under the skin, then at a certain
stage of intoxication (3 hours after injection) the most powerful
induction shocks have no effect on the sciatic of the free limb,
while a weak current easily borne by the tongue produces
energetic contractions from the sciatic of the ligatured limb.
Direct application to the muscles of either leg produces contrac-
tions, which are, however, stronger in the tied than in the free
limb.

From these facts Abelous and Langlois concluded that death
from removal of the capsules is due to the accumulation in the
blood of one or more toxic curarising substances, i.e. such as act
like curare on the end-plates of the motor spinal nerves, and in a

i INTEKNAL PKOTECTIVE SECKETIONS 51

less degree upon the muscles. Albanese, independently of the
French investigators, confirmed their results, and brought out still
more clearly the influence of muscular fatigue upon duration of
life in decapsulated frogs. He held the toxic substances of
unknown nature which determined the fatal effects to be produced
during work by the muscles and nervous system.

Abelous and Langlois performed a second series of experiments
on the guinea-pig, in which the capsules are highly developed in
relation to the total weight. Each capsule on an average weighs
12 cgrms. in guinea-pigs of 500 grrns., while in rabbits of 2 kilos,
they only reach 10-15 cgrrns., and 1 grin, in dogs. On the other
hand, accessory capsules are very rare in guinea-pigs, while they
frequently occur in rabbits and dogs.

The effects of destroying one capsule only, of partial cauterisa-
tion, and of total destruction of both capsules in the guinea-pig,
tally with the experiments on frogs, and confirm the theory which
Brown-Sequard formulated in lS5Q,i.e. that the suprarenal capsules
are organs for elaborating substances destined to modify or destroy
the toxins of curarising action which accumulate in the body after
the destruction of the adrenals.

Much work on rats, rabbits, cats, and dogs was contributed by
other observers. The divergence in their conclusions is evidently
due to the variations in operative procedure. Schiff (1863),
Tizzoni (1884), Paisso-Giliberti and Di Mattei (1886), Alezais and
Arnaud (1891), Berdach and Pal (1894), Boinet (1895), sustained
that the ablation of both capsules in rats, rabbits, and dogs was
compatible with survival, but we may now assume that they only
partially destroyed these organs, or chanced on animals with
accessory suprarenals.

The results which the brothers Marino-Zuco (1892) obtained
on rabbits agree perfectly with those of Abelous and Langlois on
guinea-pigs. Piemoval of both capsules was fatal after three to
five days, with paralytic phenomena ; removal of one capsule only
was compatible with survival, and no detrimental changes
occurred in the rabbits that were partially decapsulated on both
sides. But some time after partial capsular ablation, rabbits that
were not albinos frequently exhibited an abnormal distribution of
pigment in the skin or the oral or nasal uiucosa, viz. formation of
bronzed or grey patches in places where they had not occurred
previous to the operation (Nothnagel, Tizzoni, Marino -Zuco).
This phenomenon recalls the abnormal pigmentation of the skin in
Addison's disease.

In conclusion, the long series of experiments carried out in
Tigerstedt's laboratory, by his pupils Hultgren and Andersson
(1899), generally speaking, confirm the preceding researches ; with
the addition of some new and interesting details :

(a~) The excision of both capsules seems always to be fatal in

52 PHYSIOLOGY CHAP.

dogs or cats, after sixty-eight hours on an average : but if the
excision be effected in two or three sittings, life is prolonged by
about double the number of hours. Castrated cats survive the
longest.

(&) Excision of both capsules is fatal to rabbits after five to
six days : but if a certain period intervenes between the two
operations, the animal may live for months without any patho-
logical disturbance.

(c) Partial unilateral or bilateral excisions are compatible
with survival. More or less transitory or persistent symptoms of
functional insufficiency appear, particularly emaciation.

(d~) In the final twenty-four to forty-eight hours of survival
of decapsulated animals there is a characteristic lowering of
temperature.

(e) During this hypothermia of collapse, injection of suprarenal
extract raises the temperature again, and improves the state of the
animal. P>y such injections life may be prolonged for some
twenty-four hours.

(/) Suprarenal extract injected into the veins or beneath the
skin of normal rabbits in a given variable dose, produces death by
oedema and pulmonary haemorrhage.

XIV. Till the opening of the present century the suprarenal
bodies (on the strength of the data above discussed) were
universally regarded as glands endowed with a single, specific,
protective function.

But when further research in comparative anatomy and
embryology brought to light the important fact that the cortical
and medullary parts of the organ are composed of elements
dissimilar in nature and in origin, it became clear that the supra-
renals serve a double physiological function.

In Italy Vassale was the first to take up this position. He
established the special importance of the medullary substance by
a number of experiments (in collaboration with Zanfrognini
1902-3) on the removal of the suprarenal capsules in the cat and
rabbit. With complete ablation of the medullary substance, the
greater part of the cortical substance being left intact, the
animals die with the same acute symptoms as ensue on excision of
the entire suprarenals. If the ablation of the medullary substance
is partial, and small fragments of it are left, the animals die from
serious functional insufficiency after 3-4 weeks, with symptoms of
a special cachexia (anorexia, psychical depression, asthenia, fall of
temperature, marked emaciation).

Independently of Vassale, H. and A. Christiani (1902) excised
the suprarenal glands in rats, with the following results. With
bilateral excision death is rapid and invariable, whether the
operation be performed in one or in two sittings, even if there be
a year's interval between the two operations. Unilateral ablation

i INTERNAL PROTECTIVE SECRETIONS 53

produces no ill -effects. If one capsule is wholly, the other
partially, excised, it is sometimes found that a minute vestige of
the organ suffices to keep the animal alive, while in other cases
death supervenes, although a comparatively large portion of the
organ may remain. Histological examination shows that in the
first case medullary substance has been left, in the second it has
perished. The specific function must, therefore, lie in the
medullary substance.

Another experimental proof of the great importance of the
medullary substance appears from the results of grafting the
suprarenal bodies. Animals subjected to bilateral ablation of both
capsules die, even if other suprarenals are grafted in their bodies,
and become attached. Now, while the cortical substance is
capable of regenerating and becoming rooted in the region into
which the organ is transplanted, the medullary substance does not
survive and degenerates completely (Poll, H. and A. Christiani).
According to Vassale the chromaffine tissue is fundamentally
altered, and loses its capacity of increasing in size by hyperplasia
of its own cells, when, owing to the partial ablation of tissue, the
remainder is forced into functional hyperactivity. The phenomena
of compensatory hypertrophia with cellular hyperplasia, observed
by Stilling (1889), and Wiesel (1899), in the surviving capsule,
or the accessory suprarenal bodies, after the extirpation of one or
both suprarenal capsules, involve only the cortical and not the
medullary cells. Landau (1898) again found in his experiments
on transplantation of the capsule and unilateral capsulectomy that
the taking of the graft in the first case, and the hypertrophy in the
second, are always limited to the cortical substance, and never
involve the medullary.

From these experiments the theory of the heterogeneous
nature and double function of the cortical and medullary substance,
and of the preponderating importance of the latter, seems well-
established. Certain objections, however, may be raised, and have
to be met before the question can be regarded as settled. Kohn
(1903), makes the following criticisms :

The rare cases in which the bilateral ablation of the suprarenal
bodies was not followed by death, were explained by invoking the
vicarious action of accessory suprarenals remaining uninjured in
the body of the animal (Stilling, 1887). These accessory organs,
however, shew no trace of chromaffine tissue. On the other hand,
some mammals, e.g. cat and rabbit, in which extirpation of the
suprarenal bodies is followed by death, possess in addition to these
organs, conspicuous masses of chromaffine tissue, e.g. on the ventral
surface of the abdominal aorta. Why, he asks, are these masses
not capable of saving the animal from death, since a minute vestige
of medullary substance is able to do so ? The results which
Abelous and Langlois obtained from amphibia agree still less with

54 PHYSIOLOGY CHAP.

the modern view, because in these animals the quantity of extra-
capsular chromaftine tissue is comparatively large as compared with
the intra-capsular bulk of the same tissue.

On the other hand, the experimental results of Pettit (1896)
and Swale Vincent (1897), on Teleosteans, give support to the
modern theory. They found that eels for months survived the
ablation of the suprarenal bodies, which in these animals consist
of cortical tissue only. The chromaftine tissue, which, according
to Giacomini (1902), lies near the cardinal veins, escaped the
operation.

In conclusion, Kohn recommends that more attention should
be paid in future to the amount and condition of the whole of the
chromaftine tissue, in the individual animals operated on.

Vassale (1905) subsequently attempted by special experiments
to decide how great an importance attaches to the extra-capsular
chromaffine tissue.

In kittens, extirpation of one capsule and of the abdominal
aortic paraganglion may determine death with the same symptoms
that are observed after bilateral ablation of the suprarenal bodies,
or the bilateral removal of their medullary substance. In the
adult cat the same operation does not induce rapid death ; the
animal succumbs after about ten weeks, during which period,
although it eats with great voracity, it becomes more and more
emaciated, and perishes of marasmus. Dogs will tolerate the
removal in a first operation of one capsule and the abdominal
aortic paragangliou, and in a second, of the half of the remaining
capsule ; on the other hand, they cannot bear this triple removal
if performed in a single sitting the animal then succumbs in
twenty-four hours.

Vassale showed that in the dog and cat the extra-capsular
chromaffine tissue varied in amount from animal to animal in the
same species, and suggested on the strength of his experiments
that the survival of some animals after decapsulation in successive
sittings was to be explained by the quantity of chromaffine tissue
or of extra-capsular paraganglia. The satisfactory state of animals
operated on in one or many sittings by maximal capsulectomy, or
partial excision, leaving the animals enough capsule to keep them
alive, is due, according to Vassale, to adaptation only. Since the
remaining chromaffine tissue (he says) is incapable of hyperplasia,
although it does exhibit some functional hyperactivity, true
compensation of the lost functions cannot take place.

Admitting that the cause of death in animals exposed to
bilateral capsulectomy is to be ascribed exclusively to the sup-
pression of the medullary or paraf/angliar substance of the supra-
renal bodies, we still have to define the specific functions of the
cortical substance. Vassale and Zanfrognini have proposed the
hypothesis that the destruction of this part may be associated with

i INTERNAL PBOTECTIVE SECRETIONS 55

remote morbid phenomena, similar to or identical with the trophic
and cutaneous disturbances of Addisoris disease. The latter are
seldom obtained experimentally because, with total capsulectomy,
the animals nearly always die with acute predominating symptoms
of severe asthenia and paralysis, due to the suppression of the
medullary substances.

XV. We cannot doubt, therefore, that the protective function
of the double glandular organ formed by the suprarenal capsule
must consist in arresting the action of one or more poisons
normally formed in the body, and that the phenomena of deficiency
or functional insufficiency of these organs are phenomena of
intoxication. Numerous experiments have been made to determine
the nature of these toxins, their mode of acting on the body, and
the process by which the capsule renders them inactive.

As early as 1857 Vulpian noticed that the liquid extracted
from the suprarenal capsules contains a special chromoc/enic sub-
stance, which, when exposed to the air, turns gradually carmine-
red. The reaction is produced instantaneously with oxidising
agents such as chlorine-, bromine-, and iodine-water. Krukenburg,
in 1885, returned to the study of this chromogen, and reported
that it gave certain reactions characteristic of pyrocatechin.
Brunner (1892) confirmed the results of Krukenburg, and Moore
(1895-97) succeeded in determining the chemical properties of the
chromogen of the capsule more exactly.

Manasse (1893-94) found a substance in the blood of the
suprarenal veins which turned brown when treated with potassium
bichromate, and which is certainly secreted by the suprarenal
capsules.

It is highly probable that these facts are in relation with the
theory of Addison's disease, which attributes to the capsule
(probably to the cortical part) the function of regulating cutaneous
pigmentation. In what exactly this relation consists is unknown.

According to Nabarro (1895) the suprarenal capsules contain
globulins and nucleo-proteins that precipitate with magnesium
sulphate, and coagulate at 56, 65, and 75 C. An albumin is
also present which coagulates at 71 C.

It has been shown by F. Marino-Zuco (1888) and F. Marino-
Zuco and Dutto (1890-91) that the suprarenal capsules normally
contain a considerable amount of neurine, and that individuals
attacked by Addison's disease eliminate appreciable quantities of
this base by the urine. Guarnieri and Marino-Zuco (1888), on
injecting solutions of glycerophosphate of neurine in minute doses
into rabbits, obtained phenomena of intoxication similar to those
observed after excision of the capsules. Albauese (1892) found
great sensibility of frogs, as well as of decapsulated rabbits, to
neurine. Half a milligramme injected under the skin of the back
(an insignificant dose to a normal frog) produces serious symptoms

56 PHYSIOLOGY CHAP.

<if intoxication, and even death, if the frog is not very large. The
dose of 1 mgrin. is always fatal to the encapsulated frog, while it
takes 4 mgrins. to kill one that is normal. On the other hand, the
brothers Marino-Zuco state that either the excision of one capsule
alone, or the injection of non-toxic doses of neurine will after
fourteen to twenty-four days cause slate-grey spots to appear on
the skin, the buccal mucosa, and the under surface of the tongue.

These experimental data are the basis of the theory sustained
by Marino-Zuco and Albanese, viz. that Addison's disease and the
effects of artificial destruction of the capsule are due to neurine
intoxication, and that the function of the capsules consists in
modifying the neurine produced by the body, so as to render it
innocuous.

In order to explain the process by which the capsules neutralise
the activity of neurine, Carbone (1894) carried out a series of
experiments to determine its effects upon normal and decapsulated
dogs, tested by its elimination in the urine. He found that the
normal dog bears a hypodermic injection of small doses of neurine
without any symptoms ; in the decapsulated dog, on the contrary,
the same dose immediately produces salivation, and after a few
hours, vomiting, diarrhoeal discharges, paralysis of the hind limbs.
This led him to suspect that in the normal dog the neurine was
rapidly destroyed or fixed by the capsule, while in the decapsulated
animal it circulated and was eliminated unchanged in the urine.
In order to verify this surmise, Carbone estimated the neurine
eliminated by the urine, and found that the amount did not vary
perceptibly in the normal dog and in those which had suffered
ablation of three-fourths of both capsules. In both cases, only a
small part, at most a fourth, of the injected neurine passes into
the urine. The remainder is probably transformed or retained in
the body.

In regard to the theory that the toxins causing the cachexia
of Addison's disease consist in neurine or glycerophosphate of
neurine, Neumeister points out that the neurine and glycero-
phosphoric acid found in the capsules may come from decom-
position of their lecithin or choline, owing to manipulation of the
chemical extracts. On the other hand, Oliver and Schafer (1895)
showed that the effects of injecting phosphate and glycero-
phosphate of neurine are totally different from those produced by
suprarenal extract in toto.

Taken as a whole, these data leave no doubt as to the protective,
antitoxic action of the suprarenal capsules, but it is still uncertain
if this is effected by the removal from the blood of specific toxic
substances, or by the secretion and output into the blood and
lymph of one or more active substances, which are directly or
indirectly antitoxic.

According to a theory brought forward by Cybulski (1895), the

i INTERNAL PROTECTIVE SECRETIONS 57

entire morbid syndrome exhibited acutely after total destruction
of the capsules, depends on the depression of tone in the vasomotor,
cardiac, and respiratory centres, and also in all probability of the
centres of muscular tone.

The active substances produced by the capsules (which reach
the blood by the suprarenal veins) thus serve to keep up the normal
tone of all these centres.

This view is supported by a series of experiments carried out
partly with the collaboration of Szymonowicz, which may be
summarised as follows :

(a) After complete extirpation of both capsules (which the dog
only survives for eight to fifteen hours) the arterial pressure falls
to 20 mm. Hg below the normal ; pulse and respiration become
considerably slower. Intravenous injection of aqueous supra-
renal extract raises pressure conspicuously, slows the pulse, and
quickens respiration ; while the injection of other organic extracts
has no effect.

(&) After section of the cervical cord, injection of suprarenal
extract has no effect, showing that the increase of pressure is due
to excitation of the bulbar vasomotor centre. On cutting the vagi,
the slowing of the pulse caused by injection of the extract ceases,
showing it to be clue to stimulation of the moderator centres of
the heart.

(c) The active substance is formed not after death, but during
the life of the suprarenal bodies, passing by diffusion into the
epithelial cells of the efferent veins. In fact, if the reduced venous
blood from the capsule is collected and defibrinated, and then
injected into the veins of an animal, the same phenomena are
produced as are seen after injection of suprarenal extract, though
less acutely. The venous blood from any other vein has no effect
in the same doses. These results were confirmed by Sal viol i and
Pezzolini (1902).

(d) A long series of experiments shows that the active substance
formed by the suprarenals is not toxic in moderate doses, but
merely raises the tone of the vasomotor, respiratory, and cardiac
centres, as well as the centres for muscular tone.

(e) The transitory nature of the excitation of the above centres
by the active substance manufactured by the capsule, is explained
on the assumption that it is partly eliminated by the kidneys,
partly transformed by oxidation within the tissues. Probably the
increase of arterial pressure, the slowing of the pulse, and the
dyspnoea that accompanies the asphyxia, depend on the accumu-
lation within the body of the active substances formed by the
capsule, which under normal conditions are destroyed as fast as
they form.

The exact physiological action of suprarenal extract on various
tissues has been recently studied by Velich, Biedl, Wiesel, Gottlieb,

58 PHYSIOLOGY CHAP.

Tick, Langley, Elliott, Gioffredi, Salvioli, Patta, Vassale, Bottazzi,
and many others. Contrary to the opinion of Cybulski, most
authors now admit in explanation of the enormous vaso-constrictor
action of this substance, that it acts peripherally upon the muscular
cells of the vascular coats (directly, or indirectly by means of the
sympathetic nerve endings), as was stated by the first investigators,
Oliver and Schafer. The experiments of Velich and Biedl, who
divided and destroyed the spinal centres, give direct support to
this view, together with those of Gottlieb, who eliminated the
action of the vasomotor centres by profoundly chloralising the
animals ; and still more the fact adduced by the last author, that

FK;. 16. Effect of suprarenal extract on blood pressure in curarised rabbit. (Verworn.)
1, injection of extract ; 2, section of both vagi.

the vaso-constrictor action also takes effect in the vessels of isolated,
surviving organs (kidney, mammalian heart).

The active principle of the suprarenal capsules does not
produce the same contractile effect on all the plain muscle of the
body as is thus distinctly exerted upon the vascular muscle-cells.
On other involuntary fibres it has an exactly opposite effect,
causing their active expansion or relaxation, and depression of
tone (Lewandowsky, Boruttau, Langley).

Langley (1901) described the effects of suprarenal extract on
various organs with plain muscle, in cats and rabbits. Com-
mencing with the results of minimal doses, and going on to those
of strong doses of the extract, an enormous increase in blood
pressure due to peripheral vaso-constriction first appears (Fig. 16) ;
then relaxation of the cardiac sphincters, intestines (rabbit) and
bladder, dilatation of the pupil (cat), retraction of the nictitating
membrane (cat), opening of the eyelid (cat). Next follows con-
traction of the uterus, of the vasa deferentia, spermatic vesicles

INTERNAL PROTECTIVE SECRETIONS

59

(rabbit), salivary and lachrymal secretion, relaxation of the
stomach and gall-bladder, increase of biliary secretion, pupillar
dilatation, paralysis of the internal sphincters, etc. This shows
that suprarenal extract produces sometimes relaxation, sometimes
contraction, in different tracts of plain muscle.

Boruttau, Pal, and afterwards Langley and Bottazzi, showed
that the peristaltic movements of the intestine are inhibited by
suprarenal extract. When the active principle (known as i par-
gangline, Yassale, and adrenaline, Takamine) is applied to an
isolated strip of toad's oesophagus or stomach, Bottazzi (1904)

FIG. IT. Effect of paragangline on plain muscle fibres of toad's oesophagus. (Bottazzi.) 1, injec-
tion of extract ; 2, its removal by washing. The curves show the very slow contractions of
longitudinal fibres of oesophagus! The cylinder revolves about once in twenty-four hours.

observed a marked depression of tone in the plain muscle of these
organs (Fig. 17).

To explain the dissimilar action of the same active suprarenal
principle on various organs of plain muscle, Langley laid stress on
the important fact that the action of this substance almost invari-
ably provoked the same effects as artificial stimulation of the
sympathetic, which, as we know, induces sometimes relaxation,
sometimes contraction in different organs with plain muscle. His
pupil Elliott (1905) confirmed this fact with more ample demon-
stration by means of adrenaline for all the tissues of the body,
whether sympathetically innervated or not. Without entering
too fully into details, his conclusions are as follows :

In all vertebrates the reaction of a given group of plain muscles
to adrenaline has the same character as that produced by excita-
tion of the visceral sympathetic nerves (lumbar-thoracic) which

60 PHYSIOLOGY CHAP.

innervate the same muscles. The effect may consist in contraction
or in relaxation. If the plain muscle has no sympathetic innerva-
tion (e.g. involuntary bronchial muscles), it is indifferent to the
action of adrenaline. Neither the ganglion cells and nerve fibres
of the sympathetic, nor the muscular fibre -cells, are directly
attacked by adrenaline. Its action is, on the contrary, localised in
the end-organs, which unite the nerve fibres with the muscle
substance.

These conclusions of Langley and Elliott, based on experi-
mental data, demonstrate clearly that there is a close connection
between the active principle of the suprarenal bodies (which are
more especially provided with cliromaffine cells] and the sympathetic
nervous system. This tallies with the conclusions of embryology
and comparative anatomy, according to which, as we have seen,
ehromaffine tissue has a common origin with the sympathetic
system.

As regards the physiological action of the active suprarenal
principle, it must be stated in conclusion that various authors (in
addition to its influence on smooth muscular tissues) have ascribed
to it a characteristic action on metabolism. Blum (1901) noticed
that subcutaneous and intravenous injections of this substance
caused elimination of glucose by the urine. This glycosuria,
known also as suprarenal diabetes, was subsequently confirmed
and variously interpreted by other workers (Ziilzer, Crofton, Noel
Paton, Herter and Wakeman, Aronsohn). According to Landau
the substance which on injection produces glycosuria in rabbits
exists in the cortical and not in the medullary substance. A
causal relation exists between the capsule and the diabetes which
is produced by puncture of the fourth ventricle (01. Bernard), in
the sense that in some very small rabbits that survive bilateral
capsulectouiy, puncture of the fourth ventricle does not induce
this diabetes.

XVI. The discovery of the physiological action of suprarenal
extract stimulated the efforts of chemical physiologists to isolate
its active principle. Frankel (1896) first prepared sphygmogenine,
followed by Abel's epineplirinc, (1898), 0. von Fiirth's suprarenine,
Vassale's paragangline. In 1901 Takamine announced that both
Abel's epinephrine and von Fiirth's suprareuine were mixtures,
and that he had succeeded in isolating from the suprarenal capsules
a stable substance that crystallises, and is of constant chemical
composition, to which he gave the name of adrenaline. At the
same time, but independently, Aldrich also isolated the active
suprarenal principle in a crystalline form. F. Battelli discovered
a more practical and improved method of preparing the same
substance.

Takauiine's adrenaline is a white powder, in small crystals,
very bitter, slightly soluble in water, faintly alkaline, so that it

i INTERNAL PROTECTIVE SECRETIONS Gl

forms salts with different acids. It is not an alkaloid. It
oxidises readily, and is therefore strongly reducing, and can be
used as a developer in photography. Adrenaline has a marked
vaso-constrictor action. A cubic centimetre of O'l per cent solution
injected into the vein produces an increase in arterial pressure of
30 mm. Hg in a dog that weighs 8 kilos. When applied to the
conjunctiva it incites marked local ischaemia, of short duration, and
on this account is much used in ophthalmology. It has also been
resorted to successfully in severe catarrhal hyperaeruia of the
external mucosae. According to Vassale the active suprarenal
principle also has a therapeutic action when introduced into the
stomach in gastric and intestinal atony.

In pursuance with the idea expressed above that the suprarenal
capsules consist of two distinct organs, and that maximal import-
ance must be ascribed to the medullary substance (chromaffine
tissue, capsular paraganglion), various attempts have been made
to determine which of the two substances, cortical and medullary,
is the seat of the active principle.

Salvioli and Pezzolini noted a marked difference in the
efficiency of the extract of medullary substance, which they found
to be greatly in excess of that of the cortical substance. Oliver
and Schafer (1895) had previously concluded from their experi-
ments that the active vaso-constrictor principle of the suprarenal
capsules is contained solely within the medullary substance. The
very weak effects which they sometimes observed after injection of
cortical extracts were due to post mortem processes of diffusion of
the medullary juice and other accidental contamination. Vassale's
recent work has fully confirmed these conclusions.

On the other hand, Langlois (1898), Swale Vincent (1896-97),
Biedl and Wiesel (1902), have shown that extracts of the extra -
capsular chronmffine tissue of the lower vertebrates (Amphibia,
Selachia) have the same action, while according to Biedl and
Wiesel the extracts may be made indifferently from the medullary
substance of the capsule, or from other accumulations of chrom-
affine tissue in these animals. Vassale therefore thinks it more
correct to give the name of paragangline to the active suprarenal
principle, which he prepared exclusively from the medullary sub-
stance of the suprarenal capsules.

It must, ho\vever, be noted that Vassale's paragangline is not
a chemically pure and crystallisable substance like Takaniine's
adrenaline, but is an extract which contains the vaso-constrictor
principle in strong concentration, along with diastatic ferments,
and an abundance of lecithin, which has been demonstrated by
numerous observers in the medullary substance of the capsules
(Crofton, Alexander). Vassale himself admits "that adrenaline
is to paragangline as morphine is to opium."

Another series of recent researches was directed to solving the

62 PHYSIOLOGY CHAP.

question of the modifications suffered by the active suprarenal
principle when it is introduced into the body of the animal, as
also of its remote action when it is given many times in succession.
The following are some of the data :

Langlois (1898) attempted to clear up the mechanism of the
destruction of the active principle of the capsule. According to
him it is rapidly destroyed in vitro by the action of oxidising
agents. When introduced into the arterial system, its action on
the blood pressure disappears in less than three minutes. The
pressure can be maintained at a constant height by successive
small injections of extract of the gland, at about three-minute
intervals. The disappearance of the effect coincides with the
return to normal pressure.

The duration of the effective period is in ratio with the
activity of metabolism. In the normal tortoise, in winter, the
action on the heart persists for about 3 hours ; in the warmed
tortoise it disappears after 20 minutes. In cooled mammals the
increased pressure persists for 20-30 minutes.

The destruction of the active substance may occur in all the
tissues ; but the liver takes a preponderating part. In fact, the
fluid obtained by maceration of hepatic tissue attenuates the
activity of the suprarenal infusion more than the maceration
fluids of all other tissues. Infusion of a small quantity of the
extract into the mesenteric vein has no effect ; while blood
pressure always rises if it is injected into a vein of the general
circulation. The blood from the hepatic veins of an animal that
has received an injection of the extract is less rich in active
substances than the blood of another region. Lastly, if the
hepatic circulation be cut out, the period of arterial hypertony
is prolonged.

Still the problem of the extremely rapid destruction of
adrenaline in the body does not seem, according to the most
recent work, to be definitely solved in Langlois' sense. Neujean,
indeed, held the methods by which Langlois attacked this problem
to be inaccurate, and concluded, after more exact research, that it
was still doubtful whether adrenaline is destroyed in the body
by oxidation.

Later on Patta (1905-7) showed that when adrenaline is injected
into the muscles or subcutaneous tissue, it does not produce rise
of blood pressure, as it would if injected into a vein, because its
absorption is considerably delayed by the vaso-constriction pro-
duced at the point of application ; it remains unmodified and
physiologically active for over two hours.

INTERNAL PROTECTIVE SECRETIONS 63

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I

INTERNAL PROTECTIVE SECRETIONS 65

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VOL. II F

66 PHYSIOLOGY CHAP, i

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Physiol., 1910, xl. 317.
A. J. EWINS and P. P. LAIDLAW. The Alleged Formation of Adrenine from

Thyrosine. Journ. of Physiol., 1910, xl. 275.
C. H. H. HAROLD and M. NIERENSTEIN and H. E. ROAF. The Influence of the

Presence and Position of the Various Radicles of Adrenalin on its Physiological

Activity. Journ. of Physiol., 1910-11, xli. 308.

TRANSLATOR'S NOTE. See also " Internal Secretion and the Ductless Glands,"
by Swale Vincent (Arnold, 1912), an invaluable resume of the history and literature
of this subject.

CHAPTER II

EXTERNAL DIGESTIVE SECRETIONS

CONTENTS. I. Structure of salivary glands : cranial and sympathetic inner -
vation. 2. Nervous mechanism of secretion in salivary glands. 3. Cytological
changes in secretory epithelium during rest and secretion. 4. Selective activity
of salivary glands. 5. Chemical analysis of salivary glands and the various
kinds of saliva. 6. Structure of pancreas. 7. Innervatiou and mechanism
of its secretion. 8. Pancreatic juice. 9. Internal function of the pancreas.
10. Factors concerned in internal pancreatic secretion. 11. Structure of gastric
mucosa and glands. 12. Inner vation. 13. Gastric juice and the cells which secrete
it. 14. Zymogens which give rise to the gastric enzymes. 15. Intestinal glands.
16. Succus eutericus. 17. Mechanism of intestinal secretion. 18. Structure of the
liver. 19. Secretion of bile in digestion and fasting. 20. Influence on secretion
of changes in hepatic circulation. 21. Chemical constituents of bile. 22. Origin
and metabolic activity of hepatic cells. Bibliography.

FROM the group of glands which have no excretory duct, and
can only serve for internal secretion, we must distinguish the
group that are provided with excretory ducts, and are therefore
capable of external secretion, their products being poured out into
the gastro - intestinal canal. The principal function of these
secretions is that of chemical and physical transformation of
the ingested food, so as to render it fit for absorption and assimila-
tion, and thus to repair the losses perpetually sustained by the
tissues during the exercise of their functions.

These organs of external digestive secretion may histologically
be divided into three groups : () acinous glands, forming distinct
organs (salivary and pancreatic) ; (/>) tubular glands, scattered in
the depth of the mucosa of the digestive tube (buccal, gastric,
and intestinal) ; (c) glands with branching tubes, grouped into a
large organ which forms the liver.

The external secretion, which (with the exception of the
biliary secretion) is the chief function of these organs, does not
exclude them from serving for internal secretion also ; but this
subject will be discussed in a subsequent chapter, the better to
appreciate its nature and physiological significance.

I. The excretory ducts of three principal pairs of glands which
manufacture and secrete Saliva open into the buccal cavity.
From their position these were termed parotid, suit-maxillary, and

67 F 1

08

PHYSIOLOGY

CHAP.

sublingual. They are glands of the racemose type, i.e. they
consist of acini, which are more or less saccular or tubular in
shape, their cavities or alveoli communicating with one another

by one or more branching excretory
ducts. The acini are surrounded by
a basement membrane consisting of
a network of flattened, nucleated,
branching cells, the meshes of which
are occupied by a delicate homo-
geneous substance. Inside the base-
ment membrane (Fig. 18) the secreting
cells form an epithelial lining which

Fie. 18. Membrana propria of two l-, mnlr ](, f} 1p .,1 V pnlnr pq vitv Thp
alveoli isolated. From orbital gland DOUndS tne diveolai Cavity.

of puppy. (Lavdowsky.)

are united into lobules, either by
blood-vessels or by loose connective
many lymph spaces and a rich network

tissue, which contains
of blood capillaries.

Two kinds of secreting cells can be distinguished in the alveoli,
the serous or albuminous, and the mucous (Heidenhain). The
serous cells, which secrete
a thin fluid
serum - albumin,
in the restin

* \ "L-r

containing
exhibit
state a

protoplasm so richly infil-
trated with granules that
the nucleus is obscured
and becomes invisible.
The mucous cells, which
secrete a fluid that is ropy
from the large amount of
mucin, are large, clear,
and spheroid when the
gland is resting. They
almost fill the alveolar
cavity, their nuclei being
invisible because they lie
close to the basement
membrane, and are
pressed against it (Fig.

19). When all the alveoli
f J 1-1 -j.i

of a gland are lined with

albuminous cells (e.g. the

parotid in man and almost all mammals, the submaxillary of rabbits,

and certain glands that are scattered in the buccal niucosa), the

gland, as a whole, is termed albuminous ; when the alveoli are

lined with mucous cells alone (e.g. part of the submaxillary in man,

and the sublingual in all animals, and many simple buccal glands)

Fl(: . p.,._ s ,. ctiou of part of huill ,,,, sullimxnia ,. y g]an , L

(Heidcnliam.) On the right, a group of mucous alveoli
with demilunes of Gianuuzzi ; on the left, a group of

serous

II

EXTERNAL DIGESTIVE SECRETIONS

69

the gland is termed mucous ; when the alveolar walls are constructed
partly of mucous, partly of albuminous cells (e.g. the submaxillary
and suborbital of many mammals, part of the submaxillary in
man, and the majority of the scattered buccal glands), the gland,
as a whole, is termed mixed. In this case the albuminous glands
occupy a marginal position, and usually form little crescentic
masses known as the demilunes or crescents of Giannuzzi (Fig. 19).
The epithelial cells which line the intercalary and interlobular
excretory ducts are quite different from the secreting cells. The
ductules of lesser and medium calibre are lined with flattened,
cubical, striated cells ; the larger ducts with columnar, epithelial

Fie. "20. A, section of alveoli from human subliiigual gland. Silver eliminate method. (E.
Miiller.) I, lumen of intra-alveolar excretory ducts, stained black, and terminating in diverti-
eula which penetrate into the cells of the alveoli ; h diverticula penetrating into crescent cells.
B, section of alveolus from dog's submaxillary gland. Silver chromate method. (G. Retzius.)
Shows diverticula of excretory ducts extending into crescents of Giannu//i. Also vry tine
varicuse nerve fibrils which form a network with large meshes between the alveolar cells.

cells. If the ducts are injected before making a microscopical
preparation, or treated with Golgi's method, which stains the
entire system of excretory channels a uniform black, the lumen
can be followed into the alveoli, and is seen to end in terminal
diverticuli, which penetrate between the cells, and enter for a
short distance into the protoplasm (Fig. 20, A, B).

Both the serous and the mucous salivary glands are supplied
by two kinds of nerves, those of cranial and those of sympathetic
origin. The former, for the submaxillary and sublingual glands,
originate in the roots of the facial nerve as the chorda tympani,
unite with the lingual branch of the fifth nerve, and then run
through the submaxillary ganglion to the parenchyma of the
gland. For the parotid, the cranial fibres from the glosso-
pharyngeal nerve run through Jacobsou's nerve, the small super-

F 2

70 PHYSIOLOGY CHAP.

ficial petrosal, and the otic ganglion, and on reaching the auriculo-
temporal branch of the fifth nerve penetrate into the gland. The
sympathetic fibres rim in the cervical sympathetic to the superior
cervical ganglion, accompany the carotid artery, and penetrate with
its branches by the hilurn to the interior of the three glands.

The nerve fibres are partly medullated, partly non-medullated.
Some supply the muscular sheath of the vessels, others the gland
cells ; the former are vasomotor, the latter secretory fibres. These
last, mostly as non-medullated fibres, perforate the basement
membrane of the acini, and terminate between the alveolar cells in
a free arborescence of the finest varicose fibrils (Fig. 20, B.).
Paladino (1872) observed direct terminations of the nerve fibres in
the gland cells of the salivary gland of dogs, solipeds, and man.
He further described iutraglandular gangliated plexuses in the
submaxillary of the dog and of man.

II. It is evident that the salivary secretion is directly under
the control of the nervous system. The mere mental image of any
sapid substance, the sight or smell of a favourite food, is sufficient,
in vulgar parlance, " to make the mouth water." Stimulation of
the abdominal fibres of the vagus, in nausea, incites a copious flow
of saliva, principally during the reflux of food from the stomach
to the extremity of the oesophagus, which precedes vomiting.

To these facts of common observation which are within the
reach of all, we can add others, arrived at by physiological experi-
ment. The salivary secretion can also be excited by centripetal
stimulation of some of the sensory nerves, e.g. the central end of
the vagus or sciatic in a curarised dog (Owsjanuikow). Electrical
excitation of a given area of the cerebral cortex (the so-called
centre for facial movements) promotes secretion (Landois, Lepine,
Bochefontaine), etc. It is interesting in this connection to note
that among the forms of partial epilepsy there is one in which the
fits are characterised by an enormous secretion of saliva
(Emminghaus).

A remarkable contribution to the more exact knowledge of
reflex excitation of the salivary secretion was made by Pawlow
and his co-workers (1904). The extraordinary aptness of these
reflexes is shown by a number of experiments, the most important
of which may be briefly summarised :

If some quartz pebbles are introduced into the mouth of a dog
with a salivary fistula, the animal, after turning them over with
its tongue, lets them drop out without any flow of saliva, or at
most a few drops only, being excited. If, on the contrary, the
same stones are introduced into the dog's mouth in the form of
powder, so that it cannot push them out with the tongue, saliva
at once flows freely and carries away the quartz dust.

Dry, solid food produces an abundant secretion of saliva ; fluid
aliments, which already contain enough moisture for deglutition,

ii EXTERNAL DIGESTIVE SECRETIONS 71

excite much less. Strongly irritating substances, e.g. acids, salts,
etc., determine a copious flow of saliva, by which they are diluted
and their irritating action reduced. The saliva secreted under
these conditions is watery, and contains little mucin.

Excitation of the secretory centres of the salivary glands may
occur not only from stimuli in direct contact with the mucous
membrane of the buccal cavity, but also from excitation at a
distance, by the action of various stimuli on the different sense
organs, e.g. nose, eye, ear. Since it is impossible to find any other
explanation for this kind of stimulation, Pawlow calls it a
psychical excitation. If, e.g., a hungry animal is shown a bit of
bread or other food, a secretion results, while there is absolutely
no response on showing it to another that has eaten to repletion.
If some food or other substance that provokes nausea is shown the
dog several times in succession, the reaction is lessened till it dies
out. Yet if a little of the nauseous substance which no longer
evokes secretion is placed in the mouth, the first response reappears,
and lasts for a certain time.

The smell or other external sign of food is enough to determine
secretion. If, e.g., the hand, smelling of meat, is presented to the
dog, a flow of saliva is excited. If an acid has once been coloured
black, the sight of any black fluid will provoke secretion, assuming
of course that the black acid was introduced into the animal's
mouth on at least one occasion.

According to Malloizel's observations (1902) on dogs with a
permanent fistula, the reflex secretion of saliva is specific for
different peripheral stimuli. Thus the saliva excited by the action
of salts, sulphate of quinine, or sand, is thin and contains less than
1 cgrm. of niucin in 6 c.c. of saliva : the saliva excited by raw meat,
on the contrary, is very viscid, containing 1-2 cgrm. of mucin in
1 c.c. of saliva ; that excited by sugar is between the two. Henri
and Malloizel further found that the diastatic activity of reflexly
excited saliva varies with different stimuli ; it is greater for meat
than for salts.

