The Internal Secretions and the Principles of Medicine

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THE INNERITATIDN DF THE jFLERENAL SYSTEM,

[Sajous.]

Thyroid a, Pituitary 'hady containing adreno-thyrold canter, gland, supplied by nerves e, f, derived frcm the pituitary, c, Adrenal nerves h derived ircni pituitary body via the medulla, cervical cord d,

splne-sympathetio branches and splanchnic

g, g, S.

The Internal Secretions and the

Principles of Medicine BY

CHARLES

E.

de M. SAJOUS, M.D., LL.D.

TIIK COIaLEGK OF PHYSICIANS AND OF THE AMERICAN PHILOSOPHICAL. Society; Professor of Therapeutics in the Temple University OF Philadelphia Formerly Professor in the MedicoChirurgical College and Clinical Lecturer in Jefferson Medical College, etc.

FkLLOW of

;

VOLUME

FIRST

WITH FORTY-FIVE ILLUSTRATIONS

FIFTH

EDITION

PHILADELPHIA F. A.

DAVIS COMPANY, 1912

Publishers

E

COPYRIGHT. 1903 COPYRIGHT. September. 1908 COPYRIGHT. September. 1909 COPYRIGHT. July, 1911 COPYRIGHT. April. 1912 BY A.

F.

[Reei«ered

DAVIS

COMPANY

at Stationera’ Hall.

London. En*.]

Philadelphia. Pa.. U. S. A.

Preaa of

F.

A.

Davis

Company

WELLCOME INSTITU UBRARY

1914-16 Cherry Street

Coll

Col.

No.

s

WelMOmec

1

DEDICATED TO THE MEMORY OF

BROWN-SEQUARD

^^lIEN the

first

edition of this

work appeared (1903), the

author hardly expected that Ids views, submitted only with tlie intention of opening new fields of investigation, would, within comparatively few years, be granted an enviable position in the He can only ascribe the large patronage that practical field. the work has received from the general j^rofession to the admittedly better results obtained in practice by the adoption of the

newer principles

has introduced.

it

Besides taking into account

—

—

important organs the ductless glands in every morbid process treated, the author has tried to emphasize the value of close analysis in the treatment of disease and to

the

functions

of

which attends the present unquestionably because such an effort

cultivate a distaste for the empiricism

use of remedies.

It is

meets a corresponding desire in the profession at large that so encouraging a response has been vouchsafed.

compared to former the scope of the work in the practical field. About 400

The fourth editions,

pages of the

edition extended greatly, as

first

volume, devoted heretofore to a study of the

functions of the adrenals

and

tliyroid,

were deemed no longer

necessary to introduce the author’s views, and were replaced by

number

which questions of paramount importance to the practitioner were considered. The fifth served mainly to bring the various subjects to date, and to amplify some of them the chapter on Organotherapy for a corresponding

of pages in

—

example. 'Pile first

two chapters are devoted to the connection of the

adrenals with the lethal trend of tions.

It

is

many

infections and intoxica-

shown therein that many diseases prove

fatal

through

the fact that inhibition or destruction of the functions of the

adrenals as a cause of death diseases

include

at present overlooked.

is

As the

which unquestionably implicate so seriously these organs praetically

all

febrile

intoxications

and

infections,

especially those of childhood, the

whole can hardly be sufficiently

importance of the subject as a emphasized. (v)

*

PREFACE TO THE FOURTH AND FIFTH EDITIONS.

VI

'I’lio

m*.\t

lliive

clia])tc‘is,

matter, cover a similar

also

eoinposetl

field, in so far as

entirely

of

new

the thyroid and jiara-

thyroids are concerned, besides analyzing from a

new standpoint

the diseases due to these organs: myxeedeina, cretinism, infanti-

These prominent syndromes are rarely met with, howas compared with the less clearly identified manifestations

lism, etc. ever,

of thyroparathyroid insufficiency, treated in the present work under the caption of liypothyroidia. Many disorders grouped under the terms “rheumatism,” “neurasthenia,” “autointo.xications,” “gout,” which thwart the physieians’ efforts, are but

manifestations of this condition.

This applies also

to a large

proportion of mentally defeetive, obese, and imperfectly developed subjeets,

all

of

whom,

particularly

benefited M-hcn their true condition

is

children,

may

be greatly

recognized.

The twelfth chapter has been devoted to organotherapy. The author is not of the opinion that “internal secretions” are as numerous in the body as is generally believed ; an effort is made, therefore, to identify those which merit this designation, and also the active factor in each of the organic products that have been found of value in various diseases. This also has for its

purpose to counteract, as

much

as possible, the prevailing

empirical use of these agents, several of which, intelligently emploj-ed, are of great therapeutic efficiency.

The balance

,

of the

work has been carefully

revised,

and

where needed, as in the eleventh chapter, considerably amplified. This applies also to the second volume, but only in so far as needed corrections were concerned. The author may add that he has also received encouragement from the fact that his views are steadily gaining ground, even in the experimental

field, as will

be seen by a perusal of

the work. C. E.

2043 Wal.vut Streett, PlIILADEI.PHIA. Fourth Edition, July

1,

1911.

Fifth Edition, April

1,

1912.

DE M. Sajous.

PHEFACE TO THE SECOND AND

TIIJ

UD EDITIONS.

(Containing a snminary of the author’s newer conceptions up to 1907.)

volume was delivered to the publishers in 1902, the second volume was only finished As the latter embodied researches carried on during in 190'i'. the interval of five years between the two volumes, it became

While

manuscrijit for the

first

necessary to correct what errors the

first

tlie

contained in the light

This feature, coupled with the large patron-

of these researches.

age the medical profession has granted the work, has imposed That very few corrections have the need af new editions.

proven necessary, either by reason of these investigations or of wliat justified criticisms the work has received, is shown by the list

(see page

of additions to our loiowledge

x

et

of this

seq.

The second volume may thus be

said

only to amplify the newer functions I pointed out in the

first

preface)

it

introduces.

volume in 1902 and

The

the publication of a

a prominent ican

to illustrate their

importance in practice.

present status of Medicine precludes any apology for

member

]\fedical

work such

as this.

of the Council of

Association,

wrote,

as a science;

At present it

it

of the

Amer-

“A (1908) promising to develop

only recently

generation ago therapeutics was an art, into a science.

Professor Sollmann,

Pharmacy

:

cannot be classed as an

can only be classed as a confusion.”

Osier’s public declaration^ that of the action of

art,

nor

Indeed,

drugs “we knew

though we “put them into bodies the action of which we know less,” sustained by Llewellys F. Barker’s estimate publittle”

lished about the logical action

same time,- “that drugs

of

unhnoivn physio-

cannot conscientiously be set to act upon bodily

tissue in disease in

which we are ignorant of deviations from

the nornialf’ involves the conclusion that our ignorance applies to disease as well as to therapeutics

—

in a word, to all that which endows us with the right to accept, with any degree of selfrespect, the confidence which suffering humanity places in us. It is not

my

purpose to take issue with these frank ex-

Osier: N. Y. Sun. Jan. 27, 1901. -Llewellys F. Barker: Bull. Johns Hopkins Hosp., July-Aug.,

1

1900.

(vii)

Vlll

I’UEFACE TO THE SECOND AND THIRD EDITIONS.

2)i'6Ssions

of o|)iiuoii.

Iii

were

fact,

I

do

to

so,

would con-

I

ceal similar coneliisions reached nearly

twenty years ago, when, as editor of the “Annual of the Universal ^ledical Sciences,” it

became

many

my

lot

associates,

to

with the valued collaboration of

collate,

the multitude of

data,

and experi-

clinical

which were accumulating from year to year. Nor do they conflict with the prevailing estimate of the therapeu-

mental,

]\Iedicinc among the best-informed medical men Skoda’s dictum of several years’ standing, “that we can diagnose disease, describe it, and get a grasp of it, but we

worth of

tic

abroad.

dare not expect by any means to cure it,” has drifted along, on the ripples of time, until, hardly two years ago (1907), the president of a prominent British society. Dr. A.

found

II.

Brampton,®

opportune to declare that “if any daring member has

it

introduced a subject bearing on medical treatment,

it

has been

with an apologetic air and liumhle mien, well knowing that

remarks had any reference

his

to the utility of

if

drugs in the

treatment of disease they would be subjected to good-humored

and received by those ful with amused incredulity.” “Internal Secretions” was first banter,

me, at

least,

sitting in the seat of the scorn-

^ly aim now, as projected,

is

it

was when

to indicate

what

to

appears to be the main cause of the deplorable

state of practical Medicine,

and

if

possible to eliminate

it.

ago, I was brought face to face with material we term the “Medical heterogeneous of mass the Sciences,” and with the yearly crop of contradictory theories

When, twenty years

upon each disease, mode of treatment, etc., I soon realized that some gigantic flaw could alone account for so great a confusion. In the preface of the 1888 issue, I had stated that the “Annual” was intended “to become a helpmate to the jiractitioner in his efforts

to

correlating

relieve

suffering,

and

to

assist

the

investigator

by

thus enabling him the better to compare.” comparison was indulged in by others I can-

facts,

Whether much

not say, but the fact remains that, as far as my own position for in the matter was concerned, I began then and there to seek

must frankly confess that its identity was not difficult to find, namely: the invalidity of PhysiNever, when it came to tracing a pathological condition, ologv'.

the flaw referred

>

A. H.

Brampton:

to.

I

Lancet, Jan.

19,

1907.

PREFACE TO THE SECOND AND THIRD EDITIONS. tlic effect

of a remedy, the nature of a

many jihenomena which

of the

mount importance

ix

symptom, or any, in

fact,

to us jjractitioners are of para-

in diagnosis or therapeutics,

was

it

possible

to trace to its source the chain of events through which a normal function had more or less suddenly become abnormal.

Invariably

was.

found

it

altogether to

failed

that

the

either

physiologists

had

discern the nature of that function, or,

an attempt had been made by them to explain it, that it was laden with so many inconsistent and obviously mutually contradictory conclusions that although perhaps quite scientific if

—

—

their eyes it was more misleading than heljjful in the explanation of the morbid condition analyzed. To illustrate these statements, I will submit a few of the

in

more

salient deficiencies referred to.

The

process of respira-

which includes pulmonary respiration and oxj'genation of the blood and tissues, at once asserts itself as of capital importion,

tance, since process,

it

and

urged that

involves the functions of all organs, the vital

also every this

morbid

process.

In January, 1903, I

function as taught by physiologists failed to

satisfy our needs,

and suggested new paths for research.

years later. Professor Chas.

E.

Two

Barnes, of the botanical

de-

partment of the University of Chicago,* wrote: “I found it needful to examine the recent literature of respiration in animals, the aspect of the general subject rvith which I felt myself I found to my great surprise, that animal have eoncerned themselves very little with the essential problems of respiration.” Then, naming our bestknoivn text-books on physiology, he added: “I found no treatment whatever, indeed, no mention whatever, of the real problems of respiration, that is, of what is happening in the tissues,

least

familiar.

physiologists

tlie

The

process of which these external late Sir

phenomena

are the sign.”

Michael Foster® also closed a study on metabolism

in the last edition of his text-book with the statement that, after all, it “consists mostly of guesses and gaps.” Even the

apparently simple process through which the blood acquires its oxygen from the air in the pulmonary alveoli is at present

unlcnown to physiologists, their gasometric experiments being. '*

=

C. R.

Sir

Barnes: Science, Feb. 17. 1905. Michael Foster: cited by W. G. Little: Liverpool Med.-Chir. Jour., Jan.,

1905.

PUEFACK TO THE SECONIJ AND TIIIUO EDITIONS.

i

by Pembrey,® “very discordant” and inadequate to “the absorption of oxygen by the lungs.”

as stated ei-plaiii

If the full

their

appalling

meaning

of these dcliciencies is apprehended,

consequences will appear.

The pulmonary

the main barriers to infection; their surface is the seat of multiplication of the pneumococcus, while their walls afford a nidus for the tubercle bacillus. It is here, therefore, that the initial lesions of the two great destroyers of air-cells are

mankind, jmeumonia and tuberculosis, are formed. Now, adequate knowledge of the processes with which oxygen is concerned precisely in this location, would be a boon indeed: it would enable us probably to discern just how Nature defends the body against infection.

As

to the

morbid processes con-

nected with tissue respiration, I pointed out in the first volume,^ two years before Beard suggested its use as a remedial agent, that trypsin was the direct destructive agent in another dread disease, cancer. tissue-metabolism.

If

is now known to take part in we had something better than the

Trypsin

“guesses and gaps” referred to at our disposal to study this

next greatest foe of humanity, I venture to suggest that

would soon be conquered. Another great function

is

nutrition.