The sight or smell of different substances, again, excites a
specific secretion of saliva. Section of the chorda tympani
abolishes every secretory reflex, while section of the sympathetic
has no effect.

All these, like the preceding, are phenomena of reflex secretion,
in which the excitation travels along the afferent paths to the
centres, which then transmit it by the efferent secretory paths.
Certain experiments of Cl. Bernard, Eckhard, Loeb, Griitzner,
and Chlapowski show that the centres of salivary secretion are
localised in the bulb, probably at the origin of the facial and
glosso-pharyngeal nerves. In fact, when the bulb is separated
from the spinal cord by a cross-section, salivary secretion can no
longer be excited by the same means. On electrical excitation, or

72 PHYSIOLOGY CHAP.

better on pricking the bulb in the vicinity of these centres,
secretion is at once aroused.

Kolmstamm (1902) found that division of the nerve fibres that
arise in the chorda tympaui and pass by the lingual to the suit-
maxillary gland, was followed by degeneration of a group of cells
in the bulb near the facial nucleus, mostly on the opposite side, to
a less extent on the same side as the operation. The nerve fibres
that come in the subrnaxillary gland originate in these cells.
Hence the latter are termed by the author the salivatory
nucleus.

The interpretation of the effects of the so-called scialagogues is
doubtful. These consist in a series of toxic or medicinal substances
which, when injected under the skin or into the veins, promote a
more or less copious secretion of saliva. The principal are pilo-
carpine, physostigrnine or Calabar beans, curare, etc. Do these
substances induce a flow of saliva because they directly or reflexly
excite the secretory nerves, or because they act by modifying the
metabolism of the secretory cells ? It is probable that their action
is distributed throughout the system, and that the effect is
analogous to the secretion of saliva produced in asphyxia by the
accumulation of carbonic acid and the other katabolic products
of metabolism in the blood.

As contrasted with the substances which produce ptyalism, we
have another group, headed by atropiue and daturine, which
arrest all salivary secretion (Keuchel). These substances act
particularly by paralysing the cranial secretory nerves. The flow
of saliva excited by pilocarpine can be arrested by atropine, and,
vice versa, the arrest of secretion by atropine can be antagonised
by pilocarpine and also by muscarine.

The process of secretion, more particularly in the submaxillary
gland, which is the most accessible to experiment, has from 1851
to the present day been the subject of constant and varied experi-
ments (especially by Carl Ludwig and his school) which have
yielded very important results. The most significant of these data
and the deductions to which they lead can be summarised as
follows :

(a) If after introducing a cannula into Wharton's duct in the
dog, the lingual branch of the fifth nerve (or simply the chorda
tympani, which runs from the facial to the lingual branch and
gives off fibres to the gland) is cut, all salivary secretion ceases,
and no saliva flows from the end of the cannula (Ludwig). This
proves that secretion of saliva is normally dependent on a reflex
nervous act conveyed to the gland by the fibres of the chorda
tynipani. If the peripheral end of the lingual nerve (or the
chorda tympani) be electrically excited an abundant secretion of
saliva follows, which will in a few minutes reach, and even exceed,
the volume of the gland (Ludwig). This shows that stimulation of

ii EXTERNAL DIGESTIVE SECEETIONS 73

the nerve excites a stream of fluid which passes from the blood
capillaries to the lymph spaces, and thence to the glandular spaces,
the material contained in the gland not being sufficient for such
an abundant flow of saliva.

(&) Between the excitation of the nerve and the appearance
of the secretion there is an appreciable period of latent stimula-
tion, which may vary between 1-2 seconds (Heriug) and 24 seconds
(Ludwig).

The secretion persists for a short time after the close of
stimulation. This period, known as the after-effect, increases in
proportion with the excitability of the nerve (Ludwig). In fact,
if the stimulation lasts only for a short time, so that the nerve
is not excessively fatigued, the after-effect lasts longer. These
phenomena confirm the dependence of the secretion upon the
activity of the secretory nerve.

(c) Excitation of the cervical sympathetic (or of the
sympathetic fibres that accompany the carotid and run to the
submaxillary gland) also produces a secretion of saliva, although
much more slowly and in smaller quantities. Moreover, while
the saliva obtained by stimulation of the cranial nerve is watery
and slightly viscid, and shows under the microscope very few
salivary corpuscles and granulations, the saliva secreted by excita-
tion of the sympathetic is very dense, viscid, ropy from large
quantities of mucus, and contains numerous corpuscles and
granulations (Eckhard, Cl. Bernard).

(d) The blood -supply of the gland is modified in contrary
directions by stimulation of the chorda tympani and of the
sympathetic. In the former it is enormously increased by active
vascular dilatation, in the latter diminished by active constric-
tion (see Vol. I. p. 342 et seq.). It cannot be denied that the
marked difference in quantity, density, and viscidity of the
saliva obtained on exciting the two kinds of nerves depends at
least in part on the varying blood-supply to the gland in the
two cases. The difference is much reduced if the gland be filled
with blood by a brief stimulation of the chorda tympani before
exciting the sympathetic. In this case excitation of the sym-
pathetic produces a more copious and less viscid saliva.

Burton -Opitz (1904), using Hlirthle's haernoclrometer, esti-
mated the velocity of circulation in dogs in the branches of the
external jugular vein, and found it normally very low. By
stimulating the intact chorda tympani it was possible to increase
it from two- to six-fold. Stimulation of the sympathetic, on the
contrary, determined an almost complete arrest of the circulation.
Longer stimulation of the vasornotors fatigues them, and the
circulation then returns to the normal rate, even if the stimula-
tion be continued.

(e) The saliva secreted after stimulation of the cranial nerve

74 PHYSIOLOGY CHAP.

lias a temperature 1/5 C, higher than that of the arterial blood
which traverses the origin of the carotid. The difference in the
two temperatures is greater in proportion as the flow of saliva
from the cannula inserted in Wharton's duct is more rapid
(C. Ludwig and A. Spiess). This proves that during secretion
the oxidative processes, or the respiration of the secretory cells
of the gland, increased so that much energy is liberated in
the form of heat. This is not contradicted by the fact first
noticed by Bernard to the effect that during the stimulation of
the chorda the blood flowing back from the gland assumes the hue
of arterial blood, because the velocity of the blood current in the
gland, owing to the vascular dilatation, increases more rapidly
than the consumption of oxygen.

(/) The presence of oxygenated blood undoubtedly favours
secretion. If the principal vein that leaves the subrnaxillary
gland be occluded while the chorda is stimulated, secretion gradu-
ally ceases, recommencing after the vein has been freed, with
sufficient lapse of time for the black asphyxial blood collected in
the vessels of the gland to be replaced by red arterial blood
(Ludwig). The rate of flow of saliva thus depends not only upon
the amount of nutritive materials that reach the gland, but also
upon the quantity of oxygen, i.e. the arterial character, of the
blood circulating in it.

Barcroft (1901) noted in dogs that during the secretion pro-
duced by stimulation of the chorda the amount of oxygen taken
up by glandular tissue from the blood is three or four times
greater than in the resting gland. After injection of atropine
there is no longer any increased assimilation of oxygen on
stimulating the chorda, while more C0 2 is still given off, for a
time at any rate.

(g) If the cranial and the sympathetic nerves of the sub-
maxillary are simultaneously excited, secretion is at first aug-
mented, but soon becomes slower than when one nerve alone
is stimulated, until finally it is almost entirely suspended
(Czermak). This effect is due to interference of excitation in the
two nerves, as well as to functional predominance of the con-
strictor fibres over the dilators in the nerves of the gland, as
shown by von Frey (see Vol. I. p. 351).

(h) We have seen that secretion is arrested after section of
the chorda, even when the sympathetic is left uninjured. This
functional arrest is not permanent. After about 24 hours the
gland begins once more to pour out a continuous secretion of very
thin saliva, poor in organic substances. This phenomenon was
termed by Claude Bernard (who first noticed it) paralytic secretion.
It increases steadily in the first week : after that it slowly
diminishes, owing to the degeneration of the gland. After
excision of the submaxillary ganglion (according to Bernard)

ii EXTEKNAL DIGESTIVE SECEETIONS 75

paralytic secretion always makes its appearance. It can also
be provoked by tbe injection of small doses of curare into the
glandular arteries. It ceases in apnoea, and increases in dyspnoea.
After hemisection of tbe cord, paralytic secretion appears in tbe
gland of the opposite side also (Heidenhain). The interpretation of
these facts is very doubtful. Langley believes that the excit-
ability of the central end of the chorda increases after section, so
that it reflexly influences the secretion of both glands.

(i) A series of striking experimental data prove that the
salivary secretion excited by the activity of the nerve depends
essentially upon altered metabolism of the secretory cells, and
not on alteration of the blood-supply to the gland. Secretory
activity excited from the nerve persists for a certain time after
all the blood-vessels to the gland have been occluded, and even
after decapitation of the animal (Ludwig, Czermak, Giannuzzi).
On the other hand, when a mercury manometer is introduced into
the excretory duct of the submaxillary gland, and the chorda
tyuipani excited, secretion continues, even when the pressure in
the excretory ducts of the gland rises to a height considerably in
excess of that in the carotid artery. The pressure in Wharton's
duct may rise to 200 mm. Hg, while that of the carotids is not
.above 122 mm. Hg. This shows that the stream from blood-
vessels to lymphatics, and from these to the glandular spaces, is
not merely independent of the pressure, but actually occurs
against the laws of filtration (Ludwig).

(&) We have already seen that the injection of even small
doses of atropine and daturine suffices to abolish the secretory
activity of the chorda tympani (Keuchel). But if the state of the
glandular blood-vessels is watched during stimulation of the nerve,
it is found that their active dilatation is in no way hindered by
atropinisation (Heidenhain). We must therefore assume that the
chorda contains secretory fibres as distinct from the vaso-dilators.
Atropine paralyses the former and leaves the latter unaffected.

(/) When a substance that paralyses the activity of the
secretory cells, e.g. a dilute solution of hydrochloric acid, or of
sodium carbonate, is injected into Wharton's duct, and the chorda
tympani subjected to prolonged stimulation, all secretion is
arrested and there is marked oedema of the gland from congestion
of lymph (Giannuzzi). This shows that the dilatation of the
arteries is capable of promoting the filtration of the lymph, but
not its penetration into the gland spaces.

(in) Unilateral excision of the chorda tympani in puppies has
as a remote effect a marked diminution in weight of the corre-
sponding submaxillary, which may amount to 50 per cent. There
is at the same time a reduction in the volume of the mucous cells
and the serous cells, which form the crescents or demilunes of
Gianuuzzi (G. Bufalini).

76 PHYSIOLOGY CHAI-.

All these phenomena relate to the secretory process in the
submaxillary gland of the dog, which has been the subject of
innumerable researches. But the same facts (with slight differ-
ences) may be observed in other animals also. Thus in the rabbit,
the saliva that flows on excitation of the chorda and also that
from excitation of the sympathetic are limpid and fluid ; in the
cat, the first kind is more viscid than the second. But in both
cases excitation of the chorda produces copious secretion and
vascular dilatation, excitation of the sympathetic, scanty secretion,
and vascular constriction.

Gerhardt studied the histological changes consequent on
section of the secretory nerves on the salivary glands of rabbit,
and found substantial differences in the effects of dividing the
chorda and the sympathetic. In the former the protoplasm was
altered while the nuclei remained intact ; in the second, on the
contrary, there were marked nuclear alterations with normal
protoplasm. The two kinds of histological change were never
observed in all the gland cells, but only in foci, without any
apparent regularity, partly in big nests, partly isolated. The
nuclear alterations from section of the sympathetic were not
confined to the side of the section but spread also, although to a
minor extent, to the opposite side.

The nervous mechanism of the other salivary glands is similar
in its general features to that of the submaxillary gland, on which
we have dwelt at length. Division of Jacobson's nerve or of the
small superficial petrosal nerve, or excision of the otic ganglion,
arrests the secretion of the parotid gland (Bernard, Schiff,
Heidenhain). Excitation of these cranial fibres produces in the
parotid the same secretory and vascular effects as that of the
chorda tympani in the submaxillary. The pressure measured in
Stensen's duct rises during stimulation to 106-118 mm. Hg.
The flow of blood from the gland is accelerated and assumes
the arterial hue (Heidenhain \ The effect of stimulating the
sympathetic has, on the contrary, been much disputed. Some
deny it, others admit a simple constrictor effect on the parotid
vessels, others, lastly, assume a trophic influence upon the gland
cells, as distinct from the secretory influence (Heidenhain).

The subliugual gland is controlled by the same nerves as those
which regulate the secretion of the submaxillary. Stimulation of
the chorda tyrnpani excites secretion from the sublingual as well,
but requires a stronger stimulus (Cl. Bernard, Heideuhain).
The stimulation of the sympathetic has no perceptible effect.

III. The most obvious proof that the secretory effect of
exciting the nerves is due essentially to their trophic influence
upon the metabolism of the secretory gland-cells, is shown under
the microscope in the marked changes which these cells undergo
during secretory activity. We owe to Heideuhain (1868) this

II

EXTERNAL DIGESTIVE SECRETIONS

fine discovery, which enables us, up to a certain point, to penetrate
to the interior of the cells, and to ascertain what cytological
phenomena accompany the process of secretion.

B

FIG. 21. Rabbit's parotid. Alcohol-carmine method. (Heidenhain.) A, resting state ;
B, after stimulation of cervical sympathetic.

Microscopic preparations "of serous glands hardened in alcohol
and stained with carmine show in the resting state a colourless

O ?

Fn;. 22. Orbital gland of dog. Alcohol-carmine method. (Lavdowsky.) A, resting statr :
B. maximal degree of change which the gland is capable of exhibiting in secretory activity.

clear, finely granular cytoplasm, and a nucleus that stains red,
with wavy outlines and no distinct nucleoli (Fig. 21, A). After
excitation of the secretory nerve, and when some cubic centimetres
of saliva have been given off, the cells visibly alter in character.

PHYSIOLOGY

CHAP.

Their total area diminishes from loss of clear cytoplasm; the
granular substance on the contrary increases, so that the cell
appears more clouded, the nucleus becomes rounded with more
regular outlines, and the nucleolus is plainly visible (Fig. 21, B).

Microscopic preparations of mucous glands treated in the same
way show in the resting state large clear cells with colourless
cytoplasm, which consists of a very tine filamentous network with
large meshes, filled with an amorphous, shining, inucinogenous
substance, which resembles small granules. The nucleus stains
with carmine ; it has no visible nucleolus, and is always situated at

B

c

Fio. "23. Rabbit's parotid in fresh state. (Lan^ley.) A. rest in- stub 1 ; B, after injection of
weak doses of pilocarpine ; C, after stimulation of cerviral sympathetic; D, after more
prolonged stimulation of this nerve.

the periphery or margin of the cell (Fig. 22, A). After prolonged
secretion excited by stimulation of the secretory nerves, the cells
appear much reduced from loss of the clear inucinogenous
substance, the cytoplasm stains, the nucleus is rounded, with a
distinct nucleolus which has moved to the centre of the cell
(Fig. 22, B).

The subject of these histological researches is (as Heidenhain
points out) not the living cell, but its dead body, altered, moreover,
by the technique of hardening and staining. Yet, since the
phenomena are so constant, we may safely conclude that the
living cells also are differently constituted in the resting and in
the active state, owing to the manufacture of secretion. Eecent
comparative researches on gland cells in fragments of living gland
fresh from the body, show that while their microscopic appearance

II

EXTEENAL DIGESTIVE SECKETIONS

79

B

differs widely from that described by Heidenhain, it lends itself
essentially to the same interpretation.

In the serous glands, Langley found that in the resting state
the secretory cells exhibit a protoplasm rich in granules, which
conceal the outline of the cells and the nuclei. After prolonged
secretion, caused either by injection of pilocarpine or by stimulation
of the nerve, the alveoli become smaller, and the granules gradually
disappear, especially in the outer zone which is covered by the
basement membrane ; they collect in the inner zone, which
surrounds the lumen, and finally vanish, accumulating as secretion
in the cavities of the gland (Fig. 23).

Similar phenomena can be observed in fresh preparations of
the mucous glands. They are more conspicuous in the simple
than in the compound glands,
e.f/. those of the frog's tongue,
placed as soon as excised in
physiological salt solution
(Biedermann). In the rest-
ing state the cells are full
of dark, highly refracting
granules, which often conceal
the nucleus ; during active
secretion, on the contrary, the
granulation practically disap-
pears, and what remains is
collected at the inner margin
(Fig. 24).

From these data we learn that a substance is formed during
the functional rest of both albuminous and mucous salivary glands
which disappears during activity, and passes into the secretion,
while the cell becomes swollen. This substance dissolves
in alcohol -hardened, carmine - stained preparations; in fresh
specimens, on the contrary, it appears in the form of small
granules.

These phenomena do not decide the important question
whether during the secretory process the living protoplasm of the
cells is utilised and converted into the materials of secretion, or
whether the secretion is produced by the living protoplasm as a
direct elaboration of the lymph absorbed from the perialveolar
lymph spaces. Heidenhain adopted the former view, and con-
cluded that the cells liquefy in consequence of their secretory
activity. According to him Giannuzzi's demilunes consist of cells
intended to replace those which break up. Against this theory is
the fact that karyokinesis is rarely seen during secretion, and that
if epithelial regeneration be present, it relates not to secretory
activity, but to the life cycle of the individual cells. The second
theory, which, as we have seen, was held by Johannes Miiller, and

FIG. 24. Part of lingual gland of Rana esculenta,
IS in fresh state. (Biedermann.) A, resting state ;
B, after stimulation of glosso-pharyngeal nerve
for 3 hours.

80 PHYSIOLOGY CHAP.

adopted by Langley, is more probable, and harmonises with the
fact that, generally speaking, living cells in carrying out their
functions consume the chemical matters which they have
absorbed and elaborated, and only utilise their own protoplasm
when all other materials are exhausted.

IV. The important question of the specific property by which
the salivary glands select from the substances offered them by the
blood the constituents of an effusion that is quite unlike the blood
itself, has hitherto been treated only by a few authors, and that
incidentally. Novi (1888) estimated the amount of chlorine
contained in a sample of blood from the carotid and in one of
saliva, before and after injecting a 10 per cent solution of sodium
chloride into the jugular. He found that when the concentration
of the blood was thus increased, the rate of secretion increased
also. Novi further observed that the chloride content of the
saliva increased much more rapidly than that of the blood serum.
When, e.g., the chloride in the sodium increased from 100 to 155,
that in the saliva increased from 100 to 220. Langley and
Fletcher confirmed the observations of Novi, showing that dilute
solutions of sodium chloride, while they still augment the rate of
secretion, lower the concentration of the saliva.

Asher and Cutter (1900) on injecting sugar and urea showed
that sugar excites secretion only by causing hydraemic plethora,
and does not appear in the saliva ; urea, on the contrary, excites it,
and partly reappears in the saliva.

According to Aducco these different effects show that the
production of the secretion depends not only upon the physical
and chemical constitution of the circulating substances, but also
upon their effect on metabolism. Thus urea, which is a katabolic
product, and is not present in the normal secretion of the gland, is
capable of activating it and of stirring up the .secretory cells to
more work ; while sugar does not pass through the gland (provided
the physiological limits are not exceeded), and only acts indirectly
upon the secretion, i.e. by augmenting the mass and the dilution
of the blood.

This explanation of the phenomenon appears to us inadequate.
If under the said experimental conditions it is a fact that the
increased sugar content of the blood increases the flow of saliva,
under other conditions, e.g. in experimental hyperglycaemia and
in diabetes in general, the secretion of saliva is very scanty, much
below the normal.

Many salts when introduced into the vascular circulation
appear rapidly in the saliva (potassium iodide, lithium citrate, etc.) ;
others, on the contrary (bile salts), which are eliminated by all
other glands when present in the blood do not pass through
the salivary glands.

In regard to the selective capacity of the salivary glands,

ii EXTERNAL DIGESTIVE SECRETIONS 81

U. Louibroso, on injecting into the dog's jugular a large quantity
of pancreatic secretion collected directly from a Pawlow's fistula,
noted that the saliva did not (like other digestive secretions)
acquire any of the enzymatic properties characteristic of pancreatic
juice : bile, e.g., acquires an intense lipolytic activity, which
persists for several days after the injection.

V. Chemical analysis shows the presence of a number of
proteins in the salivary glands, among them a nudeo- protein
(Hammarsten), a substance which forms a special enzyme known
as ptyalogen, or the zymogen of ptyalin (in the albuminous glands),
mucinogen, the mother-substance of nmcin (in the mucous glands),
and the mineral salts of blood serum. With prolonged stimulation
of the secretory nerves to the albuminous and mucous glands, both
the ptyalogen and the mucinogeu disappear to form again during
the resting period.

The increase of volume and weight in the salivary glands
during rest depends largely upon the greater amount of proteins
absorbed, since this increases the nitrogen content. Glands sub-
jected to prolonged stimulation contain 7 per cent less solids than
the resting gland, but this difference depends partly on the
greater amount of water absorbed by the gland during secretion,
in analogy with the conditions that prevail during muscular work.

As regards chemical composition we must distinguish the
mixed saliva or total secretion from the simple and compound
salivary glands that open into the buccal cavity, from the separate
salivas secreted from the albuminous, mucous, and mixed glands
respectively.

Mixed saliva is colourless, with no smell, opalescent, viscid,
faintly alkaline in reaction ( = 0'097 per cent Na. 2 CO.j) or neutral,
its specific gravity being 1002-1006 in man (1007 in dog). It
is remarkable that the osmotic pressure of saliva is considerably
less than that of the blood. Nolf (1900) showed that the
saliva spontaneously secreted from the dog's submaxillary has
a freezing-point from -O'll to - 0'27, and that secreted during
stimulation of the chorda freezes at - 019 to - 0'4. The osmotic
pressure of dog's blood, on the contrary, corresponds to a lower-
ing of the freezing-point = - 0'549 to - 0'605 (see Vol. I. pp.
142, 148).

If left to itself the mucin of the saliva precipitates, along with
the old epithelial cells thrown off by the buccal epithelium. It
also becomes turbid from the precipitation of the calcium carbonate
dissolved in the saliva in the form, of bicarbonate. The microscope
shows the so-called salivary corpuscles, which resemble small
leucocytes with granulations that exhibit lively Brownian
movements.

It is not possible to obtain an exact estimation of the total
quantity of saliva secreted daily ; approximate figures only can be

VOL. II G

PHYSIOLOGY CHAP.

given. There are marked variations in the different speeies of
animals on which ohservations have heen made. While the horse
secretes 14'2 grins, saliva to every gramme of gland per hour,
during mastication, the calf only secretes 8 grins. (Tuczek). From
this point of view it seems probable that the salivary glands are
the most active. In man the secretion of saliva amounts to some
1500 grins, per diem.

The organic components of mixed saliva are :

(a) Mucin, which precipitates with acetic acid or alcohol, and
is derived from the mucinogen of the glandular epithelium.

(b) Ptyalin, an enzyme discovered by Leuchs in 1831. It is
derived from the ptyaloyen of the gland-cells, and is constant in
the saliva of man, horse, rabbit, and of herbivora in general, while
it is regularly absent in that of dogs and of carnivora in general
(Hoppe-Seyler). It is an amylolytic enzyme, the action of which
will be discussed in treating of buccal digestion.

The existence of a pro-enzyme of ptyalin (ptyalinogeri) corre-
sponding to what exists for the gastric and pancreatic enzymes
(projjepsin and protryp&in), was demonstrated by Miss Latinier.
On washing the salivary glands repeatedly with water and chloro-
form, they are freed from the active ptyalin which they contain ;
on then treating the gland with a dilute solution of acetic acid an
extract capable of saccharifying starch is obtained.

(c) A globulin that precipitates with heat, on addition of
mineral acids and also on passing a current of carbonic acid.

(d) Sulphocyanide of potassium or sodium, which is frequent
but not constant in human saliva in minute quantities of 0'016-
0'084 per thousand (Oehl), according to others in an average
quantity of O'lO per thousand (Jacubowitsch). It may possibly
be formed in the mouth by the action of special microbes.
According to Kriiger it increases in smokers.

Grober's latest investigations (1901) show that the sulpho-
cyanide is not formed by decomposition of saliva ; its elimination
probably depends on the general protein metabolism, since it is
eliminated little or not at all by persons suffering from cachexia.

(e) Traces of urea, and, in abnormal conditions, of leucine and
of lactic acid.

The inorganic compounds consist of small quantities of chlorine
and phosphoric acid combined with potash, soda, lime, and
magnesia ; small quantities of sodium carbonate and abundant
quantities of sodium chloride.

The amount both of water and of solids in the saliva may
fluctuate considerably with food or abstinence, or other changeable
factors. We must confine ourselves to citing the results of
Hammerbacher's analyses, which are of the mixed saliva (1000
parts) of a young healthy man, and which agree perfectly with
those of Frerichs :

ii EXTERNAL DIGESTIVE SECBETIONS 83

Water ... ... .

Solid substances ... . .V797

Eiiithelia and mucin . . -2--2Q-2

Ptyalin and globulin ... . 1 :',:iu

Inorganic salts ....... 2 2o.~>

Sulphocyanide of potassium .... 0041

The same author found in 1000 parts of ash of human saliva :

Potassium ... . . . . 457-3

Sodium . . . 95-9

Ferric oxide . . . 50 1

Magnesium . . . .... 1/5

Sulphuric acid . . . . . 63-8

Phosphoric acid . . ... 188'.~>

Chlorine ...... . 183'5

Iii order to obtain and analyse separately the saliva of the
respective glands, the excretory ducts of Stensen and Wharton
can be syringed with special metal cannulae (Ordensteiu, Oehl,
Eckhard) in man, and on dogs artificial fistulae of the same canals
can be established.

The parotid saliva of man is thin from absence of niucin, but
it becomes ropy and viscid if the secretion is scanty ; the reaction
is alkaline ; it is rich in ptyaliu even in the newborn ; contains
but little globulin. Constituents, 99 - 5 per cent water, 0'5 per
cent solids, of which 0'2 per cent are alkaline chlorides, - 2 per
cent carbonate of lime, and 015 per cent organic compounds, of
which 0'03 are sulphocyanide (Oehl).

The submaxillary and sublingual saliva in man is more watery,
more alkaline, more viscid, because it contains mucin : it has a
weaker diastolic action, because it contains less ptyalin ; and the
amount of sulphocyanide is less (Oehl).

Lastly, the submaxillary and sublingual saliva differs under
the microscope from parotid saliva, in containing many more
salivary corpuscles and shed mucous cells.

Colinheim's method is the best for extracting a tolerably pure ptyalin
from saliva. () The saliva is strongly acidified with phosphoric acid (using
2 litres of mixed saliva) ; (ft) the filtrate i- then made alkaline with milk of
lime, which forms a precipitate of tri basic phosphate of lime and brings
down the ptyalin ; (c) the precipitate is collected on a filter and washed
with distilled water, which dissolves ptyalin ; (d) 5-6 volumes of alcohol are
added to the filtrate, when a flocculent precipitate is formed ; this is dried
/// vacua ; (e) this precipitate is redissolved in distilled water, filtered and
reprecipitated with absolute alcohol ; the precipitate is dried, and consists of
purified ptyalin.

To show the presence of sulphocyanide of potassium in the saliva, add a
few drops of perchloride of iron, after acidifying with dilute hydrochloric
acid. The fluid turns more' or less blood-red, according to the amount of
sulphocyanide contained in the saliva (Oehl).

Solera's reaction is based on the fact that the sulphocyanide separates
iodine from the iodic acid. On adding starch paste and then iodic acid to
the saliva, the iodine is liberated, and gives a blue colour witli starch.

G 1

84

PHYSIOLOGY

CHAP.

VI. The Pancreas is a long gland, of irregular prismatic shape ;
its external secretion is conveyed to the duodenum -by the canal
or duct of Wirsung, which runs along the entire length of the
gland, buried in its substance. Its size and weight differ consider-
ably in different individuals. It is 12-13 cm. long, with a
maximum diameter of 12-25 mm. According to Krause, it weighs
66-102 grins., but Meckel gives a maximum weight of 180 grins.,
and Sommering a minimal weight of 45 grins. Its specific gravity
is 1-046.

From its structure the pancreas must be regarded as an
acino-tubular gland, resembling the salivary glands, but with

fc?A : Ip^ "

/^ ' rfev '" 'S ': -H /' X> &i@j$
:g$rl i ^ J - ... ^#.$3. r * yi ' >

l iV.i'<&fy^

^; ;^|^ :!

' "vs?.f2gf

W 1 -~ ; ^

FIG. 25. Section of human pancreas. (Bohm and \. Davidoff.) D, principal duct; C, connective
tissue ; A, alveolus or acinus ; c.c, centro-acinar cells of Langerhans ; P, commencement of
duct ; p, small alveolus without central cells.

lobes and lobules more loosely knit together by connective tissue.
The secretory alveoli consist of short tubules, which in a section
resemble rounded acini. The primary and secondary ducts are
lined with simple columnar epithelium, the cells of which become
lower in the small ducts, till where these arise in the alveoli
they are reduced to narrow, flattened, spindle-shaped cells (Fig. 25).
The number of ducts in the pancreas is not constant even in
a series of the same animals. In man they are usually two, the
principal, or duct of Wirsung, and the accessory, or duct of
Santorini. The latter may be absent (Hess), in any case it is
always very minute in the adult, while in the early stages of
development it is larger than Wirsung's duct. In the dog there
are invariably two ducts, and in a certain number of cases (30 per

ii EXTERNAL DIGESTIVE SECRETIONS

cent) a third (Hess). In the rabbit there is a secondary duct besides
the duct of Wirsung, but it is of no importance in the adult ;
U. Lombroso (1907) showed that ligatiou of the principal duct
alone causes diffuse alterations in all the organs, co-extensive with
those observed when the secondary duct is also occluded.

When freshly examined, the secreting cells at the end of the
alveoli show a clear, homogeneous, outer zone, covered with the
basement membrane, and a granular, somewhat clouded, inner
zone, which is turned towards the lumen. In very fresh prepara-
tions the granules extend over the whole of the cells, but if
the preparation is cooled they are packed towards the lumen.
In quite fresh preparations, again, the nucleus is invisible, or
scarcely seen. In carmine
preparations only the outer

zone and the nucleus stain ';$;' .... <r\ J-
(Fig. 26).

In the middle of the al- fa- '.,;&% t\ v if .,>, .
veolus Laugerhans (1869) f ^ Js&

discovered spindle-shaped ^ ',:, r ,- .,.,.. _..^ . .. ,

cells with a homogeneous .. \\ ;: - : /
body, sharp outline, and j|/ 4%

a large clear nucleus, ^ ^ ? g|f

known from their position |^ : ;0- "i

as the centro-acinar cells. ':
Saviotti, Boll, Ebner, v.

_. . ,,. i FIG. 20. Pancreas of fastins clog. Alcohol-carmine

Frey, Giannelh and many method. (Heidenhain.)

others, showed by system-
atic investigation of various kinds of animals that these cells
are constant in all vertebrates. Such centro-acinar cells are more
numerous at the neck of the alveolus than at its base, where they
may be entirely absent.

The nature of these cells has been the subject of much dis-
cussion. Langerhans, Saviotti, Heidenhain, regard them as
epithelial cells. Pniiger takes them to be nerve cells. Many
authors have supposed them to be connective tissue ; but all these
surmises have now been abandoned, and after the histogenetic
studies of Laguesse and his pupils, their epithelial character is
generally admitted.

According to Renaut and Laguesse the centro-acinar cells are
the essential factors in all the changes of form that occur within
the gland. They also participate in the external secretion.

In addition to the epithelial cells which constitute the alveolar
gland proper (acinar cells, centro-acinar, epithelial cells of ducts)
the 'pancreas of all vertebrates presents areas of tissue or com-
pact structures, which are distinct in character from the alveoli.
They stain much less freely with ordinary methods; in some
cases the individual cells have no sharp outline but resemble a

G 2

86 1'HYSIOLOGY CHAP.

protoplasmic mass, in which a number of nuclei are arranged
irregularly, so that for a long time these cells were thought to
be lymphoid. Kecent research, has, however, shown them to be
epithelial. According to some authors these epithelial bodies are
destitute of excretory ducts ; but they invariably exhibit a number
of tortuous blood-vessels which in certain cases (Kiihne and Lea)
assume the form of glomeruli. They are generally known as the
islets of Langerhaus (Fig. 27).

The special significance of these islets has recently been much

tip { *

'- -' * Q-01. "* 9

<l a >'**' "~ ;

: -. ^^ 1

^^* ; -* f ^*ii^%; ;

FIG. 27. Section of rabbit's pancreas. (Marassini.) The periphery shows a number of glandular
acini, which are darker in colour; at the centre is a large islet of Langerhans of a li^ht'-i-
colour, composed of cells with indistinct outlines.

discussed. Many observers conclude from their morphological
characters (absence of ducts, abundance of blood-vessels) that they
are responsible for the internal secretion of the pancreas, while
others claim that the alveoli, too, participate in this function.

As regards the relation between the islets and the alveoli,
Lewaschew (1880) suggested that the islets represent phases in
advancing exhaustion of the secreting alveoli. According as the
latter are more or less fatigued, they exhibit cells which ap-
proximate to the characters of the islets or the acini. He
supported his hypothesis by observations which showed that the
islets are more numerous in the pancreas of over -fed animals,
and during the action of pilocarpine. Lewaschew's theory was
adopted, as regards the possible derivation of islets from alveoli,
by Dogiel, Perdisgeat and Tribondeau, Dale, Laguesse, and many
others.

Laguesse, however, modified its physiological interpretation.

ii EXTERNAL DIGESTIVE SECRETIONS 87

aud regards this process as an alternation between the external
and internal secreting conditions of pancreatic tissue, which is
necessary to enable the organ to accomplish its double function.

The theory of the development of alveoli into islets, and
vice versa, was soon contested.

Vassale (1891) first showed that after ligation of Wirsung's
duct in rabbit, the islets remain, while the alveoli disappear.
Massari (1898) found that in eels the islets were constant and
.invariable, without any true transitional forms. Immediately
after, Giannelli, Renaut, Diamare, Jacotsky, W. Schultze, Opie,
and others, on repeating the experiments of Lewaschew's school
(hyperalimentation, pilocarpinisation, inanition, etc.), failed to find
any constant difference in the number and appearance of the
islands, in the various animals experimented on. Since that
time the theory of Lewaschew and Laguesse has been unanimously
abandoned.

It remained to be seen whether the islands were in com-
munication with the excretory ducts. The results obtained by
certain authors who attempted to solve the problem by injecting
the ducts with coloured solutions which are readily recognised
under the microscope, are directly contradictory. Thus Lewaschew
(1886), Mankowski (1901), asserted that the injected substance
penetrates to the islets. V. Ebner (1872), G. Eossi (1902), and
others affirm that it never reaches the islets. But it must be
noted that injection by the ducts does not always reach the whole
of the alveoli, as observed by Eossi. These negative results. have
therefore no decisive value.

Simple histological examination, on the contrary, does tend to
support the hypothesis of communication between the islets and
the excretory ductules. Laguesse, in a fragment of human pan-
creas, noted that out of 56 islets followed in serial section, only
4 were entirely independent. Of the other 52, many were either
in direct relation with the excretory system, or were joined to it
by the alveoli.

A highly important detail, as to which opinions differ, is the
existence of a connective capsule, surrounding the islets com-
pletely, and separating them sharply from the alveolar tissue.
Eenaut (1879) pointed out a reticulum enclosing the islets, as
did also Opie and Pugnat. On the other hand, Gibbes, Diamare,
and Hansemann denied these observations. To solve the problem
Marshall Flint (1903) employed tryptic digestion, which spares
this capsule ; and decided that it existed.

Laguesse also admitted it, but stated that the capsule
(menibrana propria) does not completely surround the islets, which
contract relations with the excretory system at the points at
which they are not invested.

Golgi's method demonstrates the origin of the excretory

G 3

88

PHYSIOLOGY

CHAP.

ductulcs within the pancreatic alveoli: like the, salivary glands,
they stain a uniform black. As shown iu Fig. 28, the excretory
duct sends lobular branches to these ductules between the cells,
and also to the interior of each cell.

The blood- vessels penetrate into tbe gland along with the
pancreatic duct, ramify in the lobes, and form a capillary network

FIG. 28. Section of two fragments of human pancreas. Silver eliminate method. (E. Miiller.)
A, longitudinal section of excretory duct, lined with columnar epithelium ; m, lobular
diir.tules, giving off small diverticula between and into the alveolar cells. B, .shows com-
mencement of ductules in alveolar cells (higher magnification).

round the lobules and the alveoli with highly uneven meshes,
some being so wide that many parts of the alveoli are scantily

irrigated with blood.

The pancreas contains nerve fibres, both medullated and
non-medullated, which unite with the sympathetic ganglia and
the isolated ganglion cells. On staining with Golgi's method
the fine nerve-fibrils can be followed into the alveoli. In some

ii EXTERNAL DIGESTIVE SECRETIONS 89

c.-irnivora, e.g. cat, numerous corpuscles of Pacini are seen in the
pancreas.

VII. The pancreatic, like the salivary, secretion is under the
control of the nervous system, for it begins a few minutes after
the food has entered the stomach, which must he due to a nervous
retiex transmitted from the afferent nerves of the stomach to the
efferent secretory nerves of the pancreas. Experiment shows that
these afferent nerves are stimulated by the hydrochloric and other
acids directly introduced into the stomach, which after a few
moments produce a copious pancreatic secretion. If the exciting
action of these acids is abolished, by neutralising them with the
introduction of alkaline fluids, the secretion is considerably
diminished or suspended (Pawlow). The same excitatory effect
is obtained when neutral fats are introduced into the stomach :
but it is probable that these excite pancreatic secretion by acting
on the afferent nerves of the duodenal mucosa ; and also because
part of the neutral fats that enter the stomach are split into
fatty acids by the lipolytic enzyme of the gastric juice (Volhard).

These facts suggest that under normal conditions the secretion
of the pancreas is connected with the introduction of acid foods
and fluids, particularly the hydrochloric acid of the gastric juice,
which reflexly excites the secretory nerves of the pancreas. Direct
observations support this theory, and show that when gastric
secretion increases, the pancreatic secretion increases also.

Subcutaneous injection of atropiue diminishes the secretion of
pancreatic juice, but does not suspend it, as in the case of saliva.
Injection of pilocarpine and physostigmine produce a contrary
effect to atropine (Gottlieb). Pilocarpine, however, does not
directly excite pancreatic secretion, but it excites a profuse gastric
secretion. The gastric juice, in its turn, on passing into the
duodenum, is able, secondarily, to determine the pancreatic
secretion. This is proved by Launoy's observation (1904) that, if
the stomach be tied at the pylorus, there is no longer any secretion
from the pancreas after pilocarpine injection, or, at most, only a
few drops of a very dense secretion.

Heidenhain showed that electrical excitation of the medulla
oblongata or cervical cord provoked pancreatic secretion if this
had been suspended, and accelerated it if the gland were already
functioning. Separation of the bulb from the cord by a transverse
section did not, however, arrest the secretion, showing that other
inferior centres besides that in the bulb affected the functions of
the pancreas.

Besides a centre for secretory nerves, the bulb appears also to
contain a centre for inhibition of secretion, since, on exciting the
central end of the vagus, the pancreatic secretion is arrested
(Bernstein). This effect is probably due to a reflex vaso-con-
strictor action, by which the blood-supply to the gland is much

90 PHYSIOLOGY CHAP.

diminished. The same result is obtained on stimulating other
sensory nerves, so as to excite nansea or vomiting.

Pawlow's subsequent work on dogs established beyond a doubt
that the secretory nerves of the pancreas run in the vagus. If in
a dog one vagus be divided in the cervical region, and the bulb
separated from the cord after 3 to 4 days by incision, artificial
respiration being given, and a pancreatic fistula established,
any stimulation of the peripheral end of the vagus by strong or
weak induced currents produces pancreatic secretion. Previous
researches carried out without these precautions had always led
to a negative result, owing to the great sensibility of the gland to
all influences capable of altering its blood-supply.

The vagus is not, however, the only nerve which contains
secretory fibres to the pancreas. According to Kudrewetzsky,
the splanchnic also supplies some, although their secretory action
is much less developed than that of the vagus.

A recent theory of Bayliss and Starling as to the mechanism
of secretion, whether of the pancreas or of other glands in the
digestive tube, has been very generally accepted.

According to these authors there is, besides the nervous con-
trol which is able in itself to excite pancreatic secretion, another
secretory mechanism, which acts independently of the nervous
system. This consists in an internal secretion by the mucous
membrane of the duodenum, of a special substance (secreting
which, on entering the circulation, travels with the blood to the
pancreatic cells, exciting them directly and causing secretion.

Their theory rests particularly upon the fact that, on macerating
the mucous membrane of the intestine (especially of the duodenum
and adjacent parts) in a solution of hydrochloric acid, a solution
is obtained on filtering, which, when injected into the veins,
produces a profuse pancreatic secretion.

This fact has been controlled by many, and invariably con-
firmed ; but it does not seem to us to justify the theory that has
been based upon it. To say that secretin thus artificially prepared
is able to excite secretion in the pancreas and many other glands
does not mean that it is elaborated and circulated under normal
conditions of the duodenum. We know from an observation of
U. Lornbroso (1903) that such is not really the case. In dogs
with a Pawlow's pancreatic fistula the secretion diminishes, and
ceases entirely after some days, if the papilla of the duct lie
destroyed, even if the secretory ducts are still open.

The same occurs if, instead of establishing a pancreatic fistula
by Pawlow's method, it is prepared in Cl. Bernard's way, which
does not respect the integrity of the duct or the papilla. Why,
in all these cases, if the secretory mechanism of the pancreas
consisted (as on the hormone theory of Bayliss and Starling) in
the production of secretin during the passage of the gastric

ii EXTERNAL DIGESTIVE SECRETIONS 91

contents into the duodenum, should the pancreatic secretion
decline and cease ? Since the duodenum continues to receive
uniform quantities of gastric juice, a corresponding amount of
secretin should be elaborated to carry on pancreatic secretion.

Popielski (1905-7) and his pupils have recently published a
series of experiments and conclusions which completely refute the
secretin theory. Popielski states that the substance extracted
after the maceration of the duodenal rnucosa with hydrochloric
acid is not specific, but may, on the contrary, Lie obtained by
simple hydrolysis, from any glandular, muscular, or even nervous
tissue. Popielski further points out that no appreciable altera-
tion of blood pressure can be observed on introducing hydrochloric
acid into the stomach to produce an abundant pancreatic secretion ;
whereas the so-called secretin has no sooner been injected (even
in small doses, with which much less secretion is obtained) than
a marked diminution of blood pressure occurs. According to
Popielski, this proves that the substance in question acts as a
vaso-dilatator.

But the following is the most cogent of Popielski's arguments.
On repeating the injections of secretin many times in equal doses,
he observed a conspicuous secretion after the first dose, less after
the second, less still after the third, till the substance rapidly
became ineffective. Now, the introduction of acid into the duo-
denum, however often repeated, invariably excites pancreatic
secretion proportional to the quantity of acid introduced. The
body evidently reacts to the introduction of secretin by forming
an anti-body capable of fixing it and annulling its action ; this
suggests that it is not a substance normally developed in the
body, but is an artificial extraneous product.

The pancreatic, unlike the salivary, secretion ceases when
pressure in the excretory duct reaches the maximum of 21 mm.Hg,
which is far below that at which the arterial blood circulates in
the gland (Pawlow). During secretion there is, as in the salivary
glands, an acceleration of local circulation, which Klihue and Lea
observed directly under the microscope, in living rabbits. The
capillaries, which are too narrow to permit the passage of more
than a single erythrocyte, dilate during activity so as to allow of
more corpuscles passing simultaneously. The pulsation or trans-
mission of the blood-wave is visible in both the capillaries and
the small veins. These are phenomena of active vaso-dilatation,
from physiological excitation of the vaso-dilator nerves by paths
which are quite unknown to us.

Pancreatic secretion appears to be continuous in herbivora,
whose gastro-intestinal tube is never empty of food, and inter-
mittent in carnivora, which have a shorter digestive tube and
intermittent digestive processes. Colin observed in calves that
the secretion is continuous, but that it ebbs and flows in relation

92 PHYSIOLOGY CHAP.

to the degree of digestive gastro-intestiual activity. According
to the observations of Heidenhain and his school, the secretion

ceases in fasting dogs, and

fcjgsse recommences during di-

fcfjli gestion, continuing with

fairly regular fluctuations
throughout the process.
The rate of secretion
reaches its height in the
first 3 hours of digestion,
then slowly diminishes, to
rise again to a second maxi-
mum between the third and

$j&# seventh hours, after which

it falls rapidly to the mini-
mum. The interpretation

PIG. 29. Pancreas of dog with permanent fistula,

showing changes in the alveolar cells owing to 01 tlllS Will be dlSCUSSed

paralytic secretion. Alcohol - (carmine method. i i

(Heidenhain.) elSeWllCie.

In dogs, too, pancreatic

secretion may become continuous if the state of the gland is
altered. In this case (which recalls the paralytic secretion of the
salivary glands) the juice secreted is fluid and highly similar to
an ordinary transuclate. The alveoli of the gland are reduced ;
the secretory cells have
lost the inner zone and
only keep the outer, so
that their whole contents

stain with carmine (Fig. K.J.T---> ^._, ^ ?sf :

29). This change is an I #* e ^v tferj^S

/ t>* ' ~"^"-. "</"* '

. n t "".._*> - . .

exaggeration of what 3r.- .

,1 i -1 /\- t- -. "y> ! :'" - '-"!.: '"'.- >-

occurs in the gland m S^-% V^'^lfe^

normal digestion. fe'W %&^3

According to Heideu- "^p-*^ 8 ^^

hain's histolosical studies r -!*v% '

- * "* '' ' ' '

of the pancreas, by the

alcohol-haematoxylin and ^ ^'&*

carmine method, in the ,^ ^^" ;

first period of digestion

(which extends to 6-10

hours after the meal) the

OUter, Staining ZOne OI Fj( ._ 30 __ Dn ,,, s pancreaSj excised during first period of
Secretory Cells IS enlarged digestion. Alcohol-carmine method. (Heideuhain.)

in dogs; the inner, granular

zone almost entirely disappears, so that the glandular alveoli
seem as a whole to be diminished in diameter. The alveoli
never show uniform changes, some being more, others less,
modified by the secretory process (Fig. 30).

II

EXTERNAL DIGESTIVE SECRETIONS

93

In the second digestive period (which includes the interval
between 10 and 20 hours after the meal) the alveoli increase in
hulk by a marked enlargement of the secretory cells. Their

FIG. 31. Dog's pancreas, excised during second period of digestion.
Alcohol-carmine method. (Heidenhain.)

inner zone is much enlarged, while the outer is more reduced
than it was during fasting ; their nuclei are no longer round, but
flat and angular (Fig. 31). From all this Heidenhain concludes
that the inner zone of cells is consumed or dissolved during the

FIG. 32. Two alveoli from pancreas of living rabbit, in state of rest and of secretory activity.
(Kuhne and Sheridan Lea.) A, resting state ; B, after secretion.

first stage of digestion, and regenerated at the expense of the
outer zone in the second, as if the one were transformed into
the other.

The later researches of Kuhne and Lea, obtained by direct
observations on live rabbits, have corrected Heidenhain's observa-
tions in accordance with the earlier doctrine of Johannes Miiller.

94 PHYSIOLOGY CHAP.

At the commencement of secretion, the cells of the tubular alveoli
undergo gradual changes which become very conspicuous. As is
partly shown in Fig. 32, the cells shrink in consequence of
secretion. The polyhedral cells become rounder ; the outlines of
the cells, which in the resting state are to a large extent invisible,
are well marked after secretion, with a double contour; the
granules of the outer zone move towards the lumen of the duct,
become smaller, less shining, and gradually disappear altogether.
It is therefore the secretory matter elaborated into granules by
the metabolic activity of the cells which dissolves and passes into
the secretion, and not the protoplasmic substance of the inner
zone of cells.

In spite of much research little is known precisely as to
the significance of the grauules pointed out by Claude Bernard
and commonly known as zymogen granules, or their relation with
the functional phases of the gland. Kolliker, Henle, v. Frey, and
others who observed them before Bernard, regarded them simply
as fat -granules, owing perhaps to their round and refracting
surface.

If fragments of the pancreas are dissociated and pounded up
in a drop of serum, the granules are set free, and float for a long
while in the fluid before they dissolve. On adding acetic acid
they dissolve instantly, while in a solution of potash they first
swell and then dissolve slowly. Heidenhain, who (as we have
seen) observed variations in the number and arrangement of the
granules during the various stages of digestion, suggested that
they might consist of masses of pro-ferment. This hypothesis
was accepted by many authors who gave them the name of
f/ranules.

But while the participation of the granules in the pancreatic
secretion is beyond doubt, there are certain observations which forbid
us to accept without further demonstration that they represent
the zyrnogen, or the whole zymogenic content of the gland.

Liversedge, Laguesse and Debeyre observed that maceration of
the pancreas with solutions capable of dissolving the granules
(acetic acid or alkali) yields an extract that is completely inactive
to protein, even on the addition of kinase which ought to activate
it (see Vol. I. p. 30).

On the other hand, U. Lombroso observed that 10 to 12 days
after ligation of the ducts, the pancreas of the pigeon, which no
longer shows any granules under the microscope, still exhibits
well-preserved enzymatic properties (amylolytic activity).

VIII. Alkaline while living, the pancreas after death gives
an acid reaction, which is probably due to the development of
lactic acid, and of fatty acids.

Chemical analysis of pancreatic tissue shows the presence of
an albumin, several globulins, nuclein and nucleo-protein (Spitzer),

ii EXTERNAL DIGESTIVE SECRETIONS 95

various nitrogenous compounds, inosite, lactic acid, neutral fats,
volatile fatty acids, uric acid, and mineral substances. The
composition of the human pancreas is according to Oidtmann

Water . . 74'53 per cent
Organic Substances ... . 24-57
Inorganic Substances 0-75 ,,

The most important substances it contains (the chemical
nature of which is still wholly unknown) are the three or four
zymogens, which are readily converted into their respective
enzymes, on which the digestive properties of the pancreatic juice
depend.

The pancreatic secretion differs entirely in its physical
characters and composition according as it is collected in a
temporary fistula of Wirs ung's duct, or from a permanent fistula.
In the first case it is stringy and syrupy, forming in the cold at
a gelatinous mass, from which a fluid serum separates out.
This gelatinous mass readily dissolves in dilute acids. Owing to
the amount of protein, the pancreatic juice thus obtained coagulates
on heating. The secretion from the permanent fistula is more
fluid, and contains a smaller amount of organic matters. Both
the one and the other juice have digestive properties, but we
must hold with Pawlow that it is only the secretion from a
successful permanent fistula that represents the normal secretion,
since the pancreas is highly sensitive to all the lesions inevitable
in making a temporary fistula.

The quantity of juice that escapes from a fistula in a given
time is very variable, and therefore very difficult to estimate.
Some hold that the human pancreas secretes 150 c.c. per diem.

This appears to us to be too low an estimate. Since Pawlow
obtained 300-350 c.c. of juice from a dog that weighed about
20 kgrm., it is probable that a man would secrete over 500 c.c.
per diem.

The actual reaction of the pancreatic juice, which is almost
neutral (Farkas), must be distinguished from the potential reaction,
which is, on the contrary, intensely alkaline, and equivalent, in
the dog to l/10n NaOH. Pawlow has observed that the alka-
linity of the pancreatic juice is equivalent to the acidity of the
gastric juice, and therefore suffices to neutralise the acidity.

Normal pancreatic juice contains a large amount of protein.
According to Zawadsky that collected from a fistula in a woman
operated on for pancreatic tumour contained in 100 parts-
Solids . 1.3-59 per cent

Total Organic Substances .... 13-25

Albumin 9-21

Ash . 0-34

90 PHYSIOLOGY CHAP.

Its most important constituents are the enzymes or soluble
ferments. These are usually three ; the diastatic enzyme
(amylopsiii), the proteolytic enzyme (trypsiri), and the lipolytic
enzyme (steapsin), to which a fourth, on which depends the
capacity of the pancreatic juice to coagulate milk (chymosin)
should perhaps be added. Pancreatic juice further contains a
substance which is precipitated by acetic acid (Halliburton) ; this
may be mucin or nucleo-protein. Besides these, xanthme, leucine,
fats, soaps, and salts, more especially alkaline chlorides, alkaline and
earthy carbonates and phosphates, have also been found.

Pure trypsin is a protein of unknown composition which in the
free state is soluble in water and insoluble in alcohol and
anhydrous glycerol, in which, however, it dissolves if -not quite
pure. When dissolved in water, the solution being acidulated
and boiled, it splits into albumin and peptone (Kiihne). This
may, however, be not a true cleavage but a separation, as the
albumin may be considered an impurity (Loewi). When dissolved
in sodium carbonate and heated to 50 C. its proteolytic activity
is destroyed after five minutes : in a neutral solution it is destroyed
at 45 (J. ; it is also destroyed by the hydrochloric acid of the
gastric juice. Its digestive activity for proteins is best developed
in the presence of a 1 per cent solution of sodium carbonate, at a
temperature of 40 C.

The formation of trypsin in the pancreas has been more
closely studied than that of any other enzyme. If from a dog
that has fasted for 24 hours a glycerol extract of half the
pancreas is made immediately after the death of the animal
(extract 1), and of the other half when it has been left 24 hours
in the air at a temperature of 40 C. (extract 2) taking in both
cases one part by weight of the pancreas (ground up with
powdered glass) and ten of glycerol, adding to both extracts a
1-2 per cent soda solution it is regularly found that the first
extract has little or no digestive action upon fibrin, while the
second extract has a marked action. This experiment shows
that the fresh pancreas contains little or no trypsin, but that it
does contain a substance that can be transformed into trypsin,
which Heidenhain termed trypsin -zymogen (also known as
trypsinogen or protrypsin).

This zymogen is insoluble in water. Its conversion into
trypsin is arrested or greatly hindered by the addition of a 1-2
per cent soda solution. But if the glycerol extract containing
zymogen is dissolved in sodium carbonate (1-2 per cent), and
oxygen passed through it for ten minutes, it becomes strongly
active by conversion of the zymogen into the enzyme. Zymogen
dissolved in distilled water that has been previously boiled
remains inactive ; in unboiled distilled water it becomes active
owing to the contained oxygen. The same transformation occurs

ii EXTERNAL DIGESTIVE SECRETIONS 97

with platinum black, with dilute acetic acid, and according to
Kiihne with absolute alcohol also.

According to Heideuhain the amount of trypsinogen in the
gland diminishes gradually from the commencement of digestion,
reaching its minimum after 6-10 hours. It then begins to
increase again, and reaches its maximum 16 hours after the meal,
when it remains constant for about 30 hours.

The other enzymes secreted by the pancreas have not been
fully worked out.

Amylopsin or pancreatic diastase was discovered by Valentin
in 1844, and again by Bouchardat and Sandras in 1846. It has
an ainylolytic or saccharifying action upon starch, similar to that
of the ptyalin secreted by the salivary glands, but is more vigorous
and .rapid, since it is able to act on raw starch. It has been
assumed capable of transforming large quantities of maltose into
dextrose ; other authors (Rohmann) maintain that this effect
depends upon another special enzyme, to which the name of
glucase has been given.

According to Korowin, Zweifel, and Sonsino the diastatic
power of the pancreas begins to develop in the second month after
birth, and is absent in the new-born.

Little is known in regard to the zyrnogen of pancreatic diastase,
as assumed by Liversedge. According to Grlitzner the amount of
diastase contained in the pancreas fluctuates during digestion like
the trypsin ; it is minimal in the sixth hour of digestion, and reaches
its maximum 14 hours after the meal, after which it decreases
slowly, though it is still higher than in the first digestive period.

Steapsin (lipase}, the enzyme which emulsifies fats, and splits
them into glycerol and fatty acid, was discovered by 01. Bernard
in 1846 ; its hydrolytic power was subsequently confirmed by
Nencki, who showed that acetic acid ester and the esters of the
aromatic series (salol, benzonaphthol) are decomposed by the same
enzyme. It has never been isolated, and is certainly the least
known of the pancreatic enzymes. It can be extracted from very
fresh glands by a watery solution of sodium carbonate (Paschutin).
It does not dissolve in glycerol ; is destroyed by alcohol and
acids ; is not found in glands that are not perfectly fresh. It
probably exists in the foetal pancreas because the meconium
contains free fatty acids. The optimum of its activity in regard
to neutral fats is reached at 38 0. Its action, like that of all
other enzymes, is destroyed by boiling. It acts better in a neutral
than in an alkaline medium.

Nothing is known of the zymogen from which lipase arises.
According to Griitzner this enzyme increases slowly in the
pancreas from the sixth to the fortieth hour after a meal, reaching
its minimum (like the other pancreatic enzymes) at the 6th hour
of digestion.

VOL. II H

98 PHYSIOLOGY CHAP.

Wo shall deal in a later chapter with all that concerns the
nature of the different digestive processes eifected by the pancreatic
enzymes, and the conditions which favour, moderate, or inhibit
them the importance, in short, of the pancreatic secretion to the
utilisation of food-stuffs in general.

Besides tin 1 pancreatic juice obtained by a temporary or permanent,
fistula of Wirsung's duct, the digestive activity of the pancreas is tested by
making an ariijiriitl f.-'h-m-t of the organ. This is prepared by grinding up
the pancreas, after dissecting away the fat and connective tissue, and drying
it in a desiccator over sulphuric acid. The dried residue is then treated
with alcohol and ether to remove the remaining fat, and macerated with a
1 per cent solution of salicylic acid at 40 C. for 12 hours, 500 c.c. of this
solution being used for every 100 grins, dried pancreas. The massj's then
filtered and squeezed through muslin. The solid material is digested for
12 hours at 40' J C. in 500 c.c. of a 2'5 per cent solution of sodium carbonate,
containing a few drops of an alcoholic solution of thymol to prevent putre-
faction. The filtrate is rendered alkaline with the same solution, and also
allowed to digest at 40 C. for 12 hours. Both from the solid material after
filtering from any undissolved residue, and from the solution, a very active
artificial pancreatic extract is obtained.

From these extracts trypsin can be prepared in a state of comparative
purity by Kiihne's method. The extracts are allowed to digest for about a
week, when all the proteoses will be transformed into peptones. They are
filtered, and ammonium sulphate added to the filtrate to saturation. A fine
precipitate results, which carries down all the trypsin. This is dissolved in
water and dialysed, to remove the greater part of the ammonium sulphate.
The remainder of the sulphuric acid is precipitated as barium sulphate by
barium carbonate, and the clear filtrate is precipitated with alcohol. The
amorphous precipitate thus found is collected on a filter.

IX. That the pancreas exerts an internal function in carbo-
hydrate metabolism was suspected long ago by clinicians (Frerichs,
Cantani, Seegeu, Bouchardat, and others), since post-mortem
examination of many cases of human diabetes showed profound
and varied alterations of this organ. But as little was known at
that time about the internal functions of glands, and there was
then no suspicion of the existence of such a function in a gland
provided with an excretory duct, they attempted to explain the
diabetes as an indirect consequence of the altered external
function of the pancreas. This gave rise to the hypothesis (to
which we must refer, because it is still maintained by certain
authors) that the food -stuffs being ill -digested, owing to the
absence of the pancreatic enzymes, developed toxic substances
which, when reabsorbed, inhibited the normal carbohydrate
metabolism.

It was long before any experiments threw light upon this
subject. The first attempts at extirpating the pancreas (Conrad
Brunner, 1788 ; Cl. Bernard, 1855 ; Berard and Colin, 1857 ; Senn,
1880 ; Martinotti, 1880) either resulted in the death of the animal
in a short time, making it difficult to analyse the phenomena, or
were so incomplete that no disturbance resulted from them, so

ii EXTERNAL DIGESTIVE SECRETIONS 99

that the function of the gland appeared not to be indispensable in
the various processes of metabolism.

Nor did glycosuria appear in other experiments (on dogs, cats,
and rabbits) in which destruction of the pancreas was attempted
in situ by ligation and section of the ducts, or their injection with
extraneous substances, such as oil, paraffin, acids, etc. (Cl. Bernard,
Schiff, Pawlow, Arnozan, and Vaillard).

In 1889 von Meriug and Minkowski successfully accomplished
the total excision of the pancreas in dogs, and stated that
immediately after the operation there appeared regularly, along
with grave disturbances of alimentary absorption, an intense
glycosuria which lasted until the death of the animal, 2-3 weeks
later. The complex of symptoms was very like that of severe
cases of human diabetes (wasting diabetes), so much so that it
was known by the name of experimental diabetes.

The results of von Mering and Minkowski were at once
confirmed by many authorities (Hedon, Lepine, Capparelli, etc.).
Since this glycosuria was evidently not due to impeded flow of
pancreatic juice into the intestine (as in the case of the permanent
fistula of Wirsung's duct), it was easy to deduce that it depended
not on the defective action of the secretion in the intestine, but on
'the suppression of some other function exerted by the pancreas.
This idea, however, was and still is combated by some authors on
the strength of the following experiments.

De Dominicis, who excised the pancreas in dogs, simultaneously
with von Mering and Minkowski, sustained emphatically that the
glycosuria was not a constant phenomenon, and not in any case
determined by the suppression of an internal pancreatic secretion.
Glycosuria and all the other phenomena by which it is usually
accompanied (pollakiuria, polyuria, polyphagia, azoturia, phospha-
turia, etc.) depend, according to De Domiuicis, upon a reabsorption
of toxines formed by the putrefaction of alimentary substances
that are not digested owing to lack of pancreatic juice. He
observed that injection of faecal extract from depancreatised dogs
produces slight glycosuria (1894), while injection of the duodenal
contents of depancreatised dogs produces an intense and persistent
glycosuria (1908).

Pniiger (1905) long refused to admit that the glycosuria conse-
quent on excision of the pancreas was due to suppression of a true
internal function of this gland. In his opinion the operative act
excites the nerve plexuses which traverse or have their terminations
near the pancreas, and which reflexly affect the centres which he
terms diabetogenic, leading to increased formation of glucose on
the part of the liver. This theory of Pfliiger, already brought
forward in 1892 by the brothers Cavazzani, was contradicted by
the experimental results of Lustig, Kaufmann, Marassini, Zaniboni,
who, on more or less completely excising the solar plexus, or

100 PHYSIOLOGY CHAP.

dividing the nerves to the pancreatic region, obtained no diabetes,
but at most a slight transitory glycosuria. Moreover, Minkowski,
Hedon, Thiroloix, Sandnieyer, U. Lombroso, showed that after the
extirpation of a large part of the pancreas (leaving only the
processus uncinatus freed from all its relations with the duodenum,
save the large vessels) there was no glycosuria in the majority of
cases, although the lesions involving the nervous system of the
region were practically identical with those consequent on com-
plete extirpation, so that it was no longer possible for the external
secretion to be poured out into the intestine.

Pniiger denied the value of this experiment, affirming that
if one nerve filament were left intact it was able to act vicariously
for all the rest, so that the presence of the nerve plexus which
accompanies the respective vessels would explain the absence of
glycosuria.

Hedou, who had already investigated the neural hypothesis,
tried to answer this last objection by dividing the neuro-vascular
peduncle of the pancreatic segment left in the body. His results,
however, proved little, because glycosuria set in after resection
of the peduncle ; still he noted that it almost always increases
when the pancreatic segment is excised.

The subsequent results of U. Lombroso in Minkowski's
laboratory may be regarded as an experimentum crucis against the
neural theory.

In a dog in which the processus uuciuatus was grafted under
the skin, and which merely showed traces of sugar in the urine
(less than 0'3 per cent), the neuro-vascular peduncle was cut a
month after the first operation. Slight glycosuria appeared, and
vanished after four days, leaving the animal in the initial state.
After twelve days, on extirpating the segment of the panci'eas so
as to separate it completely not only from the duodenum but also
from the abdominal cavity, severe diabetes at once set in, and
persisted till death.

De Dorninicis refused to admit that these experiments, like
those which proved that glycosuria does not appear after ligation
of the pancreatic ducts, had any conclusive value against his own
theory. He pointed out that after ligation of the ducts or
excision of that part of the pancreas which contains the ducts,
alimentary absorption was far better than after total extirpation
of the pancreas. This, according to De Dorninicis, showed that
the pancreatic secretion was able in some way to reach the in-
testine, either by ducts that remained open or by a new formation
of ducts.

With this is associated another question that has recently come
under discussion. Does or does not the pancreas influence food
absorption, when it is no longer pouring its secretion directly into
the intestine ?

u EXTEENAL DIGESTIVE SECRETIONS 101

De Doniinicis, and more recently Visentini and O. Hess, reply
in the negative.

According to Hess the dog's pancreas often has more than
two ducts, hence the experiment of tying the two ducts is not
conclusive. According to Visentini the divided ducts can easily
recover their functions. But these authors neglect the fact
that alimentary absorption can also be beneficially affected by
the presence of a segment of the pancreas completely separated,
not only from, the duodenum (Abelnianu, Pfliiger, Hedon, U.
Lombroso, Eosenberg), but from the abdominal cavity as well
(U. Lombroso).

Abelmann, Minkowski, Pfliiger, Eosenberg, supposed that
absorption in these last cases still depends upon the external
secretion, this being reabsorbed and carried by the circulation to
the liver or the intestinal glands, whence it is returned to the
intestine.

Lombroso opposes this doctrine. He shows that by infusing a
certain quantity of pancreatic secretion into the vein, the enzy-
matic property of the bile might be profoundly altered for some
considerable time, whereas such modification does not occur after
occlusion of the orifices into the pancreas. He therefore thinks it
probable that in such cases there is no reabsorption of the pan-
creatic secretion. He has recently demonstrated (1908) in the
laboratory of Minkowski (who previously supported the opposite
theory) that a segment of pancreas, grafted under the skin, so that
its secretion is freely poured out externally, does promote food
absorption. Fleckseder, in Vienna, simultaneously arrived at the
same results as Lombroso, and therefore supports his theory.

In view of these results it is no longer possible to put forward
alimentary absorption as a proof that the pancreas with occluded
ducts is capable of pouring the products of its external secretion
indirectly into the intestine. The internal function of the pancreas
must, therefore, be not solely the arrest of glycosuria, but also,
though indirectly, the promotion of food absorption. We shall
return to this subject in treating of the absorption of food.

The next question is whether this internal function of the
pancreas connotes a special secretory process or no. Hedon holds
that it should be possible to prove the existence of an internal
secretory function of the pancreas, by the modification of experi-
mental diabetes with the introduction of glandular extracts into the
circulation, just as the thyreopriva syndrome can be modified by
administration of thyroid extracts.

Eesearch in this direction has yielded only doubtful or contra-
dictory conclusions. Capparelli (1891-92) obtained favourable
results in depaucreatised dogs with injection of very fresh pan-
creatic pulp. Eecent observations of Ziilzer, Dohrn, and Maxer
(1908), on both human and experimental diabetes, had the same

102 PHYSIOLOGY CHAP.

result. On the other hand, the conclusions of Hedon, Gley, Lepine,
and many others were negative. To us it seems too large an order
to assert that artificial injections of glandular pulp can replace a
physiological function which develops in a continuous and regular
manner, or to give a decisive value to negative results in such
questions.

A very ingenious experiment, which tells in favour of a true,
internal secretion of the pancreas, is that of Forschbach (1908) witli
the method of paraltiosis. This consists in uniting two animals of
the same species and litter with a triple suture (cutaneous,
muscular, peritoneal). In the animals thus operated on, there is
an exchange of blood by the blood-vessels and lymphatics of the
two communicating abdominal cavities, and it has been shown
that many substances (iodine, sugars, alkali, etc.) injected into
one animal pass rapidly into the other.

On extirpating the pancreas from one of the two dogs in
parabiosis, pathological disturbances do not set in with the severity
described above : in some cases they are very slight, but become
aggravated as soon as the depaucreatised dog is separated from
the other.

Biedl observed permanent glycosuria after ligation of the
thoracic duct, or when the whole of the lymph had been drawn off
externally, and found (with Offer, 1907) that this experimental
diabetes disappeared on injecting lymph, which suggests that the
internal secretion of the pancreas may be discharged by the
lymphatic system.

These observations render the hypothesis of an internal
secretion the most probable among the many that have been
proposed to explain the internal function of the pancreas.

X. Given the existence of an internal function of the pancreas,
and assuming it to be served by a special secretion, Laguesse,
Schafer, Opie, and others formulated a theory that has been widely
accepted. The two secretions of the pancreas, external and
internal, are held to be distinct functions of different cells, the
former being served exclusively by the alveoli, the second by the
islets of Langerhans.

The morphological arguments for this theory are, however,
inadequate, and too much a matter of controversy to be conclusive.
They rest on the well-known fact that the islets are provided
with numerous blood-vessels, and on the assertion (supported by
very few authors) that they are completely invested by a capsule of
connective tissue and contract no relations with the excretory
ducts.

If this could be proved, the insular theory would obviously
have a valid anatomical basis. Even so, however, the possibility
that the alveoli also contribute to the internal secretion would not
be excluded. Moreover, the fact that the islets contain numerous

ii EXTERNAL DIGESTIVE SECRETIONS 103

blood-vessels is no proof that they serve the internal secretion to
the exclusion of the alveoli. It is still conceivable that the
internal secretion of the pancreas may be discharged by the
lymph capillaries. Biedl's observations as previously quoted
support this hypothesis.

Morbid anatomy does, indeed, support the view that the
islets are the exclusive organs for the internal secretion of the
pancreas. Numerous observations (Hanseuiann, Opie, Guteinann,
Karakascheff, Ssobolew, Herxheimer, Schmidt, Sauerbeck, Visentini,
Herzog, Reitnianu, etc.) show that the pancreas may exhibit
different features in human diabetes. In some cases there is no
alteration either of alveolar or of insular tissue. But in the great
majority of cases the pancreas is profoundly and diffusely altered,
both in the alveoli and in the islets. It is rare for the
degeneration to involve alveolar tissue only, still more rare that
the changes should be confined to the islets.

The rare cases of diabetes with a healthy pancreas prove that
this disease is not necessarily pancreatic in origin ; which does not
alter the fact that the pancreas normally discharges an internal
secretion which affects carbohydrate metabolism.

The rare cases of diabetes in which either the islets alone
or the alveoli alone are modified, cannot be taken as a decisive
argument in favour of the theory which ascribes the internal
secretion of the pancreas exclusively to the islets (Laguesse) or to
the alveoli (Hansemanu) ; at most they suggest the hypothesis
that both these tissues co-operate actively in the normal internal
secretion of the pancreas.

Experiments with the object of localising the external and
internal secretions of the pancreas in its two tissues have been
numerous.

Schultze and Ssobolew (1900) were the first who maintained
the insular theory of internal secretion, starting from the fact that
after ligation of the ducts or internal pancreatic lobes in the
rabbit, the islets were left unaltered, while the alveoli were
modified and disappeared, without causing any true diabetes.

The same fact had been described by Vassale ten years earlier,
but not with the intention of localising the internal secretion
in the islets : he merely sought to contradict Lewaschew, who
affirmed the unitary character of the two pancreatic tissues.

Mankowski and Lombroso failed to confirm the results of
Schultze and Ssobolew. They found that ligation of the ducts in
the rabbit produced alterations not merely in the alveoli but
also in the islets, which diminished in size and number.

Many other authors (Tiberti, Pende, Marassini, etc.) obtained
substantially the same results; some (Laguesse, Marassini),
however, argued from the greater resistance of islets as compared
with alveoli, that the absence of glycosuria must be referred to the