Our

first

interpret intelligently gastro-intestinal infections,

is

it

need to a

clear

understanding of ferments. A most aide physiologist, Benjamin Moore,® wrote recently: “Little is known regarding the chemical nature of enzymes, because all attempts to isolate them in a state of purity have hitherto failed.” Another au“The process through which thority, Halliburton,® also writes: the digested food-stuffs are absorbed from the alimentary canal is

quite as obscure.”

Thus, HowelB® writes:

that controls absorption resides

....

“The energy

in the wall of the intes-

presumably in the epithelial cells, and constitutes a speAccordcial form of imbibition wbicb is not yet understood.” ing to Bcddard,'^ “we know nothing of the path taken by the products of proteid and carbohydrate digestion.” HowelB* also

tine,

•

Pembrey

r

Sajous

8

» 10 11

1*

;

Cf,

:

Schafer’s “T. B. of Phy.siol.,’’ vol. vol. i., pp. 609 to 666 iiicl., i908.

i,

p. 776, 1898.

Moore : Hill’s “ Recent Advances in Phy.aiol., etc.,” p. 117, 1906. Halliburton ; “Biochemistry of Muscle and Nerve,” p. 30, 1904. Howell “T. B. of Physiol..” p. 713, 1905. Bcddard : Hill’s “Recent Advances in Physiol., etc.,” p. 043, 1906. 716, 1905. Howell: Loc. :

;

PREFACE TO THE SECOND AND THIRD EDITIONS. in which proteid

“The form

says:

is

XI

absorbed remains

....

a mystery.” Again, if, as text-books on physiology teach, the food-stufEs, duly prepared, were taken up at all by the blood, they should be found in the latter. But, as stated by Mendel, “Beyond the intestinal wall, in the blood and lymph-stream, the cleavage products seem, for the most part, to be missing.” Finally, once in the blood, the fluid proteids should be readily diffusible to penetrate freely to the tissue-cell. HowelP’* states:

“The

proteids of the blood, which are supposed to be so im-

portant for the nutrition of the tissues, are practically indiffusIt is difficult to explain their passage ible, so far as we know.

from the blood through the capillary walls into the lymph.” The problem of nutrition is evidently no more solved by physiologists than those of respiration and tissue metabolism.

The consequences

to

us are

quite

as

deplorable.

Asiatic

and kindred disorders are closely related with all intestinal functions, and in absorption How can we possibly lies the key-note to general infection. conception of all these dread diseases with such obtain a clear cholera, tyjihoid, infantile diarrhoea,

a foundation as physiology affords us?

The is

third great question

incited in an organ.

years ago, this

is

is

the

manner

in which function

As shown by Claude Bernard, over

fifty

due to dilation of the arteries of that organ

more blood passing through it, it functionates. Notwithstanding considerable work done upon the problem ever since, the manner in which this function is carried out is quite unknown. Naturally, to admit more blood into an organ, the nutrient arteries must be dilated. Now, in his summary of vasomotor actions,. Foster,^-''* for instance, says, referring to the

of dilator nerves in muscles:

“There

is

presence

no adequate evidence

that these vasodilator fibers serve as channels for tonic dilating

impulses or influences.”

While Landois,'® in the

last edition

of his text-book, holds that “although a center for vasodilator

or vessel-relaxing nerves has not yet been demonstrated, the existence of such a center in the medulla may nevertheless be suspected/’ J. G.

Curtis'’'^ states

that “it

is

not

known whether

13

Mendel; Med. News, May Howell: JjOC. cIC, 7 >. 88 fi.

’3

Foster: “T. B. of Physiol. sixth American edition, n. 229, 1805. I.andois ‘'T. B. of Physiol.,” tenth edition, ji. 771. 190.5. J. G. Curtis; “ Ainer. T. B. of hysiol.," vol i, p. 199, 1900

1“

”

20, 1905.

:

I

PREFACE TO THE SECOND AND THIRD EDITIONS.

All

a vasodilator center of the question

is

The

iiresent in the bulb.”

actual state

aptly suniiuarized hy H. C. Chapman,'®

when “Though numerous e.xplanations have been otlered of the manner in which the vasodilator nerves aet, it must be admitted that none of them are satisfactory, and that it is not yet understood how this stimulation causes dilatation of the is

he says:

blood-vessels.”

Now,

the bearing of this physiological process ujion patho-

genesis and therapeutics total

number

since all

may

be said to be limited only by the

of diseases to which the

human frame

disorders are functional or organic, and

diseases impair function at a given time.

suggests

A

all

organic

possible exception

namely, the nervous system.

itself,

exposed,

is

Ilut here, again,

the clcus ex machina of the function as a whole, the nerve-

impulse, has remained hidden.

As Landois"’

says, “the nature

of the physiological nerve-stimulus in the normal body

known.”

among

This

accounts

for

the

prevailing

is

not

discouragement

the devotees of a great specialty, neurology, as expressed

in the recent statement of a very diligent worker in that line,

Joseph

Collins,-® “that

we know very and the

etiology, pathogenesis,

of nervous diseases, organic

little

more concerning the

clinical display of the majority

and functional, than we did twenty

years ago.”

These are hut a few of the evident shortcomings of PhysiI ology; others will be referred to in the body of the work. wish to state, however, that their enumeration

by a spirit of criticism ciency

is

;

is

not inspired

they are mentioned because each

defi-

subjected to a searching inquiry in the second volume

with a view to

its

elimination

:

Indeed, any one

ined physiological loro as closely as

I

who has exam-

have, cannot but admire

the enormous and patient lalior that physiologists have devoted to the solution of the

tions of the

multitude of problems which the funcinvolve, including the many un-

human organism

must now, after writing the second volume, em])hasizo a feature which T merely sug-

solved ones to which

gested in the

many

first

1

refer.

volume,

viz.,

functions referred to

is

But

T

that their failure to ex]ilain the

due to the fact that they have

H. C. Chapman: ‘‘Human Physiology,” second edition, p. '•Landois: Lor. cit., p. fi.91. Joseph Collins: Monthly Cyclo. of Pract. Med., Feb., 1905.

G92, ,

1S99.

PREFACE TO THE SECOND AND THIRD EDITIONS.

Xlll

have overlooked the cardinal functions of the organs to which I pituitthe thyroid, the given special attention: the adrenals, ary body and the leucocytes. text will show, various branches of biology have been studied, but many of the facts which have served to

As the

from Professor Pawlow, of

elucidate function were obtained

great physiologist.

A

clinical medicine. St.

Petersburg, wrote

a few years ago,-^ after stating that physicians had pointed out the existence of gastric secretory nerves a question which,

—

I

may

add, has been greatly elucidated, thanks to his “Physiologists, on the other hand, had

labors:

own

fruitlessly en-

deavored for decades to arrive at definite results upon this question. This is a striking, hut by no means isolated, instance where the physician gives a more certain verdict concerning physiological processes than the physiologist himself;

nor

is it

phenomena is nothindeed strange. The ing hut an endless series of the most different and unusual combinations of physiological occurrences which never make world of pathological

their appearance in the of physiological

normal course

It

of life.

experiments which Nature and

is

a series

life institute,

often with such an interlinking of events as could never enter into the

mind

sources at our

and which could by means of the technical re-

of the present-day physiologist,

scarcely he called into existence

command.

Clinical observation will consequently

always remain a rich mine of physiological facts.”

There are precedents, therefore, upon which a legitimate belief may be based that the conclusions I have reached are sound. They afford,

moreover, a clear explanation of the inability of physi-

ologists to discern the functions

my

researches have led

they are partly hidden in a

discover:

field

me

could not legitimately be expected to scrutinize, owing to

In this connection,

vastness.

it

is

to

that physiologists its

mainly, therefore, as a

contribution of pathological biology to normal biology, of which physiology is a subdivision, that the two volumes of “Internal

Secretions” are offered.

Among the more important features which the views I advance therein appear to me to point out for the first time Pawlow

:

“The Work of tho Digeslive Glands,” Thompson’s

transl., p. 4G, 1902.

;;;

; ;

;

;

—

;

—

——

—

PREFACE TO THE SECOND AND THIRD EDITIONS.

XIV

(as far as the literature

and the experimental and

within niy reach have enabled

As bearing

direetly

me

clinical facts

to judge) are the following:

upon Biology:

The main function

of the adrenals, viz., to supply an internal secretion which absorbs the oxygen of the air to carry it to the tissues; and, as a result of this fact: 2. Pulmonary respiration, and 3. Tissue respiration; 4. The identity of the albuminous moiety of the litEmoglobin molecule, viz., the oxygenized adrenal secretion; 5. The identity of the oxidase of the blood, i.e., the oxygenized adrenal secretion referred to (after the thirteenth chapter) as “adren1.

oxidase” 6. The identity of the red corpuscles as storage-cells for adrenoxidase and as purveyors of this body to the tissues; 7. The general composition of ferments; 8. That the adrenal principle is the one ferment which endows all other body-ferments with their properties as such; 9. The identity of “secretin” as adrenoxidase; 10. The identity of “enterokinase” as adrenoxidase plus nucleo-

proteid 11. That the granulations of the leucocytes ser\-e to build our tissues and to nourish them 12. That the substances out of which the leucocytes form their granulations (anabolism) are the proteids and carbohydrates ingested by them in the intestinal canal, its epithelium and villi, and in the blood; And, in virtue of these facts; 13. The process of absorption, and 14. The process of general nutrition; 15. That it is the function of leueoc3'tes to convert the. constituents of the ingested proteids into living proteids; If). That the granulations thej’ supply to the tissue-cells are living substance 17. That the principle which endows the constituents of proteids with life in the leucocj'tes is the adrenal active principle; 18. That the adrenal principle is the d.vnamic element in the vital process 19. That the granulations of leucocj-tes once in the tissue-cells live temporarily therein and are, when worn, broken down by ferments (catabolism), and voided by the cellular vacuoles into the pericellular Ij-mph-spaces And, in virtue of the foregoing conclusions: 20. The process of metabolism 21. That all the ferments and carbohvdrates found in the tissues and other immobile cells are brought to them by leucocytes and are derived from the alimentary sj’stem, especially the pancreas (trypsin)

and

liver

(glj-cogen)

;

That a portion of the pancreatic ferments forms an internal secretion which passes to the splenic vein and thence into the portal 22.

system 23. That the splenic internal secretion (probably nucleo-proteid) also passes out into the splenic vein and thence into the portal sj'stem; 24. That on reaching the portal system from the alimentary canal, secrethe leucocytes absorb the pancreatic ferments and splenic infernal tissue-cells and tion (probably nucleo-proteid) which they supply to the with which they carry on their intrinsic functions;

;

;

;

;

— —— ——

;

PREFACE TO THE SECOND AND THIRD EDITIONS.

XV

tissues, is com25. That the nervous system, in keeping with other leucocyte-granulaby nourished and developed likewise posed of cells tions, and traversed by the oxygen-laden adrenoxidase the ground substance and Nissl granules of nerve-cell2(1.

That

bodies and the myelin of their axis-cylinders or nerves are to the nervecell what the cytoplasm is to other tissue-cells; • 27. That the neuro-fibrils, including those oi the axis-cylinders, are nerve-capillaries through which the nerve-cells are supplied with oxygenladen adreno.xidase 28. That these neuro-fibrils receive their adrenoxidase-laden plasma from the general circulation through the intermediary of the neuroglia fibers (also capillaries) and the neuroglia-cells which regulate the volume of plasma admitted into the neuroglia fibers; And, in virtue of the last four conclusions: 29. The circulation of the nervous system; 30. That the myelin of nerves is not a mere insulating material or sheath, but a compound rich in phosphorus which, when in contact with the oxygen-laden adrenoxidase circulating through them, generates

nerve-energy 31. That the ground-substance, the Nissl gi-anules and the myelin in the cell-bodies of neurons and their dendrites, are also phosphorusladen compounds which, when in contact with the adrenoxidase circu-

lating through them, generate nerve-energy And, in virtue of the last two conclusions: 32. The source and nature of the nerve-impulse; 33. That the pituitary body is the general and governing center of the spinal system, which includes the gray substance of the base of the brain, pons, bulb and spinal cord, and the nerves derived from any of these structures, cranial or spinal, though subsidiary centers are also present in the bulb and spinal cord; 34. That the pituitary body is the governing center of all vegetative functions, i.e., the somatic brain; And, in virtue of these two conclusions: 35. The identity of the pituitary body as the most important of all organs concerned with the vital functions of invertebrates and vertebrates, including man 36. That the brain (as differentiated from the somatic brain) is the organ of mental processes and not the governing organ of motor functions; though capable, through the voluntary impulses it transmits to the spinal system, of having its mandates carried out; And, in virtue of these two conclusions: 37. The identity of the brain (as differentiated from the somatic brain) as solely the organ of Mind. 38. That neither the anterior nor the posterior pituitary body is a secreting gland; 39. That the anterior pituitary body is a lymphoid organ which, through the intermediary of a center located in the posterior pituitary body and a nerve-path in the spinal system, the upper dorsal sj'mpathetic ganglia and the splanchnic nerves, governs the functional activity of the adrenals; And, in virtue of this conclusion: 40. That the anterior pituitary body governs, through the posterior pituitary body, all tbe oxidation processes of the body; 41. That the center in the posterior pituitary body through which the anterior pituitary body governs the adrenals also controls the functional activity of the thyroid gland, and thus constitutes the “adrenothyroid” center; 42. That the pituitary body, the adrenals and the thyroid gland (including the parathyroids) are thus functionally united, forming the ^

“adrenal system;”

;

—

—

;

PREFACE TO THE SECOND AND THIRD EDITIONS.

x\a

43. That the posterior pituitary body is the seat of the highly specialized centers wliich govern all tlie vegetative or somatic functions of the body, and of each organ individually; 44. That tlie posterior pituitary body receives all the sensory impressions belonging to the field of common sensibility: pain, touch, muscular sense, etc., initiated in any organ, including the mucous membranes, skin and brain 45. That owing to this fact, the posterior pituitary body is the

sensorium traumatic

commune upon which

—concussions,

functions being conditions;

tlie

etc.,

react,

—

emotions, shocks psycliical or the resulting impairment of its

all

cause of the morbid phenomena observed under such

46. That the sj'mpathetic system is also governed by a center, and 47. Tliat the sympathetic center is likewise located in the posterior pituitary body and constitutes one of the most sensitive of its

centers 48.