104

PHYSIOLOGY

CHAP.

~~~ ~~~ ^N b" - -_^~" v 1

survival of the islets, the internal secretion being served by the

i slots only.

Lornbroso objected that the necessary counterproof was

wanting. It is not known whether complete extirpation of the

pancreas (as far as possible) would
produce glycosuria in the rabbit.
It is known, indeed, that complete
ablation of the pancreas is not followed
by glycosuria in all animals. It is
absent in many granivorous birds
(pigeons), while it is seen in caruivora
(crows, falcons). Moreover, the effects
of total excision of an organ, and of
the slow and gradual suppression of
its function, may differ considerably.
Even in the dog, according to Hedon,
glycosuria may be absent or very slight
when a pancreas previously altered by
injection of paraffin into its ducts is
excised.

After tying or cutting the ducts,
and after transplanting a segment of
the pancreas in the dog, numerous
observers (He"don, Moruet, Laguesse,
Ssobolew, De Dominicis, Hansemann,
Lombroso) found that conspicuous
groups of alveoli or of islets might
survive in perfect preservation, even
for a long time after the operation.
It was only in grafts upon animals
which had rapidly perished, that both
alveoli and islets were found to be
degenerated. On these data Lombroso
founded his theory that islets and
^^m^^mfflM^.g. alveoli both co-operate in the internal

FIG. 33. Section through the coats of secretion of the pancreas.

the stomach. Diagrammatic. (Mall.) /nnfy qn rl MQVPV pvtpnrlpfl tViP

m, mucous membrane ;e, epithelium; AUHIZ ana lUaye

./, orifice of giaud duct; mm, muscu- period of observation with doo-s thus

laris mucosae ; sin, subrnucous coat ; i y*

cm, circular muscular layer ; hn, operated on to 440 days, and obtained

longitudinal muscular layer; s, ser- ,1 -i, T ' -i -ir-

ons coat, the same results as Lombroso. V isen-

tini, on the contrary, out of 24 dogs

operated on by tying and cutting the two pancreatic ducts, found
in two of them (after 160 and 212 days, respectively, after the
operation) that the alveoli were not in the normal state, while the
islets, on the contrary, were well preserved. He omitted, however,
to notice the effect of excising the pancreas when thus altered, so
as to see how far it had been capable of functioning as an organ

ii EXTERNAL DIGESTIVE SECRETIONS 105

of internal secretion. Lornbroso's observations indicate a constant
relation between the degree of glandular degeneration in cases
when a segment is grafted under the skin, and its function before
and after excision. The less the segment is altered, the better it
accomplishes its internal function, and the more acute are the
effects of extirpation.

All this evidence is at present" too inconclusive to determine
whether the internal secretion of the pancreas is exclusively
confined to the islets of Langerhans, or if the alveoli also
contribute to it. This question must be left in abeyance for
future research.

XL The walls of the Stomach, in a vertical section, show four
coats or layers, known from without inwards as the serous,
muscular, submucous (or areolar) and mucous membranes
(Fig. 33).

The mucous membrane of the stomach, which alone concerns
us, is in two parts, the pyloric end, which is pale in colour,
with fewer longitudinal folds, and the
fundus, which is reddish, yellow, or brown,
with more frequent and irregular folds
forming a network. Beside these coarse
folds (which are obliterated when the organ
is distended with food), a lens shows pro-

*- , FIG. 34. Epithelium of surface
jectlOllS On the internal SUriaCe Ol the of stomach examined fresh.

stomach, with corresponding depressions of gg y magnili
polygonal shape, which become larger and

deeper near the pyloric orifice. These are the mouths of the
tubular glands with which the gastric nmcosa is beset.

Taken as a whole, the columnar epithelial cells which cover the
mucous membrane of the stomach (Fig. 34), may be regarded as a
secreting organ which is not, like the glands we have been
discussing, gathered into a small space, but is spread out over the
surface. The function of this secreting surface does not differ
specifically from that of the simple and compound mucous glands
found in the buccal cavity and along the mucous membrane of the
oesophagus. The columnar epithelial cells of the stomach are,
however, richer in albumin than the mucous cells of the sub-
maxillary gland, and behave very differently from them when
treated with acetic acid ; they do not become clouded, but are
clear and swollen. With mineral acids, and on hardening with
alcohol, the submaxillary cells scarcely cloud at all, while those of
the gastric epithelium become quite turbid (Heidenhain).

The appearance of the columnar epithelium differs to a marked
extent in the state of rest and of digestive activity. In the
latter, many of the cells become goblet-shaped, open to the out-
side, and half -empty, owing to escape of the niucin which is
elaborated from the mucinogen formed inside the cell.

Flo. 35. (Left.) Pyloric gland, from a section of dog's stomach. (Ebstein.) m, mouth ; n, neck,
tr, deej) portion of a tubule cut transversely.

FIG. 36. (Right.) Cardiac gland, from dog's stomach. Highly magnified. (Klein and Xoble
Smith.) d, duct and mouth of gland ; b, base or fuiulus of a tubule. On the right is the
base of a tubule more highly magnified ; c, central cell ; p, parietal cell.

CHAP, ii EXTEKNAL DIGESTIVE SECKETIONS

107

The specific secretory organs of the stomach consist of two
kinds of glands, which differ both in the character of the cells that
line the duct and in the nature of their secretion.

Most of the glands at the pyloric end have a long neck, lined
with cells identical with those on the surface of the rnucosa, and
a short body, which is nearly always made up of a number of
tubules, lined with an epithelium that is quite different from that
of the neck or excretory duct. It consists
of finely granulated columnar cells, which
are never goblet-shaped, and which react
specifically to various stains (Fig. 35). In
the glands of the fundus the duct is
narrower, the neck shorter, and the body
longer. But they differ from the pyloric
glands mainly in having two kinds of
secreting cells : those which Heidenhain
termed chief the central or peptic cells,
and those he calls border the parietal or
oxyutic cells. The first are similar to the
cells of the pyloric glands, the second are
larger, more irregular in form, darker when
hardened in alcohol, more easily stained
(Fig. 36). It was formerly supposed, in-
correctly, that the first kind of glands were
found exclusively in the pyloric region, the
second in the curvature and fundus. In
reality the former are more abundant in
the pyloric and the latter in the fundic
region (Stohr).

As we have seen for the salivary
glands, so in the gastric, the duct which
runs through the tubule is prolonged into
canaliculi between the cells, and forms a
basket-like capillary network round the
parietal cells (Fig. 37).

The stomach is richly supplied with
blood by numerous vessels from the caeliac
trunk, which form a plexus beneath the submucosa. Each tubule
is lined with a capillary network, from which the veins form again.
They are few in number, but are larger than the arteries, with a
stronger muscular coat than is usual in veins, and many valves
(Hochstetter).

The lymphatics of the stomach arise in a rete of lacunar spaces
that lie between the tubules of the gland and form "a more ample
plexus in the submucosa, whence the efferent lymphatics emerge
to traverse the muscular coats and the lymph nodules situated
along the two gastric curvatures.

Fir;. 3V. Secreting duct of gastric
gland. Golgi's silver cliromate
method. (B. Miiller.) The cells
are not represented, but the
lunii'ii extending into the net-
work surrounding the parietal
cells is deeply stained.

108 PHYSIOLOGY CHAP.

The nerves to the stomach consist of the terminal gastric
branches of the vagus, and the sympathetic fibres of the solar
plexus. Both are almost invariably composed of non-medullated
fibres. Numerous small ganglia (according to Eemak) form
plexuses with these nerve fibres, either between the layers of the
muscular coat or in the submucosa. From these plexuses, nerve
fibres run through the muscular tissue, or the glandular tissue of
the mucous membrane.

XII. Until recently the direct influence of the nervous system
on gastric secretion was regarded as doubtful. The results of
experiments were either negative or less obvious than for the
salivary secretion. Kecent experiments have fully elucidated this
point.

The flushing of the gastric mucosa owing to active vascular
dilatation during digestion, the increased rate of circulation which
causes bright red blood to flow through the veins that differs
little from that in the arteries (Claude Bernard), are phenomena
perfectly analogous to those observed during salivary secretion.
They show the existence of vasomotor nerves to the stomach, and
justify the conjecture that special secretory nerves control the
gastric, like the salivary, secretion.

A stronger argument for the direct nervous control of gastric
secretion lies in the fact that in fasting animals with a gastric
fistula, the mere sight or smell of some favourite food causes a
flow of gastric juice through the fistula (Bidder and Schmidt,
1842 ; Schiff, 1865). This is not due to deglutition of saliva,
which might excite the gastric mucous membrane, because the
same thing is seen when the ducts of the salivary glands or the
oesophagus are occluded in the dog. The secretion "psychically
excited " by sight or smell does not begin immediately, but only
after some (5-15) minutes, and persists for a long time after
cessation of the stimulus (Sanotzky, 1892).

Greater interest attaches to Bichet's observations (1878) on a
girl who had stricture of the oesophagus and was fed through a
gastric fistula. Each time she was made to chew or taste a highly
sapid substance (sugar, lemon juice, etc.) while fasting, a con-
siderable quantity of juice flowed from the fistula. This was
undoubtedly a reflex secretion, but it was uncertain whether the
reflex directly promoted the secretion, or if, by dilating the vessels
of the stomach, and contracting its muscular coat, it determined
the secretory phenomenon indirectly.

Pawlow and Mme. Schumovva-Simanowskaia (1889) made a
series of striking experiments in order to decide this question and
clear up these phenomena of the innervation of the gastric glands.
They established the usual gastric fistula on dogs, and in a
subsequent operation divided the oesophagus half-way up the neck,
and sutured the two ends to the lips of the cutaneous wound, so

ii EXTEKNAL DIGESTIVE SECKETIONS 109

that when the animal fed the alimentary bolus dropped out
through the oesophageal fistula. For food to reach the stomach it
was necessary to introduce it either through the lower orifice of
the oesophageal fistula or through the gastric fistula.

When an animal thus prepared was made to masticate and
swallow food that dropped out again through the oesophageal
fistula (sham or imaginary feeding), a marked secretion of gastric
juice (psychical secretion) was invariably noted 5-6 minutes later.
On section of the vagi (the right below the point at which the
cardiac branches and the inferior laryngeal are given off, and the
left at the neck) this reflex secretion ceased entirely. On exciting
the peripheral trunk of the left vagus with two induction shocks
per sec. the flow through the fistula reappeared.

These results, which were constant under the given con-
ditions, contradicted the previous negative results of vagus
excitation obtained under other experimental conditions by many
physiologists, Heidenhain included. They prove beyond doubt
that the centrifugal nerves that regulate the gastric secretion are
contained in the trunk of the vagus.

Von Mering (1899) showed that atropine and pilocarpine pro-
duce similar effects on gastric secretion to those which Heidenhain
obtained on salivary secretion : the former diminishes or suspends
secretion of gastric juice, the latter increases it even fourfold.
These effects can only be explained by admitting that atropine
has a paralysing, and pilocarpine an exciting, action on the
secretory fibres contained in the vagus.

Other facts, however, show that the gastric secretion does not
depend exclusively upon the secretory fibres of the vagus, since
the stomach is capable of sufficiently digesting the alimentary
substances introduced into it, even when the vai have been

' o

divided. This suggests that other secretory fibres, spinal or
sympathetic in origin, influence the gastric glands : but there are
at present no experimental proofs of this conjecture. Experiments
made with this object (section of splanchnic, excision of caeliac
plexus) have given negative results. Heidenhain assumed that
the digestive capacity of the stomach persists after division of the
centres of all cranial and spinal nerves to the stomach. It is
probable (although it has not been experimentally demonstrated)
that the gangliar plexuses in the walls of the stomach represent a
system capable of special reflex activation of secretion.

The stimuli that normally determine gastric secretion by reflex
paths are the food -stuffs, which excite the nerves of taste and
other centripetal nerves to the mucous membrane of the mouth,
pharynx, oesophagus and stomach. The fine experiments of
Pawlow and his collaborators (1889-97) have established as an
indispensable condition of the production of a flow of gastric juice
by the aliments introduced through the mouth, that the animal

110 PHYSIOLOGY CHAP.

shall have appetite for the food offered it. Mechanical or non-
sapid stimuli applied to these sensory surfaces are not effective in
promoting gastric secretion to any appreciable extent (contrary to
what was formerly held). When, on the other hand, sham feeding
has been carried on for only five minutes with the oesophageal and
gastric fistulae, the secretion of gastric juice lasts 23 hours or even
longer. This can only be explained by assuming that the excita-
tion of the taste centre persists for the whole of this time.
Section of the vagi, by which the psychical influence is trans-
mitted to the gastric glands, in fact suffices at once to arrest the
secretion.

Cohnheim and Soetbeer (1903) showed that in new-born
puppies, which had a gastric fistula with divided oesophagus
(Pawlow's method), the act of sucking produced an abundant
psychical secretion of gastric juice. Psychical secretion, therefore,
appears to be a congenital reflex as hereditary in these animals
as that of sucking, and not accpuired by individual education and
force of habit.

It is very probable that the mechanical acts of mastication and
suction may not in themselves have any influence upon the secretory
work of the stomach. This agrees with Hornborg's observations
(1904), showing that when a bit of gutta-percha, i.e. an indifferent
substance, was masticated there was no gastric secretion, while
mastication of sapid substances is always followed by secretion, or
by an obvious increase of the flow.

According to Schiile (1901) pure psychical secretion in Pawlow's
sense is seldom manifested in man. The acid secretion of the
gastric glands is excited by the action of a purely chemical reflex,
due to the alimentary substances which come into contact with
the gastric mucosa. He further remarks that in man the act of
mastication in and by itself, independent of psychical associations
(taste, smell), must come into play in determining the secretion
of gastric juice, as well as the direct contact of the food stuffs.

In order to study the process by which gastric secretion occurs
when food is present in the stomach, Heidenhain, in a bold
surgical operation, separated a portion of the fundus of the dog's
stomach, and reduced it to a closed sac or pouch communicating
with a fistulous opening to the outside, after which he restored con-
tinuity to the remainder of the viscus by stitches. In this operation
the branches of the vagus, by which the taste centre transmitted
the secretory stimulus to the gastric glands, were divided. There
was no secretion in the isolated sac of the fundus during the
mastication and deglutition of meat. It only begins 15-30 minutes
after ingestion, and lasts a longer or shorter time, according to
the nature and amount of the food ingested, i.e. 13 to 14
hours after a moderate meal, 16 to 20 hours after a heavy one.
If instead of meat the animal is given some very indigestible food,

ii EXTERNAL DIGESTIVE SECRETIONS 111

e.g. Hit" incntum nuchae coarsely cut up, there is no secretion in
the sac. This only appears when, after such a meal, the animal
is given drink, but in this case it lasts a very short time, from
1 }, to 4 hours at most.

This fact was confirmed by Sanotzsky (1892), who held, like
Heidenhain, that it depended on a reflex excitation (other than
that of the secretory fibres of the vagus), or on a direct excitation
of the secretory gland cells, clue to the action of the digestive
products absorbed by the walls of the stomach.

Khizhin (1895) held, on the contrary, that the secretion was
due to chemical excitation of the centripetal nerve-endings of the
gastric mucosa by certain special foods, previous to their absorption.
Direct mechanical stimulation of the mucous membrane also
produces secretion, but to a negligible extent.

There can be no question as to the gastric secretion being, at
least in the first instance, determined by nervous stimuli. On the
other hand, the influence on which the continuation of the
secretion depends is still debateable. According to Pawlow, it is
a chemical action on the peripheral nerve-endings, of the digestive
products of the proteins. He observed a profuse secretion when
peptones, extract of meat, etc., were introduced into the stomach,
without the animal being aware of the same.

But after Bayliss and Starling published their hormone theory
(mentioned above in treating of pancreatic secretion), which
obtained a large following, experiments were set going to see
whether the same might not hold good for gastric secretion also.

Edkins (1905) demonstrated that it was possible to extract a
substance from the pyloric mucosa which produced a secretion of
gastric juice when injected into the circulation, while extract of
the mucosa of the fundus had, on the contrary, no effect.

This substance pre-exists in an inactive state, and becomes
active on adding acids, or on boiling (which proves it not to be an
enzyme).

Frouin (1905) noted that the subcutaneous injection of 40 c.c.
of gastric juice considerably increased the gastric secretion in dogs
with isolated stomachs, from which he deduced the existence in
the gastric juice of substances that have the property of increasing
the secretory activity of the gastric mucous membrane.

Without questioning the data cited by these authors, it seems
a little premature to use them (with the followers of Bayliss and
Starling) as arguments in favour of the hormone theory, which
has been shown, in speaking of secretin and the pancreatic secretion,
to be ill-founded.

The amount of juice secreted by the small stomach ahvays bears
the same ratio (taking into account the extent of the secreting
surface) to the amount secreted by the large stomach, in sham
feeding. The degree of acidity, too, is much the same, but the

112 PHYSIOLOGY CHAP.

digestive power is decidedly weaker. This digestive power de-
creases from the first to second, or first to seventh hours, then
rises again and reaches its maximum at the fifth, or according to
other experiments, the eighth hour.

Pawlow and his co-workers have recently succeeded in isolating
a closed pouch or cul de sac from the stomach, without injuring
the vagus fibres that control secretion (infra, page 114). From
the animals thus operated on, they have collected important data
relative to the influence upon the secretion of the blind sac
of certain alimentary substances introduced into the stomach. In
order to exclude reflexes by the secretory fibres of the vagus
excited from the surface of the mouth, pharynx, and oesophagus,
the food is introduced into the stomach by the sound. The results
may be summarised as follows :

(a) Water, 01-0'5 per cent solutions of hydrochloric acid,
O'01-l per cent salt solutions, introduced into the stomach in
amounts of 100-150 c.c., produce only a very weak secretion of
juice in the blind sac.

(b) Water, 0'5 per cent salt solution, 10 per cent solutions of
cane-sugar or starch, in quantities of 500 c.c., produce a stronger
secretion, which commences 13 to 29 minutes later, and lasts some
60 to 135 minutes.

(c) These substances do not affect the secretion of the blind
sac in themselves, but in virtue of the water in which they are
dissolved. In fact, if plain distilled water is injected into the
stomach, a secretion of equal quantity and duration is evoked.

(d) When, on the contrary, peptone is introduced into the
stomach by the sound (this being, as we shall see, the principal
product of the digestion of proteins by the gastric juice), there is,
after about 13 minutes on an average, an abundant secretion in
the pouch which lasts for some 3 hours.

(e) Neither ov-albumin nor proteoses produce a similar effect.
They only cause a weak secretion for a short time, which may be
due to the amount of water in which they are dissolved. We may
conclude that peptone is a specific stimulus for the secretory
elements of the stomach, probably because it is capable of exciting
the centripetal nerve-endings of the mucous membrane, which
determine the secretion reflexly by the centrifugal paths of the
vagus, and possibly also by way of the sympathetic.

(/) Other observations show that after the secretion from the
sac has been started by the stimulus of peptone, it increases
considerably when egg-albumin is introduced into the stomach,
though this by itself is ineffective.

(//) The gastric secretion excited by the presence of food in the
stomach reaches its maximum in the first and second hours (after
ingestion of milk only in the third hour). After that it gradually
diminishes, and then ceases entirely. For any given kind of

ii EXTEENAL DIGESTIVE SECRETIONS 113

food the absolute amount of juice secreted increases with the
amount ingested. For different kinds in equal quantities, the
absolute amount of secretion varies ; it is greater for meat than
for bread, for bread than for milk (Khizhin and Lobassoff, 1897).

(h) The introduction of carbohydrates excites no secretion of
gastric juice (Barbera, 1898) ; that of fats may cause its diminution
or arrest if it is already present (Khizhin, 1895 ; Lobassoff, 1897).

This inhibitory action of gastric secretion by fats has been
carefully studied by Pawlow's pupils. Their observations show
that not only is the total quantity of gastric juice diminished, but
the enzymic activity of the secretion is also depressed. Thus,
e.g., on administering 400 grms. of flesh to a dog provided with
Pawlow's miniature stomach, about 40 c.c. of secretion was obtained
in the first four hours, with a peptic digestive power (measured by
Mett's method in rnm.) equal to 5 '00. On adding 75 c.c. olive oil
to the 400 grms. flesh, a secretion of only 18 c.c. was obtained,
with a digestive power lower by 3 rnm.

The inhibitory action of fats is shown particularly in the first
period of digestion (in which the influence of psychical factors is
specially felt). Sham feeding in a dog operated on by Pawlow's
method, when the large stomach contains oil, or has been subjected
for some time to the action of oil, produces a secretion much less
in quantity and activity than the same sham feeding when the
stomach has not been acted on by fat.

These observations have an important practical significance,
since they justify the long-established use of fats in therapeutics,
for the cure of gastric ulcers, or of gastric hyper-secretion which
predisposes to ulcers.

(i) Alcohol in moderate doses excites, in excessive doses arrests
gastric secretion (Bernard, Lussana, Albertoni). Many observa-
tions have been made upon the use of alcoholic beverages (wine,
beer, liqueurs) in relation to the gastric secretion. Many authors
admit that these excite gastric secretion. But it is still unknown
whether this is by simple psychical reflexes (sight, smell, agreeable
taste) or by direct excitation of the mucous membrane.

Frouin and Pekelharing showed that on administering alcoholic
solutions per rectum the increase in secretion was to be attributed
to the absorption of alcohol in the blood, by which the cells of the
gastric glands are excited immediately, or mediately by the nerves,
to an extent corresponding with the amount of alcohol absorbed.

(&) With an empty stomach there is normally no gastric
secretion, provided there are no central taste stimuli to provoke it
reflexly. On opening the tap of the cannula of a gastric fistula in
a dog that has fasted for over twenty-four hours, only mucus as a
rule flows out, which usually gives an acid, more rarely a neutral
or alkaline reaction. In a woman with oesophageal occlusion due
to cancer of the cardia, operated on by gastric fistula by Postempski,

VOL. II I

114

PHYSIOLOGY

CHAP.

Bocci constantly observed an acid reaction from the gastric inucosa,
twelve hours after the last meal. We must not assume from this
that gastric secretion is continuous. When gastric juice, with
all its chemical and physiological characters, flows from gastric
fistulae in animals or man, with a perfectly empty stomach, under
perfect physiological conditions, it can easily be shown that this
apparently spontaneous secretion is aroused by psychical taste-
suggestions (Pawlow).

In order to study the course of gastric secretion, i.e. its quantitative and
qualitative modifications during digestion, it is convenient to employ

B

Fin. 38. A, stomach of dog previous to Pawlow's operation, showing direction of principal
nerves. B, stomach after the operation, which has divided it into two, the large (I 7 ), and the
miniature stomach or blind sac (S), which is sutured to the abdominal walls (A A), and com-
municates with the exterior by means of a fistula. ,5, serous coat; muse., muscular coat;
muc., mucous membrane of wall of stomach operated on.

Pawlow's " miniature stomacli " or pouch, which served for most of the
experiments we have been discussing. It is prepared as follows :

The first incision A, B (Fig. 38, A), which begins in the fundus of the
stomach, 2 cm. from its junction with the pyloric portion, is carried in the
longitudinal direction through all the coats of the anterior and the posterior
wall for 10-12 cm. along the great curvature. A triangular flap C, C is thus
formed. A second incision is made exactly at the base of this flap, but only
through the mucous membrane. The serous and muscular coats are left intact,
and pass from the main stomach into the flap, while the mucosa is completely
separated from it. The edges of the mucous membrane of both stomach and
flap are detached from the submucous tissue for 1-1| cm. from the wall of
the stomach, and 2-2^ cm. from the wall of the flap. The posterior and
anterior margins of the mucous membrane of the stomach are then brought
together and sutured in a straight line from cardia to pylorus. The flap
is converted into a cup. Lastly, the margins of the incision in the walls of
stomach and flap are stitched together. The cavity of the stomach is thus
restored, and the flap remains as a pouch, or small appendicular stomach

ii EXTERNAL DIGESTIVE SECRETIONS 115

(Fig. 38, B), which is united to the main stomach by the two outer wall>.
The two cavities lined with mucous membrane are completely separated by
a double septum consisting of the sutured mucous coat of the stomach and
that of the cup-shaped nap. The opening of the pouch is stitched to the
abdominal wall (A, A).

XIII. The chemical composition of the gastric juice must be
studied before discussing the process by which it is formed.

The gastric juice obtained by C. Schmidt from a healthy
woman with a gastric fistula, after the ingestion of peas and a
little water, was found to be a clear thin fluid, much less acid
than that of the dog, with specific gravity of 1-0022-1-0024. It
became slightly cloudy on boiling, and left a solid residue of
about 2 per cent.

The gastric juice obtained by Fawlow and his co-workers and
pupils from the dog by the above method of sham feeding is
certainly purer, as well as that obtained from the fundus sac by
Tawlow's method, which preserves the integrity of the vagus
fibres.

This pure secretion, which is free of all alimentary residues, is
as clear as water, acid, with no extraneous taste, specific gravity
r0030-l'0059. It turns the plane of polarisation to the left
(from 0'70 to 0'73 in a layer of 20 cm.). On evaporation it leaves
a solid residue of 0'29-0'60 per cent; 0-10-017 per cent ash on
combustion. It constantly contains a little protein, but no
peptone, leucine, nor tyrosine. On lowering the temperature it
becomes cloudy, and forms three layers : the top one clear, the
middle turbid, the lower consisting of a deposit of homogeneous,
highly-refracting granules.

According to the chemical analysis made by Mme. Schumowa-
Siinanowskaia of the secretion obtained from the dog by sham
feeding, its composition is as follows :

Acid . . 0-46-0-56 per cent.

Chlorine 0-49-0'62

Dry residues 0-43-0-60

Ash ... . 0-09-0-16

Substances coagulated by alcohol . 0'14-0'19

Substances coagulated by boiling . 0-13-0-18

Substances precipitated at C. . OOll-O'OOS

Phosphoric acid ..... 0'004

As we shall see elsewhere, the digestive activity of the gastric
juice is due to the hydrochloric acid and the enzymes which it
contains, these being the specific secretory products of the gland
cells. The quantitative variations of these products, and the
process and seat of their formation are as follows :

(a] The acidity of the gastric juice, owing to the constant
presence of a free acid, is well established for all vertebrates.
Prout (1824) was the first who suggested that this free acid was

116 PHYSIOLOGY CHAI-.

hydrochloric acid; but C. Schmidt (1852) first proved it, and
showed that the gastric juice of the dog and pig contained chlorine
in excess of what was required to combine all the inorganic bases
obtained by calcination of the solid residues of the gastric juice.
This fact shows that a considerable part of the chlorine is
combined with hydrogen in the form of free hydrochloric acid.

Other acids can be detected in the gastric juice, lactic acid in
particular, which is also thought by many to be a secretory
product of the gastric glands. Everything, however, points to the
probability that lactic acid is a decomposition product of carbo-
hydrates produced by special bacteria, that are able to live inside
the stomach. The same applies to the butyric acid that has
occasionally been found in the gastric juice.

The amount of hydrochloric acid in the gastric juice varies
considerably in different animals. It is much more abundant in
dogs ( = 0'46-0'oS per cent) than in man ( = 0'1*7 per cent on an
average). But the exact determination of the amount of hydro-
chloric acid and its variations during digestion presents serious
difficulties, because the acid enters into chemical combination
with the proteins introduced into the stomach, the pepsin and the
digestive products, and also replaces the phosphoric acid of the
phosphates contained in the food. Yet at all phases of digestion
the contents of the stomach are acid, because a much larger
quantity of hydrochloric acid is always present than is required
for combination with the proteins and the bases of the alimentary
phosphates. According to Kretschy, Eichet, Uffelmann, the
amount of free acid increases constantly during digestion in man.
Heidenhain, on the contrary, found no marked differences in the
dog in this respect.

The experiments made with the object of determining the seat
of formation of the acid of the gastric juice all point to the
conclusion that it is secreted by the glands of the niucosa of the
fundus. In fact, in the fasting animal these often exhibit an
acid reaction, while the mucous coat of the pyloric portion is
alkaline. The value of these observations is, however, impaired
by the fact that the pyloric portion always contains a denser
stratum of alkaline mucus which may neutralise the acidity of the
secretion. That the acid is not formed on the surface as Cl.
Bernard supposed, but comes from the secretory cells of the
glands, was demonstrated by Briicke on the compound glands of
the fowl's stomach. These have a central cylindrical duct into
which all the tubules of the gland open, and in which a consider-
able quantity of secretion collects. He found that under these
conditions the secretion collected within the gland has an acid
reaction.

Heidenhain by indirect arguments arrived at the conclusion
that the cells which secrete the acid are the external or border

ii EXTEENAL DIGESTIVE SECEETIONS 117

cells of the fundus glands. The pyloric glands, which are destitute
of these cells, yield a persistently alkaline secretion. Miss Green-
wood provided direct evidence in favour of this theory, by showing
that when the gastric mucosa is treated with silver nitrate the
border cells alone stain black, while all the other cells, which do
not secrete acid, are unstained.

(6) The dissolving (proteolytic) action of the gastric juice upon
proteins, which we shall examine in discussing digestion, is due to
a special enzyme, guessed at or noticed by Spallanzani, Eberle,
Beaumont, and Joh. Miiller, and to which Schwann in 1836 gave
the name of pepsin.

Wassman first isolated it in the impure state. Briicke,
Wittich, Pettit, and others, perfected the methods of extraction
and purification in various ways, but little is even yet known as
to its chemical constitution, or if it contains nitrogen, and it is
doubtful whether it belongs to the protein group.

Pepsin is an amorphous substance, greyish-yellow, odourless,
soluble in water and in glycerol, particularly if acidulated, insoluble
in alcohol, which precipitates it from its solutions. It is not
dialysable, and can thus be easily separated from the acids, salts,
and peptones, which dialyse readily (Hainmarsten).

An acid medium is an indispensable condition to the exhibition
of the digestive activity of pepsin. In neutral solution it is inert ;
it is destroyed in an alkaline medium. It neither increases nor
diminishes in quantity during the process of digestion, but
according to Griitzner it loses some of its activity.

In consequence of Wassniann's experiments, which showed
that the artificial juice prepared from the mucous membrane of
the fundus digests a given quantity of fibrin in an hour and a
half, while with that made from the mucous membrane of the
pyloric portion the same digestion requires 6 to 8 hours, it was
supposed that only the fundus glands secrete pepsin, and that the
pyloric glands secreted mucin only, the small amount of pepsin
they contain being due to infiltration of that secretion from
the fundus.

The ingenious experiments of Heidenhain and his disciples
Ebstein and Griitzner, however, showed that the pyloric glands
also secrete pepsin, although to a minor extent, because the
glandular substance is less abundant there. Langendorff, again,
found pepsin in the pyloric part of the calf's embryo. But the
most decisive proof of the digestive activity of the juice secreted
by the pyloric end was given by Klemensiewicz and Heideuhaiu,
who showed that this part of the stomach when isolated and
converted into a cul de sac, secretes an alkaline juice containing
pepsin, so that it is capable of digesting protein on the simple
addition of acid. According to Klemensiewicz, this pyloric juice in
acid solution usually digests better than the secretion of the

118 PHYSIOLOGY CHAP.

Hindus, tlius excluding the objection that the digestive action of
the pyloric juice is due to the presence in the pyloric mucosa of
some of the glands which predominate in the mucous coat of
the fundus.

(c) It was formerly held that milk coagulates, on coining
into contact with gastric mucous membrane or its extract,
owing to the gastric juice, because on merely acidifying fresh
milk its casein comes down in a flocky precipitate. But after
the experiments of Selnii and Heinz, and the exhaustive work
published by Hammarsten in 1872, and confirmed by A. Schmidt,
it was recognised that the extract of gastric mucous membrane is
able to clot milk even in a neutral or alkaline medium. This
phenomenon is therefore independent of acid and is due to a
special enzyme, distinct from the pepsin, which is called cliymosin
(or rennin^).

Hammarsten succeeded in separating the chyinosin from the
pepsin by neutral lead acetate, which precipitates pepsin but not
chymosin. Of unknown chemical constitution, cliymosin has all
the properties common to other digestive enzymes. In neutral
solutions it is destroyed at 70" C., in acid solutions at 65 C. It is
not diffusible ; its maximal activity is reached at 38-40 C. Its
action is exerted exclusively on the caseinogen of milk, and differs
from that of acids, as we shall see in the chapter on Digestion.
According to Hammarsten, one part of cliymosin is able to clot
400,000-800,000 parts of casein.

Chymosin is present in large quantities in the stomach of
sucking animals, especially calves, lambs, and kids. Schurnberg
found it in 15 out of 34 stomachs of adult men, and in 4 out of 6
of new-born infants. It is probably decomposed by the alkalinity
of the intestinal juice, or absorbed like other ferments, since it does
not occur in the faeces. It seems -to originate like pepsin from the
pyloric glands and the chief cells of the glands of the fundus.

(d*) The existence of a lipolytic enzyme in the stomach had
long been suspected (Cash, 1880 ; Ogata, 1881, etc.). Others,
however (Contejean, 1894 ; Boldireff, 1904), denied the value of
previous researches, carried out for the most part in vitro and with
artificial extracts of mucous membrane, or with gastric juice
extracted by the sound, and attributed the results described
either to the adulteration of the substances or to the presence of
pancreatic juice that had flowed back into the stomach. Finally,
Volhard (1900-1902) demonstrated in a series of experiments that
a very active lipolytic enzyme is produced in the stomach,
which acts particularly on emulsified fats. This enzyme is
contained chiefly in the mucosa of the fundus (in man) or of the
pyloric region (dog, cat, pig). Its action is reduced in the presence
of acids, and may be altogether inhibited ; this does not, however,
occur during the physiological digestion of fat, since the secretion

II

EXTERNAL DIGESTIVE SECRETIONS

119

of gastric juice, and still more its acidity, is much diminished
when fat is present.

Among the many proofs of the presence of a lipolytic ferment
in the gastric mucosa, those adduced by Laqueur (1904) are of
special importance, because he makes use of Pawlow's miniature
stomach, in which there can be no question of any possible reflux
of pancreatic juice.

Laqueur points out one essential difference between the
gastric and the pancreatic lipolytic enzymes, viz. that the former is
not aided by bile, which multiplies the activity of the pancreatic
juice twenty or more, times. With this reservation, the lipolytic

'

-^

Fic. 30. Cross-section of cardiac glands from human stomach during fasting. (Bohm and v.
Davidoff.) 4 i". c, central cell ; I, lumen of gland ; p, parietal cell ; t, connective tissue between
glands.

enzyme of gastric juice behaves like the lipolytic enzyme of succus
entericus.

XIV. Heidenhain and Ebstein, in their alcohol - hardened
preparations of gastric niucosa, studied the cytological changes
that occur in the secretory cells in hunger and in the digestive
process. These changes are quite similar to those suffered by
the cells of the serous salivary glands and the pancreas. In the
fasting state, and during the intervals of digestion, the chief cells
of the fundus glands enlarge and look clear ; while the parietal
cells are small, and triangular in section. During the first hours
of digestion, the former continue large, but become clouded ; the
latter, on the contrary, increase in size and grow round, bulging
forward to the outer surface of the tube. From the sixth to the
ninth hour of digestion, the chief cells are reduced and grow more
turbid, while the lining cells remain large or become still more
swollen. At the fifteenth hour the cells begin gradually to resume
the appearance and characters which they exhibited during hunger.

120

PHYSIOLOGY

CHAP.

These phenomena noted on the dog were confirmed for man, as
shown in Figs. 39 and 40.

Langley repeated these observations on fresh preparations of
the gastric mucous membrane, and noted changes which, although
different, lead to the same interpretation as that of Heidenhain.
In abstinence the chief cells are strongly and uniformly granular ;
during digestion they become clearer, and are differentiated into
two zones, the outer of which (f or ^ the cytoplasm) does not
exhibit granules, which only appear in the inner zone. Since, as
we shall see, the extracts of gastric rnucosa contain more pepsin

iP?P ? ? f / ^-HM^^ IS

A W3^fflf^l^wa-;v x <'/7, : v\-iVda : ^ y^ 2

r.<V#/tf3*:k ^ ;-iv^/yV f N4>fx -' vv^ 1 - '

'

FIG. 40. Cross-section of cai'diac glands during digestion. (Bohmandv. Davidoft".) V".

References as in Fig. 39.

and chymosin, according as the number of granules in the chief
cells of the fundus and pyloric glands is greater, this confirms the
theory which attributes the formation of the enzymes of the
gastric juice to these cells.

The granules seen in the cells of the gastric gland in the
fresh state do not, however, represent the enzymes of the gastric
juice, but contain the zymogens, i.e. the proteins from which pepsin
and chymosin are formed during the process of secretion.

Schiff first recognised that active pepsin comes from the
transformation of an inactive substance found in the gland cells,
which he called propepsin. The experiments of Ebstein and
Griitzner confirmed this theory. They gave the name of peptic
zymogen or pepsinogen to the inert substance which is converted
into pepsin. They found that in a watery, non-acidulated, or
glycerol extract of gastric mucosa, a certain amount of pepsinogen

ii EXTERNAL DIGESTIVE SECRETIONS 121

was extracted with the pepsin, and yielded a further quantity of
pepsin when hydrochloric acid or even sodium chloride were added.
Langley afterwards found that on extracting the gastric mucous
membrane with a 1 per cent solution of sodium carbonate, and acid-
ulating with hydrochloric acid, the extract contained pepsin, as
shown by its digestion of proteins. As sodium carbonate abolishes
the activity of pepsin, the gastric glands must contain a substance
other than pepsin, which is not destroyed by the soda solution,
and is readily transformed by acids into pepsin. This substance
is pepsinogen.

Griitzner performed a series of experiments to determine the
maximal quantity of pepsin which can be extracted by excess of
acid, with long digestion at 40 C., from the fundus and pyloric
mucous membrane of dogs killed at various hours after a meal.
He found that the pepsin is maximal in the fundus glands during
hunger, and minimal nine hours after a meal : in the pylorus glands
it increases in the first hours after a meal, reaches its maximum
at the ninth hour, and then decreases slowly. This fact agrees well
with the modifications observed in the cells of the pyloric glands,
which (unlike the changes in the fundus) increase in the first
hours after a meal, and then decrease slowly, signifying that
in the first hours after a meal more pepsinogen is formed than
is simultaneously excreted as pepsin.

The process .by which pepsinogen is normally transformed
into pepsin during the digestive period is still imperfectly known.
It was suspected, on the analogy of the transformation by the
pancreas of trypsiuogen into trypsin, that the formation of
pepsin from pepsinogen might also be due to the action of an
internal secretion of the spleen, which becomes actively turgid
during digestion. This hypothesis, which Baccelli advanced in
1868, has not been fully worked out, possibly because excessive
value has been put upon the fact that animals deprived of their
spleen are able to live and digest perfectly. This objection might
be met by the further and well-established fact that it is also
possible to live without a stomach. At all events the assumption
that the spleen takes part in the formation of pepsin does not
exclude the possibility of the formation and secretion of pepsin
without a spleen.

The congested spleen of a dog in full digestion is excised, and
divided into small fragments, which are rubbed up in a mortar
with powdered glass. This paste is placed in a retort, with five
times its volume of 4 per cent boracic acid. This is digested in
a stove at 37 C. for six hours, and on filtering a transparent dark-
red fluid is obtained.

Two equal parts of this extract, 15 c.c. each, are poured into
two small flasks, with 15 c.c. solution of 04 per cent hydrochloric
acid, and ^ gramme of raw fibrin, ready swollen by the action of

122 PHYSIOLOGY CHAP.

O2 per cent HC1, in which it has been standing in the cold
for 30 minutes.

In order to compare the effect of the acidified splenic extract
with that of the plain hydrochloric acid on the raw fibrin, the
same amount of swollen fibrin is placed in two other flasks, with
15 c.c. of 4 per cent boracic acid, plus 15 c.c. of 0'4 per cent HC1.

On placing the four flasks to digest in the oven at 39 C., the
fibrin with splenic extract is seen after two hours to be about half
digested, while that with hydrochloric acid alone shows no trace
of digestion. After 3i hours the other flasks are examined, and
the splenic extract is found to have digested almost all the fibrin,