That

it

is

the function of the sjunpathetic center and of the

sympathetic system to govern the caliber of all arterioles, and to regulate. through the spiral muscular coat of these vessels, the volume of blood admitted into the capillaries of any organ, including those of the brain and nervous system; 49. That the vasomotor center governs the caliber of the larger vessels only, i.e., of all vessels that are larger than the arterioles; 50. That active vasodilation exercised through vasodilator nerves is limited to the arterioles; 51. That dilation of an arteriole is due to constriction by the terminal fibers of a cranial nerve (the vagus, for example) of the vasa

vasorum which supply its walls with adrenoxidase-laden plasma, thus causing ischaemia and relaxation of its muscular coat; 52. That while this process, “stricto-.dilation,” serves to admit an excess of blood into an organ when the functional activity of the latter is to be increased, the sympathetic fibers, when the organ’s functions are to cease, restore the arterioles to their normal caliber; And, in virtue of the facts embodied in the last seven conclusions: 53.

The mechanisms

As bearing

of vasodilation

directly

and function.

upon Immunity:

54. That the sensory organ in the partition between the two lobes pituitiiry body is morphologically the homologue of the “test-

of the

organ” or “osphradium” of mollusks and other Invertebrates, which has for its purpose to protect the animal against noxious materials that may be present in the water admitted into its organism; 55. That all \’ertebrates, including man, are protected, as are Invertebrates, against noxious materials that may be present in the blood (a chemical homologue of sea-water), their test-organ, a sensory structure, being sensitive to certain poisons as the olfactory area, which it resembles histologically, is to odors; 56. That the test-organ of Vertebrates, including man, reacts under the inlluence of any poison brought to it by the blood or its leucocytes (phagocytes) capable of exciting it, by increasing, through the adreno-thyroid center, which it governs, the functional activity of the

adrenals and of the thyroid and parathyroids; 57. That by increasing the functions of the adrenals it enhances the bacteriolytic and antitoxic powers of the blood and its phagocytes; 58. That by increasing the functional activity of the thyroid and parathyroids it increases, through their secretions, the sensitiveness of all cells, including bacteria, and their vulnerability to phagocytes, inasmuch as

—

—

;

PREFACE TO THE SECOND AND THIRD EDITIONS.

XVII

parathyroids jointly form 59. Tlie secretions of the tliyroid and opsonin and agglutinin of tlie blood; And, in virtue of the last six eonclusions:— pituitary body, the GO That the adreual system, composed of the immunizing mechanadrenals and the thyroid apparatus, constitutes the ism of the body; and, furthermore, , for its purpose to 61. That inasmuch as the adrenal system has functional activthe enhancing is by it disease, protect the body against disease; ity of the adrenal system that we can overcome in the blood C2. That the adrenal system causes the appearance, (qualitative) chema “auto-antitoxin,” of excess an of phagocj’tes, and ical honiologue of diphtheria antitoxin and other antitoxins; is G3. That this “auto-antitoxin” (as well as all other antitoxins) composed of the internal secretions of the adrenals (adrenoxidase: Eliriich’s amboceptor), of the pancreas (trypsin: Ehrlich’s complement), and of the thyroid and of the spleen and leucocytes (nucleo-proteid) parathyroids (thyroidase; Wright’s opsonins) 64. That it is to the excess of auto-antitoxin that the increased bacteriolytic arid antitoxic properties of the blood and pliagocytes (the true vis mcdicatrix naiurw) are due. tlie

,

,

;

As bearing

directly

upon Pharmacodynamics:

65. That rational Therapeutics, in so far as the cure of pathogenic processes based on toxemias is concerned, should include measures wliich promote the formation of auto-antitoxin in the blood and

phagocytes 66. Tliat we have drugs, of which thyroid extract, mercury, and iodine are types, which provoke energetically the formation of autoantitoxin 67. That the production of an excess of auto-antitoxin in the blood, under the inlluence of bacterial toxins or endotoxins, or of any poison capable of exciting the test-organ (and through it the adrenal system) sulliciently, is the phenomenon known as “fever,” and that the “thermogenic” or “heat” center is thus located in the pituitary body; And, in virtue of this conclusion: 68. The nature of fever and its mode of production; 69. That we can by means of agents which stimulate concomitantly the test-organ and the vasomotor and sympathetic centers or any two of these centers, enhance metabolism and nutrition and the production of auto-antitoxin, as cxemplilied by belladonna, stryebnine, coca, quinia and other drugs; 70. That we can supply the body with the constituents which its blood and tissues lack and that these agents are adjusted to the needs of each organ by the leucocytes, as exemplified by iron and phosphorus; 71. That all drugs are taken up by leucocytes in the intestinal canal and blood and transported by them to all parts of the body; 72. That the sympathetic center in the posterior pituitary body is the sleep center; 7.3. That the sympathetic center provokes sleep by lowering the functional activity of the anterior pituitary body and of the adrenal system, and causes thereby a general relaxation of all arteries, accumulation of blood in tbe splanchnic area, and ischasmia of the cerebrospinal system; ;

74. That drugs of which opium is the type, produce sleep by stimulating the .sympathetic center; 75. That drugs of the type of chloral, the bromides, etc., produce sleep by depre.ssing the vasoTuotor center and causing accumulation of blood in the splanchnic area and isehiemia of the cerebro-spinal

system

^

;

—

;

—

—

;

PREFACE TO THE SECOND AND THIRD EDITIONS.

XVI 11

And,

in \nrtue of the four last conclusions:

The manner in which sleep is provoked; 77. That anajsthetics of which chloroform and etlier are types, produce sleep and ana;sthesia by e.xciting powerfully the vasomotor center, causing thereby general vasoconstriction followed by hypenemia of all capillaries, including those of the ccrebro-spinal system, and ven76.

osity of their arterial blood; 78. That anajsthetics of which nitrous o.vide is a type, produce sleep and aniesthe.sia by replacing the o.xygen of the air and producing venosity of the blood in the capillaries of the cerebro-spinal system and

other organs; 79. That ])ain is due to hyperaimia of the sensory-nerve terminals, of the nervi nervorum, etc., and that any agent which indirectly or directly causes diminution of this hyperaimia counteracts pain; An.d, in virtue of this conclusion: 80. The nature and mode of production of pain 81. That analgesics of the type of opium counteract pain by stimulating the sympathetic center, and by thus causing the dilated arterioles which supply the painful area to resume their normal caliber; 82. That analgesics of the type of antipyrin, acetanilid, etc., counteract pain in the same way, but, being more violent in their action, are apt to cause hyperconstriction of the arterioles and cyanosis; 8;i. That drugs of the type of amyl nitrite, nitroglycerin, etc., produce dilation of the arterioles by inhibiting the functional activity of the sympathetic center; 84. That drugs of the type of veratrum viride, the bromides, etc., lower the vascular pressure by inhibiting the functional activity of tho vasomotor center; 85. That alcohol is a fictitious stimulant and in reality a depressant, owing to the fact that it deo.\idizes the plasmatic adreno.xidase; 86. That the mineral salts fulfill so important a role in the preservation of the osmotic properties of the body fluids and their alkalinity, that their replacement in all diseases in which they are actively reduced is an essential feature of the curative procecs; 87. That purgatives produce their beneficial elTects by causing either rellexly or by centric action, according to the purgative u.sed, an increase of bacteriolytic and antito.xie auto-antitoxin in the intestinal canal 88. That all emetics produce their elTccts by provoking irritation of the giistric mucosa: the local emetics (mustard, zinc sulphate, etc.) by irritating it directly; the general emetics (apomorphine, tartar emetic, etc.) by depressing markedly the vasomotor and sympathetic centers and thus cau.sing dilation of the arterioles and hyperajmia of the gastric glandular elements; 89. That dia])horetics act similarly, the sweat glands (as well as all other glands) being rendered hj'pera;mic and overactive.

Bearing directly upon Pathogenesis and Therapeutics

:

90. That the vulnerability of the organism to infection is inversely proportional to the efficiency of the adrenal system, the relative amount of auto-antitoxin in the pulmonary and intestinal secretions, and tho bacteriolj'tie activity of the phagocytes; 91. That the diseases which are most fatal to mankind: cancer, tuberculosis, pneumonia, Asiatic cholera, bubonic plagiie, etc., are due to agencies, endogenous or exogenous, which interfere with, or paralyze, the functions of tho test-organ and through it the adrenal system; 92. Tliat all these diseases can be treated successfully, when s(wn late, by means of remedies which excite with adequate activity too not

—

PREFACE TO THE SECOND AND THIRD EDITIONS.

XIX

the test-organ, and provoke through it an accumulation of auto-antito-xin and tliyroidase (opsonin) in the blood; tetany, tetanus, epilepsy, puer93. That the convulsive diseases: peral eclampsia and rabies, are all due to the accumulation of to.xic waste-products in the blood; 94. That all these convulsive diseases can be arrested by measures which prevent the accumulation of toxic wastes in the blood and which provided organic increase the proportion of auto-antitoxin in the latter, lesions in the cortex (gliosis) have not been given time to develop; 95. Tliat all the diseases grouped under “gouty diathesis:” gout, migraine, neuralgia, sciatica, etc., are due to hypoactivity of the testorgans and the adrenal system; And, in virtue of these six conclusions: 96. Tliat the most fatal and distressing diseases of mankind have not been mastered because the cardinal role of the adrenal system in their pathogenesis, prevention and cure, has been overlooked.

—

As previously

stated, this list includes only the

portant I’unetions that

my

researches

inves-

analysis

tigations in the laboratoiy, clinical observations,

of

fund of knowledge available in literature

the vast

brought to

more im-

—including personal and —have

Were

light.

enumerated, including those intro-

all

duced in the departments of “PharmacodjTiamies” and “Pathogenesis

and Therapeutics” (where they are designated by asterdrug and disease studied), they would aggregate

isks in each

several hundred.

This fact

trate the far-reaching

is

only referred to in order to

illus-

importance of the functions of -the internal

secretions in all processes, normal, morbid, or protective,

the large

The

number

of gaps they

and

fill.

—

which I have been led those submitted in the second volume are not offered as mere theories, but as solutions carefully worked out from the abundant matefinal conclusions to

—

my

disposal. My labors as editor of the “Annual of the Universal Medical Sciences” and the “Cyclopaedia of Practical rial at

having shown tliat it was to the habit of theorizing with a few facts as foundation into which investigators, and i\Iedicine”

particularly laboratory workers, have fallen, that the confusion

which characterizes the Medicine of our day was due, the lowing working plan was adopted The literature of each :

ject,

folsuli-

my own

collected,

ex]ierimental and clinical observations, etc., were sulidivided and filed. When a given subject was

taken up, each paper available was analyzed and the sound experimental or clinical facts or observations were noted and

arianged in

scries.

In physiological questions, the teachings of zoology and cytology were added. All

physiological botany,

— P1U5KACE TO TUB SECOND AND THIRD EDITIONS.

XX

data (amounting to several luindrcds in some instances)

tliese

—

were treated as factors in the search of a solution the solution submitted at the cud of each section, in italics in the first seventeen chapters, and thereafter in large type.

The

reached in each instance was submitted to a rigid viz.,

final solution test,

however,

absolute concordance with all other solutions in the ivorh

—

a process which brouglit to light any defect, not only in the solution itself, but likewise in all conclusions previously adduced.

The chances

framework was elaborated

solid

minimum,

of error were thus reduced to a

while a

for future discoveries by other

investigators.

These others

details are given not only with the object of aiding

who might wish

to Avork

on

parallel lines, but to illus-

my

trate another salient feature brought to light by

editorial

work upon the “AnnuaP and the “Cyclopajdia,” namely, that the present tinsatisfactor ij condition of Medicine

is

due

to the

fact that investigators do not avail themselves of the enormous

array of solid data available to ascertain the truth. Blinded by the fallacious idea that the Avorth of a contribution to our knoAvl-

edge should be gauged solely by the ncAV experiments and clinical observations

it

adds to those already

aA-ailable,

they lose sight of

tbe fact that such experiments and observations are but bricks and mortar out of Avbich a coherent and truly useful Medicine

—can be

one indeed Avorthy of ranking as a science

The

built.

conception of ]\Iedicine'presented in the second

—and foreshadowed in this direction.

in the first

—

is

volume

submitted only as an

effort

It aims to replace the empirical and hazardous

use of remedies Avhich has undermined increasingly the confidence of our best observers in them, by a system of therapeutics based on solidly established facts Avhich makes

it

possible to trace

the centers influenced every phase of their action to its source, many levers through so may thus be used by the physician as which he can regulate the defensive agencies of the organism

and the mechanisms Avhich

distribute .them, precisely as a gen-

eral can govern the defensi\'e field.

As

the

disease-causing

movements substances,

of an

army

toxins,

in

the

endotoxins,

through toxic wastes, etc., are also sboAvn to produce by our remedies, a morbid action upon the centers influenced their effects

they

may

antagotbus be met directly Avhere they strike and

nized before they can destroy

life.

PREFACE TO THE SECOND AND THIRD EDITIONS.

X,\l

The work introduces no elixir of life, no universal panacea, nor even a new serum, the weapons recommended are available to all, viz., the identical remedies

—

daily use

shows,

I

which for years have been in It

the forty or fifty that have stood the test of time.

believe, that it is

not because we have been lacking

agents capable of successfully coping with disease that confidence in remedies has been steadily decreasing, but because they

were used blindly and often, therefore, injudiciously.

There

is

now not the least ground for doubt as to the efficiency of our I shall be amply repaid if 1 have suctherapeutic rcasources. ceeded in proving this fact, and if “Internal Secretions” to any degree instils into

its

readers the

unbounded confidence

in the

power of our remedies to antagonize and even master disease tliat a broad survey of the scientific facts at our disposal and considerable practical experience have instilled into me.

The plan

of the second volume, as stated in the preface,

included only “Applied

Therapeutics,”

i.e.,

the

physiological

action of drugs in morbid processes, but thanks to the liberal-

my

ity of

publishers, the F. A. Davis

Company,

I wa's able to

add a department in which the pathogenesis and treatment of the most fatal and distressing diseases with which we have to contend are treated in

Hence the comparatively large

full.

size

of the second volume. It

is

with great pleasure that I acknowledge the encour-

agement and moral support

1 have received during the rather arduous task the preparation of this work imposed upon me,

from

my

friends,

Davis Company,

Mr. F. A. Davis, president of the F. A. publishers, and Dr. J. Madison Taylor, my

my

associate in the editorial

management

ptedia of Practical Medicine.”

“Monthly Cyclo-

of the

Several of the microphotographs

presented in this volume were prepared by

my

son. Dr. Louis T.

de M. Sajous, from slides.

owe

to the kindness of

Some

of these I

Professors George A. Piersol and D. J. l\IcCarthy, of the Medical

Department of the University of Pennsylvania, to express

my

to

whom

I

wish

thanks. C. E. UE

M. Sajous.

^ .

f >

•


V,

Uusslnn Arcliives of Pathology, Clinical Med., and Bact., March, 1898. Gottlieb: Archly fUr exp. Path., Bd. xxxvlil, 1896. De Cyon: PflOger's Archly filr Physiol., yol. 1x11, p. 370, 1898. Vellch: Wiener med. Blatter, Noy. 11, 1897.

Mankowsky

No.

“

—

3,

:

vol.

EFFECTS OF SECRETION ON THE HEART AND VESSELS.

13

and efferent impulses of which and the portion of the cord immediately below it

established a cycle of afferent

the medulla

the

represent

The

center.

of

effects

structures can easily be foretold.

destruction

of

these

As showm by Strieker nearly

and by other physiologists since, extirpation of the cervical and dorsal portions of the cord causes arrest AYhen to this is added destruction of of the heart’s action. the medulla, the certainty of immediate death is but enhanced. forty years ago

Again,

agents

certain

known

—

chloral

hydrate,

the functional activity

to abolish

for

instance

—are

of the cord and

to

vagus had been severed. Applying these classical data to the question in jioint, it becomes evident that, if the inhibitor or augmentor centers were directly or reflexly stimulated by suprarenal extract, the effects of extirpation of these centers or of the cord would affect the heart as if the

not be counteracted receive

b}'’

its

use since there would he no center to

and transmit impulses.

The

arrest of the heart’s action

would therefore be permanent. But experiments have shown that the injection of suprarenal extract at once causes this organ to resume its beat notwithstanding total extirpation of the entire cord. the medulla

cut

mammals; to

9

and,

oblongata

when

millimeters,

and removed the entire cord of

injected

suprarenal

ralized rabbits until the heart-beats

restored

slow.

An

Biedl'*'*

the blood-pressure had become reduced

injection

of

This at once

extract.

brought up the pressure to 160 millimeters. cessively

Thus,

Gottlieb'*'*

chlo-

became in’egular and

suprarenal

extract

at

ex-

once

and volume of the pulse. He tried the pulse was no longer registrable by the manometer; a similar result was obtained, and the heart almost immediately resumed its nonnal action. Isaac Otrt” the

regularity

the same experiment

etherized a

when

rabbit,

cut the cord above the atlas, severed all the cardiac nerves in the neck, and verified the section of the cord post mortem. Injections of suprarenal extract were then used repeatedly as soon as the pressure became greatly lowered. Tliey brought it up from 24 to 144 the first time, from 17 to “Biedl:

« «

Wiener

klin. Wochenschrift, Bd. ix, 189G. Archlv fUr exp. Path, und Phar.. Bd x.xxviU 1896 Isaac Ott: Experiment No. 11, Medical Bulletin, Jan., ’l898.

Gottlieb:

’

— THE PHYSIOLOGY OF THE ADRENALS.

14

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

which others of a similar kind could They distinctly show that, conthe conclusions of Cybulski, Wallace and Jilogk, Man-

Tliese experiments, to

be added, speak for themselves. trary to

kowsky, Gottlieb, and other observers, the inhibitory centers are not directly stimulated by the suprarenal extract.

And, indeed,

tbeir

conclusion

removal of the medulla and cord

and with injections the

—would

left

is

—does

cardio-inhibitory

mental result on injecting heart

apparently justified,

an only guide.

—an

experi-

affirmative

mammals

into

—slowing

of the

—

always be obtained, while the crucial test

tion of the vagus

—would

In

suprarenal extract directly

centers? it

if

out of consideration,

of suprarenal extract as

other words, to the question affect

is

sec-

at once confirm the conclusions pre-

viously reached by causing great increase in the rapidity of

But

the heart’s action.

division of the cardiac nerves in the

neck, including the vagus, and of the cord in no

way preventing

the action of the extract, the only logical deduction that imposes itself is

that the suprarenal extract exercises a siimulating action

directly

upon the cardiac muscle

irrespective of

any action upon

the inhibitory centers.

The Adrenal Secretion Elements. question.

—The

as Constrictor of Muscular

last deduction implicates other jffiases of the

Prominent among these

is

the

effect

ascribed

to

suprarenal extract upon the vasomotor system by various physiologists and clinicians. which are but little, if at

in

respect to their

before reaching

Is there all,

any such action?

Veins

infiuenced by the cardiac impulse

rhythmical changes of caliber, the blood

them having

to penetrate the capillary system

—

This .may be clearly seen by are distinctly contractile. examining the great veins opening into the heart, and in those of bat’s wings. ‘Although,” to use Foster’s^'^ words, “similar rhythmical variations, also possibly due to rhythmical contractions,

but possibly also of an entirely passive nature, have been observed in the portal veins, very little is known of any nervous

arrangements Foster;

goveiming

“Text-book

the

veins.”

of Physiology,” 1895.

Granting

that

veins

;

EFFECTS OF SECRETION ON THE HEART AND VESSELS.

endowed

are not

witli

we

a vasomotor snpidy,

15

find that they

nevertheless contract under the influence of suprarenal extract. Szynionowicz'’'^ observed that the pressure rose and fell in the

external jugular vein, along with the pressure caused in the

hy injections of this substance. Auld'*® states that, when suprarenal e.xtract was injected into a vein “which had been clamped as high as practicable, on releasing the vein after a few minutes a marked diminution of pressure was recorded as compared with that produced by injection into the free vein.” This arteries

shows a direct action on the vein while the extract was held in situ by clamping. While it is difficult to account for the general increase of vascular pressure caused by the extract without in-

cluding vasomotor nerves in the process, a direct action upon the vascular muscles themselves might underlie the result attained

which can only be elucidated by stripping the vessels of all their nervous connections and then watching the effects of the extracts. This procedure has been resorted to by Oliver and Schafer,®® and these physiologists have shown that a vessel a question

Even a

will contract after all the nerves to it are cut.

excised vessel influence

—

—

one,

therefore,

obviously freed of

all

freshly

nervous

an aqueous

will respond to the contracting effects of

solution of suprarenal extract, and, if a large vessel be used for the experiment to render the change of caliber

more

appreeiable,

the diameter will be found reduced nearly one-sixth.

Further-

more, these investigators®^ have found that it acts directly on the muscles of the blood-vessels, and that this action occurs equally well after section of the cord.

As we have

seen, destruction of

the adrenals or annihilation of their functions

extreme muscular weakness; conclusion

that

this

is followed by normally led them to the

—

muscle

striated, non^the and the cardiac muscle (which histologically partakes of both kinds of muscular tissue) are stimulated by the exall

varieties

of

striated,

—

traet.

Observing also that the latter caused a rapid increase of blood-pressure, and that

Szymonowicz:

gave a steep rise to the kymograph-

Archiv fUr die gesam. Physiol., Bd. Ixiv, 189G. British Medical Journal, June 3, 1899. Oliver and Schiiter: Journal of Physiology, vol. xviii, p. 420.

*“AuId:

“

it

Ibid.,

p.

230.

THE PHYSIOLOGY OF THE ADRENALS.

16

curve, they concluded that there

had been a strong constriction of

small arteries: strong, in their sense, meaning the relative constriction as compared to that of other vessels. This is fully

tlie

accounted for by the greater relative supply of muscular tissue vessels. As is well known, arteries are endowed with a coat of muscular fibers, which assumes increased thickness and relatively greater mechanical power as

in

peripheral

these

the capillaries are approached; so that in the smaller arteries the muscular layer

is

Nor

relatively quite thick.

to emphasize, in view particularly of the

is it

necessary

work done

in recent

years, that the adrenal active principle enhances the tone of the blood-vessels.

That

all

organs are similarly affected owing to their vas-

cular supply was also

shown by Oliver and

Schiifer

by means

of the plethysmograph, not alone the limbs, but such organs as

the sjileen and the kidney being contracted from 20 to 25 per cent,

intravenous injections of the extract.

after

These ex-

periments also showed that great vascular constriction in the splanchnic area was caused.

Veins,

we have

seen, are likewise

by suprarenal extract; they also contain muscular Although the supply of muscular in their thinner walls.

constricted fibers

elements

is

important than in the

compensated by

degree, va.scular

it

specific

contains,

is

principle,

beyond

Can we conclude from is

arteries,

greater lumen.

tJie

system of the organism

suprarenal

which

less

is

this

is,

That the

to

a

entire

thus acted upon hy the

owing to the muscular

tissues

que.stion.

these data that the vasomotor center ? As will be shown and adrenal extractives

never influenced by the suprarenal extract

later on, the secretion of the adrenals

enhance metabolic activity in living elements.

Their action on vessels

is

cells,

including vascular

thus independent of any

uixni the vasomotor center except in so far as their influence

on general metabolism is concerned, in which case this center would merely participate in the exaltation common to all tissues.

Briefly, Schiifer’s statement that “the intravenous injection

of suprarenal extract produces a powerful physiological action

upon the muscular system

in general, hut especially

upon the

muscular walls of the blood-vessels, and the muscular wall of the

EFFECTS OF SECRETION ON THE HEART AND VESSELS. heart”

may

be accepted as the basis of

tlie

conclusion

tliat

17 supra-

and vascular contraction hy stimuthe muscular elements of the heart and vessels,

renal extract causes cardiac Iflting

directly

and not hy exciting directly the vasomotor center. Action of the Adrenal Secretion upon the. Heart. We liave seen that destruction of the medulla and cord and

—

section of the cardiac nerves in the neck does not prevent the

the vasomotor center being thus func-

rise of blood-pressure;

tionally eliminated, it

clear that constriction of the vessels

is

does not occur under these conditions, as a result of impulses

Such being the case, it becomes a question whether Oliver and Schafer’s e.xplauation in respect namely; that to slowing of the heart by supi'arenal extract

transmitted, through them.