while there is no trace of digestion in the fibrin left in the plain
acid solution.

This fact, many times repeated in our laboratory by Lo
Monaco and Tarulli, proves that extract of congested spleen
contains pepsin, or at any rate an enzyme with an identical
capacity for digesting fibrin in an acid medium. The living
spleen probably contains not pepsin proper but some zymogen
capable of transformation into pepsin during the manipulations
necessary for the preparation of the extract.

Hedin and Eowland (1901) further showed that the spleen
contains a proteolytic enyzme, which exhibits its maximal activity
in an acid solution. They also found it in many other organs
(lymph glands, kidneys, liver, and to a less extent the muscles
also ; infra, also Vol. I. p. 34).

XV. Two kinds of glands are found in the mucous membrane
of the Intestine those of Bruuner, which are confined to the first
portion of the duodenum, and those of Lieberkiihn, which extend
throughout the canal.

The duodenal mucosa of certain rodents also presents groups
of cells which are structurally exactly like the acini of the pancreas
(particularly the duodenal pancreas described in rabbit). Accessory
pancreases in the duodenum are not imcommon in man.

The mucous coat of the small intestine differs from that of the
stomach in having not only small ridges or folds that are obliter-
ated by distension, but also large permanent folds in the form of
crescentic projections of the mucous membrane, placed transversely
to the axis of the bowel, at a short distance from one another
(valvulae conniventes or valves of Kerkring). The whole surface,
including the valvular folds, is closely beset with villi, of varying
length, cylindrical in the jejunum, filiform in the ileum (Fig. 41),
which enormously increase the intestinal surface. The mucous
coat of the large intestine is smooth, and destitute of villi
(Fig. 42).

Between the villi of the small intestine, in every part, are
the simple tubular glands, Lieberkiihn's crypts, which resemble
the fingers of a glove, the orifices being somewhat dilated at the

II

EXTERNAL DIGESTIVE SECRETIONS

123

extremity. These crypts are more numerous in the large intestine,
owing to the absence of villi (Fig. 42).

The epithelium by which the crypts are lined is exactly
similar to that which clothes the surface of the villi. It consists
of irregular columnar cells, with a large nucleus, and striated

. ti

Fie. 41 (Left). Section of intestinal mucous membrane (infant), shows three villi, with crypts of
Lieberkiihn. (Bohm and v. Davidoff. ) >y. e, K, epithelium of villus ; c, connective tissue of
villus ; re, goblet cells ; cr, Lieberkuhn's crypts ; rli, connective tissue at base of gland ; mm,
muscularis mucosae.

Fi.i. 4-2 (Right). Section of mucous membrane of human colon, showing three crypts of Lieber-
kuhu. (Bnhm and v. Davidott'.) 2ju. e, epithelium ; I, lumen of , gland; cc, goblet cells; ti,
interglaiidular tissue ; ta, areolar tissue of mucous membrane ; mm, muscularis mucosae.

cuticular layer, and a somewhat flattened end which is attached
to the surface of the basement membrane, without extending
(as was formerly supposed) into the reticulated tissue of the villi.
Leucocytes are seen here and there between the epithelial cells
(Fig. 43).

Goblet cells produced by mucoid degeneration of the ordinary
columnar cells are seen between the latter, the outer half of these

124

PHYSIOLOGY

('MAI'.

swelling and filling with mucus, which hursts through the free
end, and is discharged externally. The number of gohlet cells
varies with the animal and the state of abstinence or digestion.
They are specially abundant in the mucous coat of the large
intestine, while in the small intestine they are wanting altogether.
Brunner's glands are situated in the upper part of the duodenal
mucosa ; they also extend beyond the pyloric antruni of the
stomach, and may be found in the mucous membrane between the
crypts of Lieberkiihn. They are small acino- tubular glands,
which consist of branching and twisted tubules, ending in pro-
longed dilatations or alveoli, which unite into a secretory duct
lined with epithelial cells similar to those of the alveoli. These
cells resemble those of the pyloric glands of the stomach (Fig. 44).

B

Fia. 43. Columnar epithelium from rabbit's intestine. (Sehiifer.) A, two isolated cells after
maceration in very weak chromic acid, showing striated border, and the bright disc which
separates them from the cell protoplasm ; , nucleus with internuclear network ; c, thin pro-
jection of cell, which probably fitted between two adjacent cells. B, row of columnar cells
from intestinal villns of rabbit; str, striated border; w, smaller cells of the nature of lymph
corpuscles, between the epithelial cells.

Little is known about the secretion of Brunner's glands.
According to Hirt, they undergo the same modifications during
digestion as the pyloric glands ; in the lasting state their
cells are comparatively large and clear, in digestion they are
small and clouded. Griitzner found that at different distances
from the pylorus the glands are in a different functional state.
A watery extract of Brunner's glands, freed as far as possible
from the duodenal mucosa, contains (according to Krolow) a
ferment which digests fibrin, but not boiled egg-albumin, in an
acid medium. They must therefore secrete pepsin like the
pyloric glands. According to Griitzner, the enzyme (or zymogen)
accumulates during hunger, and discharges during digestion, when
the secretory cells become smaller. Mendeldorp also finds a
diastatic enzyme in the extract of gland substance. From the
little we know as to the nature of the secretion of Brunner's glands
their product appears to mix with the acid chyme which passes
rhythmically from the stomach to the duodenum, through the
pyloric valves, after the first hours of digestion.

II

EXTERNAL DIGESTIVE SECRETIONS

125

XVI. To study pure succus entericus (which is the product of
all the secretory cells of the small intestine, both in the external
epithelium of the villi, and in the epithelium which lines the
crypts of Lieberkiihn internally) it is necessary to isolate a loop
of intestine, closing one end by stitches while the other is sutured
to the wall of the bowel, after bringing together the two ends
of cut intestine, so as to re-establish the continuity of the gut
(Thiry's method). It is more convenient to stitch both ends of
the intestinal loop, separately, to the abdominal walls, so as to

Km. 44. Section of mucous membrane through commencement of duodenum at pylorus. (Klein.)
v, villi ; b, apex of a lymphoid nodule ; c, crypts of Lieberkiihn ; m, muscularis mucosae, ; s,
Brunner's glands cut more or less obliquely ; d, ducts of pyloric glands of stomach ; g,
oblique section of .same ; I; deeper tubes in submucous tissue, corresponding with Brunner's
glands of intestine.

make two fistulous apertures communicating with each other by
the loop (Vella's method).

During inanition, according to Boldireff (1905), the secretion
from Vella's loop is scanty, with a rhythmical maximum and
minimum cycle of about 2 hours- 5-6 c.c. of succus entericus can
be collected altogether in 8 to 10 hours.

Some authors say that mechanical stimuli (sounds, sponges,
etc.) introduced into the loop are able to excite a true secretion
there, even during hunger. But according to U. Lombroso,
these stimuli only excite a small increase in the flow of secretion,
which is probably due to increased peristalsis.

Electrical stimuli are more effective than mechanical. The
effects of chemical stimuli are better known (Frouin, Lombroso,

126 PHYSIOLOGY CHAP.

Delezenne). When acetic, hydrochloric, lactic, or weak carbonic
acid is injected, a certain amount of secretion is observed. The
secretion obtained with these acids is serous, fluid, colourless if
the solution is weak, lemon-yellow or pinkish if more concentrated.
It has a very slight Hpolytic action. Acids combined with pepsin
or with the alimentary proteins also excite enteric secretion. The
higher fatty acids dissolved by bile, and soap solutions (which at
once set free the fatty acids when introduced into the loop of
Vella) are more powerful than any other substance in exciting
enteric secretion.

Besides being more copious, the secretion excited by the
higher fatty acids (oleic acid) has quite different physical
characters ; it is dense, ropy, and contains a number of enzymes.
Bile and alkalies produce no noticeable secretion.

Masloff obtained rich secretions from the intestinal fistula
(preternatural anus) in dogs, with subcutaneous injections of
pilocarpine. Vella confirmed the same on his isolated loop of
intestine.

The physiological conditions for the secretion of succus
entericus during digestion are as follows. In the isolated loop,
where no food can penetrate, a secretion of juice (more or less
abundant according to the nature of the food) is seen some time
after the meal. This tends to increase for a certain time, and
only ceases at the seventh to eighth hour of digestion. The time
at which the secretion reaches its maximum varies greatly, and
seems to depend on the varying nature of the food. The total
quantity of secretion that can be collected after 8 to 10 hours
does not exceed 8 to 12 c.c.

Data in regard to the chemical composition of the succus
entericus differ with the animal used and the method by which

/

it is collected. The fluid that issues from the isolated loop of the
lower tract of the small intestine (ileum), is, according to Thiry,
thin, opaline, yellowish, strongly alkaline, of specific gravity I'OIO.
It con tains-
Water ....'... 97-2-97-9 per cent-
Solids 2-2- 2-8

Protein 0'7- 0-12

Ash . 0-7- 0-8

In addition to sodium chloride the ash contains large quantities
of sodium carbonate, as on adding acids the succus eutericus
effervesces. It always exhibits a few enzymes, to which its weak
digestive powers are due. Its action is diastatic on starch and
glycogen, invertive of saccharose into dextrose, curdling on milk,
emulsifying on fats, similar to that possessed by all alkaline
fluids. Succus entericus is further credited with the property of
splitting up fibrin, which cannot be very important, but Schiif,

ii EXTERNAL DIGESTIVE SECRETIONS 127

and afterwards Vella, stated that it had the property of digesting
all proteins, which (if true) would raise the physiological value of
succus entericus to that of pancreatic secretion. The best work
with artificial digestions of succus entericus and boiled egg-
white, flesh, and proteins in general (putrefaction being avoided),
has, however, given entirely negative effects (Thiry, Wenz, Boccardi,
Malerba and Jappelli, Bastianelli, Klug, Pregl, and others).

But if succus entericus is incapable of digesting coagulated
albumin and natural proteins, it does contain a special enzyme,
Cohnheini's erepsin (1902), which acts on peptones, and splits
them into their final crystallisable products. All authors do not
agree in giving erepsin the importance which Cohnheim attributes
to it. Kutscher maintains that tryptic digestion alone is capable
of completely splitting the proteins until the biuret reaction
disappears. Bottazzi experimenting with intestinal extract-
denies, on the strength of his results, that this particular pro-
teolytic enzyme is secreted by the intestinal mucosa. He refers it
to the activity of the trypsiu secreted by the pancreas, and left to
a greater or less extent adherent to the intestinal mucosa. We
shall return to this in discussing intestinal digestion.

The existence of a lipolytic enzyme (or lipase) in succus
entericus was long a subject of discussion. Early experimenters
(Vella, Schiff) were inclined to admit its presence ; but later work
with the natural secretion, given necessary precautions for pre-
venting putrefaction (Malerba, Jappelli, Bastianelli, Pregl, and
others), proved that there was no true lipolytic action, or that
it could only be minimal. Thus Lombroso, on investigating
the succus entericus secreted naturally by a loop of Vella during
digestion, or after injections of pilocarpine, observed that it had
a very slight lipolytic activity. He found, however, that the
intestinal secretion poured out in large quantities when a higher
fatty acid is introduced into the loop, is actively lipolytic to an
extent approximating to that of the pancreatic secretion.

But the lipolytic enzyme of intestinal, unlike that of pancreatic,
juice is not aided in its action by bile. Lombroso's observation
cannot be met by the objection made to earlier workers, viz. that
the positive result is due to the presence of pancreatic enzymes
in the mucous membrane of the intestine, for the succus
entericus exhibiting this lipolytic activity is excited only by
definite stimuli (fatty acids), and does not diminish even when,
by repeated experiment, many hundred c.c. of juice have been
secreted by the Vella's loop.

Besides these enzymes, which are normally contained in the
mucous coat of the intestine, there is in mammals during the
secreting period an enzyme (lactase) capable of transforming
lactose (which is not directly utilisable by the body) into glucose
and galactose (Beyerick, Fischer and Niebel, Portier, Orban).

128

PHYSIOLOGY

CHAP.

"1 c-

Sisto showed that the mucous membrane of adult mammals,
which does not normally contain lactase, can produce this enzyme
after a diet containing a large quantity of lactose, extending over
several weeks. Birds, too, can be induced to secrete lactase by a
still longer period of alimentation.

The glandular crypts of the large, unlike those of the small,
intestine do not secrete any digestive juice. The food -stuffs
introduced into the large intestine, after making an anus preter-

naturalis, undergo no diges-
tive modification. It is
impossible, by any means,
to obtain any considerable
quantity of secretion from
this part of the gut. The
small amount that can be
obtained by little sponges
enclosed in wire capsules
introduced by the fistula
is clear, gelatinous, neutral
in reaction, laden with floc-
culi of mucus (Klug and
Koreck). Injections of pilo-
carpine, which exaggerate
all secretions of the gastro-
intestinal tube, change the
appearance of the mucino-
genous epithelial cells of
the large intestine, so that
they exactly resemble those
which line the crypts of
the small bowel (Fig. 45).

FIG. 45. Glands of large intestine of rabbit. (Heklpn- Tills fact, noted by Heiden-
a ;'res^ aftereOPiOUSSeCreti0n0fm "' hain>S pupils, sllOWS that

the glandular epithelium of
the large intestine is more subject than that of the small bowel to
mucosal changes during rest, and that during secretory activity the
mucus formed is excreted, and the primitive cells which predomi-
nate in the small intestine are regenerated, by a new formation of
the cytoplasm which surrounds the nucleus. Secretion of mucus
(which is very useful in facilitating the expulsion of the faecal
matters, which harden in the last part of the intestine by
absorption of water) thus seems to be the only well-ascertained
function of the secretory cells of the mucous coat of the large
intestine.

XVII. Little definite is known as to the dependence of the
intestinal secretion on the nervous system. According to Thiry
and others, stimulation of the vagus produces no effect. According

ii EXTEENAL DIGESTIVE SECKETIONS 129

to Budge, extirpation of the caeliac plexus causes increase of
intestinal peristalsis, with increased secretion of succus entericus.
Moreau's results are more important (1868). After making an
intestinal loop, he cut the mesenteric nerves which accompany
the vessels of the loop, and at once, or shortly after, saw an extra-
ordinary amount of juice secreted in the loop, but not in the
contiguous parts of the intestine in which the nerves were intact.
This excessive secretion may amount to T \ of the body- weight ; it
lasts for several hours, becomes less after 4 to 5 hours, and only
ceases after 24 hours. The secretion is at first a clear liquid,
which presently becomes clouded with flocculi of mucus. Some-
times it looks milky, and it contains large quantities of detached
epithelial cells.

This enormous formation of intestinal juice (which has the
same properties as the normal secretion collected in the loop of
Vella) is not explained by simple paralytic dilatation of the vessels.
We must assume that the phenomenon depends on lapse of control
by special nerves, of the secretory processes of the epithelia.
Since the secretion is in this case the effect, not of excitation, but
of severance of the nerves, we are forced to assume that the latter
inhibit the intestinal secretion, i.e. normally serve to keep it in
bounds by their tonic action. Nothing similar has, however, been
produced on stimulating the nerves to these glands. Moreau's
phenomenon plainly recalls Cl. Bernard's discovery of paralytic
secretion for the subrnaxillary gland, and presents the same
difficulties of interpretation.

According to the supporters of Bayliss and Starling's theory
(see p. 90 et seq.), the intestinal secretion, also, is due to the produc-
tion by the duodenum of secretin, which, on absorption and circula-
tion in the blood, comes into contact with the intestinal epithelia
of the gut, and excites them to secrete. This theory rests on
certain observations on secretion in a Yella's loop after the
injection of secretin. We have already pointed out the inadequacy
of these observations, and it is unnecessary to recapitulate the
objections in reference to intestinal secretion also.

According to Delezenne and Frouin, the succus entericus, after
undergoing the action of acids in the intestinal cavity, is reabsorbed
and excites secretion in other parts of the intestine. They
observed that succus entericus, acidified with hydrochloric acid
and subsequently neutralised and injected into the vein, excites
an abundant secretion. Moreover, in a dog provided with two
Thiry's intestinal fistulae, the introduction into one of the
fistulae of substances that excite secretion (hydrochloric acid, ether,
water) produced secretion in the other fistula also. This secretory
action at a distance is determined, according to Frouin and
Delezenne, not by the propagation of secretory stimuli by nervous
paths, but by the action of the reabsorbed succus entericus.

VOL. II K

130 PHYSIOLOGY CHAP.

U. Lombroso opposes this theory by a number of data worked
out in our laboratory. He observed the secretion in a Vella's
loop, made at a certain distance from the duodenum, on many
occasions, and for many hours. He has proved that there is
always a very scanty secretion (4-6 c.c. of juice) in 6 to 8 hours, even
after meals that are rich in flesh and fat, or consist of fat alone.
But if a solution of oleic acid or of soap is introduced directly into
the loop, an abundant secretion is at once called out. With 25 c.c.
oleic acid dissolved in bile, it is possible in a few minutes to obtain
30-40 c.c. or more of succus entericus.

It is a familiar fact that soap and fatty acid dissolved in bile
are found throughout the intestine after giving fats. If no
secretion occurs in Vella's loop, even after the digestion of large
quantities of fats, this must mean that the hormones which
activate secretion in the isolated tract of the loop are either not
produced or not absorbed during digestion.

But if it be proved that enteric secretion is not excited by
hormone stimuli ; if, on the other hand, Lombroso's observations
tell against the hypothesis that the mesenteric nerves convey the
secretory stimuli to the intestinal mucosa (as we said above, they
appear rather to have the task of inhibiting the intestinal secretion),
the question still remains open as to whether the said secretion
results solely from the direct action of chemical stimuli, or if these
may determine it by reflex paths from other regions that are not
directly excited, e.g. the stomach.

Lombroso's observations on the ordinary Vella's loop have not
solved the problem, because the operative act completely destroys
the relations of continuity of the nerves that run throughout the
extent of the intestinal walls, so that they can no longer propagate
the secretory stimuli.

Lombroso has accordingly modified his method of operation.
He separates a fairly long segment of intestine (50-80 cm.) as if
making a Vella's loop. After suturing the two extreme ends of
the divided portion to the abdominal walls, he attaches 3-4 cm. of
the middle part of the loop to the same wall. When adhesion
takes place, i.e. in 3 to 4 days, he slits up the middle of the loop so
as to bring it into relation with the exterior. This produces twin
loops of Vella, which preserve connection with the nerve plexuses
that run along the coats of the intestine.

On introducing a substance that excites secretion into the
first loop, the second loop does not secrete unless the same sub-
stance is made to pass into it by bringing the two lips together.
This indicates that direct action of the proper chemical stimuli
on the mucous membrane is necessary to excite the intestinal
secretion.

XVIII. The Liver in its structure and functions is a gland,
which in adult man weighs about 1579 grins. (1526 grrns. in

II

EXTERNAL DIGESTIVE SECRETIONS

131

woman), with an average volume of 1720 c.c. (Vierordt). This
gigantic development, and the intimate relations by means of the
portal system with the gastro-intestinal system, point to the true
physiological function of the liver as a laboratory for complex and
mysterious chemical operations, in which the preparation of the
bile that is formed and poured out into the gall - bladder and
duodenum is probably only a secondary process. The amount of
bile secreted daily by man rarely, in fact, exceeds 800 grins., while
the little parotid gland (which only weighs 24-30 grms.) daily
discharges as much as 1000 grms. of secretion. In this chapter,
however, we shall only consider the liver as the organ of Hie

Fio. 40. Diagram of fragment of liver from a six -months' foetus. Silver chromate method.
(G. Retzius.) The bile canaliculi are stained black. They have not yet anastomosed, and
give off minute twigs between the hepatic cells, with a terminal dilatation.

secretion. Its complex metabolism and internal secretions will be
discussed elsewhere.

Morphologists regard the liver as a tubular retiform gland,
consisting of cells arranged round glandular spaces which form a
very fine capillary network, the bile canaliculi. These appear to
have no membrane propria, and to be merely grooved out between
adjacent liver-cells, running on into the bile ducts, which have
walls and unite in larger and larger branches, till they converge
into the excretory, hepatic duct.

In the lower vertebrates, and the embryos of birds and
mammals, the liver is a tubular gland. The tubules do not
anastomose to form a network, but end in small branches, the ends
of which are often enlarged and penetrate into the hepatic cells
(Fig. 46). In adult vertebrates, on the contrary, the ramifications
of the canaliculi do anastomose to form an intercellular network,
which communicates with special vacuoles in the cell protoplasm

132

PHYSIOLOGY

(Fig. 47). Whether these vacuoles leading into the network of
the bile canaliculi, and first observed by Ptiiiger and by Kupffer,
and confirmed by others, are permanent structures, or whether
they are only formed at the moment of secretion, or produced
artificially by the staining fluids injected through the bile ducts
(which may fairly be excluded seeing that nothing of the sort has
been met with in other injected tissues), is unknown.

The peculiar structure of the hepatic parenchyma is determined
by the arrangement of its blood-vessels, which (with the lymphoid
connective tissue connected with Glisson's Capsule) constitutes
the scaffolding or framework of the hepatic cells. Unlike all
other organs, the afferent vessels of the liver consist not only of an

FIG. 47. Section of liver from adult animals, with injected bile capillaries. (Kupffer.) A, bile
canaliculi of rabbit's liver, artificially injected from hepatic ducts with Berlin blue solution.
They give off minute projections like a pin's head, which penetrate into the protoplasm of
the liver cells. B, the same from frog's liver, after natural injection with sulphindigotate
of soda. Here the projections form a network of fine fibrils inside the hepatic cells, with
terminal dilatations.

artery the hepatic artery, but also of a vein the portal vein,
which is formed by the union of the efferent veins from the
stomach, intestine, pancreas, and spleen ; these form a venous
trunk with exceptionally robust and muscular walls, and a much
larger calibre than the hepatic artery. The efferent vessels are :
the hepatic veins, with thin walls, which arise in the portal
capillaries, run towards the posterior surface of the liver, and open
into the inferior vena cava ; and the lymphatics, which are large
and numerous in the liver, originating in the lymph sinuses round
the portal capillaries, and which accompany and to a large extent
enclose the branches of the blood-vessels, and leave by the portal
fissure with the portal vein, the hepatic artery, and the bile or
hepatic duct. This last leads by the cystic duct to the gall-
bladder, and the junction of the two ducts (hepatic and cystic)
form the common bile duct or ductus clioledoclius, which pours

II

EXTERNAL DIGESTIVE SECRETIONS

133

the bile into the duodenum during digestion, 7-10 cm. from the
pylorus.

By a special system of distribution, capillary formation, and
reconstitution of these vessels, the hepatic parenchyma is divided
into a number of lobules or acini varying in diameter from
1 to 2 mm. polyhedral or spheroid in shape, which profoundly
modify the original tubular form of the gland. The branches of the

Fn::. 4S. Section of liver lobule, with blood-vessels and bile-ducts injected. (Cadiat.) I, I, inter-
lobular veins ; a, intralobular vein ; c, interlobular bile-ducts, with which the bile canaliculi
of the lobule are connected. The latter are only injected in the peripheral parts of the
lobule.

portal vein and hepatic artery penetrate as the interlobular veins
and arteries between the lobules, sending twigs to the interior
of the lobule which soon form a dense capillary network, from
which the intralobular veins re-form, and lead into a central vein
(Fig. 48). The intralobular and central veins are the beginning
of the efferent hepatic veins, which traverse the lobule in a radial
direction, and unite in the sublobular veins ; these form into larger
and larger branches, converging towards the posterior surface of
the liver, where they open, as we said, into the inferior vena cava.

134

PHYSIOLOGY

CHAP.

The interlobular course of the hepatic duct is similar to that
of the portal vein and the hepatic artery, but its interlobular
branches form a much finer network of canaliculi than that
formed by the blood-vessels, as shown in Fig. 48.

The hepatic cells lie in the interstices of the network of blood
capillaries, and round the closer meshes of the bile canaliculi.
They are polyhedral, 17-22 /j. in diameter, destitute of cell
membrane, and have a clear nucleus, with intranuclear network,
and one or two nucleoli.

The finely reticulated cytoplasm, the deutoplasmic content,

and the aspect as a whole of
the liver-cells change consider-
ably (as we shall see below)
according to whether they are
examined in the fasting state
or after food. Fig. 49 shows
the relations and respective size
and position of the hepatic cells,
the network of blood capillaries,
and the finer network of bile
canaliculi.

The nerves to the liver are
branches of the vagus and of
the solar plexus of the sym-
pathetic. They enter by the
portal fissure, accompanying the
hepatic artery and the portal
vein. They consist partly of
medullated, partly of non-medul-
lated fibres. The latter are dis-

FIQ. 49. Section of rabbit's liver after injection tl'ibllted almost exclusively to
of intracellular network of bile capillaries. , , . 1,1 , ,

(Herin-.) Thick section, showing two or the arteries and the veins ; the

three layers of cells and relative size and f nrmpr p n rp r flip lnlmlp<3 whprp
position of blood capillaries, b, b ; bile canali- les > W11616

cuii, c, c ; and hepatic ceils, e, e. they i ose their medullary sheaths

and ramify between and over
the cells, in a network of fine filaments (Fig. 50).

XIX. The external secretion of Bile produced by the liver
is distinguished from the four secretions above described, by
being continuous although it presents considerable fluctuations,
particularly in relation to the state of digestion or fasting; by
having no specific enzymes; and by being apparently regulated
merely by the hydraulic conditions of the hepatic circulation and
absorbed digestive products, independent of any direct influence
of secretory nerves, to which the other digestive secretions proper
are subordinated. For all these reasons the biliary secretion
presents more analogy with the secretion of urine as performed by
the kidneys than with the secretions of digestive juice which we

II

EXTEKNAL DIGESTIVE SECRETIONS

135

have been considering. But there is one fundamental difference
between the biliary and the urinary secretions, i.e. the specific
components of bile are, as we shall see, formed exclusively by the
metabolism of the hepatic cells, while the constituents of the urine
eliminated by the kidneys are mainly pre-formed in the blood, and
represent the products of the metabolism of other tissues.

The bile, secretion is studied in animals by making a fistula of the gall-
bladder (Schwaiin, 1844), either leaving the bile-duct free or tying it. In

a

a

FII,. 50. Plexus of nerve fibrils within hepatic lobe of pigeon. Methylene blue method.
(Korolkow.) a, a, axis-cylinders of nerve-tibres passing between cell-trabeculae of the lobule ;
b, b, fibrils ramifying over the cells ; c, c, hepatic lobules.

the first case (incomplete fistula), if the fistula of the gall-bladder is properly
closed, the bile can flow, as normally, into the duodenum ; in the second
(complete fistula), it is compelled to flow out to the exterior. In order
to study the process of bile secretion, it is necessary to make the fistula com-
plete and permanent, so as to be sure that the whole of the bile secreted
escapes by the orifice of the fistula. In cases of fistula of the gall-bladder
observed on man (Ranke, 1871, down to Noel Paton and J. M. Balfour,
1891), the fistula is always incomplete, and in these: cases it is seen by the
colour of the faeces that some of the bile secreted by the liver does not
pass through the opening of the fistula, but escapes by the bile duct and
discharges into the duodenum.

The innumerable experiments on bile secretion by complete or
incomplete fistulae of the gall-bladder in man and animals have

136 PHYSIOLOGY CHAP.

yielded very divergent results, especially as regards the influence
of the various foods ingested. Heidenhain recognised these dis-
crepancies, but held to the opinion that the secretion of bile not
only increases during digestion, but exhibits two rises during this
period, one 3-5 hours, the other 13-15 hours after a ineal. Not
being satisfied with these results, which differed from those
obtained by Spiro with Ludwig, we advised Baldi in 1881 to
repeat the same experiments in our laboratory, on dogs with a
complete biliary fistula, when they had quite recovered from the
operation and were in good physiological condition. He found a
surprising irregularity in the flow of the bile secretion, and was
unable to show any constant influence of digestion in general, or
of the nature of the foods administered to the animals.

Oil comparing the quantity of bile secreted in the space of a
few hours before and after a meal, he obtained a certain increase
during the period of digestion ; but the difference was not very
conspicuous, and may be interpreted as the effect rather of
increased blood-supply during digestion than of secretory excita-
tion of the hepatic cells. The entirely negative results obtained
with the so-called cholagogues (podophyllin, rhubarb, jalap, pilo-
carpine, aloe, etc.), in comparison with the immediate and con-
spicuous increase of the biliary secretion observed after injecting
ox bile, caused Baldi to revive the ancient doctrine of Aristotle,
Galen, and Morgagni, according to which the bile is a complex of
the products excreted by other tissues, the hepatic cells being only
the instruments of their selective elimination, as the cells of the
renal canaliculi are for the urinary products.

Later work has shown this position to be untenable ; but it
was certainly owing to Baldi's experiments that attention was
once more directed to this important problem.

With regard to the process of bile secretion and the influence
exerted on it by various foods, Barbara's results (in a series of
publications, 1894-98, which sum up the methodical researches he
made in Albertoni's laboratory) are particularly interesting.

Barbera carried out a number of comparative experiments
under identical conditions on dogs with a complete biliary fistula,
healed some time previously (at least four months) from the opera-
tion, when they had regained their initial body -weight, and
were accustomed to remain quietly in a Cyon's holder. The
day before each experiment, the dogs received a scanty meal of
mixed food, which was always identical in quality and quantity.
Twenty-four hours after, the animal was fixed to Cyou's holder,
and about three hours after fixation received the test meal, which
varied in its nature in different experiments on the same animal.
By this mode of procedure, it was possible to avoid any influence
of the preceding meal on the flow of secretion, while the effect of
the test meal was fully brought out.

II

EXTERNAL DIGESTIVE SECRETIONS

137

Barbara's results are plain from the accompanying diagram
(Fig. 51). As it shows, during an absolute fast the quantity of
bile secreted in each hour oscillates slightly round a minimum
(4-5 grins, in a dog of about 20 kilos.). This amount of bile,
secreted during hunger, is not perceptibly affected by the ingestion
of water, even in considerable quantities, provided the animals had

FIG. 51. Diagram to show course of bile secretion in fasting and with different kinds of diet, in a
healthy dog of 20 kilos., operated on four months previously by complete and permanent
fistula of gall-bladder. (Burbera.) Continuous line shows course of bile secretions during
abstinence or injections of water only ; the line of crosses, after injection of 500 grins, horse-
flesh ; the dotted line, after ingestion of 100 grms. cane-sugar ; the broken and dotted lint-,
after ingestion of 100 grins, fresh butter ; the broken line, after mixed diet of 300 grm.s. flesh,
30 grms. butter, and 300 grins, bread.

not previously been deprived of water for any length of time, in
which case the bile is denser than usual.

A meal of protein is followed by a very marked increase in bile
elimination, which commences after about 30 minutes, reaches its
maximum after four hours, and then declines till it ceases entirely
in about fourteen hours.

A meal of fats is followed by marked increase in bile
secretion, which commences after about one hour, reaches its
maximum after about five hours, and drags on with a slow decline
till it stops after about twenty hours.

A meal of carbohydrates is followed by a slight increase in

138 PHYSIOLOGY CHAP.

secretion, which commences suddenly, reaches its maximum at the
third hour, and ceases entirely during the sixth hour.

After a mixed meal the increase may be marked, when proteins
and fats predominate (see diagram), or slight, as when the carbo-
hydrates predominate.

These striking results, along with what is known of the
metabolism of the hepatic cells, suggest interesting considerations,
which we shall discuss in a future chapter, in studying the liver
as an organ of internal secretion. Here we must confine ourselves
to stating that the formation of bile is not activated by the
presence of food-stuffs in the gastro-intestiual tube, as a reflex
along nerve paths, but only when the alimentary substances
reach the liver by way of the portal vein, after digestion and
absorption. In fact, the experiments of Barbera show that the
influence of the food on bile secretion is conditioned by digestion
and absorption. When injected per rectum, those food-stuffs only
increase the secretion of bile which are absorbed (carbohydrates
and proteins), not such as are non-absorbable by this method
(fats).

The production of bile continues to a less extent, even when
the products of food digestion no longer reach the liver. During
a fast protracted till death occurs from inanition (Chossat, Luciani,
Albertoni), the amount of bile secreted gradually diminishes,
but is not arrested, up to the end. Albertoni, who studied
this phenomenon methodically (1893), saw that in fasting the
quantity of bile secreted diminished daily, while its specific gravity,
i.e. the relative amount of solid residues, nitrogen, and sulphur,
increased.

Bile is also formed from the third month of intra-uterine life,
and during the lethargic period of hibernating animals, though
only in small quantities (as in the fasting state).

According to Brand (1902), who studied the secretion and
composition of human bile in nine cases of fistula of the gall-
bladder, the amount of bile that flows out in man (from a complete
fistula) varies considerably from hour to hour. The daily amount
oscillates between 500 and 1100 c.c. The biliary secretion dimin-
ishes in the night, and falls to its minimum in the early hours of
the morning ; it then increases rapidly, reaches its maximum
about noon, and is usually succeeded by another maximum in the
evening. G. Galli (1906) obtained similar results in an analogous
case of fistula of the gall-bladder in a woman.

This proves that the secretion of bile, unlike the other secretions
which we have previously studied, is not co-ordinated with the
digestion of foods, since it is effected under conditions in which no
digestion takes place in the intestine, and increases when digestion
and absorption have already occurred. Biligenic and cholagogic
materials, such, i.e., as are capable of being transformed in the liver

ii EXTERNAL DIGESTIVE SECRETIONS 139

into bile, or of exciting the secretory metabolism of the hepatic
cells, are continuously circulating in the blood that courses through
the liver, independent of the digestive products absorbed.

Evidently these bile-forming and eliminating substances must
be katabolic products, both of the cells circulating in the blood and
of the fixed tissue-cells. This is proved by the fact that transfusion
of blood (particularly when heterogeneous) conspicuously increases
the production of bile (Landois). The so-called cholagogues of the
pharmacologists are ineffective, save in so far as they destroy the
cells of the blood and tissues, the waste products being then
elaborated by the liver (Noel Paton, 1886). If dogs with fistula
of the gall-bladder are made to ingest the products of nitrogenous
consumption, e.g. extractives of meat and uric acid (provided this
be rendered soluble and absorbable in the form of potassic urate),
there will be a constant augmentation of the bile secretion, with
increase of urea in the urine. Ingestion of urea, on the contrary,
even in very large doses, does not excite biliary secretion. When
it reaches the liver, the urea is entirely taken up by the central
veins of the lobules, and excreted by the kidneys. This fact,
established by Barbera (1898), proves the continuity of the bile
secretion, showing that the extractives and the uric acid which are
never absent from the blood of animals, either under ordinary
conditions or in fasting, excite metabolism in the hepatic cells, by
which they are transformed into urea. Urea, on the contrary, has
no action on the liver-cells, because it is the end-product of the
oxidation of nitrogenous substances, and is excreted unchanged by
the kidneys.

Barbara's later work (1902) also confirms this theory. Instead
of administering the various substances by the mouth or rectum,
he injected them subcutaneously in dogs, and studied their action
on the bile secretion. Injections of distilled water, of solutions of
glucose (up to 10 per cent), of medium doses of sterilised olive oil,
and of 5 to 7 per cent solutions of somatose had no effect on the
elimination of bile. On the other hand, he observed increase of
the secretion on injection of more concentrated solutions (glucose
20 per cent and more, somatose 10 per cent and more), or of large
doses of non-sterilised olive oil. But since these last injections
simultaneously induce local phenomena of irritation at the point
of injection, accompanied by increased elimination of urea and
slight rises of temperature, Barbera came to the conclusion that
the increase of bile secretion depends not on any direct action of
these substances on the hepatic cells, but, indirectly, upon the
increased destruction of proteins, the cleavage products of which
excite augmentation in the biliary secretion of the liver.

Another fact worth noting is that the secretion normally
poured by the liver into the gall-bladder is not all newly-formed
bile : a considerable part of it is only bile reabsorbed from the

140 PHYSIOLOGY CHAP.

intestine, conducted back to the liver by way of the portal vein,
and eliminated once more from the liver by the bile ducts. This
kind of entero-hepatic circulation of the bile was worked out
particularly by Schiff, Lussana, Baldi, Tarchanoff, and Wertheimer.
It is only necessary to give bile by the mouth, or to inject it
directly into the duodenum, of a dog with a fistula of the gall-
bladder, in order shortly after to see a flow from the fistula,
proportionate to the amount of bile administered. Again, on
injection by the veins, the bile is not excreted by the ureters but
entirely by the hepatic duct, if a moderate amount be injected.
On injecting ox-bile, which is green (owing to the large preponder-
ance of biliverdin), the secretion flowing from the biliary fistula of
the dog loses its orange colour (due to preponderance of bilirubin),
and assumes the hue of ox-bile (Baldi). This fact demonstrates the
specific excretory function of the hepatic cells for the constituents
of bile, which is of great importance, since it extends not only to
these but also to many other toxic and medicinal substances
introduced into the gastro-intestinal tube, which on reaching the
liver are carried back to the intestine with the bile (Lussana,
Moroni and Dyall, Acqua, Schiff, and others). Barbera (1898)
rightly insisted on a phenomenon which is not easy to explain by
known laws of physics and chemistry. If fasting dogs with a
fistula of the gall-bladder are made to ingest large quantities of
bile and urea together, then although both substances are taken
up by the portal vein, and carried to the liver, the whole of the
bile is constantly eliminated by the bile-ducts, while the whole of
the urea passes into the capillaries which lead to the central veins
of the lobule, and is excreted by the kidneys. To account for this
fact, he assumes a differentiation into two parts of the hepatic cells ;
the one in contact with the bile canaliculi, the other in relation with
the blood capillaries which lead to the central veins of the hepatic
lobules. These two parts must have different excretory functions,
due possibly to a difference in cytological structure, which we are
unable by our present methods to detect. But without invoking
any unfounded hypothesis, the fact may be explained as depending
on the selective attraction of the hepatic cells for biligenic sub-
stances (positive ckemotaxis), while they repel urea (negative
chemotaxis).

XX. The biliary secretion can be modified not only by the
composition of the blood that circulates round the hepatic cells,
but also by the amount of blood that flows to the liver, and the
vascular tonicity of the portal vein and hepatic artery. The
augmented secretion that occurs during digestion is partly due, no
doubt, to the active vascular dilatation which accompanies the
secretory work of all organs that function during the digestive
processes.

Just as the bile secretion is promoted by a rapid and abundant

ii EXTERNAL DIGESTIVE SECEETIONS 141

How of blood through the liver, so the interruption of the blood-
stream by ligation of the hepatic artery and portal vein arrests it
(Rohrig). After tying the hepatic artery alone, bile may still be
copiously secreted, fed from the portal blood alone (Simon, Schiff,
Schmulewitsch, Asp). The hepatic artery supplies the nutrient
vessels of the gall-bladder, bile-ducts, and iuterlobular branches of
the portal system, while it takes no direct part in the formation
of the intralobular network of blood capillaries. For this reason,
ligation of the hepatic artery gives rise after some time to the
formation of multiple necrotic foci in the liver, the larger of which
are converted into cysts, while the smaller are replaced by con-
nective tissue, so that hepatic cirrhosis develops (Cohuheim and
Litten).

The rapid and complete occlusion of the portal vein speedily
produces the death of the animal, owing to stasis and excessive
congestion of blood throughout the portal system. But if one
branch alone be tied, leading to one lobe of the liver, the biliary
secretion may continue in that lobe, fed solely by the artery
(Schmulewitsch, Asp). The same is also seen when ligation is
gradually applied to the entire portal trunk (Ore, Osier) ; also
when the blood of the hepatic artery is led directly into the
opened portal vein (Schiff).

When arterial pressure is lowered, either by haemorrhage, or
from vascular paralysis consequent on section of the cervical
medulla, there is diminution or arrest of the bile secretion. It
increases, on the contrary, after section of the splanchnic, because
in this case, although arterial pressure is diminished, the flow of
blood to the liver is increased, owing to paralytic dilatation of the
vessels at the roots of the portal system. By a diametrically
opposite effect, the bile secretion diminishes with electrical excita-
tion of the cord, of the splanchnics, or on strychinisation of the
animal (Heidenhain, I. Munk).

Circulation in the blood-vessels of the liver can be modified,
not only by the effects of constriction or dilatation of the roots of
the portal, or by increase or decrease of aortic pressure, but also
by the constrictor or dilator action of the nerve fibres which
regulate the tone of the branches of the hepatic artery and the
portal vein in the liver. According to certain experiments of
E. Cavazzani and G-. Manca (1894-95), the vaso-constrictor fibres
of the branches of the portal come directly from the splanchnics
and the caeliac plexus, and the vaso-dilators mainly from the
vagi. The branches of the hepatic artery, on the contrary, receive
their vaso- constrictors mainly from the vagi, their vaso-dilators
mainly from the caeliac plexus. During asphyxia, phenomena of
dilatation are mainly obtained in the branches of the hepatic
artery, and phenomena of constriction in those of the portal vein.
Electrical stimulation of the vagi and branches of the caeliac

142 PHYSIOLOGY CHAP.

plexus produces opposite phenomena in the region of the portal
vein and in that of the hepatic artery ; while the former contracts
with excitation of the plexus, and expands with stimulation of
the vagus, the latter contracts on exciting the vagus, and enlarges
with excitation of the caeliac plexus. While section of the vagus
abolishes the effect of asphyxia on the artery, it does not affect its
action on the branches of the portal vein.

Although the influence of these changes in the tone of the
venous and arterial hepatic vessels upon the process of biliary
secretion was not studied by the above workers, it may on analogy
be taken as highly probable that vascular constriction (particularly
of the portal branches) determines a slowing, and dilatation an
acceleration, of the flow of bile.

While there can be no doubt that the secretory activity of the
liver, like that of the other glandular organs, is indirectly affected
by the nerves which regulate vascular tonicity, there are at
present no data to demonstrate the existence of secretory nerves
to the liver, exerting a direct control upon the secretion of bile.
All the nerves to the liver can be divided without causing arrest
of the biliary secretion ; all branches of the nerves to the liver can
be excited one after the other, without causing a flow of bile, if
the secretion was suspended, or accelerating it if already taking
place (Heidenhain).

Falloise (1903) found on dogs that application of hydrochloric
acid to the mucous membrane of the duodenum, or upper part of
the small intestine, provoked increase of the biliary secretion. At
the same time it may be questioned whether this is a true reflex,
as asserted by Fleig. Falloise interprets the phenomenon by
admitting the transformation of pro-secretin into secretin, which
on reaching the liver increases the formation of bile by local
stimulation. In reality this pretended cholagogic action is
abolished neither by narcotics, nor by strong doses of atropine.
On the other hand, Henri and Portier (1902) observed that the
injection of secretin caused an acceleration of biliary secretion.
The same objections apply here in regard to the " secretin hypo-
thesis " as were raised for the pancreatic and intestinal secretions.

Friedlander and Barisch (1860) connected the hepatic duct of
the guinea-pig with a vertical glass tube, so as to determine the
point to which pressure can be raised in the bile ducts. They
saw that the bile ascends in the glass tube with a gradually
decreasing velocity, which ceases when it has reached a certain
height, varying from 184-212 mm. Since the pressure in the
portal vein, according to the determinations made by von Basch
on dogs, varies from 7-16 mm. Hg, corresponding to a column of
bile about 191-208 mm., the pressure under which bile is secreted
is always more or less higher than the pressure at which the blood
circulates in the portal system. This was confirmed by comparison

ii EXTERNAL DIGESTIVE SECRETIONS 143

of the two pressures, measured simultaneously by Heideuhain on
dogs. This phenomenon, perfectly analogous with that which
Ludwig found for the salivary secretion, shows that the bile
secretion cannot, even if it fluctuates with the variations in the
circulatory conditions of the liver, be regarded as an effect of
simple filtration through the vessel walls, but must depend on the
activity of the hepatic secretory cells.

In proportion as the elimination of bile by the excretory duct
is obstructed, it is reabsorbed, and the phenomena of jaundice
appear. The skin and conjunctiva of the eye become yellow,
which is the external sign of cholaemia, or admixture of bile with
blood. The bile is not absorbed directly by the blood-vessels of
the liver, but by the lymphatics, which convey it to the thoracic
duct, whence it is poured out into the blood torrent. This fact,
already surmised by Sanders in 1795, was demonstrated experi-
mentally by von Fleischl in 1872. Harley has recently shown
that if after ligation of the choledochus the thoracic duct is also
tied in a dog, there will for 17 days be no constituents of bile,
either in the blood or the urine, and no external sign of jaundice.
In this case, all the bile collects in the gall-bladder, and along the
thoracic duct and its roots in the liver.

XXI. The bile collected from the gall-bladder of dead bodies,
or obtained by fistula from man and other animals, is a mixture
of the secretion from the hepatic cells, and that of the epithelia
which line the bile ducts and gall-bladder. Along the excretory
ducts, the products of the hepatic cells are mingled with mucus
and cells in process of disintegration, which make it more dense,
more viscid, and less limpid and transparent. The reaction is
alkaline from the carbonate and phosphate of sodium, the colour
varies in different animals (golden-yellow in carnivora, grass-green
in herbivora, greenish-yellow in man), the taste is bitter. That
of man, exclusive of mucus, contains O'5-l per cent solids, of
which 0'7-0'8 per cent are mineral. Within the gall-bladder it
condenses from absorption of water ^till the solids amount to
16-17 per cent with specific gravity 1-010-1-040.

The specific constituents of bile are the Hie acids and
pigments.

The Hie acids are never found in the free state, but always in
the form of sodium salts (potassium salts in sea fishes). They are
acids containing nitrogen, and are composed of cholalic acid (or
related acids), glycine and taurine. It is remarkable that the
quantity of cholalic acid never varies sensibly in animals of the
same species. On the other hand, in different biles the relative
amount of glycocholic and taurocholic acid may vary, although
the former always exceeds the latter in quantity. Besides
cholalic acid, according to Schotten and Lassar Cohn, human bile
contains two other related acids fellinic and choleinic acid, which

144

PHYSIOLOGY

CHAP.

last is constantly present, and according to Lutschinoff forms the
fundamental acid of ox-bile.

Chemists distinguish a numerous series of '-bile pigments, which
represent various degrees of oxidation in the same molecular
aggregate. Under physiological conditions only two of these
pigments appear in the bile, the red or bilirubin, and the green or
biliverdin. The first is less oxidised, and represents the mother
substance of all the other pigments, and it is readily transformed
into the second by simple exposure to air (Maly). Biliverdin
is, vice versa, converted into bilirubin by a process of reduction.
By action of hydrogen in the nascent state these pigments are
converted into hydrobilirubin, which, as we shall see, occurs
continually in the intestine ; a certain amount of hydrobilirubin
can, however, be found even in human bile. Bilirubin and
biliverdin usually co-exist in the bile, but the first largely
predominates in the bile of carnivora, the second in that of
herbivora, while the one or the other predominates in that of man
(omnivora) according as the food is mainly animal or vegetable.

Hammarsten's analysis of the chemical composition of human
bile, taken from the gall-bladder of persons operated on for
cholelithiasis, and from patients with a fistula of the gall-bladder,
give the following results :

In 100

Parts.

Bile from the

Bile from the Gall-

Fistula.

Bladder.

Water

96-5 -98-3

82-96-83-98

Solid substances

3-5 - 17

17-03-16-02

Mucin and pigments
Alkaline bile salts .

0-27 - 0-9

1-8 - 0-26

4-19- 4-43
9-69- 872

Glychocholic acid
Taurocholic acid

1-6 - 0-2
0-05 - 0-3

6-95- 678
274- 1-93

Fatty acids (from soaps)
Cholesterin . *

0-024- 0-14
0-04 - 0-16

1-11- 1-05
0-98- 0-87

Lecithin .

0'06 - 0-17

0-22- 0-14

Fat .

0-06 - O'lO

0-19- 0-15

Soluble salts

0-7 - 0-8

0-28- 0-3

Insoluble salts

0-02 - 0-05

0-22- 0-23

As shown by this table, besides the bile salts and pigments
(which are the specific substances of bile), fats, soaps, cholesterol,
and lecithin are never absent ; these substances are compounds
present in other tissues and secretions. In the bile of certain
animals there is also a diastatic enzyme ; this is probably not
hepatic in origin, but is absorbed from the pancreas, and eliminated
by the liver in the bile. Choline and glycero-pliosplioric, acid are
also found, which are probably decomposition products of lecithin.

n EXTEENAL DIGESTIVE SECRETIONS 145

Normally the bile also contains urea, particularly that of the
cartilaginous fishes. As regards mineral substances, sulphates are
almost entirely absent from the bile, which shows traces of copper,
zinc, and particularly of iron, in an amount that varies with the
nature of the food. According to Novi, the quantity of iron is
less in dogs fed with bread, greatest in a flesh diet ; according to
Dastre, the iron content of the bile varies even with a uniform
diet, according as the haematopoietic or the haematolytic processes
predominate. The iron introduced in a medicinal form is also,
according to some authors, retained by the liver and eliminated in
the bile (Novi, Kunkel), this being disputed by others (Hamburger,
Gottlieb, and Anselm).

According to Craciunu (1901), the composition of bile varies
with age. The bile of young animals up to three years old
contains less water and more solids than that of adults (9'8-10 - 5
per cent against 8-8 "1 per cent solids). In young animals there
are also more mucin, more mineral salts, cholesterol, and bile salts :
in adult animals more fats and lecithin.

Pettenkofetfs Reaction is used to detect the presence of bile acids. The
acids or fluids containing them are treated with a little 25 per cent solution
of c.-uie sugar, and sulphuric acid is carefully added, so that it forms a layer
imd-r the solution. A reddish-purple colour appears at the junction of the
liquids, and also where it comes into contact with any froth at the surface.
The presence of nitrates may disturb the reaction.

In testing for bile acids in the blood and urine, the following is the best
method :

Dilute the blood with two volumes of water, and coagulate the proteins by
heating with a few drops of acetic acid. Filter off the coagulum and
evaporate the solution on a water-bath. Extract the residue with absolute
alcohol which dissolves the bile salts, while the proteins remain undissolved,
and evaporate off the alcohol. Dissolve the residue in water containing a
little sugar, and add sulphuric acid diluted with an equal volume of water
and cooled. On gently warming, the originally cloudy solution clears up, and
turns successively orange, yellow, red, ;md purple. To detect bile acids in
urine, it is only necessary to evaporate it to dryness, then extract with
alcohol, and proceed as described for blood.

A im>iv convenient method has recently been introduced, based on the
i'aci thai the presence of l>ile acids enormously inuva-es the surface tension
of urine. We shall give this method in detail when discussing the katabolic
products of urine.

1,'ni'lin'if fMt for l>ili> jiiiinii ///.-'. Pour 5 c.c. nitric, with a drop of nitrous
acid, into a watch-glass, then carefully introduce the fluid to be examined by
a pipette, without allowing it to mix with the reagent. At the point of
contact of the two fluids, rings of different colours are formed, which are
green, blue, violet, red, and yellow, a.- they spread from the centre to the
periphery. Each colour represents a successive stage in the oxidation of
the liile pigment.

The tests for cholesterol are also interesting. Chulrxfeml is the chief
constituent of the calculi formed in the bile-ducts and gall-bladder, which
give rise to hepatic colic.

1. On adding a few drops of .-ulpliuric acid diluted with one-fifth its
volume of water to some cholesterol in a porcelain capsule, a carmine-red
colour results (Moleschott).

VOL. II L

146 PHYSIOLOGY CHAP.

2. On adding a few drops of a mixture of 2-3 volumes concentrated HCL,
and 1 volume of dilute perchloride of iron to some cholesterol, and evaporat-
ing, a residue is olitained, which is at first red-violet in colour, afterwards
I due-violet (U. Schiff).

XXII. Far more is known of the origin of bile salts and
/iif/ments (though the data are still incomplete) than of the
formation of the other secretory products which are poured into
the intestinal tube.

The fundamental question is whether these specific constituents
of the bile are pre-formed in the blood, the liver only having the
task of eliminating them, as the kidneys eliminate the constituents
of urine, or whether they are exclusively formed in the liver, i.e.
are they specific products by external secretion of the hepatic
cells, and not the products by internal secretion of many or all
the tissues of the body. The first theory (already adumbrated
by Aristotle and Galen) was upheld in more recent times by
Morgagni, van Swieteu, and Glisson ; the second by Sanders, Job.
Miiller, Kunde, Moleschott. In accordance with their opposite
points of view, the former admit the possibilities of a haematogenous
as distinct from a kepatof/enous jaundice ; the latter regard
cholaemia and jaundice as invariably due to the reabsorption of
the bile formed in the liver, i.e. as being essentially hepatic in

origin.

Till quite lately, the arguments in favour of this last theory
were not adequate to solve the question :

() The blood that supplies the liver contains (it was said)
neither acids nor bile pigments ; these must therefore be formed
in the liver. But (as Baldi pointed out) this argument loses all
value if we reflect that, many kilos, of blood pass through the
liver in the 24 hours, and that the amount of biliary products
the blood must contain as the equivalent of what the liver secretes
during the same period is excessively small, certainly less than
3 grins, per cent, and therefore not to be detected by the
chemical means at our disposal.

(&) After extirpation of the liver in the frog (J. Miiller, Kunde,
Moleschott), the bile constituents do not accumulate in the blood,
as they do after tying the bile-duct. The frogs in which
Moleschott excised the liver lived 15 to 21 days, without any appear-
ance of cholaemia or jaundice. To this Baldi replies that the
metabolism of frogs is so sluggish that enough bile would not
collect in a few days in the blood or urine, to be detected chemi-
cally. In fact, when Leydeu tied the bile-duct in frogs there
was no sign of jaundice after 14 days. Kobner, in Heidenhain's
laboratory, did detect bile acids in the frog's urine, after ligation
of the bile-duct. But even if this argument proves that the
liver forms bile, it does not exclude the possibility of its formation
by other tissues also.

ii EXTEENAL DIGESTIVE SECRETIONS 147

*

(c) Secretion of bile ceases in cases of fatty degeneration of the
liver, yet there is no jaundice. Frerichs cites a clinical case in
which no bile salts were found in the urine. But Baldi, on
poisoning dogs with a fistula of the gall-bladder by small doses
of phosphorus which produced fatty degeneration of the liver,
observed that bile still flowed from the liver up to a few days
before the death of the animal. When, owing to catarrh of the
bile-ducts, the flow from the fistula ceased, bile salts were found
to be present in the urine. He noted, moreover, that after long
abstinence the hepatic cells of frogs became atrophied, while the
gall-bladder swelled, owing to the enormous accumulation of bile,
till it equalled or exceeded the volume of the liver. He further
observed that transfusion of ox-blood into dogs with fistula of the
gall-bladder not only increased the flow of bile freely given off by
the fistula, but caused the passage into the urine of bile acids and
pigments. From this it is legitimate to conclude that bile is not
an exclusively hepatic formation, and that the heterogeneous blood
transfused gives rise by decomposition of haemoglobin (as held by
Landois) to the bile pigments, and may possibly, by decomposition
of protein, account for the formation of bile acids.

(d) It is impossible, either during abstinence or in digestion,
to demonstrate the presence of bile constituents in normal hepatic
tissue by micro-chemical means. The varying aspect of the hepatic
cells in these two periods (which we shall study elsewhere) seems
to be exclusively connected with the formation of glycogen (Cl.
Bernard), and not with the formation of Hie. This fact seems
to favour the ancient doctrine of the diffuse formation of bile,
rather than the theory which regards it as the exclusive secretion
of the liver cells.

None of these data, as can be seen, gives a decisive answer in
regard to the exclusively hepatic origin of the specific products of
bile. Other more recent work, however, leaves no doubt as to
this point. We may summarise the most cogent and conclusive

arguments :

(a) If bile, like urine, were the excretory product of different
tissues, its nitrogen and sulphur content would vary in proportion
to the total protein consumption of the body. Kunkel (1870)
and Spiro(18SO), on the contrary, show on dogs with fistula of the
gall-bladder that only a small part of the nitrogen and sulphur
from the proteins of the food are eliminated with the bile, and
that this quantity does not increase proportionately with the
amount of protein ingested. When the amount of protein intro-
duced as food is increased eight times, the amount of nitrogen
and sulphur in the bile is only doubled. Barbera (1896) showed
that this increase of nitrogen in the bile is also seen after the
ingestion of fats. It does not therefore depend on the greater
quantity of nitrogen circulating in the blood, but solely on the

148 PHYSIOLOGY CHAP.

fact that both proteins and fats excite the hepatic cells and
accelerate the secretory function.

(fi) Stern's experiment on pigeons (1885) is more decisive.
After total occlusion of the liver in these birds, by ligation of
all the vessels that enter or leave it, including the bile-duct,
urinary secretion is arrested, and bile pigments do not appear
either in the blood serum or in extracts of the tissues, even with
Gmelin's highly sensitive test. When, on the other hand, Stern
confined himself to occluding the bile-duct only, the pigments
appeared in the urine after an hour and a half, and after five
hours they could be detected in the blood serum. This shows
plainly that the bile pigments in circulating blood are formed
exclusively in the liver.

(y) The experiments of Minkowski and Naunyn (1888) on
geese are no less important. They destroyed a considerable pro-
portion of the erythrocytes of two geese, in one of which the liver
had been excised by inhalations of arseniuretted hydrogen, and
observed that after half an hour the goose with a liver gave off
urine containing biliverdiu and bile acids, while the goose with
no liver gave urine which contained abundance of haemoglobin
with no trace of pigments or bile acids. On then removing the
liver of the first goose, and occluding all the vessels, including
the bile-ducts, they noted after some time that the serum of the
blood contained neither bile pigments nor bile acids. These
experiments are complementary to those of Stern, showing that
not only the bile pigments but also the bile acids have an
exclusively hepatic origin.

(S) The same interpretation holds for the experiments per-
formed by v. Fleischl with Ludwig on dogs. Having tied the bile-
duct and inserted a fistula in the thoracic duct, he showed that the
lymph that escaped from the fistula contained the constituents of
bile, which are absent when the bile-ducts are not occluded. On
tying both the bile-duct and the thoracic duct on the other dog
at the same moment, he saw that the latter swelled from the
accumulation of lymph, while no trace of bile salts could be
detected in the blood. This result, which was subsequently con-
firmed by Harley, shows not only that bile is exclusively produced
by the liver, but also that after occlusion of the bile-ducts it is
reabsorbed exclusively by the lymphatic paths to the thoracic
duct. Both these experiments of Fleischl and those of Minkowski
and Naunyn with inhalations of arseniuretted hydrogen show
that the haematic or extra-hepatic origin of jaundice can, under
no circumstances, be admitted, even where the latter is confined
to the accumulation of the bile pigments in the blood. The
presence of bile pigments in the urine of a patient invariably
denotes reabsorption in part at least of the bile by the
lymphatics of the liver. Occlusion of the larger bile-passages is

ii EXTEKNAL DIGESTIVE SECKETIONS 149

not essential to this absorption. A slight obstruction to the out-
flow of bile in any of the primary bile -ducts suffices to cause
overflow of the secretion stagnating in these passages into the
lymphatics, and thence into the blood.

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150 PHYSIOLOGY CHAP.

For Succus Entericus.
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L. THIUY. Sitzungsber. k. Akad. in Wien, 1864.
A. MOREAU. Comptes rendus de 1'Acad., 1868.
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Ferment from its Zymogen. Journ. of Physiol., 1901-2, xxvii. 323-325.
H. M. VERNON. The Conditions of Conversion of Pancreatic Zymogens into

Enzymes. Journ. of Physiol., 1901-2, xxvii. 269-322.
H. M. VERNON. The Conditions of Action of Pancreatic Rennin and Diastase.

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W. M. BAYLISS and E. H. STARLING. On the Causation of the so-called " Peri-
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1902, xxviii. 448-473.
L. B. MENDEL and L. F. RETTGEU. Experimental Observations on Pancreatic

Digestion and the Spleen. Amer. Journ. of Physiol., 1902, vii. 387-404.
W. M. BAYLISS and E. H. STARLING. On the Uniformity of the Pancreatic

Mechanism in Vertebrata. Journ. of Physiol., 1903, xxix. 174-180.
H. M. VERNON. The Precipitability of Pancreatic Ferments by Alcohol. Journ.

of Physiol., 1903, xxix. 302-334.

F. A. BAINBRIDGE. On the Adaptation of the Pancreas. Journ. of Physio!.,

1904, xxxi. 98-119.

W. M. BAYLISS and E. H. STARLING. The Proteolytic Activities of the Pancreatic
Juice. Journ. of Physiol., 1904, xxx. 61-83.

ii EXTERNAL DIGESTIVE SECEETIONS 151

R. BuRTON-Orrrz. A Method to Demonstrate the Changes in tin 1 Va.-i-nlarity of

the Submaxillary Gland on Stimulation of the Secretory Fibres. Journ. of

1'hysiol., 1901, xxx. 132-142.
H. H. DALE. The "Islets of Langerhans " of the Pancreas. Proc. Roy. Soc.,

London, 1904, Ixxiii. 84.
W. M. BAYLISS and E. H. STARLING. The Chemical Regulation of the Secretory

Process. Croonian Lecture. Proc. Roy. Soc., London, 1904, 310.
0. MAY. The Relationship of Blood-Supply to Secretion with Especial Reference

to the Pancreas. Journ. of Pliysiol., 1904, xxx. 400-413.
L. A. E. de ZILWA. On the Composition of Pancreatic Juice. Journ. of Physiol.,

1904, xxxi. 230-233.
J. BARCROFT and E. H. STARLING. The Oxygen Exchange of the Pancreas.

Journ. of Physiol., 1904, xxxi. 491-496.
W. M. BAYLISS and E. H. STARLING. On the Relation of Enterokinase to Trypsin.

Journ. of Physiol., 1905, xxxii. 129-136.
P. W. COBBE. Some Observations on the Carbohydrate Metabolism in Partially

Depancreated Dog. Amer. Jouru. of Physiol., 1905, xiv. 12-15.
J. M. HAMILL. On the Identity of Trypsinogeu and Enterokinase respectively in

Vertebrates. Journ. of Physiol., 1905-6, xxxiii. 476.
J. S. EDKINS. The Chemical Mechanism of Gastric Secretion. Journ. of Physiol.,

1906, xxxiv. 133.
W. SALANT. The Effect of Alcohol on the Secretion of Bile. Amer. Journ. of

Physiol., 1906-7, xvii. 408.
A. J. CARLSON. Vaso-dilator Fibres to the Submaxillary Gland in the Cervical

Sympathetic of the Cat. Amer. Journ. of Physiol., 1907, xix. 408.
A. J. CARLSON, J. R. GREER, and F. C. BECHT. The Relation between the Blood

Supply to the Submaxillary Gland and the Character of the Chorda and the

Sympathetic Saliva in the Dog and the Cat. Amer. Journ. of Physiol., 1907-S,

xx. 180.
N. B. FOSTER and A. V. S. LAMBERT. Some Factors in the Physiology and

Pathology of Gastric Secretion. Journ. of Experim. Med., 1908, x. 6.
H. C. BRADLEY. Human Pancreatic Juice. Journ. of Biol. Chem., 1909, vi. 133.
W. E. DIXON and P. HAMILL. The Mode of Action of Specific Substances with

Special Reference to Secretin. Journ. of Physiol., 1909, xxxviii. 314.
J. S. EDKINS and M. TWEEDY. The Natural Channels of Absorption evoking the

Chemical Mechanism of Gastric Secretion. Journ. of Physiol., 1909, xxxviii.

263.
A. J. CARLSON and A. L. CRITTENDEN. The Relation of Ptyalin Concentration to

the Diet, and to the Rate of Secretion of Saliva. Amer. Journ. of Physiol.,

1910, xxvi. 169.
J. L. TrcKETT. On the Production of Glycosuria in Relation to the Activity of

the Pancreas. Journ. of Physiol., 1910-11, xli. 88.

CHAPTER III

MECHANICS AND CHEMISTRY OF DIGESTION IN THE MOUTH

AND STOMACH

CONTENTS. 1. Historical. 2. Mastication, insalivation, formation of aliment-
ary bolus, and saccharification of starch. 3. Mechanism of deglutition. 4. Innerva-
tion. 5. Artificial digestion t vitro to determine action of gastric juice on different
food-stuffs. 6. Influence <>( spleen on gastric digestion. 7. Natural digestion
in the stomach. 8. Effects of total gastrotomy. 9. Active movements of
stomach in gastric digestion. 10. Mechanism of vomiting. 11. Peripheral and
central inuervation of stomach. Bibliography.

THE term " Digestion " usually denotes the complex of mechanical
and chemical changes effected in the food-stuffs by the muscular
tissue of the gastro-mtestinal canal and by the secretions of the
glands discussed in the last chapter. By these changes the food-
stuffs are reduced to the form necessary for their rapid absorption,
assimilation, and transference to the blood stream.

By "food-stuffs" in the widest sense, we mean all those
substances which are normally contained in the blood plasma,
or can readily be converted into the same, and which do
not represent the end-products (or metabolites) of tissue
consumption, destined as such to be eliminated from the body.
A perfect diet' must therefore contain (a) protein; (I) fats; (c)
carbohydrates ; (d~) water ; (e) various salts, the bases of which
are Na, K, Ca, Mg, Fe, and hydrochloric, sulphuric, and phosphoric
acid. The three groups of organic substances (proteins, fats, carbo-
hydrates) are oxidisable, i.e. they contain potential energy which
is greater or less in proportion to their capacity for oxygen ; the
mineral constituents (water and salts), on the contrary, are not
capable of being oxidised, and are therefore useless as sources of
energy, and merely fulfil the role, of common solvent, or passive
material of construction. We shall discuss the physiological
classification of foods, according to the functions of each group of
substances (which is fundamental to the theory of nutrition},
elsewhere, when we consider metabolism, i.e. the material
exchanges of the body as a whole.

Of the oxidisable organic substances on which we subsist, sugar

152

OH. in DIGESTION IN THE MOUTH AND STOMACH 153

and certain proteins only are soluble in water ; starch, coagulated
protein (e.g. meat and boiled egg-white), and fats are insoluble.
The mechanical and chemical object of digestion is to modify
these substances, and to render them soluble and readily diffusible.
Mineral constituents being soluble need undergo no change in
the gastro-intestinal canal to fit them for entering the blood.

The mechanism of digestion is so bound up with its chemistry,
that to treat them separately seems to us no less grave an error
than to discuss the theory of nutrition before that of digestion.

I. The first series of methodical experiments on Digestion were
those of Reaumur (1683-1757). The Accademici del Cimento,
disciples of Galileo, and founders of the iatro-mechanical school,
had previously experimented on ravens, and seen that the stomach
of these birds is capable with its powerful muscles of pulverising
the hardest bodies, which lent support to the view that digestion
consisted essentially in trituration (Borelli, Pitcairn, Boerhaave).
It was known, however, that in man and mammals, where the
digestive powers are very great, the stomach has such thin walls
that digestion can only be conceived as the effect of chemical
solvents (Wepfer, Viridet, Valisnieri). In order to decide between
the mechanical and the chemical theory, Reaumur carried out a
series of experiments in which ostriches were made to swallow
perforated metal tubes containing food. The first results were
negative or very doubtful, but his later work on birds of prey,
which have a membranous stomach, yielded conclusive results, and
convinced him of the chemical character of the forces that, in the
majority of cases, effect digestion. When, however, he attempted
to digest in ritro by means of gastric juice obtained from sponges
which his tame buzzard was made to swallow and fehen regurgitate,
after which the fluid which the sponges had imbibed was squeezed
out, his results were negative, and he gave up the experiments.

Nearly half a century later the same experiments were taken
up again by Spallanzani (1783) with complete success, and he
confirmed the discovery of Reaumur, and further demonstrated
the possibility of artificial digestion in vitro, without the inter-
vention of mechanical factors. He suspected the presence in the
gastric juice of a ferment of neutral reaction, as discovered by
Schwanu in 1837, a ferment on which the solvent power of the
gastric juice depends. Lastly he made a most important dis-
covery from the standpoint of medicine and hygiene, i.e. the
non-putrefaction of gastric juice, to which is due its sterilising
action on the foods introduced ; this being possibly, as we shall
see, the most important function of the acid secretion of the
stomach.

The Congress convened at Paris in 1823 by the Academic cles
Sciences with the object " de determiner par une serie d'experiences
chimiques et physiologiques, quels sont les phenoinenes qui se

154 PHYSIOLOGY CHAP.

succedent dans les organes digestifs durant 1'acte de digestion," led
to the publication of two important monographs, one by Leuret and
Lassaigne (1825), the other by Tiedemann and Gnielin (1826), in
which the entire process of digestion was for the first time
submitted to an experimental criterion. The work of the two
German authorities in particular must be regarded as the starting-
pi tint of subsequent experimental researches, since they established
the foundations on which the whole of the modern doctrine of
digestion rests.

In collecting the gastric juice, Tiedemanu and Gmelin intro-
duced a modification of the method pursued by Reaumur and
Spallanzani, since they caused dogs to swallow insoluble bodies in
order to stimulate the walls of the stomach. They then killed the
animals, collected the juice secreted, and studied its solvent action
on food in vitro. A few years later (1833) Beaumont published
his experiments on the Canadian trapper, Alexis St. Martin, who,
in consequence of an accident, had a large gastric fistula, which
made him a convenient subject for the study of the phenomena of
natural digestion. And shortly after (1834) Eberle published his
discovery of artificial cjastric juice obtained from extract of mucous
membrane, with whic4i numerous series of artificial digestions in
vitro were carried out by himself, by Joh. Miiller, Schwann,
Wasmann, Vogel, Valentin, etc. This return to Spallanzani's
method indicates a marked progress in the positive knowledge of
the nature and properties of the digestive process.

Among the more complete monographs on digestion, of special
historical interest, are those of Blondlot (1843), Frerichs (1846),
and Bidder and Schmidt (1852).

II. The Digestive System, which is a canal extending from
the mouth to the anus, has on an average a length of about nine
metres. The part that lies in the head, neck, and thorax measures
from the mouth to the cardiac orifice of the stomach some 38 to
46 cm. ; the remainder, situated between the abdomen and the
pelvis, is almost twenty times as long. The former includes the
mouth, the pharynx, and the oesophagus ; the latter the stomach,
the small intestine, and the large intestine. This anatomical
division clearly indicates the lines we must follow in studying the
mechanical and chemical changes in the food-stuffs introduced into
the digestive canal.

The first 'secretion which the food encounters is the saliva
poured into the buccal cavity, in a daily quantity (according to
Bidder and Schmidt) of more than 1500 c.c. Prima diycstio fit in
ore, as the ancients phrased it. At first sight it appears as if the
saliva, secreted in such abundance, must have a highly important
chemical function. Everything, on the contrary, indicates that
the operations effected on the food in the mouth are mainly of a
mechanical character,

in DIGESTION IN THE MOUTH AND STOMACH 155

Fluids, whether taken into the mouth by sucking or drinking
(i.e. imbibed or gulped down), are immediately swallowed; solids,
on the contrary, are masticated before swallowing.

If a fluid is taken up by imbibing, this is effected by the
negative pressure which is produced in the buccal cavity during
an inspiration, provided the communication between the pharynx
and the nasal fossae is closed by elevation of the palate. In
order that the liquid shall be imbibed, the edges of the lips
must be applied to the edge of the glass and to the surface of
the fluid. When a fluid is gulped down, the mouth is half-open,
and the lower lip makes a funnel which conducts the fluid to
the mouth.

Sucking, by which the infant draws its nourishment from the
glands of the breast, is effected by the vacuum produced in the
mouth by depression of the roof, retraction of the tongue towards
the throat, and sometimes by dropping of the lower jaw (Auerbach),
while the lips completely enclose the nipple. The negative
pressure which determines the flow of milk into the buccal cavity
oscillates, according to Herz, between 3 and 10 mm. Hg ; this last
figure, however, seems to us exaggerated.

Mastication of solid foods is accomplished by the voluntary
movements of the lower against the upper jaw, assisted by the
movements of the tongue, by which the food is pushed between
the two rows of teeth, which are the passive instruments of
trituration ; the canines and incisors serve particularly for pulling
and tearing, the molars for biting up the food.

The teeth make their appearance in the first two years of
childhood these being the milk teeth destined to be gradually
replaced by the permanent teeth from the seventh year onwards.
The milk teeth are 20 in number : 8 incisors, 4 canines, 8 molars ;
the -permanent teeth are usually 32 : 8 incisors, 4 canines, 8 pre-
rnolars, and 12 molars. Comparison of the form of the teeth in
man and in the carnivora and herbivora, gives a plain anatomical
proof that a mixed diet is that best adapted to the nature of man.
This is confirmed by the length of his intestine, which holds the
mean between that of herbivora, which is much longer, and of
carnivora, which is much shorter.

Elevation of the lower jaw is effected by means of the temporal,
masseter and internal pterygoid muscles ; its depression, by gravity,
and by the action of the anterior surface of the digastric, mylo-
and genio-hyoid muscles, and the platysma ; the forward movement
by the simultaneous action of the external pterygoids ; the
retraction by the simultaneous movement of the internal ptery-
goids ; and the sideway movements by the alternate action of the
external pterygoids on both sides (Fig. 52, A and B).

The masticatory movement is regulated by the tactile sensibility
of the teeth and the buccal mucous membrane, and by the

156

PHYSIOLOGY

CHAP.

muscular sense of the muscles that come into play ; it is activated
ly the motor roots of the third branch of the trigeminals, aided by
the hypoglossal and facial nerves. The immediate common centre
of the masticatory movements, according to Schroder van der
Kolk, lies in the medulla oblongata; this view is not, however,
supported by any definite anatomical evidence. Since the move-
ment is complex and voluntary, its centre probably lies in the so-
called motor zone of the cerebral cortex. In fact, the electrical
excitation of a circumscribed area in the lower lateral part of the
(( irtex of the anterior lobe of the brain in rabbits readily produces

FIG. 52. A, internal pterygoid muscles viewed from outside. (G. D. Thane.) The masseter
muscle, greater part of zygomatic arch, temporal muscle with coronoid process, and a large
part of the ramus of the jaw have been removed ; 1, external pterygoid, the figure is placed
on the lower head ; 2, internal pterygoid. B, lower part of skull and face to show attach-
ment from behind of pterygoids and some other muscles. (Bonrgery.) a, body of spheroid,
beneath which are the posterior nares ; /, section through temporal bone ; c, hard palate ;
il, posterior part of condyle and neck of lower jaw, above which are the synovial cavities of
the joint separated by the inter-articular tibro-cartilage ; c, symphysis me.nti ; 1, left internal
pterygoid muscle; 1', lower part of same muscle, on right side, the middle is cut away to
show external pterygoid ; -I, lower head of external pterygoid ; 2', upper head of the muscle,
attached in part to the inter-articular disc; 3, origin of mylo-hyoid and genio-glossus muscles
from the mental spines ; 4, origin of mylo-hyoid ; 5, attachment of anterior belly of digastric ;
6, 6, masseter muscles.

movements resembling those of mastication. The centrifugal
paths from this area lead through the corona radiata to the median
segment of the internal capsule, and may be followed into the
anterior mesial part of the cerebral peduncle.

Simultaneously with mastication comes the insalivation of the
food, by which its particles are worked into a mass, which, when
carried to the back of the tongue, becomes rounded and is called
the bolus. The movements of the tongue, besides shifting the
food to and fro between the rows of teeth, help in shaping the
bolus from the fragments already chewed and insalivated.

According to Gaudenz (1901) a mouthful suited for mastication
normally has a volume of about 5 c.c. Its weight depends on the
specific gravity of the foods. Such a mouthful in a normal man

in DIGESTION IN THE MOUTH AND STOMACH 157

is sufficiently chewed in half a minute to determine the reflex of
deglutition, independent of the nature of the food. The masticated
pulp contains a certain quantity of coarse particles from 7-12 mm.
in diameter, according to the nature of the food ; the smallest
particles are only 0*01 mm. in diameter. Pieces larger than
12 mm. in diameter are retained in the mouth during deglutition
of the pulp, and subjected to fresh trituration. As a rule vegetable
foods are better masticated than animal matters.

The most important function of saliva is certainly the prepara-
tion of a bolus from the masticated food, which is then ready for
deglutition. Saliva has no chemical action on the greater part of
the food-stuffs, and is limited to the conversion of the starch into
dextrin and sugar, with absorption of water. This action takes
place rapidly on cooked starch, very slowly upon raw, and is due
exclusively to the ptyalin, which acts in a slightly alkaline, or
even in a faintly acid medium, so that its action must cease in the
stomach, as soon as the acidity of the gastric juice exceeds that of
0'5 per cent HC1. The saccharifying power of the enzyme is less
when it is made to act on a large amount of starch ; moreover, it
is easily exhausted.

Cannon and Day (1903) studied salivary digestion in the
stomach of the cat by isolating the different parts of the stomach
with ligatures, at a given time after the ingestiou of food, and
testing them singly for the sugar content. They found that in
the fuudus, the contents of which do not mix for a long time with
those of the pyloric region in the cat, the saliva produces a con-
spicuous formation of sugar from the starch, without disturbance
by the hydrochloric acid of the gastric juice.

The amylolytic or diastatic action of the saliva is accomplished
in stages, i.e. it passes through certain intermediate products.
The first stage of starch conversion is that of amidulin (Nasse) or
soluble starch, which turns blue with iodine like insoluble starch ;
amidulin is then transformed into erythrodextrin (Briicke), which
turns deep red with iodine ; the erythrodextrin changes into
achroodextrin (Briicke), which no longer stains with iodine ; lastly,
a portion of the achroodextrin is converted into maltose (von
Mering and Musculus), and a small portion into glucose
(Zimmerniaun), which give the ordinary sugar reactions.

Besides maltose, there is always a certain amount of dextrin
and unaltered starch in the end-products of the amylolytic action
of saliva, as exerted by ptyalin on starch. According to Sheridan
Lea, 3'412 grms. of boiled starch, left to digest for a number of
hours with 100 c.c. of saliva, yield 2'83S grms. of maltose, and
0'505 grin, of dextrin. On the other hand, it is certain that a
small quantity of saliva suffices to saccharify a large amount of
starch (Briicke).

Clemm (1902) showed that simple salivary digestion con-

158 PHYSIOLOGY CHAP.

tinned for three days at body temperature, produced sugar,
both from animal starch (glycogen) and from vegetable starch
(potato) ; the whole of the maltose was split into two molecules of

glucose.

Surprising as is the readiness with which ptyalin acts upon
cooked starch, the time of its action is very short, and incom-
parably less in intensity than that of the analogous enzyme of
pancreatic juice.

Recent 'researches prove that salivary digestion has a much
greater importance than was formerly supposed.

J. Miiller (1901), e.g., found that saliva converts 50-70 per cent
and even more of the alimentary starches into soluble products
closely related to maltose. In cases of weak acid secretions in the
stomach, only very minute fractions of starch, as a rule, remain
undissolved. The saccharification of starch is therefore most
intense at the commencement of gastric digestion. Gaudenz
(1901), too, found that in the ingestion of starchy foods, such an
amount of saliva was secreted even after half a minute that it
induces a peculiarly energetic process of saccharification, and is
capable of dissolving large quantities of vegetable foods like
macaroni, potatoes, turnips, etc., while animal foods are only
dissolved to the extent in which they contain substances soluble

in water.

The saliva of carnivora, although it is secreted in great
quantities, is entirely destitute of ptyalin, as might be expected
from teleological considerations. The saliva of infants, up to a
year old, is also lacking in ptyalin, and therefore in diastatic
properties (Schiff and others). This is the best proof that the
principal function of the saliva is mechanical, i.e. formation of the
bolus. It must, however, lie added that saliva by its alkalinity
also serves to protect the teeth from the corrosive action of acids,
which are readily formed in the mouth by the fermentation and
decomposition of alimentary residues. One argument in favour of
this theory of Bunge is the fact that Cetacea that live in water are
entirely destitute of salivary glands, which are rudimentary in the
Pinnipeda. The emulsifying action of saliva on fats claimed by
some authorities (Colin, Longet, Corona, Ellenberger, Hofmeister)
is due to the mucin which it contains. According to others,
saliva promotes gastric secretion when it reaches the stomach, by
its alkalinity (Strieker); but this fact is not conspicuous or
constant enough to render it of importance. Dogs are apparently
none the worse for the extirpation of all the salivary glands, aud
only require to drink more frequently than usual during their
meals (Fehr, 1862).

III. The formation of the bolus is succeeded by the act of
Deglutition, which carries it from the mouth to the stomach,
through the pharynx and oesophagus. The analysis of the

in DIGESTION IN THE MOUTH AND STOMACH 159

mechanism of this act is one of the most difficult problems :
" difficillima particula pliysiolocjiae," as Haller termed it.
Magendie (1808-13) was undoubtedly the one among modern
physiologists who occupied himself most with this phenomenon,
and his description, by its simplicity and clearness, leaves nothing
to be desired. He was the tirst to distinguish three stages in
deglutition : the first directed by the will, during which the bolus
passes from the mouth to the isthmus of the fauces ; the second
involuntary, of a reflex character, very rapid and almost con-
vulsive, in which the bolus passes the pharynx and reaches the
upper part of the oesophagus ; the third involuntary, very slow,
carrying the bolus into the stomach. The mechanism by which