—

it is

due to reflex inhibition of this organ through the constric-

tion of the arterioles induced

—

We

holds.

still

look, in this connection, tlie fact that the active

which the heart

is

must not

over-

agency through

slowed, according to their views,

is

not the

suprarenal extract, but the impulses from the center to which the reflex inhibition

attributed,

is

and

it

is

plain that in the

absence of this center “inhibition” cannot occur.

slowing of the heart takes place

removed,

it

must be

clue to

Suprarenal extract, secretion of

tlie

when

this

Hence, as

center has

been

some other cause.

if its

action is similar to that of the

adrenals, should,

it

seems to

us, be

regarded

and not be confounded with toxics which pervert normal conditions, nor with elements foreign to existing structures. Considered from this standpoint, the adas a physiological agency,

dition of a given proportion of glandular substance to the

sum-

contained in the organism, or the removal of some by any method, should involve a corresponding augmentation total of that

or a diminution of the

normal manifestations that represent

suprarenal functions, whatever these suprarenal

of

extract,

we have

may

be.

The

injection

and marked increase of blood-pressure by stimulating the cardiac and vascular muscles. When, therefore, we speak of stimulating seen,

produces a rapid

these structures we imply contraction of the muscular fibers and approximation of the vascular walls toward the center of

Where is the need of “reflex inhibition,” evidently an obscure phenomenon, for, as Langley says, “wo

the blood-stream.

—

— THK

18 are

still

far

from any

inhibition”

in

I'lIYSlOLOGY OP

—when

real

a

THE ADRENALS.

knowledge of the processes involved

familiar clinieal faetor, the inereased

resistance offered to the contractile effort of the heart by the

augmented blood-pressure, affords a logical explanation of the slowness and increased power of the cardiac contractions?' We need not go beyond this explanation, therefore, to conclude that the slowing of the heart by adrenal extract

is

due mainly

to the

resistance which the increased blood-pressure caused by the extract offers to the cardiac contractions.

Functional Eelationship Between Arteries and Their Capillaiues Under the Influence of the Adrenal Secretion. The very marked contractile power that supra-

—

renal extract also possesses over the muscular coat of vessels

plays an important indirect role in the organism which seems to

have been overlooked so far:

i.e.,

that, as capillaries are not

supplied with muscles, their walls consisting of endothelial plates, they are not contracted as are arteries and arterioles.

This embodies two kindred prominent features of pathology:

i.e.,

the fact that

when

vessels supplied tvilh a

muscular coat

contract their capillaries dilate owing to the increased pressure to

which the

arterial contraction gives rise within

when

while the opposite relative mechanism

the latter,

vessels supplied

with a muscular coat dilate their capillaries contract

owing

to the resiliency of the latter

recedes.

In other words, while, in the

crowded outwardly, in the second

The

it is

—

when the blood first case,

prevails

in

them

the blood

is

crowded inwardly.

physiological importance of these propositions will be

shown in subsequent chapters, l)ut their bearing and soundness seem sustained by the fact that they alone, of all solutions so far advanced, can

nomenon

—

a

true

satisfactorily

suprarenal

explain an experimental phe-

paradox

—encountered

by

Lan-

and Charrin in the course of their earlier laboratory work.''" These observers, in order to study the action of suprarenal substance upon toxic agents and toxins, injected equal doses of virulent cultures into two groups of gujnea-pigs, the glois

animals constituting one of the groups having each been deprived of one suprarenal gland, d’he group of normal animals

“ 1890.

Lnnglols and Charrin:

Comptes-Rendus de

la Socl£>t6

de Biologie, July

10,

;

VARIATIONS IN ADRENAL FUNCTIONAL ACTIVITY. altogether

lived

138 hours;

mutilated animals

of

that

19

150

Several e.xperiments of the same kind were iicrformed

hours.

from which one gland

invariably did they find that the animals

had been e.xtirpated lived longer than those left in their normal condition. The differential contractility of vessels and capillaries referred to render this phenomenon a normal con-

The

sequence under the circumstances:

caliber of the

muscular

having and become enlarged and their walls relaxed by the loss of suprarenal stimulus, engorgement of the larger trunks occurred, and vessels,

arteries

veins,

the mutilated animals

of

caused depletion of the remote capillaries, including those of the central nervous system.

main primary

The

virulent toxins injected producing

upon the latter, and, the quantity them in a given time being smaller than in a normal animal, the longevity of the latter was protheir

effects

of toxic blood transported to

longed in proportion. I

frequently

shall

relative

behavior of

vessels

We

secretion or extract.

in

refer

subsequent chapters to this

under the

effects

will see also that it is

of

suprarenal

an important

feature, not only of the physiological action of certain drugs,

but also of various toxins, that of the pneumonia bacillus, for example. The conclusion, therefore, that vessels supplied with

muscular

a

tion

and

and

coat

dilation

capillaries are

antagonistic in

contrac-

only submitted as a postulate for the time

is

being.

AND DRUGS IN LARGE DOSES AS INHIBITORS OF ADRENAL FUNCTIONS.

TOXINS, POISONS, VENOMS,

Analogy suggests renal activity, there to

a certain extent,

proached. sufficient

normal standard of supramust be inadequate activity, physiological but pathological when extremes are apthat, besides the

Pending considerable testimony to

recall

that insufficiency

We

recognized as a clinical entity.

of

to this

the

effect it is

adrenals

is

now

have seen that hajinorrhage

into both adrenals can cause death,

and 'we shall see presently that various poisons likewise cause, mainly by variations of the blood-pressure, cessation of the adrenal functions. Is this result due to direct annihilation of the latter by the poison, or must 2

THE ADRENALS

20

IN DISEASE

AND POISONING.

be ascribed to some indirect factor, such as the variations of general blood-pressure, caused, as is well known, by many it

poisons, including certain toxins, affect the adrenals as well as other

and

wliicli

must

necessarily

organs?

This question may perhaps be elucidated by trying to account for the lupmorrhages that occur as a complication of local

These at

disease.

vast majority of

first

seem to afford a ready answer, since the

them are traceable

to organic lesions of the

glands that practically annul their efficiency by destroying the greater

part of their

organs and

substance.

Partial

destruction

the

of

corresponding loss of activity follow each other

any conclusion other than that,

so logically that

in accord with

the prevailing view, all poisons, toxins especially, act morbidly

upon the adrenal yet the

we have effect

tissues per se

would seem unwarranted.

And

in cerebral luemorrhage or “apoplexy” evidence to

that

adrenal

haunorrhage,

which Arnaud

termed

“adrenal apoplexy,” might also be due to high general bloodpressure, with rupture of the adrenal vessels, particularly

Again, poisons being carried to

these vessels are diseased.

parts of the organ

when

we should,

if

all

their action were direct, find

the lesion in the functional cellular elements throughout the entire organs.

Not only

is

this not the case, but the lesions

are essentially vascular.

While studying the pathological histology of suprarenal haemorrhage, Arnaud found that it was not in the medulla proper, as generally believed, that these haemorrhages occurred,

but in the tissues of the internal cortical zone. this

fact,

he states: “It

is

at

this

In emphasizing

point that the capillaries

When the tear under the influence of a powerful congestion. haemorrhage is important, it is due to rupture of one of the branches of the capsular vein at any point of its walls, and occurs into the medullary substance or into the central conThe medulla proper maj’^ be rejunctivo-vascular sheath.”

some probalily weakened part of the intrinsic portion of the vein hy the local disease constituting the yielding structure. Furthermore, Nature seems to protect the last vestiges of the medspected to the last, either a capillary peripheral to

—

it,

or

—

ullary substance even after a localized haemorrhage.

suggested by the fact that Arnaud found

in

This

such areas

is

evi-

THE ADRENALS

AND POISONING.

IN DISEASE

21

dent signs of organization, at times indicating a local inter-

inflammatory process, at others a retrogressive meta-

stitial

morphosis

observed

that

recalling

Iniematomata.

in

Briefly,

“The normal anatomical elements of the suprarenal gland may he found in a more or less perfect state

using his words:

of integrit}', either in the peri 2ihery of the growth or at one of its extremities.”

Toxins would hardly be so

Further analysis of this question

symptoms which characterize the

elicits

selective.

the fact that the

primary or-

jirogress of the

ganic disease of the adrenals differ totally from those attending Wliile the former

the liaBinorrhage proper.

may

suffering or be totally obscured by the signs of

disorder present, the

hardly cause

any concomitant

symptoms attending hiemorrhage are par-

and sudden, the patient abruptly screaming from excruciatingly intense pain in the abdomen, or dropping ticularly violent

coma from which he never rallies. more vivid picture of the hmmorrhage. Yet luemorrhagic foci

at once into apoplectifonn

Cerebral apoplexy does not furpish a

overwhelming

effects

of

found

in various stages of organization are

at autopsies.

Thus,

one of Arnaud’s cases suddenly fell into apoplectiform coma, and died in 48 hours; the only organs found diseased after death were the adrenals, which contained old hamiatomata, and various more or less organized hffi,morrhagic foci which showed that local hiemorrhages into them had repeatedly occurred.

The suprarenal substance was

entirely destroyed

ex-

cepting a narrow zone toward the inferior edge of the right

The

organ.

urine, during life,

and the kidneys, after death,

were

found normal.

Obviously we

acute

symptoms

primary organic

to the

cannot

well

lesion, since

ascribe

the

they appear

suddenly, practically without warning, and' promptly lead to a fatal issue.

Excessive,

i.e.,

disruptive congestion again suggests

itself.

Confirmatory evidence

is

also

afforded by the facts that,

irrespective of infectious diseases, adrenal hcemorrhage

may be caused by cardiac and renal disorders in which high blood-jiressure results from purely mechanical causes, and that, as is often the ease, fatal adrenal haimorrhage may occur irrespective of anv evidence of local disea.se or the presence of any bacteria. is

well

shown

This

in Andrewe’s case, referred to on page G, in wliich

THE ADRENALS

22

IN DISEASE

AND POISONING.

neither cultures nor stains showed the presence of pathogenic

organisms.

There

good ground for the belief, therefore, that the prevailing view that poisons act directly upon the adrenal tissues is

does not always apply,

i.e.,

that, besides the insufficiency of the

caused by disease of these organs, there

adrenals

brought on by the general blood-pressure when this

is

a form

is sufficiently

elevated (as in the course of to cause

mtense congestion

some mfections and intoxications) of the adrenals and rupture of some,

of their blood-vessels.

The morbid likely to

influence of high blood-pressure

manifest

itself

when part

—

been destroyed by local disease

the more

of the adrenals liave already

since the disruptive pressure

—

concentrated upon a smaller number of vessels

or

when

is

lesions

atheroma, for instance, have diminished their

of the vessels,

power to

is all

centrifugal pressure.

resist

nection, however,

Important in this con-

the fact that, contrary also to the prevailing

is

ground for the belief that hypertrophy of the adrenal secretory tissues, which has been observed by Langlois, Charrin, Petit, Stilling, and others in animals (see page 36) under the influence of injected poisons, does not appear to exert any compensative influence when local disease has destroyed

opinion, there

is

any part of the

medullar}'' zone of the gland.

As shown by Langlois, Gourfein, and tinue to live, when all but one-eleventh

—

been extirpated

add

—

mammals

con-

of their adrenals

had

others,

or destroyed by cautery or disease

we might

some compensative action or some accessory organ be present, death occurs when this limit of normal adthat, unless

renal substance

the medulla

is

reached.

itself

It seems logical, therefore, that, were

capable of assuming compensatory activity,

so large a

supply for emergencies (the nature of which will be

described

later

on)

would

hardly

have

been

provided.