these three acts are performed is essentially the same ; it consists
in a peristaltic movement by which the bolus is driven onwards
and forwards in the first period by pressure of the tongue
against the palate, owing to contraction of the longitudinal lingiuil
and the mylohyoid muscles ; in the second by the contraction of
the constrictors of the pharynx, which surround and constrict the
bolus, carrying it forward, while the larynx and hyoid bone are
elevated, and the passage of the bolus through the aperture of the
glottis is accelerated ; in the third by the progressive contraction
of the circular fibres of the oesophagus, dilated by the pressure at
which the bolus is driven forward by the contraction of the
pharynx.

Many details in Magendie's description are the fruit, not
merely of anatomical, but also of direct physiological, observation.
This explains how his theory came to be generally accepted,
subsequent physiologists only introducing slight modifications and
additions, with the object of completing and perfecting it in
various ways.

In 1880, however, after the work of Kronecker and his pupils
and co-workers, doubt was for the first time cast on this doctrine in
regard to its central concept, viz. that the passage of the bolus from
the mouth to the stomach was effected by a comparatively slow
peristaltic contraction, by which it was driven from section to
section till it reached the stomach. In a paper with Falk, Kronecker
notes that when iced water is drunk, there is a feeling of cold in the
stomach directly after the first gulp, i.e. before peristalsis of the
pharynx and oesophagus can occur. Forensic medicine, again, has
described cases of poisoning by swallowing of corrosive fluids, which
showed on examination that the oesophageal lesions were confined
to certain isolated points, the greater part of the mucous membrane
being uninjured which would not be the case if the liquid
swallowed were propelled down the tube by peristalsis. Patho-
logical observation further shows that while paralysis of the
oesophagus makes deglutition difficult it does not inhibit it.
Kronecker concluded from these facts that the fluid or semi-

160 PHYSIOLOGY CHAP.

lluid liolus is shot into the stomach hy the contraction of the
striated muscles, before peristalsis of the oesophagus can take
place. Manometric observations show that at the commencement
of the act of deglutition there is a rapid increase of pressure equal
to about 20 cm. water near the base of the tongue, and also in the
gullet, but not in the stomach.

Meltzer performed an interesting series of experiments on
himself, to prove that this increased pressure in the retro-buccal
space at the commencement of deglutition suffices to drive the
bolus rapidly into the stomach. When a sound with a very light
rubber balloon at one end (see Vol. I. fig. 192, p. 429), and a
recording tambour at the other, is passed down the oesophagus to
various measurable depths, two elevations are marked on the

FIG. 53. Curves of deglutition obtained from himself by Meltzer, on introducing two separate
sounds into pharynx and oesophagus. F, tracing from pharyngeal sound ; K, tracing from
oesophageal sound, passed 4 cm. down the oesophagus ; s, time tracing in seconds. A little
liquid was swallowed at A ; more at B ; a large amount at C.

rotating drum at each act of swallowing, which Kronecker terms
" signals of deglutition " (Schluckmarken) : the first signal appears
immediately after the act, independent of the depth to which the
sound lhas been introduced into the oesophagus; the second, on
the contrary, appears later in proportion as the sound goes
deeper. On introducing a second sound into the pharynx, and
repeating the above experiment, Kronecker and Meltzer obtained
the curves of Figs. 53 and 54.

The rapid rise of the curve from the pharyngeal sound of
Fig. 53 signals the moment at which the bolus (or liquid mouthful)
shoots down the pharynx, and compresses the balloon. A, B, C
show that the height of the elevation is in proportion with the
amount of fluid swallowed. The oesophageal tambour marks no
rise at A to coincide with that of the pharyngeal tambour, owing
to the small amount of water swallowed ; but at B and C the
passage of the fluid into the oesophagus is clearly signalled by
elevations which coincide with those of the pharynx. All three

in DIGESTION IN THE MOUTH AND STOMACH 161

curves then show a second elevation (about 1 sec. after the first),
which depends on the contraction of the constrictors of the
pharynx and oesophagus set up by the passage of the bolus. In

B

FIG. 54. Curves of deglutition as in Fig. 53. In A and B the oesophageal sound was passed
12 cm. beyond the opening of the oesophagus ; in C, 16 cm. Less water was swallowed at A
and C than in B.

fact in the tracings of Fig. 54, in which the oesophageal sound
had been introduced farther into the oesophagus, the second rise
occurs much later than the first, which practically coincides
with the pharyngeal signal.

The first signal indicates the rise of pressure in the gullet

VOL. II M

PHYSIOLOGY CHAP.

owing to compression 1'roin the bolus (solid or liquid), which is driven
through the oesophagus hy the forcible contraction of the mylo-
hyoid muscles; the second is due to the successive contraction
of the pharyugeal and oesophageal constrictors of the pharynx
and oesophagus. The increased pressure in the mouth determines
the rapid propulsion of the bolus (fluid, or solid reduced to a
pulp) into the cardia ; the subsequent contraction sweeps away
from the gullet any particles of food that are adherent to its walls,
and overcomes the resistance of the cardia, driving the bolus into
the stomach.

According to Meltzer, the human oesophagus does not contract
by peristalsis, as is usually accepted, but in three sections (the
first being 6, the second 9, the third 6-7 cm. long), each of which
is emptied successively like the several segments of the heart.
When the upper part is in maximal contraction, the lower part
begins to contract, so that the solid bolus (which cannot like
fluids be directly propelled by the thrust of the mylohyoid
muscles) is forced to descend towards the stomach. Meltzer
succeeded! in determining the interval between the contraction of
the rnylohyoids and of the pharyngeal constrictors (0'3 sec.),
between the contraction of the pharyngeal constrictors and that
of the first section of the oesophagus (0 - 9 sec.), between the
contraction of the first and second sections of the oesophagus
(l - 8 sec.), between the contraction of the second and third sections
of the oesophagus (3'0 sec.). The sum of these differences
represents 6 sec., which indicates the time necessary for the
bolus to descend from the mouth to the extremity of the
oesophagus, and to overcome the resistance of the cardia and
enter the stomach.

Meltzer confirmed his theory by the simpler method of
auscultation. On listening with the stethoscope in the region of
the stomach, or laterally, at the xiphoid process, a murmur is
almost always heard during the act of deglutition. This coincides
with the moment at which the bolus (or fluid mass) overcomes
the sphincter closure of the cardia and penetrates into the
stomach, which takes place 6-7 sec. after the commencement of
deglutition, and it is therefore called the terminal murmur. In
a much smaller number of cases there is, on the contrary, at the
initial moment of swallowing, a sharp whistling murmur, as if
the liquid swallowed had been shot forcibly and directly into the
stomach. When this sound, which may be called the initial
murmur, is very distinct, the terminal murmur is not heard ;
when, on the contrary, it is very dull, the terminal murmur is
clearly heard as well, though faintly. In a small number of
cases no murmur is perceptible on auscultation during the
deglutition of liquids.

Meltzer noted that many persons in whom the initial murmur

in DIGESTION IN THE MOUTH AND STOMACH 163

alone is heard, exhibit atony of the cardia, since during coughing
regurgitatiou of food from the stomach into the oesophagus readily
occurs ; in those, on the contrary, in whom the cardia is normally
closed, which prevents the bolus from entering the stomach imme-
diately, it remains at the lowest part of the oesophagus, until the
contractile movement of the latter overcomes the resistance of the
cardia, and produces the terminal murmur, which, as seen above,
occurs 6'7 seconds after the commencement of deglutition.

The human cardia is thus normally closed, so that the bolus
(or fluid mass) must remain at the extreme end of the oesophagus,
until the contractile movement of the latter forces it into the
stomach. This closure of the cardia explains why the increment
of pressure determined by Krouecker and Falk in the gullet
during deglutition, does not occur within the stomach.

Kronecker, therefore, differs from Magendie, in not admitting
three successive stages in the act of swallowing. He maintains

O t O

that deglutition occurs in one single act in which the bolus (liquid
or pulp) is shot with great velocity and under a relatively high
pressure, as far as the cardia. This, he says, is the fundamental
mechanism of deglutition, in which neither the muscles of the
pharynx nor those of the oesophagus participate, the bolus being
allowed to slide through passively. The whole canal contracts in
successive sections only when the bolus has already reached the
cardia, and this accessory movement is an act complementary to
the normal act of swallowing, which may acquire vital importance
in cases in which a bolus too large or too hard is being swallowed,
and sticks in the oesophagus owing to the insufficient impulse,
producing painful sensations of choking, which have to be removed
by repeated acts of swallowing and drinking of fluid.

The principal factor in the normal act of deglutition is repre-
sented by the muscles of the mylohyoid group, as already recognised
by Magendie, Tourtual, Ludwig. Of this we have direct evidence
iu the fact that on dividing the mylohyoid fibres of the motor
branch of the fifth nerve, while the filaments that supply the
digastric muscles are left intact, the animal is no longer able to
swallow, unless it resorts to the expedient of throwing its head
back quickly with the mouth open, so as to jerk the food into the
throat, when the pharyngeal constrictors can come into play
effectively. The muscles innervated by the hypoglossal are also
important to the act of deglutition, which is disturbed by their
resection, owing to the consequent paralysis of the longitudinal
lingual muscle and of the hypoglossal. By the almost simultaneous
contraction of this group of muscles (with which is associated that
of the group of elevator muscles of the hyoid bone and larynx), the
bolus conveyed to the back of the tongue is pressed between tongue
and palate, and driven under strong pressure towards the point of
least resistance, i.e. towards the retro-buccal cavity, while the

Kil

PHYSIOLOGY

('HAT.

surface of the root of the tongue, which in the state of rest is
turned backwards, retracts, and carries the epiglottis witli it, so
that the glottis closes mechanically. At the same time, the palate
is raised and stretched, not passively, but by the contraction of
the elevator and tensor muscles of the palate, so as to occlude and
separate the nasal from the pharyngo-buccal cavity, with the
assistance of the palato-pharyngeal and the superior constrictor
muscles of the pharynx, which contract and bring forward the

t

7

\

FICI. 55. Diagram showing position of soft palate, tongue, glottis, pharynx, etc-. A, at rest ;
B, during deglutition. (Zaufal.) t, Salpingo-pharyngeal fold; I, fold of levator palati ;
c, nmsculo-superior constrictor; a, azygos uvular which completes the closure of the nasal
cavity.

pharyngeal walls forming Passavant's swelling, as shown in Fig.
55. This, according to Kronecker, comprises the fundamental
mechanism of deglutition : the rest, as minutely described by
certain authors, is accessory, and serves principally to prevent the
food or drink from taking the wrong path to the glottis or nasal
fossae, and to clear the canal of the food residues, or to drive the
bolus (when it is blocked at the lower end of the oesophagus) into
the stomach, by overcoming the resistance of the cardia.

Another important fact discovered by Kronecker and Meltzer
is that every active movement of swallowing carried out in the
primary segment of the alimentary canal, particularly from the
contraction of the myloliyoid or hypoglossal muscles, produces an
inhibition of the movements of the deeper segments. When, on

in DIGESTION IN THE MOUTH AND STOMACH 1G5

drinking a fluid, a series of swallowing movements, separated by
an interval of 1-2 seconds, occurs, the subsequent contraction of
the oesophagus is produced only after the flnal gulp. This is
easily proved by the method of the oesophageal sound, as seen in
the curves of Fig. 56, which also show that the pause which occurs
between the signal of the last act of swallowing, and that of the
subsequent contraction of the oesophagus, is so much longer in
proportion as the number of previous acts of swallowing is greater,
as if the production of the acts of deglutition gave rise to a

FIG. 56. Signals of deglutition, recorded by Meltzer from himself, by oesophageal sound intro-
duced as far as the second segment^ of the oesophagus, <'.. 1:2 cm. below its commencement.
In curve 1 (top, left-hand) water was only swallowed once, and the second signal occurred
3 sec. after the tirst. In curve '2 (top, right-hand) fluid was swallowed six times, and the
second signal occurred 4 sec. after the last swallow. In curve 3 eight acts of swallowing were
performed, and the second signal occurred sec. after the last.

delay in the conduction of the excitatory process by which the
peristaltic movement of the oesophagus is developed.

But if this new theory of the mechanism of deglutition pro-
pounded by Kronecker and his school is applicable to fluids and
to substances reduced to a pulp, it is doubtful whether it applies
to soft alimentary boluses, and to solids, which are sometimes
swallowed without, or with imperfect, mastication and salivation.
We are indebted to Cannon and Moser (1898) for the valuable
observations which have solved this doubt and elucidated the act
of deglutition in birds and the higher mammals. They applied
the Iio'ntgen rays to this purpose, bismuth subuitrate being added
to the food to render it opaque. The fluorescent screen employed
was marked at intervals of centimetres with cross lines. A
vibrator marking tenths of a second was interrupted whenever the
shadow cast by the bolus passing through the gullet crossed a line.

1GG PHYSIOLOGY CHAP.

lly this method the following conclusions \vcn- arrived at :

The mechanism of deglutition varies according to the animal
and the nature of the food swallowed.

In fowls, the movement is slow and peristaltic whatever the
consistence of the food. Any jerking of fluid is obviously
impossible, because the parts surrounding the buccal cavity are
too hard and rigid. Gravity has a predominating importance
over the propulsive power of the mouth. Each time the mouth is
tilled with fluid the head is raised, so that the liquid descends by
its own weight into the oesophagus, where it is carried forward by
peristalsis.

In cats, according to these authors, the movement of deglutition
is always peristaltic and much more rapid than in fowls. The
bolus takes 9-12 seconds to reach the stomach. In the upper part
of the oesophagus, fluids move more rapidly than semi-solids. In
the lower or diaphragmatic parts the velocity, for both liquids and
solids, is much less than in the upper parts.

In dogs, the bolus descends to the stomach in 4-5 seconds.
It is always propelled rapidly in the upper part, and more slowly
below. For fluids the rapid movement may be maintained even
in the lower part.

In man and in the horse, fluids are shot into the oesophagus at
a velocity of several decimetres per second, owing to the impulse
from the rapid contraction of the mylohyoid muscles. Solids and
semi-solids are propelled slowly forward throughout the gullet by
peristalsis only, and Kronecker's theory is therefore justified in
regard to the deglutition of liquids and pulp ; but for the degluti-
tion of solids and semi-solids the old doctrine of peristalsis still
holds, although it must be understood in the restricted sense

O

imposed by the experiments of Kronecker and Meltzer.

The later work of Zwaardemaker and Eykrnan, Schreiter,
Kindernianu and Kahn has not contributed anything really new
to the subject.

IV. Deglutition is a characteristically reflex act. It is true
that it commences as a voluntary process, but this, which Magendie
regards as the first period of deglutition, during which the bolus
reaches the isthmus of the fauces, has nothing to do with the act
of deglutition proper and may be logically regarded as the final
moment of mastication (Morat and Avloing, 1880). Magendie
devised the following experiment in order to demonstrate the
necessity of the peripheral stimulus i.e. the bolus or fluid to
the act of deglutition :

" Cherchez," he said, " a executer de suite cinq on six mouve-
ments de deglutition, dans lesquels on avalera la salive contenue
dans la bouche : le premier et meine le second se feront facile-
ment ; le troisieme sera plus difficile, car il ne restera que tres pen
de salive a avaler ; le quatrieme ne pourra etre execute qu'au bout

in DIGESTION IN THE MOUTH AND STOMACH 167

d'un certain temps, quancl il sera arrive de nouvelle salive dans
la bouclie ; enfin le cinquiume et le sixieme seront impossible,
parcequ'il n'y aura point de salive a avaler."

Since deglutition normally takes place when the bolus or fluid
reaches the isthmus of the fauces, it is evident that the starting-
point of the reflex is represented by the contact of the food with
the sensory nerve-endings distributed to this region. Wassilieff
(Bern, 1888), however, did not succeed in the human throat in
finding any point on the tongue, palate, or posterior and lateral
walls of the pharynx, at which mechanical, chemical, or electrical
stimuli incite the act of swallowing, as the stimulation of the
nasal inucosa incites sneezing, and contact with the glottis
coughing; we must assume that preparatory movements in the
isthmus of the fauces are required in order to excite swallowing in
man, these being absent during experimental excitation when the
throat is kept quiet. In the rabbit, on the contrary, deglutition
is infallibly excited on touching the central part of the anterior
surface of the soft palate, which is some 2-5 uim. broad, and 2 cm.
long, extending from the hard palate halfway along the tonsils.
The least contact in this region produces a complete act of
swallowing. Wassilieff succeeded in evoking fifty in succession
without finding any fatigue of the reflex nervous mechanism.

It. H. Kahn (1903), who did much careful work on the reflexes
of deglutition, found that they were excited in the rabbit by
stimulation of the soft palate (trigemmal), in the dog and cat by
stimulating the dorsal surface of the pharynx (glosso-pharyngeal),
in monkeys by stimulation of the upper part of the palatal arch
(trigeminal).

Both in rabbits and in man, anaesthesia of the sensory region
with a concentrated solution of cocaine (10-20 per cent) makes
the swallowing reflex impossible for some time (about a quarter of
an hour). This is the best proof that deglutition is not dependent
on will, as the respiratory movements are under certain conditions.

The sensory fibres to the soft palate, which are the starting-
point of the swallowing reflex in the rabbit, derive from the
trigeminal, the sensibility of the palate to reflexes of deglutition
being permanently abolished after intracranial division of this
nerve.

In 1865 Bidder and Blumberg noted that stimulation of the
central end of the superior laryngeal nerve also provokes move-
ments of swallowing. This fact was confirmed by A. Waller and
J. L. Prevost in 1870 for both cats and rabbits.

They further found to their surprise that section of both
superior laryngeals produced no marked disturbance of deglutition,
particularly in rabbits, which survived for months after this
operation. On Kronecker's new theory this is not surprising,
since division of the superior laryngeals leaves intact the essential

1.68 PHYSIOLOGY CIIAI-.

mechanism of the swallowing reflex, which is effected by way of
the trigeminal.

As regards the glosso-pharyngeal nerve, both Schiff (1867),
and Waller and Prevost found that swallowing was never excited
by its stimulation, and concluded that it does not contribute in
any way (at least in rabbits) to the reflex phenomena of deglu-
tition. Schiff also noted that the division of those nerves in the
same animals produced no disturbance of deglutition. It was left
for Kronecker and Meltzer (1883) to discover that the glosso-
pharyngeal must be regarded as a nerve which reflexly inhibits
the swallowing movements. In order to bring out this fact
Wassilieff performed the following experiment on rabbits. When,
after lateral exposure of the superior laryngeals and glosso-
pharyngeals, the former alone are excited, movements of swallow-
ing are performed; when the latter are simultaneously excited
with weak induction currents the phases of deglutition occur
irregularly and are much delayed ; when, lastly, they are stimu-
lated with strong currents, the effect of the superior laryngeals is
altogether abolished.

The inferior laryngeals or recurrent nerves also contain centri-
petal fibres which are capable of exciting the reflexes of deglutition.
This fact, as already surmised by Valentin (1846), and by Waller
and Prevost (1870), was fully elucidated by Kronecker and
Liischer (1897). They found in a series of experiments on rabbits
that the recurrens sends four branches to the cervical part of the
oesophagus, the lowest of which innervates the upper part of the
thoracic oesophagus also (Fig. 57), and that when the peripheral
trunk of one of these filaments is excited even with weak currents,
a tetanic contraction occurs exclusively in that segment of the
oesophagus in which it ramifies (Fig. 57). When, on the contrary,
the whole trunk of the recurrens is excited, the entire cervical
part of the oesophagus contracts simultaneously. The peristaltic
form of the oesophageal movement that takes place in deglutition
must accordingly depend on a delay in the excitation which
descends to the three branches of the recurrens in succession from
the nerve centre. This agrees with Mosso's earlier and important
observation (1873), to the effect that the peristaltic wave of the
oesophagus is not arrested in swallowing by ligatiou, nor by section,
nor by extirpation of a quarter of its length ; the wave continues
to be propagated from the upper to the lower segments. It ceases
only after division of the oesophageal nerves. This fact shows
that the peristaltic wave of the oesophagus is not a local pheno-
menon propagated from tract to tract by the muscular coat, as in
the intestine ; but that it results from the nerve impulses that
descend successively by the three branches of the oesophagus from
the nerve centres.

Liischer further noted that stimulation of the central trunk

in DIGESTION IN THE MOUTH AND STOMACH 169

of the recurrens in the rabbit produced the same effect as that
of the superior laryngeal, i.e. a swallowing movement confined
to the upper tract which is innervated by the trigeminal, the
oesophagus being paralysed owing to the occlusion of the centri-
fugal paths contained in the two nerves resected. In morphinised
rabbits, reflex deglutition from the two laryngeals occurs less
readily than in the normal ; sometimes, however, when the
superior laryngeal is out of court, deglutition can be excited by
the interior laryngeal. After bilateral section of the two inferior
laryngeals, rabbits die in a few days from pneumonia owing to
the blocking of the oesophagus from the paralysis of its muscles.

Fie. 57. Diagram of the four branches of the recurrens which supply different parts of the
oesophagus in rabbit. (Liischer.) c, va^us ; /, recurrens; 1, -i, 3, 4, its brandies ;
oesophagus; tr, trachea; It, border-line of thorax.

The nerve centres which preside over and co-ordinate the
movements of swallowing lie in the upper part of the medulla
oblongata, for destruction of the brain above the respiratory
centres (more exactly above, and external to, the ali cineraee of
the rhomboidal sinus) does not abolish the movements of deglu-
tition (Wassilieff, Marckwald). We know, on the other hand,
from pathology that the so-called Imlbar paralysis produces
disturbance or inhibition of the act of deglutition. Nothing,
however, is known as to the localisation of these centres, on which
depends the co-ordination of the successive movements in the
various tracts (buccal, pharyngeal, oesophageal) of the alimentary
canal.

The centrifugal paths (as may easily be inferred from the
above experiments) lie in the motor portions of the trigeminal
and hypoglossal nerves for the mylohyoid, hypoglossal, and lingual

170 PHYSIOLOGY CHAP.

muscles ; in the vagi ami spinal accessory for the muscles of the
palate, pharynx, and oesophagus.

The cardia belongs by its movements to the oesophagus, its
function being co-ordinated witli the swallowing movements in
the latter ; it contracts after the last part of the oesophagus, and
loses its tonicity when the oesophagus is relaxed under the
inhibitory influence of the glosso-pharyngeal nerves.

V. On reaching the stomach the alimentary boluses remain
there for several hours, according to the nature of the food, and
suffer various changes of a chemical character. The importance of
the stomach was formerly exaggerated, since it was held to be the
centre of the digestive system ; and the mass of the food-stuffs
transformed by it was known as chyme, meaning by this term
a pulp differing far more in constitution from the raw materials
ingested than it does in reality. As it became recognised that
the action of the gastric juice is almost entirely confined to
protein, and that even this property is not limited to the stomach
but is common to the intestine also, a more reasonable conception
prevailed of the functional value of this viscus. The fact that
food remains a long time in the stomach is not enough to give it
a predominating importance in digestion. The surface of the
stomach being relatively small in comparison with the ample
surface of the intestine, while it secretes an acid peculiar to itself,
it would be necessary (in order that the gastric juice may act
effectively) to compensate the limited surface of the organ by a
prolonged stay of the food within it. It has, on the contrary, been
proved, as we shall see, that food remains longer in the small
intestine as a whole than it does in the stomach. Lastly, it is
important to note that surgeons (Czerny, Kaiser and others) have
succeeded in keeping dogs and man in good condition for mouths
and even years after the excision of practically the whole of the
stomach. These facts show that the stomach is in no sense
absolutely essential to life. In another connection we shall
analyse the details and effects of the operation.

Two methods are employed to study the digestive action of the
gastric juice : that of natural digestion, which consists in observ-
ing the changes the food undergoes in the stomach (when intro-
duced in muslin bags by fistula) ; and that of artificial digestion in
vitro, in which the various foods are brought into contact with
natural or artificial gastric juice, at a proper temperature. The
first method, inaugurated by Beaumont, serves to give an idea of
the process as a whole ; the second, instituted by Eeaumur and
Spallanzani, yields a minute analysis of the different phases of the
process and the various products resulting from it.

It is easy with artificial digestions to show that the funda-
mental digestive action of the gastric juice consists in the so-
called peptonising of the proteins, by which these substances,

in DIGESTION IN THE MOUTH AND STOMACH 171

whether dissolved, or coagulated and insoluble, are transformed
into soluble and readily diffusible substances, called by Lehmann
peptones.

We cannot enter upon the exposition and critical analysis of
the various opinions successively put forward as to the nature of
peptonisation, and must confine ourselves to enumerating the
more positive of the experimental data :

(a) No protein is (caeteris paribus) more readily digested by
the gastric juice than fresh fibrin extracted from the blood, and it
was therefore chosen by Briicke as the common measure of com-
parison between the digestive power of artificial and of natural
gastric juice. Next to fresh fibrin, casein is the most rapidly
digested ; next, boiled fibrin ; next again, coagulated egg-white.
As a rule it may be said that proteins of animal origin are digested
more easily than those of vegetable origin.

(&) Apart from the disparate nature of the proteins, the rapidity
of their digestion and solution depends on the degree of tem-
perature, the amount of pepsin, and the amount of acid which
the digestive juice contains. The optimum degree of temperature
is approximately that which is normal to the body. Below 35 C.
digestion is retarded, at C. it is entirely suspended. The
amount of pepsin required to obtain a marked digestive action is
very small, certainly less than 0'067 per cent. According, how-
ever, to Schiitz (infra), when the amount of the enzyme is
increased, the quantity of acid and protein to be digested remain-
ing constant, then on estimating at regular intervals the amount

o o o

of protein dissolved, it is found that the rapidity of digestion
increases in proportion with the square root of the concentration of
the pepsin. If the amount of acid is varied, while the amount of
pepsin and of protein remains constant, it is found that excess
or deficit of acid retards or suspends digestion, while the
optimum amount of acid varies with the nature of the protein to
be digested (e.g. for fibrin the optimum is 0'9 per cent of hydro-
chloric acid, for coagulated egg-white on the contrary it is l - 2-l - 6
per cent).

An admirable method for the quantitative determination of the proteo-
lytic power of the gastric juice and therefore of its pepsin content is ha>ed
upon the Schiitz law. This method, as first described by Mett (1894), can
also lie used fur testing the digestive power of trypsin, and is as follows :

Fresh, liquid egg-white is aspirated into a glass tubr with a lumen of
1-2 nun., which is plunged for one minute into water heated to 95 C. The
tube of coagulated albumin is then slowly cooked, and cut with a tile into
small pieces, taking care that the cylinders of egg-white fit exactly the
end of each tube, so that no empty space isleft in the latter. The glass tubes
are then plunged into 1-2 c.c. of the digestive fluid and left for 10 hours at a
temperature of 37-40 J C. The albumin is evenly dissolved during this time
lii'Ui the outer end of the tube inwards. At the end of the time the length
of the. little tube and of the column of egg-white left undissolved are
measured. The difference gives the length of the cylinder of digested egg-

172 PHYSIOLOGY CHAP.

albumin. Since by Schut/.' l;i\v the rate of digestion or amount of protein
dissolved in the time unit are proportional 1o I lie square root of the quantity
of ferment, the quantity of pepsin or trypsin contained in (lie specimen
investigated must equal tlie square of the length of the column of egg-white
which it has digested in the given period. Supposing, c.;/., tliat the gastric
juice .1 dissolves a column of albumin of 2 mm. while the juice B dissoh <>
of 3 mm., it follows that the amount of pepsin present is as 4 : 9.

(<') The presence of the digestive products, particularly of
peptones, delays the final digestion of proteins and eventually
suspends it. If the mixture be then diluted with water, digestion
is resumed. If the peptones are removed by diffusion through a
dialyser as fast as they are formed, so that the original concentra-
tion of pepsin and acid is maintained, the mixture recovers its
initial digestive force. This must occur during natural digestion
in the stomach, because the peptones are absorbed as fast as they
are formed. In fact, only a mere trace of them can be found in
the contents of the stomach during the digestion of protein.
Briicke, on the strength of this, assumes that pepsin undergoes no
change during its digestive action. Griitzuer's latest results,
however, make it probable that a little of the pepsin is consumed,
or loses its enzymatic properties (possibly by combining with other
colloidal substances), because even under the most favourable
circumstances the digestive power of any juice declines slowly.

('/) The addition of concentrated alkalies or acids destroys
the digestive action of pepsin, as does heating to 70 C. Bile, too,
suspends the action of gastric digestion in vitro, even in such a
small quantity that the acidity of the juice is not neutralised.
This seems, however, not to occur during natural gastric
digestion, since Oddi noted no digestive disorders in dogs in
which the gall-bladder had been put in communication with the
abdominal cavity by a fistula. It is probable that the bile poured
into the stomach under these conditions is rapidly absorbed
again without admixture with the gastric contents. Or it may
be assumed that the absence of digestive disturbance is due to
the fact that in dogs the suspension of the gastric function is not
of much importance, since it is readily compensated by a more
active duodenal digestion.

(e) The peptonisation of proteins by the gastric juice is not
immediate, but takes place in stages, several intermediate substances
being formed before reaching the end-substances represented by
the peptones by a process analogous to the action of saliva on
starch. These modifications of protein by the gastric juice can
only be demonstrated by prolonged artificial digestion. After
some hours of digestion in vitro (at 35-45 C.) of a given quantity
of boiled fibrin (or cubes of coagulated egg-albumin) in a very
active, artificial gastric juice, at least three different kinds of
proteins can be detected in the mixture : an acid albumin or

111 DIGESTION IN THE MOUTH AND STOMACH 173

syntonin, a proteose (formerly called by Schmidt-Miihlheim pro-
peptone), and a peptone.

Syntonin is the first stage in the transformation of fibrin effected by the
gastric juice. When the liquid is slowly neutralised by successive drops ol'
sodium carbonate solution, the syiiloiiin precipitates, and can be- separated
by nitration. To convert boiled fibrin into syntonin, it is only necessary i<
use a simple solution of 1 per cent HC1, keeping it in the warm chamber for
1-2 days. But if a little pepsin be added to the acid, the conversion into
svnloiiin is much accelerated. Fluid egg-white, on the contrary, according
to Meissner, is converted into syntonin in a few minutes, at 40 J C. in simple
acid solution.

The jinili'o*' differs from peptone in being precipitated with arctic acid
and potassium ferroc.yanide in the cold, and redissolved on heating. With
concentrated nitric acid there is also a precipitate, which disappears on
warming and comes bark on cooling. When treated with ammonium
sulphate, it is thrown out like all other proteins, and this is the best
method for separating and estimating the peptone, which remains in .-olntion
and passes through the filter.

The jit'/itnix- which remains after separation of all the other proteins
from the digestive mixture, occurs in comparatively small quantities, showing
that gastric digestion is only partial, and is mainly a preparation of the
alimentary proteins for more complete digestion in the intestine. On add-
ing excess of caustic, soda or potash and a few drops of copper sulphate to the
mixture, it becomes pink (biuret reaction). But proteoses also give the
same reaction. In a faintly acid solution the peptones precipitate with
phosphotungstic and phosphomolybdic acid, which are therefore used for
the isolation of peptone from all the other proteins. It is to be noted that
commercial peptone contains a large amount of proteose and very little true
Peptone.

The proteolytic or peptonising process by which fibrin, egg-
albumin, and the other proteins are transformed into syntouin,
proteose, and peptone has been the subject of numerous and
minute researches, particularly by Kiihne and his school ; these
are to be found in special treatises of chemical physiology. Here
we must confine ourselves to stating that the collective term
2iroteose includes several similar substances, which are dis-
tinguished from one another by various more or less definite
chemical characteristics, and that the end-products or peptones
must also be distinguished according to the nature of the original
protein from which they are derived.

This sequence of the transformations of proteins is not due
to any specific action of the gastric enzyme : it can be obtained
artificially by prolonged boiling with plain water or, better,
dilute mineral acids, or by steam at high pressure, by treat-
ment with strong alkalies, lastly by the putrefactive processes
produced by bacteria. According to Neumeister, however, the
products obtained by these different methods are not identical.

The gastric juice has a solvent action upon all proteins except
certain sclero-proteins. It transforms collagenic substances into
gelatin, which loses its faculty of coagulation, and is converted
into the so-called gelatin-peptone. Mucin, too, is converted into

174 PHYSIOLOGY CHAP.

a carbohydrate substance akin to the peptones. On the other
hand, the gastric juice has no effect on keratin, elastin, and certain
other substances of this group.

The analysis of the percentage composition of proteins, pro-
teoses, and peptones, as performed by Kithne and Chitteuden,
suggests that the proteolytic process effected by the pepsin and
gastric juice consists not so much in a profound alteration of the
structure of the large original protein molecule, as in its sub-
division, accompanied by hydration, i.e. taking up of water. This
theoretical concept explains why many properties are common to
all the chemical aggregates represented by the products of diges-
tion in particular, the great facility with which the peptones
and their ammo -acid derivatives are reconverted into natural
protein in order that the body may utilise them.

Gastric juice acts on the caseinogen of milk and clots it
in virtue of its chymosin or rennin, which (as we saw in the
last chapter) is an enzyme distinct from pepsin. According to
Hauimarsteu's admirable researches, this curdling is a process
quite distinct from the flocky precipitation of caseinogen, which
takes place in the presence of hydrochloric acid, and redissolves
on neutralisation. Chymosiu splits the caseinogen of milk into
two substances a proteose, which remains dissolved in the serum
of milk, and is not precipitated by boiling or the addition of acids,
and the so-called casein or paracasein, which in combination with
the calcium salts of milk forms the true clot or cheese, which is
then digested by the action of the pepsin and hydrochloric acid.

A phenomenon apparently analogous with curdling is that
first described by Danilewsky (1886) of the precipitation of a
clot from a highly concentrated solution of proteoses and peptones
(Witte's peptone) by chymosin, pepsin, and papain, as well as by
extracts of many organs (pancreas, liver, small intestine, etc.). If
the mixture is placed in the thermostat at 35 C., a more or less
abundant precipitate is formed after a certain time, to which
Sawjawlow gave the name of plastein and Kurajew of coagulose,
and as to the nature of which nothing definite is known.

Since the normal stomach (or intestine) never contains a
concentrated solution of proteoses and peptones, Danilewsky's
phenomenon cannot be utilised in the complex study of digestion.

It was believed for a long time that the gastric juice had no
important action on fats, starches, and sugars. According, however,
to Cash (1880) and Ogata (1881), neutral fats can be split up in
a minor degree, with liberation of fatty acids. Volhard (1900-2)
demonstrated a lipolytic ferment in the gastric juice. His pupil,
Stade, not only confirmed the existence of this ferment, but also
showed that it conforms to the Schiitz law.

On the strength of this, Connstein (1904) concluded that the
lipolytic ferment is of great importance in the assimilation of

in DIGESTION IN THE MOUTH AND STOMACH 175

certain fats, particularly where, as in inilk, the fats are emulsified.
This especially affects the new-born, who have no pancreas to
secrete ferments. The fact that after extirpation or destruction
of the pancreas there can still be a certain cleavage and assimila-
tio-u of alimentary fats, finds partial explanation by the presence
of a lipolytic ferment in the gastric juice.

According to Nasse, hydrochloric acid has some solvent
action on starch, transforming it into amidulin or soluble starch,
which is then, according to Briicke, converted into erythrodextrin ;
according to Leube, saccharose and lactose are split into mono-
saccharides.

VI. The influence of the spleen on the digestion effected by
the gastric juice deserves special consideration. This point was
taken up in our laboratory by Tarulli and 1'ascucci (1901), who
repeatedly compared on different dogs the digestive activity of
the gastric juice, before and some days or weeks after the extir-
pation of the spleen, as well as the digestive power of the gastric
juice in splenectoniised animals before and after administration of
a watery infusion of congested spleen, i.e. spleen excised from dogs
in full digestion.

Tarulli and Pascucci collected the gastric juice from a fistula
made in large dogs by Claude Bernard's method. Before feeding
them with the experimental meal (100 grms. cartilage and tendons)
which was to promote the flow of gastric secretion, they were
given a preparatory meal (500 grins, cooked meat, 500 grms.
broth, 200 grms. bread), with the object as far as possible of
exhausting the pepsin accumulated in the gastric glands ; and
after 16 hours the mucous membrane of the stomach was washed
out with an isotouic and slightly warmed solution of sodium
chloride.

For digestion in vitro, a small cube of boiled egg-white
weighing 1 grin, was placed in contact with 10 c.c. pure gastric
juice at a temperature of 39 C. for 24 hours. From the loss of
weight in the egg-albumin, the digestive power of the gastric
juice could be determined with sufficient accuracy.

The results of the experiments performed by this method may
be summarised in the two following propositions :

(a) After extirpation of the spleen the digestive power of the
gastric juice is constantly weakened in a greater or less degree.

(b) The administration by the mouth of an infusion of con-
gested spleen 8 hours before the experimental meal increased the
digestive power again for one, two, or even three days.

In order to form a concrete idea of these effects, three series of
experiments performed on three dogs may be studied in a diagram
(Fig. 58, A B C).

It should be noted that the lowering of the digestive power of
the gastric juice after splenectomy is apparent not merely in the

176

PHYSIOLOGY

CHAP.

lirst days after the operation, but even two to three months after
the removal of the spleen. On the other hand, if splenic extract
from aii insufficiently congested spleen (excised 2-3 hours after
food, or from fasting animals) be administered to the splenectomised
animal by the gastric sound, there is no perceptible increase of
digestive power in the gastric juice : whereas this is constantly

B

s

F 1(: . 5S. Diagram to show digestive power of gastric .juice before and after spleuec.tomy, and

bnfore and after administration of extract of congested spleen. (Tarulli and Pascucci.) The
ordinates express the amount of boiled egg-white digested in cgrms. ; the abscissa lines indicate
the days on which the experiments \ve,re made ; J, indicates the fall of digestive power con-
sequent on ablation of spleen ; ^ shows the rise due to dosage with extract of congested
spleen.

the case when a well-congested spleen (excised 5-6 hours after a
meal) is used for the extract.

These results seem on the whole to agree with the old
hypothesis of Baccelli as regards the influence of the spleen upon
gastric digestion. It is, however, desirable to obtain more
definite knowledge of this influence. From what was said above
(p. 121), it seems that we may logically assume that the spleen
during gastric activity elaborates a pepsinogenic substance which,
when carried into the circulation and absorbed by the gastric glands,
increases the amount of pepsin secreted.

in DIGESTION IN THE MOUTH AND STOMACH 177

VII. When we pass from digestion in vitro to consider the
iii it anil digestion of food in the living stomach, a preliminary
question at once arises, to the effect that it is not possible from
the peptonising power of the stomach, as described above, to arrive
at any conclusion as to the process and the degree of digestion
normally carried on in the stomach. How far do proteins undergo
peptouisation in the stomach before they pass through the pylorus?
Is it only the solid or coagulated proteins that are wholly or
partially peptonised in the stomach, or the natural proteins as
well, which we ingest already dissolved ?

With the object of solving this problem, Jaworski and
Grluzinaki (1885) performed a series of experiments 'in the medical
clinic of Cracow upon healthy individuals and on those who
suffered more or less from digestive trouble, pumping out the
contents of the stomach at different periods after a meal, in order
especially to determine the quantity of pepsin contained, and the
degree of acidity. The gastric contents of a healthy man pumped