If

analogy be again accepted as guide, other organs do not compensate for what insufficiency organic disease may produce in them by overtaxing remaining normal structures; collateral chromaffin tissues, supernumerary or accessory organs, vicarious functions,

and hypertrophy being

all

added elements, thus con-

stituting either auxiliary resources per se or auxiliary resources j)lus compensative growth. Even in the case of the organs

THE ADRENALS

IN DISEASE

23

AND POISONING.

of special sense, wlierc the loss of one organ imposes all the physiological labor upon the other, the existing tissues are not

overtaxed; they are brought to their highest proficiency by the increase of nutrition which the additional functional use in-

Whatever evidence we have, therefore, tends to show that the remaining normal structures of a diseased adrenal are not replaced by new adrenal tissue, and that they are increasingly exposed to disruptive congestion as the local morbid process volves.

advances. It

is

because of this that adrenal hiemorrhage

is

observed

Moreover, Laba-

with relative frequency in Addison’s disease.

found experimentally that lesions of the adrenals showed

zine®®

that these organs possessed very little regenerative power. large

portions, of

When

the glands were excised no restoration of

parenchyma occurred. Toxics which Produce Congestion or Venous Stasis IN THE Adrenals. The list of disorders to which adrenal hiemorrhage has been attributed is steadily increasing. Pneu-

—

monia,

thrush,

diphtheria,

meningitis,

cancer,

scarlatina,

variola,

sejiticiemia,

(toxic wastes), burns (toxic wastes

purpura,

tuberculosis,

uraemia,

asphyxia

and detritus), typhoid, jaun-

and eclampsia seem, however, to stand out most prominently all of which present as militant agent either a toxin or some toxic intermediate waste. The effect of burns is illustrated by Amaud’s case, in which sudden death followed a burn of the arm. Andrewes’s case, in which death occurred 36 hours after the first symptoms of an acute disease which he thought bore some points of resemblance to haemorrhagic smalldice

—

po.x,

also

illustrates

this

class.

In

fact,

instances

such

as

Andrewes’s have so often been noticed by clinicians that StilP'* has proposed a distinct category of cases in which “after an acute illness lasting only two or three days, usually with

a

purpuric or bullous eruption,” death occurs, “and the suprarenal lesion appears to he a part of the fatal issue.”

That general intoxication can thus act as an original cause shown experimentally. Thus, Eoger'^'’’

of haimorrhage has been Labazine:

Arch,

des

Sciences

Blologlques

de

St.

vol. xl, 1905.

“Still:

“Roger:

Lancet, May 7, 1898. Berliner kiln. Wochenschrlft, Jan.

21,

1894.

Petersbourg,

n.

249.

21

ADltKNALS IN DlSliASE AND POISONING.

Tllli

loimd that inoculation of

guinea-i)ig with a culture of the pnouiiiohacillus of Frietllaiuler was followed by i)i-ofuse haanorrhage into both capsules, the blood actually bursting througli tlio

the great capsular vein, or causing necrosis of the surrounding

elements by mechanical compression. strated

that suprarenal hiv.morrhage

the bacillus pyocyaneus.

Langlois®“

reached

the

demon-

could be brought on by

Charrin” found

hemorrhagic

by injecting which in some was not alone

that,

— —

diphtheria, toxins into guinea-pigs, congestion

instances

also

stage

caused, but he also observed that small doses used repeatedly

and during prolonged periods caused hypertrophy of the gans. fishes

Petit®'*

in

also

or-

noted, after introducing Loftier bacilli in

which the suprarenal structure

is

clearly glandular,

that all the phases of excessive reaction could be brought on.

Ilamiorrhagic foci were found by Wybauw®” in the adrenals of a child

which had died

of

broncho-pneumonia the

result of a

Kiesmann found the staphylococcus and Hamill and Dudgeon the pneumococcus.

tracheotomy for croup. aureus and albus,

That the functions

of the adrenals are actually inhibited

these various pathogenic agencies has been

shown

in

by

various

Mott and Halliburton, for example, found that after death from exhausting diseases the proportion of active princijile present in the adrenals was either absent or greatly reduced. ways.

By

ascertaining the relative proportion of chromaffin granules

in the adrenals of

50 adults who had died of various diseases.

Bainbridge and Parkinson**® were able to note the absence of the agent in the medulla of the organs of cases which had died of infectious diseases, peritonitis, shock, or whei’e a low blood-pres-

sure had existed.

Luksch*'®® ascertained

tlie

degree of functional

disturbance caused in the adrenals by disease, by ascertaining the relative

pressure-raising power

of

their

.material

While show any

extracts.

certain conditions, starvation, simple fever, did not

change in this direction, various infectious diseases;

uraemia and phosphorus poisoning, caused the extracts not to display the normal pressure-raising property.

“

Le Bulletin Medical, Feb. 7, 1894. Mddicale, June 3, 1896. La Semaine Mddicale, June 3, 1895.

nanglois:

”Charrln;

“ Petit: “ Wybauw:

La Semaine

Annales de la Socifetd Royale des Sciences M6d. et Nat. de Nos. 2 and 3. 1897. Bainbridge and Parkinson: British Med. .Tour., May 11, 190(. Luksch: Wiener kiinische Wochenschrift, B. xvli. No. 14, April 6, l» 0 a.

Bruxelles, vol.

vi,

Of

course, a certain proportion of these cases

uted to exhaustion of the glands

That the morbid

disease.

tlie

by the location of

blood-vessels,

veins, the proximity of the inferior

be attrib-

mainly due to excessive

variations of the blood-pressure is suggested its

may

during the course of

effects are

the organs, the richness of

25

AND POISONING.

TIIH ADKISNALS IN DISEASE

especially of its

vena cava, which receives the

blood almost directly from the gland on the right side.

Pressure

during labor upon the inferior vena cava and the suprarenal

and the

gland, located, as they are, between the liver anteriorly vertebral

column

posteriorly,

may

also give rise to congestion of

the vessels of the glands and result in Inemorrhage.

may

Various drugs

bring on hyperasmia, congestion, and

haemorrhage of the suprarenal glands, as shown by

Pilliet,®”'^

who

observed these phenomena after the use of nitrate of uranium.

Essence of cloves has also been found capable of stimulating tliem to such a degree as to bring

on macroscopically

visible

lesions.

On

the whole, the conclusion seems warranted that so

many

common

effect

toxic substances' cause adrenal hcemorrhage that

of all

these poisons

on

a

the general blood-pressure, sufficient to

cause active or passive congestion or venous stasis in the adrenals, is

necessary to explain the genesis of this class of cases.

Increased Functional Activity of the Adrenals as A Predisposing Cause op Adrenal Hemorrhage. The view

—

that the

adrenal

specific

principle

itself

possesses

powers has suggested to those who have accepted

it

antitoxic

the con-

clusion that a high degree of toxaemia, by overtaxing the organs,

caused congestion, and,

if

this reached

beyond certain

limits,

This conception was mainly based on the view of Brown-Sequard, who was led, by the toxic effects of blood taken from decapsulated animals upon normal ones, to ascribe lueniorrhage.

to the glands themselves a direct antitoxic '

function.

It

met

with further support in the fact that violent toxamiia invariably follows the removal of both organs, and was therefore accepted

by many investigators. It was also .maintained by Dubois,®^ v'“Hare:- Therapeutic Gazette, No. 519, 1887. Simonin: Centralblatt fUr Chlrurgle, 234, ’>*Falck: Deutsche Klinlk, vol. xl, 1859. Angelesco: La Seniaine M6dlcale, Dec. 14,

1877.

1891.

63

the adrenals in disease and poisoning.

Mercury was found by Kuperwasser^-* to be differentiated. lower the temperature 2° C., in some instances, when admin-

Opium and

istered in injudicious doses.

its

alkaloids are re-

ferred to as causing the skin to become cold

Oxalic acid in poisonous doses also gives

given in toxic doses. to livid surface

rise

when

tended,

and moist when

and cold

Phosphorus

skin.

ingested in toxic doses, with

often at-

is

what Wood terms

in the temperature,” the lowest point re-

“a remarkable corded some hours before death being 31.2° C. (88.2° Physostigma brought the temperature of a strong man fall

to

96.6°

F.

Santonin poisoning

coldness of the surface.

is

also

P.).

down

attended with great

Silver salts have likewise been found

to lower the temperature of animals.

Strychnine

another agent which tends also to show the

is

correctness of the contention that a low peripheral temperature

means an increased

central temperature.

observations of Ivionka,

who showed

Wood

refers to the

that “the primary eleva-

which occurs in strychnine poisoning, both in man and the lower animals, is in animals followed by a pronounced fall, which takes place even if the convulsions persist,” and to the affirmations of Mosso,^^® that, “even in curarized dogs a very pronounced rise of rectal temperature may be produced by strychnine.” Very suggestive in this connection

tion of temperature

is

the

denial

credited

to

Delezenne,^^®

'Vho

states

curarized animals the exhibition of strychnine

is

that

always

in fol-

lowed by an abatement of the central temperature, which is often, but not always, followed by an increase of the temperature of the surface.”

This increase Delezenne explains by “the

supposition that the drug has the power of dilating the peripheral

vessels.”

It

now becomes evident

that the only discrepancy

between the observations of Mosso and Delezenne latter

is

that the

used smaller doses of strychnine than the former, thus

producing central contraction and peripheral dilation, instead

and peidpheral contraction. trum, and zinc show corresponding effects, list of agents whose temperature variations of central dilation

Kuperwasser: 6,

Archives des Sciences Biologiques de

1898.

’’“Mosso: Archives italiennes de Biologie, 1886. Delezenne: Bulletin Mfidlcal du Nord, xxxiv,

1895.

Tobacco, vera-

and are St.

close

the

considered

Pdtersbourg, No.

— THE ADRENALS

54

along with

other

toxic

IN DISEASE effects.

AND POISONING.

All

present

a reduction of peripheral temperature as a sign of advanced poisoning; none

show simultaneous central and peripheral hyiiothermia several incidentally show that, when peripheral hypothermia is ;

present, there

is

simultaneous internal hyperthermia.

The personal view

that the adrenal secretion becomes con-

verted in the lungs into the oxidizing principle of the haemo-

globin

(see next chapter),

and thus sustains oxidation

in

all

accounts for the morbid effects of poisonous doses of

tissues,

drugs and venoms

on

temperature.

the

adrenals, active or passive,

is

Congestion

doses, of raising or depressing the blood-pressure.

gestion or engorgement

haemorrhage, adrenals,

may

it

is

of

the

caused by drugs capable, in full If this con-

excessive, or sufficient to cause adrenal

inhibit

or arrest

the

functions

of

the

and thus cause hypothermia.

A'enoms, which lower the teniperature mainly by dissolving the blood-cells, thus inhibiting the o.xygenizing power of the blood, also inhibit the functions of the adrenals by this process;

but they likewise do so by causing excessive variations of the blood-pressure as do other poisons, thus affording an additional cause of hypothermia.

SulIMAHY OF THE ^lOUBID EFFECTS OF DrUGS AND VENOMS ON THE Adrenals. In the light of the conclusions sub-

—

mitted in the foregoing sections (pages

3-i to

54) cnmcerning the

which the functions of the adrenals are compromised by variations of the general blood-pressure, on the one hand, and the morbid inlluence on the blood-pressure and through it on the adrenals of toxic doses of drugs, on the other, I submit

manner

in

the following conclusions as important in the clinical field: 1.

Drugs, such as antipyrin, alcohol, belladonna, cocaine, mercury, opium, strychnine, quinine, etc., whose

digitalis, ether,

action in full doses asthenia, hypotonia

produce,

among

is

to raise the blood-pressure, cause

and hypothermia in toxic

other effects:

acute

marked

doses, because they

congestion

and perhaps

hiemorrhage of the adrenals, and thus inhibit or arrest the functions of these organs. 2.

Drugs, such as aconite, arsenic, antimony, chloral, hydrowhose action

cyanic acid, jdiysostigma, tobacco, veratrine, etc., in

full

doses

is

to

lower

the

hlood-pressiire,

cause

marked

;

THE ADRENALS asthenia, hypotonia prodiiee,

among

IN DISEASE

and hypothermia

other ctreets

and perhaps hannorrhage

:

AND POISONING. in toxic doses, because they

passive conejestion or venous stasis

of the adrenals,

and thus inhibit

or

arrest the functions of these organs.

The symptoms produced by the

arrest of adrenal functions are

in both groups of drugs, viz., weakness, lowering of the

same

blood-pressure and temperature; but these same also

symptoms

the most prominent ones in Addison’s disease

are

and after

removal of both adrenals.

We

have seen on page 38 that

to toxins 3.

—

Venoms.

Noe and

all this

applies equally well,

a subject treated at length in the next chaj^ter.

—The

labors of Delezenne, Flexner

others having

and others

rattlesnake,

shown that some venoms

—caused

(1)

and

—

ISToguchi,

cobra, viper,

haemolysis, thus depriving

oxidizing power, and (2) proteolysis, thus exposing various tissues to necrobiosis and the vessels to softening the blood of

its

the adrenals receive blood incapable of sustaining their functions though destructive to their vascular their secretory activity being

and secretory elements;

impaired or arrested, the asthenia,

hypotonia and hypothermia from this source intensify

symptoms due

to the effects of this disorganized

-the

same

blood upon other

tissues.

Destined to suggest new lines of thought, the present work

would have

to

be restricted to this chapter, in so far as the

adrenals are concerned, were the prevailing views as to their

functions

—

-that

they serve to sustain the tone of the cardiac

—

and vascular muscles taken as sole guide. But, as is now well known, I have held for several years that this role is but an

—an

incidental feature of their true functions fully to sustain in the next chapter.

assertion I hope

ClIAPTEli

II.

THE FUNCTIONS xVNiJ DISEASES OF THE ADKEXALS. UNEXPLAINED PROPERTIES OF THE ADRENAL SECRETION.

—

As we have

seen, adrenal preparations

extracts, tlie

pow-

dered gland, the active principles, epinephrin, supracapsulin, adrenalin, etc. cause a rise of the blood-pressure with slowing

—

of the heart-beat, a minute dose sufficing to produce a

But, as liowelP

effect.

“the effects produced

states,

extracts are quite temporary in character.

marked l)y

few minutes the blood-pressure returns to normal,

as also tbe

heart-beat, showing that the substance has been destroj'ed in

way is

in the body, although

not known.^

where and how

such

In the course of a

some

this deslruciion occurs

According to Schafer, the kidneys and the

adrenals are not responsible for this prompt elimination

or

Several observers have shown

destniction of the active substance.

marked

on

satisfactorily that the material

producing

the heart and blood-pressure

present in perceptible quantities

is

this

effect

in the blood of the adrenal vein, so that there can be but little

doubt that

The

first

it

is

a distinct internal secretion of the adrenal.”

question which imposes

itself,

What

therefore, is:

is

the fate of the adrenal secretion in the body beyond the adrenal

vein ?

Adrenal preparations are

all

endowed, as

first

observed by

Vulpian many years ago, with marked reducing activity, i.e., with a marked tendency to take up ox}"gen. Abel, who isolated the adrenal active principle he termed “epinephrin,” for instance, so marked that Takamine noted that the

proved

a source of incon-

found this tendency

it

venience.

colorless aqueous solution of

his “adrenalin” \vas easily oxidized

color

changing from pink

to

rod,

by contact with the and eventually

to

air, its

brown.

Cybulski also observed that the addition of potassium permanganate, a powerful oxidizing agent, destro)"ed the activity of '

Howell:

“

The

Lor.

Italics are

(5d)

rif.,

my

p.

842.

own.

UNEXPLAINED PROPERTIES OF THE ADRENAL SECRETION.

the relatioiisliip between this reducing

ailreiial e.xtract.

What

property and

blood-pressure raising power?

tlie

is

Various experinieiiters ]\Iorel,^

57

clinicians, including lleichert,^

and

and Lepine,“ have observed that even non-toxic doses of

Others, caused a rise of temperature. prografts could adrenal Courmont,“ for example, found that duce such a rise as to warrant the iihrase “formidable hyper-

adrenal preparations

Conversely

thermia.”

we know

Addison’s disease,

adrenals,

that destructive disorders of the

example, or removal of the

for

adrenals, cause a rajiid decline of the gests that the adrenal secretion

temperature.

This sug-

must be endowed with oxidizing

power, and yet we have seen that it is a reducing agent. How account for this anomaly and for the power of adrenal products

temperature?

to raise the

When nephroma

the adrenal tissue of children, there

The

tion of the subject.

is

excessive,

is

in the hyper-

as

excessive oxidation

and overnutri-

process of growth and development are

such in some cases as to cause a child to appear several times age

—

its

a child of 4 years, for example, being as large as one of 16.

How

account for this phenomenon as a result of an excessive

when

production of adrenal secretion, which presumably occurs the secreting elements are also in excess?

Xot

all

extractives.

vessels are influenced

A

by the adrenal secretion or

striking fact in this connection

exemption of the pulmonary tissues to the

is

the apparent

effects of the secretion.

Wallace and iMogk' found that, while adrenal extract caused a rise

of the

systemic blood-pressure due to the contraetion of

the arterioles, the pressure in the

pulmonary

are the others.

Dixon.®

ments

arteries

is

This observation was confirmed by Brodie and

Velich,® on the other hand, found, by a series of experiinstituted

existed for the

to

ascertain

pulmonary

whether

vasoconstrictor

vessels, that adrenal extract

to but a slight rise of pressure.

Wann

fibers

gave rise

adrenal extract, which,

“Reichert: Univ. of Penna. Med. Dull., April, 1901. * Morel: Le ProgrOs MOdlcal, Aug. 3, 1903. “Lepine: La Semaine medical e, Feb. 18, 1903. “ Courmont: CongrSs de MOdecine Interne, Montpellier, 1898. Transactions of the Physiological Society, 7 Wallace and Mogk: 28“30, 1898.

Brodie and Dixon: Journal of Physiol., vol. xxx, p. "Velich: Wiener med. Wochenschrift, No. 26, 1898. 8

not

being acted upon as

raised, these vessels, in their opinion, not

416,

1903.

Dec.

FUNCTIONS AND DISEASES OF TUB ADRENALS.

58 wlien

apj)lic'(l

to exercise

even to

was found liy him upon tlie surface of the lungs. This familiar fact upon u-hich Parhon and (Jolstein*®

no such

accounts for the

skin, causes pallor,

tlio

cll'ect

lay stress, that intravenous injections of adrenalin can produce afcute

pulmonary

cedenia,

owing doubtless to the marked

Why

blood-pressure in the rest of the organism.

rise of

this exception ?

Such were the questions which I attempted to answer edition of this work, which appeared eight years ago.

in the

first That some functional relationship with the respiratory process should have suggested itself as at least a working proposition seems selfevident when the avidity of the adrenal product for oxygen, its influence over general oxidation and nutrition, and the invulnerability of the lungs to its action, on the one hand, and tlie fact that both pulmonary and tissue respiration still belonged to the domain of conjecture, on the other, are taken into account. That this relationship actually exists, is also sustained by a large number of solid data, biological, histological and clinical, and by the fact that it explains not only the mooted points just

many

enumerated, but

others which the prevailing doctrine fails

to elucidate.

THE ADRENAL SECRETION AS THE OXIDIZING AGENT OF THE H.EMOGLOBIN. That the prevailing view on the physiology of respiration, based on the diffusion of gases, has not been, and is not now, “When,” endorsed by all physiologists is now well known. caused is animal “an writes Professor ]\lathias Duval," of Paris, to breathe in the smallest possible space its

lungs

—

it

uses

up

all

the oxygen

hamioglobin, in virtue of

oxygen as fast as latter,

this gas is

always despoiled,

is

its

—the

air

in the air.

chemical

dissolved

m

affinity,

the

imprisoned in

This

serum

never able to satisfy

is

takes ,

its

because

vp the

so that the

absorption

coefficient for o.xygen, however low be this coefficient, and however slight be the tension of the oxygen in the surrounding air. As to the exhalation of carbonic acid, it is not produced so simply as would a priori seem, by mere gaseous diffusion or by

'I

Parhon and Golstein; Lor. rit., p. 725. Mathias Duval: Cours de Physiologle,

“

All Italics are

'o

my

own.

1892.

59

THE ADRENAL SECRETION AS THE OXIDIZING AGENT.

-

the mere giving off of a gas in solution, because of of the

in tlie

giis

suiTounding atmosphere.

tlic

Indeed,

scarcity

tlie

air in

the pulmonary vesieles contains 8 per cent, of carbonic acid, hardly a favorable eondition for the escape of carbonic acid from

the blood, especially since a portion of this gas is not dissolved, but combined M'ith the serum salts. It is therefore probable that the pulmonary tissues are the seat of an action having for This action object to rapidly dislodge the carbonic acid.

its is

Whenever oxygen is probably of a chemical nature. during experiments, the vitro in. even venous blood, mixed with One is led to admit, carbonie acid is immediately given off. .

that

therefore,

the

.

combination of

.

oxygen with the blood-

corpuscles (oxyhaemoglobulin) plays a role analogous to that of

and involving the elimination of carbonic acid from venous blood.” He refers to Eobin and Verdeil’s view in respect to the existence of a hypothetic “pneumonic acid” and to the an

acid,

experiments of Garnier,^^

who observed

that ultramarine blue,

sprayed into the lungs of living guinea-pigs, lost

its

color:

phenomenon which could only occur through the presence

a

of a

strong acid, neither taurin nor carbonic acid being capable of

producing

“Chemical analysis of the lung has not disclosed

it.

a specific acid, however.” “It is, perhaps, wrong,” adds Professor Duval, himself a prominent physiologist, “for physiologists to continue to only

phenomena mere results of endosmosis of liquids and of diffusion of gases through an inert membrane.” As a clinician, I would urge that this theory is harmful in its far-

see in these

reaching consequences. ter,

upon which

and that

it

is

it is

I

have pointed out that the aerotonome-

mainly founded,

is a

defective instrument,

because of this that the results recorded by

various physiologists have been divergent to such a degree that,

some instances, the diffusion of oxygen should occur, to corits indication in the wrong direction, i.e., from the haemoglobin to the alveolar air, the tension of oxygen in the arterial blood being actually higher than the pressure of ox 'gen 3 in

respond with

in the air-cells. I characterize the prevailing theor}^ as “harmful” because the physiologist, engrossed in his own field, does not realize that

Gamier:

Comptes-Rendus de I’Acaddmie des Sciences, July

26,

1886.

— FUNCTIONS AND UISFASES OF THE AURENAXS.

(30

dealing witli the foundation of probably the most important i)roblem of our day in its influence over human life, viz.,

lie is

immunity not only

—

in the tissues at large, but at the very thresh-

pulmonary alveolar surface, and the alimenshown later. ximtENAL Secretion in Pulmonary Pespiratton.

old of infection

the

tary canal, as will be

The In the

work (lil03) 1 advanced the view, sustained by considerable evidence, that the adrenals took edition of the present

first

a leading part in the respiratory process

by supplying a secrewhich absorbed the oxygen of the air in the pulmonary alveoli, then became a part of the hannoglobin and of the bloodtion

plasma, •which in turn carried

it,

as oxidizing principle, to all

tissues.

Three years after this opinion was formulated, a noted English physiologist, Peinbrey, wrote''* in an impartial review of the recent advances in physiology and bio-chemistry:

“It

is

impossible to give a satisfactory account of the gaseous exchange

between the blood and the alveolar

air.”

.

.

.

“The body

of

evidence has been steadily increasing in favor of the secretory theory, especially as regards the absorption of oxygen.”

theory

is

This

that of Bohr, advanced in 1891, which attributes the

oxygen-absorbing power and the excretion of carbon dioxide to active secretory processes carried on by the lining

membrane

of

While the need of a secretion capable of absorbing the oxygen has been steadily growing in favor, however, the the air-cells.

secreting

This

my

from

membrane has not been found. is

explained Avhen the respiratory process

viewpoint:

reducing secretion below,

its

is

properties

It

is

is

considered

not hy a local membrane that the

As shown and itinerary are precisely those required produced, but by the adrenrds.

for the process, while its presence can be ti'aced at every step to

the haemoglobin

A

itself, of

which

it

fomis part.

succinct review of the experimental evidence which has

invalidated the diffusion doctrine, and of that upon which

conception

better than a prolonged analysis of the question (for which

reader

is

my

of the respiratory process is based, will perha]')S serve

referred

to

previous editions)

to

tlie

convey the actual

status of the question. Pembrey: p. 549, 1906.

Hill’s

"Recent Advances

In

Physiology and Bio-Chemlstry,”

61

THE ADRENAL SECRETION AS THE OXIDIZING AGENT. Paul

P>erl/'”' tliirty

years ago, .showed experimentally that the

absorption of oxygen by the pulmonary blood persisted, even when Muller also observed the pressure of this gas was almost nil. that a strangulated animal exhausted the air in its lungs of all its

oxygen, while Setschenow and Holmgren,^'' Zuntz,’’ and others

found but traces of oxygen in the arterial blood of asphyxiated This suggested that the diffusion doctrine was defecanimals. tive, and that the absorption of oxj^gen from the air was due to

some This conclusion was substance capable of taking up this gas. sustained by the researches of Bohr,^® Haldane and Lorrain Smith,^“ Vaughan Harley,-“ and Bohr and Henriciues,"^ the last-

the presence, in the blood circulating through the lungs, of

named

referring

investigators

to

as

it

a

substance

greater avidity for oxygen than the blood itself”

“having

and presumably

“a kind of internal secretion.” This view has been antagonized by some of the advocates of

(whose aerotonometric figures are sugges-

the diffusion theory

tively discordant), but as

we have

seen the “evidence has been

steadily increasing in favor of the secretory theory, especially as

regards the absorption of oxygen.”

Having repeatedly noted the powerful reducing properties of adrenal extractives,

adrenals might

the

it

occurred to

fulfill

various lower animals and in

this

me

role.

man, and

that the secretion of

Anatomical studies in a systematic research in

the literature of the subject, demonstrated that

it

met

all

the

conditions required to satisfy so important a function.

The The

first

deduction imposed by these researches was that

secretion

of

the adrenals has a

marlced affinity for

oxygen, and inevitably reaches the pulmonary

air-cells.