out three-quarters of an hour or one hour after the ingestion of
egg-albumin gave no peptone or syntonin reaction. Seven hours
after a meal of beefsteak the gastric contents of a healthy man,
which were very abundant and acid, contained many fragments of
meat, but only traces of peptone, although the nitrate was capable
of digesting bits of coagulated egg-white in the warm chamber, and
then yielded a strong peptone reaction. On the other hand, in a
person suffering i'roni febrile intestinal catarrh, the stomach, half
an hour after the ingestiou of an egg, yielded a highly acid fluid,
which contained fragments of coagulated egg-albumin, and gave a
strong peptone reaction.

From a number of fairly concordant experiments, these authors
concluded that the formation of digestive products in the stomach
is usually very small, and that under normal conditions of gastric
digestion an accumulation of such products was never present.
In pathological conditions, on the other hand, the acidity of the
gastric juice and the amount of digestive products might be very
much increased. They concluded that the egg -albumin intro-
duced passed after a certain time (1 or 1| hours) into the intestine,
almost entirely undigested, and that the more quickly the stomach
was evacuated, the more normal was its function. So that, accord-
ing to Jaworski and Gluzinski, the stomach must be regarded less
as an organ of chemical digestion, than as a receiver providing for
the gradual transit of the food into the intestine where true
digestion takes place. Gastric disturbance is thus the consequence
of abnormally increased digestive chemistry.

This theory, which tends to minimise the digestive importance
of the stomach, appears to us to be exaggerated. These observers
have not reckoned with the probability that the stomach walls are
capable of absorbing peptone as rapidly as it is formed, so that it

VOL. II N

178 PHYSIOLOGY CHAP.

never accumulates in the chyme or pulp of the gastric contents
during digestion. If this accumulation can take place under
pathological conditions, the phenomenon most likely depends on
the reduced absorbing capacity of the epithelium, consequent on
its catarrhal alterations.

Still it is undeniable that the peptonisation of proteins is very
imperfectly accomplished in the stomach, the dissolved protein
passing from the pylorus to the intestine before it has time to
become peptonised. This is evident from the observations made
by Busch (1858) on the famous case of fistula established in the
upper part of the jejunum in a woman of thirty-one. Four hours
after ingestion of raw egg-white, a ropy fluid which was faintly
alkaline, mixed with bile, and free of coagulum, began to flow
from the upper end of the intestine ; on dilution with water and
heating, or treatment with nitric acid, this coagulated in large
flocculi. It follows that a considerable part of the egg-albumin
ingested passes not only the stomach but also the duodenum,
without being attacked by the digestive juices. We shall return
elsewhere to the significance of this fact.

Our knowledge of the changes which natural food-stuffs and
viands, i.e. foods modified by cooking and other manipulations,
undergo in the living stomach, rests more particularly on the
classical work of Frerichs and Schroder, as confirmed by later
observers.

Milk is curdled previous to peptonisation. The caseinogen of
cows' and goats' milk forms a firm clot which is more resistant to
the action of gastric juice than the caseinogen of human milk,
the latter accordingly being the most suited for the alimentation
of infants.

Of muscular flesh, viscera, and membranes of animals the
collagenous substances of the connective tissues are first digested ;
they soften and become transparent and eventually dissolve ; next
follows the digestion of the muscular fibrils, and parenchymatous
cells. The fat which infiltrates the connective tissues, and that
with which many viands are impregnated, resists the digestive
action of the gastric juice, and greatly delays the digestion of the
proteins of which tissue protoplasm is built up. For this reason
pork is more difficult to digest than the lean meat of beef or veal.

Bone, too, is digested by the combined action of the hydro-
chloric acid which attacks the phosphates and carbonates of
calcium, converting them into soluble carbonates and phosphates,
and the pepsin which digests the ossein.

Vegetables and plant tissues in general are more slowly
digested than animal tissues, owing especially to the comparative
resistance to the action of gastric juice of the cellulose and starch
which surround the proteins. Bread, which is the commonest
form of food, is reduced to a soft and partially digested pulp in

in DIGESTION IN THE MOUTH AND STOMACH 179

the mouth, and undergoes few changes in the stomach from the
action of the gastric juice, which is confined to starting peptonisa-
tion in the gluten.

The duration of gastric digestion, i.e. the evacuation by the
stomach of the food, varies with the quantity and quality of the
latter, according to the individual and to the more or less normal
state of the digestive organs. Busch stated that after a copious
meal, the flow from the upper end of the fistula in the woman
above referred to commenced about half an hour after the meal,
and almost or entirely ceased after 3-4 hours.

Many of the sclero-proteius are refractory to the digestive action
of gastric juice : e.g. elastin, chitin, fibroin, chondrin. The nucleins,
too, are entirely exempt from the action of gastric juice, a fact
utilised by Miescher in separating them. Lastly, mucin and the
amyloid substances are also very resistant to the action of enzymes
in general.

The digestibility of the various foods or viands, i.e. the time
required for their digestion and absorption, can only be determined
in the stomach by the very relative criterion of their longer or
shorter retention there. The tables drawn up from the observa-
tions of Beaumont upon the famous Canadian, St. Martin, and his
gastric fistula, have therefore little value. The same may be said
of similar researches more recently made by other workers. Those
of Fermi, however, have a certain value, particularly from the
hygienic standpoint.

It is more important to form an approximate notion of the
time that the foods which consist mainly of the proteins that can
be digested by gastric juice remain in the stomach. In a dog
with a gastric fistula, 100 grins, of boiled egg-white enclosed in a
muslin bag are digested and disappear after 5 hours ; 200 grms.
of boiled and minced meat were not completely digested in the
dog's stomach for over 12 hours (Schmidt - Miihlheim) ; 500
grms. raw minced meat were not all digested after 12 hours
(Barbera). All these facts confirm the statement that the task
of the stomach is confined to merely initiating the digestion of
proteins.

One very important function of the gastric juice is certainly
that of sterilising the food and drink ingested, by killing the
germs of putrefaction and innumerable pathogenic microbes, and
destroying and rendering innocuous the toxines and ptomaines
which are formed as the products of their metabolism, or from the
putrid corruption of the tissues. This sterilising and antiseptic
action, which constitutes one of the great defences of the organism
to many uiorbigenic causes, results from the incapacity of the
gastric juice to putrefy, and its antiseptic properties, discovered
by Spallanzani (1780). He proved in a series of ingenious ex-
periments, which Buuge justly praises as a model owing to the

180 PHYSIOLOGY CHAP.

scientiiic acumen they reveal, that the gastric juice kept for long
periods in closed vessels does not putrefy, although it gradually
loses its antiseptic properties; that fresh meat steeped in gastric
juice keeps for a long time without putrefying ; that putrid
meat wholly or partially loses its had smell in gastric juice, and
that the foetid odour disappears in proportion as it is digested,
when it is forcibly fed to ravens (attached to a thread by which it
can be examined at different intervals) ; lastly, that when en-
closed in finely perforated wooden tubes, and introduced into his
own stomach, " it lost even the slightest trace of putrescence."

Modern workers have shown that the process of putrefaction is
effected by specific bacteria, and that the antiseptic action of the
gastric juice is due to its free hydrochloric acid. In fact Sieber
(1879) found that the amount of H(J1 necessary to retard the
putrefaction of meat is approximately equal to the normal acid
content of the gastric juice, and that a 0'5 per cent solution of
this acid suffices to hinder the development of the saprophytic
bacteria. Miquel (1884) confirmed this observation, and found
that the addition of 0'2-0'3 grrns. HOI to 100 c.c. beef-tea
prevented it from putrefying.

The antiseptic and bactericidal power of the gastric juice, of
course, has its limits. Some bacteria, particularly in the spore
stage, exhibit such resistance to chemical agents that they are
only destroyed by hydrochloric acid at a higher degree of concen-
tration than that of the gastric juice. Falk (1883) found the
latter inadequate to destroy the tubercle bacillus, while it did kill
the anthrax bacillus, leaving the spores intact (Perroncito). Ac-
cording to Nicati and Eietsch, and to Koch (1884), the cholera
bacillus is easily killed by a dilute solution of HC1, so that
introduction of this culture into the stomach of an animal does
not infect it. On the other hand, infection ensues if the culture is
introduced into the small intestine or the stomach, after injection
of a soda solution. According to Fermi (1894), the gastric juice
has no sterilising action on hyphomycetes and blastomycetes.
which therefore develop in it and alter its digestive activity. The
bacteria of lactic and butyric acid fermentation also seem to resist
the gastric juice, since after ingestion of much carbohydrate there
is nearly always a slight fermentation with development of lactic
and butyric acid. With abnormal catarrhal conditions of the
gastric mucosa, the amount of free HC1 in the gastric juice
diminishes in proportion with the increased secretion of the
alkaline mucus. Under these conditions all the bacteria that
excite fermentation, particularly those of lactic, butyric, and also
acetic and alcoholic fermentation, are able to germinate freely in
the stomach. In consequence of this fermentation lactic, butyric,
and acetic acid and alcohol develop at the expense of the carbo-
hydrates ingested. At the same time gases are developed, i.e.

in DIGESTION IX THE MOUTH AND STOMACH 181

carbonic acid, hydrogen, methane or marsh gas, and occasionally
sulphuric acid (Kuhii, Boas, 1892).

VIII. The effects of complete or almost complete resection of
the stomach are highly important from the physiological point
of view, in order to form a clear concept of the significance as
a whole of its digestive and protective functions.

The dog which survived the almost complete extirpation of its
stomach by Czerny and Kaiser, was able 2 months after the
operation to nourish itself on the mixed diet of a normal dog,
without vomiting or other disturbance. Its weight, 5850 grins,
previous to operation, rose in 9 months to 7000 gruis. The
faeces were normal in constitution. When it was killed 6 years
later the post-mortem showed that only a small portion of the
stomach was left near the cardia, which had assumed the form of
a bladder filled with food.

Ludwig and his pupil Ogata employed another method to
suppress the influence of the stomach on the digestion. They
introduced the food directly into the duodenum by a fistula made
near the pylorus, and to prevent the gastric juice from entering
the intestine, closed the pylorus by a small rubber balloon, the
distension of which was regulated by means of water introduced
through the neck of the balloon, which projected from the gastric
fistula. The various foods introduced in large quantities directly
into the duodenum (beaten-up eggs, minced meat) were perfectly
digested without producing any disturbance. Two injections a
day sufficed to keep up the animal's weight. Microscopic examin-
ation of the faeces showed that the connective tissue of raw meat
was not perfectly digested ; boiled flesh was not digested, and was
excreted by the rectum after a few hours, little or not at all
modified. Raw pork was hardly digested at all, cooked pork was
to a much larger extent. These authors concluded that the
stomach was not absolutely necessary to the nutrition of the body,
either as a reservoir of food or in the formation of gastric juice.

In 1893 Carvallo and Pachon successfully repeated the
almost total extirpation of the stomach on a dog ; in the first
20 days after the operation, the animal only tolerated milk,
which w r as imperfectly digested. Two months later it was still
unable to digest the connective tissue of meat. Three months or

O

more from the operation, it was estimated from the nitrogen
content of the food and the faeces, that the digestion of cooked
foods had become almost normal, while that of raw foods was
still imperfect. Five months after, the animal was made to eat
putrid meat without any ill effects, a fact which does not minimise
the antiseptic importance of the gastric juice, because after such a
long period some functional adaptation might ha.ve occurred in
the animal to compensate for the lapsed antiseptic function of
the stomach.

182 PHYSIOLOGY CHAI-.

De Filippi iii anotlier dog, on which Monari (1893) had
performed almost total gastrotomy, repeated the results of
Carvallo aud Pachou. The latter (1894) also succeeded in keep-
ing a cat of 2 kilos, alive after total excision of the stomach.
After 25 days the animal weighed 420 grins, less. The milk
administered was not well digested, and clots of it, were seen in
the faeces.

Among the cases of gastrotomy performed on man was one
recorded by Schuchardt, at Stettin. In 1895 he excised the
stomach of a patient to a somewhat smaller extent than in
Czerny's dog, and the man lived two and a half years in good
condition. At first he was only able to take small quantities
of food at each meal, but eventually he fed like a normal in-
dividual. At the post-mortem a small stomach (formed from a
portion of the cardia that had been left) was found which had
gradually acquired a capacity of 500 c.c.

The case of the Zurich surgeon Schlatter was more remarkable.
In 1897 he excised the whole stomach from a woman of fifty-six
in whom it had formed into a hard tumour. Being unable to
suture the cardia to the duodenum, he turned the latter into a
blind sac, and bound the cardia with a loop of the small intestine.
The patient survived this amazing operation, and increased in
weight. During the first 8 weeks the food had to be given
in very small quantities, and always in a liquid or finely
minced form.

A month after the operation, Wroblewski examined the
urine and faeces of this patient. For 13 days he found iudole
in the urine to an amount in excess of the normal, and for 3 days
in normal quantity ; the scatole was also rather in excess of
the normal.

Four months after the operation, Hoffmann made further
investigations on the same case and estimated the nitrogen intro-
duced with the food and eliminated with the faeces and urine.
He found that the proteins were digested and absorbed in a
ratio approximating to the normal. The same was found of
the fats.

Five months after the operation, as an index of the putrid
processes in the intestine, he determined the amount and ratio of
the inorganic sulphuric acid and the ethereal sulphuric acid in
the urine. He concluded that, after 5 months, putrefaction was
not in excess of the normal. Seven months after the operation
the patient had put on about 6 kilos, weight.

In November 1898, Tricomi succeeded in operating on another
woman of forty -eight with complete success. This patient
suffered from diffuse cancer, like Schlatter's case, and here the
very small portion of the cardia that had remained healthy was
utilised for the suture, so that this may be regarded as an almost

nr DIGESTION IN THE MOUTH AND STOMACH 183

total gastrotomy. On suturing the duodenum into a blind sac,
the continuity of the digestive canal was re-established by uniting
the cardia with the duodenum.

Some time after the operation, Deganello performed an in-
teresting series of experiments on this patient with the object of
determining (a) the digestion, assimilation, and consumption of
proteins, which he calculated from the amount of nitrogen intro-
duced and excreted by the faeces and urine ; (6) the intensity of
the putrefactive processes in the intestine, calculating from the
ratio between the inorganic and the conjugated sulphuric acid, and
the amount of aromatic substances in the urine, more particularly
of the phenol, indigo blue, and indigo red.

The most interesting of his results may be summarised as
follows :

(a) Forty days after the operation (first period in Deganello's
experiments) the digestion and assimilation of nitrogenous sub-
stances were not normal. The faeces, under the microscope, showed
almost intact muscle fibres ; and of the ingested nitrogen 1S'22 per
cent was eliminated with the faeces, the physiological average of
excreted nitrogen not exceeding 6-11 per cent.

(fi) At this time the faeces also gave indications of very
intense putrefaction, as shown not merely by their foetid odour,
but also by the marked reaction of indigo blue and red, and by
the ratio between the ethereal and the inorganic sulphuric acid of
the urine, which had altered from 1 :4'5 to 1 : T72.

(y) Three mouths after the operation (second experimental
period) the digestion and assimilation of proteins had considerably
improved, the nitrogen excreted in the faeces having come down
to 12'92 per cent of the nitrogen ingested. This agrees perfectly
with the data of Carvallo and Pachon, De Filippi, and Hoffmann,
who made their observations some time after the operation and
found that nitrogen assimilation was almost normal.

(8) In this second period the ratio between the ethereal and
inorganic sulphuric acid varied between 1 : 84 and 1 : 5'6, showing
a marked diminution of the putrefactive processes in the intestine
as compared with the first period. This result agreed with that
obtained by Hoffmann, who investigated Schlatter's patient 5
months after the operation, and found the ratio almost normal.

From these complex results we may conclude that the
stomach is not absolutely indispensable to life. After its total
resection the digestion and assimilation of proteins diminish in a
first period, while the putrefactive processes of the intestine are
much increased. In a second period all these processes are
improved and gradually approximate to the normal, by a process
of compensation as to the nature of which we are ignorant. At
the end of February 1900 (i.e. more than 2 years after the
operation) this patient was reported by the surgeon to be well, and

IS- 1

PHYSIOLOGY

CHAP.

ill iln to take nourishment of all kinds in frequent, though not
abundant meals.

I X. While the stomach is, in virtue of its glands, a digesting
organ, it is from its muscular coats an organ of special movements,
which serve in the first place to churn up the iugesta and bring
them into contact with the gastric juice, and in the second place,
to propel the semi-digested chyme onwards into the duodenum.

Beneath the external serous coat the stomach has three
layers of plain muscul ir tissue. These are (from the direction of
their fibres) the longitudinal (outer), the circular (middle), and
the oblique (inner). The longitudinal fibres are directly con-
tinuous with those of the oesophagus ; they radiate from the

FIG. 59. A, section through pyloric part of stomach and commencement of duodenum, from
specimen hardened in situ. (J. Symington.) a, a, a, longitudinal folds of mucous membrane in
pyloric part (if stomach; 1>, section of mucous membrane; e, circular muscular liluvs of
stomach ; the longitudinal fibres are just visible to the naked eye as a narrow line internal to
the circular fibres ; D, duodenum ; P, pyloric orifice. B, diagrammatic view in perspective of
portion of coats of stomach and duodenum, including pylorus. (Allen Thomson.) g, inner
surface of gastric mucous membrane; </', section of mucous membrane with pyloric gastric
glands ; v, villmis surface of mucous membrane of duodenum ; i, section of same with crypts
of Lieberkiihn ; p, p, ridge of pyloric ring, \\ith section of its component parts ; mi, circular
layer of muscular fibres, seen in the section to form pyloric sphincter; me, longitudinal
layer of muscular fibres ; i, serous covering.

cardiac orifice, are more abundant along the curvatures, and thinly
scattered over the remaining surface of the stomach as far as the
pylorus, where they form a thick uniform layer, which passes over
the pylorus and becomes continuous with the longitudinal fibres
of the duodenum. The circular fibres form a close and complete
layer over the whole of the stomach. At the pyloric end they
become much thicker, and at the pylorus itself they form a
bundle within a circular fold of the mucous membrane, known as
the pyloric sphincter. Lastly, the oblique fibres are continuous
with the circular fibres of the gullet on the left of the cardiac-
orifice, where they form a considerable stratum ; from this point
they descend obliquely, and spread out in different directions
upon the anterior and posterior surfaces of the stomach ; they
disappear at the pyloric antrum, mingling \\ith the circular fibres
which predominate there (Fig. 59).

In proportion as the stomach fills with food, it dilates, and

in DIGESTION IN THE MOUTH AND STOMACH 185

changes its form and position ; the lower, great curvature moves
forward, and the upper, small curvature turns backward. This is
effected, when the walls become distended, by a passive rotation of
the stomach round its axis, which passes through the fixed points
represented by the cardia and the pylorus.

As the stomach fills with food, a series of active movements are
set up which proceed from the cardia along the body of the
stomach, and terminate at the pyloric orifice. They are peristaltic
in character, the mass of ingesta being churned up, and driven
towards the pyloric antrum and back along the lower curvature,
so that the upper portion of the gastric contents is continually
forced down below. These peristaltic movements are sometimes
accompanied by antiperistaltic contractions, which originate in the
pylorus, and proceed towards the cardia, but usually stop about
half-way down the stomach. The double movement helps to
mix up the mass of ingesta, and to saturate it with the gastric
juice. At the beginning of digestion the contractions are weak
and irregular ; afterwards they become more active, to decrease and
die away when the formation of chyme is completed.

The evacuation of the stomach during digestion is commonly
supposed to be effected by a rhythmical closing and opening of the
pyloric sphincter.

These data are mainly due to the observations of Wepfer,
Schwartz, Haller, Spallauzani, Magendie, Beaumont. Wepfer
(1679) was the first to describe active peristaltic and anti-
peristaltic movements of the stomach ; Magendie (1838) first
noted a constriction of the stomach due to the muscles of the
pyloric antrum ; Beaumont (1834) first observed most of the
phenomena enumerated in man. Ponsgeu (1882) published a
monograph on the motor functions of the stomach, which reviews
the entire literature of the subject, and cites over 500 authors.

Morat (1882) used a gastric sound attached to a large rubber
balloon with thin walls, which could be inflated with air, the
other end of the sound being connected with a tambour. With
this he recorded three kinds of abdominal movements on man and
dogs respiratory (predominating), cardiac, and gastric ; but this
method obviously tells nothing as to the form and localisation of
the peristaltic movements.

Pfungen (1887), by the manometric method, succeeded in
counting on an average three contractions of the antrum per
minute, each lasting 6-12 sees. He noted, in confirmation of an
observation by Hofmeister and Schiitz, that solid bodies introduced
into the antrum were driven back towards the fundus of the
stomach by an antiperistaltic movement.

Moritz (1895), with an elastic balloon of medium size attached
to the end of a flexible sound passed through the oesophagus,
registered the variations of gastric pressure, and recorded the

186 PHYSIOLOGY CHAP.

movements exactly. According to his observations the fundus
and the pyloric antrum must be distinguished : the former has
mainly a digestive, the latter a motor function, as exhibited in
rhythmical contractions varying in number from 2-6 per minute.
Since the antrum fills in consequence of slight peristaltic waves
in the fundus, which are set up under very low pressure (2-6 cm.
water), the passage of the solid constituents of the gastric contents
into the duodenum is prevented. But the balloon which Moritz
introduced into the fundus is unable to transmit the peristaltic
movements as they succeed each other in the individual segments,
and minimises or cancels their effect on intra-gastric pressure. On
the other hand (given the relatively small size of the pyloric
antrum, and the almost synchronous systolic or diastolic move-
ments of its walls), it is obvious
that the elastic balloon can re-
cord considerable rhythmical
variations of pressure, up to a
maximum of 50 cm. of water.

Ducceschi (1897) took up
this interesting question again
in Fano's laboratory, and pub-
lished an accurate account of
the excellent results he obtained,
which covered many lacunae and
conduced to a clear and satis-

FIQ. 00. Oscillations of tonus in cardiac part 01 factory tllCOlT of the active

stomach,! obtained with a sound introduced / ,. , i

into do- by gastric fistula. (Ducceschi.) The movements OI the Stomach in

lower tracing represents the respiratory move- , > -_<._

ments recorded by a Marey's pneumograph. reiaUOU LO gaSb llge..

His experiments were carried

out on four large hounds previously provided with a gastric fistula.
This operation abolished the negative pressure which distends the
stomach ; its walls therefore tend to adhere, and a small balloon,
4-5 cm. in diameter, inserted between the two surfaces of the
abdominal walls, transmits the movements of the part of the
stomach in which it is placed to a tambour with tolerable
accuracy.

The animal is made to lie quietly on its side on a table (at
least 6 hours after a meal) and the cannula placed in the fistula
is opened ; through this the sound fitted with the balloon is
introduced into the part of the stomach to be explored. Next the
balloon and sound are emptied of air by aspiration, and filled with
water, and then connected with a vertical glass cylinder, closed
above by a cork provided with two glass tubes, one long and
dipping into the water, the other short and communicating with
the column of air above the water. On joining the latter to a
Marey's tambour, the gastric curves are directly recorded, the
respiratory curves often being registered as well by a second

in DIGESTION IN THE MOUTH AND STOMACH 187

tambour connected with a pneumograph. The distension of the
exploring balloon is regulated by raising or lowering the cylinder
which is fixed in a holder.

PIG. gi. Oscillations of tone in cardiac stomach, complicated by more rapid contractions and

passive respiratory movements, recorded from dog, as in Fig. (JO. (Ducceschi.) Time tracing
marks intervals of 5 sec.

When the sound is passed into the cardiac, fundic, or middle
region of the stomach in a state of comparative rest, slow, irregular
contractions, slight in degree, are observed, which are probably
automatic oscillations of tonicity in the
gastric muscles (Fig. 60). In a period of
greater motor activity, other more rapid,
simple contractions appear along the line
of this slow primary wave, which are com-
parable with those that commonly appear
in plain muscle (Fig. 61). These oscilla-
tions of tonus and contractions vary con-
siderably in duration and intensity ; they
are never regular and rhythmic. The
primary waves on an average last 50-60
sees., the secondary 15-30 sees.

If the glass cylinder be somewhat
raised so as to increase the swelling of the
balloon, and with it the distension of the
gastric walls, another form of movement
appears with a highly characteristic curve.

This is very probably an expression of the FIG 62- _ Tracingg of peristaltic
peristaltic movement propagated through
the stomach from cardia to pylorus. A
schema of this movement is shown in
Fig. 62. More frequently, however, the
tracing of this wave is less simple, and is interrupted by slight
notches due to the respiratory movements ; the siiccession of these
is very irregular, and abortive forms and a variety of combina-
tions with the oscillations of tonicity already referred to are not

movements obtained under
same conditions as Fig. 60,
with sound introduced into
cardia and fundus of stomach.
(Ducceschi.)

188 PHYSIOLOGY CHAP.

infrequent. These waves have a period of 35-55 sees. ; their
amplitude usually exceeds the excursion of the writing lever.

When the sound is introduced into the pyloric antrum, a very
distinct form of rhythmical movement appears, consisting of
systoles and diastoles in regular succession, which are determined
by the total contraction or relaxation of the muscles of the antrum
(Fig. 63). Each revolution takes 10-30 sees., i.e. a shorter period
than each peristaltic wave. No other form of contraction due to
the tonic state of the walls is ever seen in the antrum, probably
because the circular fibres predominate so largely.

The study of the conditions which produce these movements
of the stomach and their co-ordination with the several phases
of gastric digestion was very incomplete prior to Ducceschi's
observations.

B

FIG. 63. Rhythmical systolic and diastolic movements obtained with introduction of sound into
pyloric antrum. (Ducceschi.) A, the lower tracing represents the respiratory rhythm.
B, time tracing marks 10 sec.

According to some authors, the gastric movements after a meal
begin after a brief period of tonic contraction, i.e. shortly after the
ingestion of foods (Eberle, Blondlot, Briuton, Beaumont, Busch,
Kussmaul). According to others, on the contrary, the meal is
followed by a period of tonic contraction lasting about an hour,
after which the movements set in with increasing intensity,
reaching their maximum after 3-4 hours (Magendie, Adelon,
Schiff, Leveu). All, however, agree that liquid foods pass rapidly
through the pylorus into the duodenum a few minutes after
ingestiou. The best observations have been made on man, or on
dogs with a duodenal fistula (Busch, Kiihne, Hirsch, v. Mering,
Moritz), which show that the contents of the stomach, particularly
the liquid parts, are spurted into the duodenum a few moments
after the meal.

Leven (1902) specially investigated the time during which
fluids remain in the stomach. A measured quantity of water was
administered to dogs that had fasted for 24 hours ; they were

in DIGESTION IN THE MOUTH AND STOMACH 189

then killed at different periods, and the quantity of water left in
the stomach was measured. In the first 12 minutes nothing was
absorbed or expelled by the pylorus ; after 15 minutes evacuation
commenced and was completed after 30 minutes.

In children the water in the stomach can easily be detected
radioscopically. The rapidity of expulsion varies very much ; in
some children it begins at once, in others after 13 minutes. In
some the horizontal level of the fluid sinks gradually, no waves of
muscular contraction being perceptible; 100-125 c.c. of water
required 8-13 minutes for evacuation ; 250 c.c. 19 minutes ; warm
water disappears faster than cold ; the presence of solids in the
stomach delays evacuation to a remarkable extent. In another
group of children muscular contraction obviously co-operates.
The time required by the stomach for evacuation varies consider-
ably, according to the nature and quantity of the food. Nearly every
one, however, agrees that after 5-7 hours the stomach is usually
almost empty, unless there has been an excessively abundant meal,
us we saw in discussing gastric digestion.

By some the distension of the stomach walls by the presence
of food is held to be a mechanical stimulus to the excitation of
gastric movements. Spallanzani first pointed this out in birds.
A guinea-fowl that had fasted for a day was made to swallow
hazel-nuts, and its stomach watched through an aperture made in
the abdomen. " As long as the stomach contained only a few
nuts, no movement was visible, but as it became filled I saw it
swell out, and suddenly get flat again," i.e. it exhibited systoles
and diastoles similar to those observed in the dog's pyloric
autrurn.

Schiitz observed regular peristaltic movements in a dog's
stomach, isolated from the body, after insufflations of air through
a cannula tied in the oesophagus. This is a reflex phenomenon,
discharged by the mechanical stimulus, and effected by the ganglion
plexus situated in the stomach.

Many authors have verified Magendie's discovery that a solid
body introduced into the pyloric antrum is at once shot out, and
tails into the fuudus. This proves the excitability of the stomach
to mechanical stimuli, under conditions not far removed from the
physiological.

Some interesting details can be deduced from the work of
Ducceschi. Twenty-four hours after a meal the stomach is
immobile, its movements commencing immediately after food.
Introduction of an exploring balloon into the empty stomach,
however, at once excites the movements. In proportion as the
distension of the balloon increases by the introduction of a
constantly increasing amount of water, the gastric movements
become more ample while their rhythm is approximately constant.
There is, however, a limit to the distension of the stomach,

190

PHYSIOLOGY

CHAP.

after which its movements diminish, and are finally abolished
(Fig. 64).

Fio. 64. Tracings of pyloric rhythm and its variations under the influence of progressive incre-
ments of pressure. (Ducceschi.) At 1, the exploring balloon exerted very weak pressure on
the walls of the antrum ; at 2, the pressure was increased by addition of 50 c.c. water ; at 3,
4, 5, 6, 7, respectively, 50 c.c. water were added, by which the balloon became more and more
distended.

On exciting the stomach by a sound with a rough surface,
peristaltic movements are set up in the cardiac portion and fundus ;
in the region of the pyloric antrum, on the contrary, the rhythm

in DIGESTION IN THE MOUTH AND STOMACH 191

becomes disorganised, antiperistaltic waves occur, or there is
tetanic contraction of the walls (Figs. 65 and 66).

'\f\J\

FIG. 65. (Left.) Tracing 01 pyloric rhythm and its modifications under rapid mechanical
excitation. (Ducceschi.) At A, the experimenter jerked the sound. Time tracing marks each
5 sec.

FIG. 66. (Right.) Tracing from fundus of stomach. (Ducceschi.) At A, a marked increase of
movement was obtained by rapidly shifting the sound.

As regards the chemical stimuli that excite movements in the
stomach, Briicke ascribes great importance to the acid content of
the gastric juice, and proves that the movements are more or less
energetic in proportion with
the digestive work. Accord-
ing to Schiff, on the other
hand, chemical stimulation
of the stomach is more par-
ticularly due to copious
absorption of the digestive
product (peptone), which is
supported by the fact that
towards the end of digestion
there is constant reinforce-
ment of the movements of
the stomach.

Ducceschi, to test these
views experimentally, intro-
duced 30-50 c.c. of 015 per
cent HC1 in the vicinity of
the exploring balloon, and found that in the region of the cardia
and fundus, particularly in the former, movements were clearly
excited, so much so as to produce typical peristaltic waves
(Fig. 67). In the region of the antruin, on the contrary, he
obtained quite different results; a 01 per cent solution of acid

FIG. 67. Tracing from cardiac stomach in which
peristaltic movements were excited by introduc-
tion of HC1 solution. (Ducceschi.) At 0, 40 c.c.
of 0"25 per cent HC1 were injected near the ex-
ploring balloon.

192 PHYSIOLOGY CHAP.

produced a delay in the systolic and diastolic rhythm ; stronger
solutions disorganised its course, and weakened its intensity;
stronger solutions still were able to arrest it, or to incite anti-
peristaltic movements (Fig. 68).

On injecting solutions of peptone (1-2 per cent), Ducceschi
obtained increased tonicity of the gastric walls, and reinforcement
of the movements proper to the several regions of the stomach.

These and other effects of thermal and electrical stimuli on
the different parts of the stomach, led Ducceschi to conclude that
the excitability of the ueuro-niuscular apparatus of the stomach
did not merely vary quantitatively, but was also qualitatively

p IG 68 Tracin" of rhythm in pyloric antrum, profoundly altered by PxiMtation due to introduc-
"ti.m of HC1 solution. (Ducceschi.) At 11, 40 c.c. 0.4 per cent HC1 were injected near the
exploring balloon.

different and almost antagonistic in the region of the pyloric
antruui, as compared with other regions of the stomach.

This important conclusion agrees perfectly with the results
arrived at by Openchowski and his school (1889) in their valuable
work on the innervation of the stomach, to which we shall refer

below.

Ducceschi reconstructs the motor functions of the stomach, in
co-ordination with its digestive processes, as follows : The descent
of the food into the stomach produces distension of its muscular
coats, which determines the peristaltic movements in the region
of the cardia, fuudus, and body of the stomach, while the secretion
of the gastric juices occurs at the same time with an increasing
deoree of acidity. This factor again reinforces the movements,
and in proportion as the digestive process advances, the tonic and
partially motor action of the peptone is added to the motor action

in DIGESTION IN THE MOUTH AND STOMACH 193

of the hydrochloric acid. This explains how the movements arise
and are kept up in the greater part of the stomach.

The rhythmical movements of the pyloric antrum follow a
different course, in consequence of the same mechanical and
chemical stimuli. The food which fills and distends this region
suppresses the rhythmical movements by the acidity of the juice
with which it is saturated and the solid particles which it contains,
obstructs the pyloric orifice, and produces antiperistaltic waves,
which carry the food back towards the middle and fundus of the
stomach. The pyloric antrum thus contributes to the churning up
and mixing of the ingesta, which is a necessary condition in order
that they may be saturated with the secretion, and digested.

At a certain stage in digestion the motor processes of the
stomach undergo an important modification. The solid con-
stituents of the food-stuffs are almost entirely dissolved, or at any
rate the mechanical effects of contact are much diminished, and
the acidity of the chyme reduced, on which the antiperistaltic
motions of the antrum subside, and it resumes the rhythmic
(systolic and diastolic) movements proper to it, while the tonic
spasm of the sphincters or pyloric valve ceases. Then at each
revolution of the antrum there is a little spurt of chyme into the
duodenum, synchronous with the opening diastole of the pyloric
orifice, as has often been observed directly in duodenal fistulae.

There is thus, according to Ducceschi, a complete correspondence
between the chemical and dynamical functions of the stomach,
which justifies the assumption that (like the adult heart, according
to Kronecker) it possesses a nervous, self -steering, regulating
apparatus, for its functions as a whole (infra).

Moritz (1901) has recently investigated the influence of the
nature of the food-stuffs on the rate of gastric evacuation in dogs
with duodenal fistulae and in man. The experiments on man
(principally on Moritz himself) were conducted as follows : Some
time after a test meal of known quantity and quality, a measured
amount of a known solution of some chemical product which can
be readily estimated and is not normally present in the ingesta,
was introduced into the stomach by the sound. After thoroughly
mixing the liquid with the gastric contents, by introducing air
into the stomach and violently shaking the body, a portion of the
mixture was drawn out again by the sound. From the lowered
concentration of the test substance (usually glucose), it was easy
to determine the quantity left behind in the stomach. Moritz
found that the mechanical consistency of the food was an essential
factor in the evacuation of the stomach. The gastric contents are
not passed on into the intestine in the form of solid pieces, nor
exclusively in the fluid state, but largely in the form of pulp.
Fluid foods (broth) are, however, more rapidly evacuated than
thick soups or sops.

VOL. II

194 PHYSIOLOGY CHAP.

The consistency of the food is not, of course, the sole factor that
determines the rate of gastric evacuation. If this were so, all
mobile fluids would leave the stomach with the same rapidity,
which is not the case. On introducing half a litre of water,
60 per cent is eliminated in 15 minutes, while if the same
quantity of heer is introduced, only 11 per cent is excreted.
Milk, soup, sops, again, stay longer in the stomach than would
be expected, judging merely from their consistency. Moritz
interprets this fact as meaning that all these substances (unlike
water, which is an indifferent substance) function as stronger
chemical, and partly also as mechanical stimuli, as shown also by
a greater secretion of acid. On the strength of this fact, Moritz
holds soups to be a food, particularly adapted to prepare the
stomach for the introduction of more solid viands.

The application of radioscopy (by admixture of bismuth sub-
nitrate with the food) to the study of the movements of the stomach
in digestion, has led to a distinct advance in methods and compara-
tive results. The most interesting researches in this direction are
those of Cannon (1898), and Roux and Balthazard (1907), both
with the usual animals experimented on and with man.

According to these authors the stomach may functionally be
divided into two portions, the fundus (or cardia) and the pylorus.
The latter is mechanically the most active part of this organ, and
exhibits, radioscopically, ample peristaltic movements throughout
the whole period of digestion.

The cardiac region only shows rare waves of contraction which
propel the food-stuffs towards the fundus. In the fundic part the
chyme travels very slowly in the direction of the pyloric antruni.
The movements of the pyloric antrum are set up in the part
nearest the fundus (pre-antral constrictions), and are mainly
effected by the circular fibres ; the antrum contracts vigorously
and assumes the form of a tube. The (peristaltic) contraction
waves are separated, both in animals and in man, by an interval
of 10-20 sees. The pyloric orifice rarely opens in the first period of
digestion, while towards the close it relaxes in response to each
contraction of the antrum.

The chyme is almost stationary in the fundus : it passes slowly
into the pyloric antrum where the food is thoroughly mixed with
the digestive juices and dissolves, owing to the vigorous move-
ments in this region. The alimentary mass, while continually
passing from fundus to antrum, perpetually flows back (especially
in the first periods of digestion) from antrum to fundus owing to
the increased pressure, which gives rise to the peristaltic waves in
the antrum when the pylorus remains closed. The chyme passes
more quickly and in larger quantities into the intestine, in
proportion as it is softer and more liquid in consistency. The
pyloric orifice opposes the passage of solid foods. On mixing

111 DIGESTION IN THE MOUTH AND STOMACH 195

some hard boluses of bismuth subnitrnte with the soft foods, the
pyloric sphincter is seen, radioscopically, to close sharply on the
arrival of the bolus.

These results are particularly important because they confirm
to a great extent for uninjured man or animals, the observations
made by means of fistulae, or other methods, in which the normal
conditions of gastric digestion have been more or less modified.

X. Since it is one of the most important modifications of the
ordinary motor processes in the 'stomach, special attention must be
given to vomiting. In the majority of cases it is a pathological
phenomenon, but is under certain conditions a true physiological
act, by which the body relieves the stomach of excessive work, and
eliminates noxious substances ingested or developed in situ by
abnormal processes of fermentation. Vomiting is excited either
by excessive distension of the stomach, or by the acrid substances
developed in abnormal digestive processes, or by the action of the
so-called emetics which are particularly adapted to excite the
nervous mechanisms that give rise to vomiting.

The fundamental question in regard to the mechanism of
vomiting is to decide what part the stomach plays by its con-
tractions, and what is due to abdominal compression, which
consists in the synchronous contraction of the abdominal and
diaphragmatic muscles.

The older physicians held vomiting to be purely an effect of
the antiperistaltic movements of the stomach, with simultaneous
closure of the pylorus and dilatation of the cardia. Bayle and
Chirac, and after them Magendie, sustained the opposite opinion,
viz. that the stomach was passive in vomiting, and that the
process rests upon the violent impulse of abdominal com-
pression.

Schwartz demonstrated that the stomach, when exposed and
freed from the pressure of the abdominal muscles and diaphragm,
was no longer capable of emptying