Vulpian,^- over fifty years ago, found that adrenal juice reduced iron perchloride and iodine. Cybulski-® recorded a similar action

on potassium permanganate; Langlois-* noted,

however, that adrenal extract lost

its

reducing properties in vitro

’^Paul Bert: C. r. de I’Acad. des sci., Oct. 28, 1878. Setschenow and Holmgren, cited by Ludwig: Wiener raed. Jahrb., 21st

year,

i,

p.

1865.

145,

"Zuntz:

Hermann’s “Handbuch.”

iv. part 2, p. 43, 1882, Skandin. Archly fUr Physiologie, p. 236, 1891. J^S^'^one and Lorrain Smith: Jour, of Physiol., xxii. No, 3, p. 231, ^Vaughan Harley: IhUI., xxv. No. 1, p. .33, 1899. "Bohr and Henriques: Arch, de physiol., ix, pp. 459 and 819, 1897. jrXulplan: C. r. de I’Acad. des sci., p. 663, Sept. 29, 1856. - Cybulski Gaze-ta Lekarska, 2d series, xv, pp. 299-308, 1895. Langlois: Arch, de physioi. norm, et pathol., x, p. 124, 1898,

Bohr:

:

1897.

FUNCTIONS ANU UISKASKS OF THE AUUENALS.

62

when

oxidizing compounds were added. As to the action of the atmosphenc oxygen, Battclli*® found that adrenalin did not lose its jirojicrties when contact with air was iirevcnted, while Ahel,-“ 'rakainine,-' and others refer to this property as a source of

trouble in laboratories, the latter chemist specifying, in fact, that

adrenalin becomes oxidized by contact with the

air.

That the adrenal secretion inevitably reaches the evas

made

clear

air-cells

by a study of the anatomical relations between

the adrenals and the lungs.

The

blood of the efferent vessels of

the adrenals, their veins, passes to the inferior vena cava, directly

on the right

and by way of the renal vein on the

side,

The

left.

actual presence of the adrenal secretion in the blood of the

adrenal veins

is

shown by many experimental

Gottschau,-*

facts.

for example, traced hyaline granules (found subsequently to be

from the interior of the adrenals to their veins. This observation was confirmed and amplified by Manassc,-“ Aulde,®“ and Stilling.®' Pfaundler®® traced the same granules from the interior of the organ along the adrenal veins to the vena cava itself. It is doubtless the adrenal secretion and no other which is carried by the blood of the vena cava, for, when blood originating from the adrenals on its evay to this great trunk was injected into animals by C}'bulski and Scynionowicz,®® it protheir secretion)

duced the characteristic were confirmed by

effects of

adrenal extract.

Riedl,®'* Langlois,®®

These results

and Dreyer.®*

Scymono-

wicz, Riedl, Dreyer, Salvioli, and Pizzolini®' found; moreover,

that such effects could not be obtained with venous blood obtained

from other parts of the body.

The next

On

fact to assert itself

reaching

the

air-cells,

was that the

adrenal secretion

absorbs

o.xygen and becomes a constituent of luemoglobm and of the red corpuscles.

®®Battelli: C. Bull.

“Abel:

r.

de

la Soc.

de

biol.,

Johns Hopkins Hosp.,

liv, p. 1435, 1902. p. 215, Sept. -Oct.,

1898.

Takaniine: Therapeutic Gazette, p. 221, April 15, 1901. “Gottschau: Arch. f. Anat. u. Physiol., Anat. Abth., p. 412, 1883. “ Manasse: Arch. f. Path. u. Physiol., cxxxv, p. 263, 1894. “Aulde: Brit. Med. Jour., May 4, 1804. Arch. f. path. Anat., cix, p. 324, 1897. Stiiling: »» Pfaundicr: Sitzungsber. d. k. Akad. d. Wissensch. Mathem., cl, p. “ Cyhulski and Scymonowlcz: Gazeta Lekarska, 2d scries, xv, pp. 1895: Archiv f. d. ges. Physiol., Ixiv, Nos. 3 and 4, p. 97, 1896. “Biedl; Archiv f. d. ges. Physiol., Ixvli, part 9-10, 1897. “Langlois: Arch, de physiol, norm, et pathol., ix, p. 152. 1897. “ Dreyer: American Journal of Physiology, 11, p. 203, 1899. ” Salvioli and Pizzollni: Gazetta degll osped.. Mar. 23, 1902.

3,

1892.

299-308,

THE ADRENAL SECRETION AS THE OXIDIZING AGENT.

63

While a reducing substance has been found necessary, we have seen, to account for the absorption of oxygen from the

happened that the greater part of the htenioglobin molecule was composed almost entirely of an albuminous substance which had remained unidentiiicd. Gangce,*'’® for instance, alveolar air, it

states

that “hamioglobin exists in the blood-corpuscles in the

form of a compound with a yet unknown constituent of the corThis body he defines as the “albuminous moiety of the puscles.” molecule”

liamioglobin

and,^”

as

representing

per

96

cent,

of this molecule, the remaining 4 per cent, being the iron-

laden haematin.

Now,

I

found that

of haemoglobin corresponded in

ether,

and

“unknown

constituent”

physicochemical properties

insoluble in absolute alcohol, chloroform, benzol,

is

all

this

Gamgee,'*" for example, states that

with the adrenal secretion. haemoglobin

its

organic solvents

:

Vulpian'*^

had already noted that, showed this

of all glandular produets, that of the adrenals alone peculiarity.

Gautier,'*- Moore,'***

and Takamine

also refer to

it.

Again, according to Moore and Purinton,'*'* adrenal extracts are rapidly destroyed by alkalies; this

haemoglobin.

This pigment likewise

resists

point; this applies also, according to others to adrenal extract.

a characteristic of

also

is

heat up to the boiling Moore,'*®

C}'bulski,'***

and

Finally, Mulon'*' found that the red

corpuscles gave the histochemical reactions of the active principle of the adrenals, thus showing that these blood-cells actually coutain this principle.

Since then the adrenal reaction has been

obtained from blood-elements wherever sought, including that of the placenta.

In confirmation of this conclusion

The oxygen-laden adrenal

is

secretion

the fact that is

a constituent of the

albuminous hcemoglobin in the blood-plasma. BattellP® isolated from the blood a product the chemical properties of adrenalin. is

That

endowed with

this adrenal principle

a constituent of the albuminous portion of liamioglobin voided

“Gamgee: Gamgee: Gamgee; ‘’Vulplan: *=

«

Gautier:

Schafer’s “Text-book of Physiology,” Ibid., p. 207, 1898. Ibid., p, 206, 1898. C. r. de I’Acad. des scl.

Chimie biologique,

p.

355,

i.

de Paris, Sept.

p.

29.

189,

1898.

1856.

1892.

Moore;

Journal of Physiology, xvii, p. xlv, 1894-95. “Moore and Purlnton: American Journal of Physiology, “Cybulskl: Gazeta Lekarska, Mar. 23, 1895. “ Moore: Loc. cit. “Mulon; Personal Commun'eat'on. “Battelll: C. r. de la Soo. de biol., liv, p. 1179. 1902.

iii,

p.

15,

1900.

FUNCTIONS ANO DISEASES OF THE ADRENALS.

()4

by red corpuscles herg,^“

slioAved that

plasma suggested

in the

when Scluniede-

itself

Ahelous and Biarues/’*

Jaquet,"®

and other chemists

hlood-plasma contains an o.xidizing substance, sub-

Kot only was

sequently knoM’n as oxidase. at least uj) to the boiling point

and

found to

it

resist

heat

to possess otlier chemical char-

acteristics of the adrenal principle, hut the actual presence of the

latter is confirmed

by other

facts.

Thus, in 1853, Traube had

concluded that htemoglohin could not functions ascribed to

fulfill

the physicoehemical

without the aid of a catalyzer.

it

showed that the adrenal principle was a

PoehP-

catalyzer, while Jolles''*

pointed out that the activity of a given volume of blood as a catalyzer corresponded with the

number

of red corpuscles

It is because of this that Oliver

tained.

it

con-

and Schafer found that

oxidation of the adrenal principle does not occur in the blood; acting as a catalyzer

monary

simply transfers oxygen from the pul-

it

air to the tissues

without being

modified by the

itself

Indeed, Miller®'* found that the blood of a rabbit which

contact.

a dose of adrenalin caused a typical rise of blood-

had received pressure

when

injected into the blood of another rabbit, although

the effects of the adrenal principle upon the

first

animal had

Additional evidence to this effect and an explanation of

ceased.

the role of the red corpuscles were afforded by the next conclusion

reached

:

That corpuscles, after absorbing the oxygenized adrenal

The red

secretion {the albuminous constituent of their h(Emoglobin) yield it to the blood-plasma in the form of droplets, the so-called “blood-platelets.”

under the influence of various chemical agents, “undergoes a decomposition of which the chief products are, an albuminous substance or substances, and a coloring matter which contains the whole of tlie iron”; Init,

As Gamgee®®

teaches, luemoglobin,

as he also says, “the coloring matter of the red corpuscles is not This does not, however, extracted from them by the plasma.”

apply to their albuminous substance.

That they discharge the

Schmiedeberg: Archiv f. exper. Path. u. Pharm., v p. 23.'?, ISiG. “Jaquet, cited by Salkowski: Archiv f. path. Anat., Jan. 4. 1897. series, Ahelous and Blarn6s: Arch, de physiol, norm, et pathol., .Gth

«

,

pp. 195, 239, 1895.

Poehl: “Jolles:

May

Indian Lancet,

22,

1904.

MQnch. nied. W'och.,.p. 2083. Nov. “ Miller: Jour. Amer. Mod. Assoc., May 18,

“Gamgee:

Loc.

cil.,

1,

p.

189,

1898.

1904. 1907.

22.

vii,

THE ADRENAL SECRETION AS THE OXIDIZING AGENT. latter in the

plasma

is

rendered evident by various

()5

Louis

facts.

Elsberg/® thirty years ago, observed “a projection of a pediculated granule or knob” from tlie periphery of red corpuscles. Hirschfeld®^ traced these granules from the interior of tliese

up

cells,

through one or more minute apertures which closed the surrounding plasma. Brockbank’’'’® gave recently a beautiful microphotograph of “platelets in, or being extruded from, red cells.”

again, to

Again, Detemann'^® noted that the buds on the surface first are attached to the cell by protoplasmic

of the red cells “at

processes and contain

hemoglobin”; but

become separated from the

that, “later, the

buds This

losing their hemoglobin.”

cell,

does not militate against Gamgee’s statement that the coloring

matter remains in the corpuscles, but

albuminous constituent

is

it

indicates

that

the

voided into the plasma.

These albuminous droplets (which, in 1903,®“ I identified as absorbed o.xygen in the lungs,

the familiar hlood-iP.atelets)

should, in the light of preceding deductions

and owing

to the

catalyzing property of their adrenal principle, be able to sur-

render their oxj'gen to any agent in the blood or tissues possessed

power to appropriate it. That this applies shown by the reaction to certain stains. Litten®^ and others found, for example, that blood-platelets derived from of sufficient reducing to the droplets is

the red corpuscles are best stained Avith methylene-blue; Stengel,

White, and Pepper®®

state, in fact, that

the only positive results.” certainly rieh in oxygen

—

as

their identity as the oxygenized

—

adrenal seeretion would suggest the

conditions

“essential

“methylene-blue gave

This indicates that the droplets are

to

for, as

the

Ehrlieh teaches, one of

methylene-blue

reaction”

is

“oxygen saturation.”®®

A

study of the melanins then showed that

The alhuminous constituent laden adrenal secretion^

is

of the hcemoglohin, or oxygen-

distributed by the red corpuscles to all

parts of the body as an oxidizing agent.

“

Louis Elsberg: Annals of the N. Y. Acad, of Sci., i, 1879. Hirschfeld: Virchow’s Archiv, clxvi, part 2, p. 195, 1901. Brockhank: Med. Chronicle, Mar., 1908. Determann: Deut. Archiv f. klin. Med., Ixi, part 4, p. 365, 1898. ““ Sajous: The present work, 1st ed., vol. i, p. 715, 1903. “'Litten: Deut. nied. Woch., No. 44, Nov. 2, 1899. ““Stengel, White, and Pepper: Amer. .lour. Med. Sci., May 9, 1902. “ Quoted hy L. P. Darker: New York Medical Journal, May 15 et scg., 1897

“

to 1898.

— FUNCTIONS AND DISEASES OP THE ADRENALS.

(i()

Leonard

most

Hill/'*

llirschfeld,

Chittenden and

Albro,”'' and upon melanins, the brown and black certain forms of sarcoma, in the tissues, the

classic writers look

pigments found in

blood, the urine, etc., in various morbid states, as ha.mioglobin

While Mbnier, Hrandl, and L. Pfeiffer"® found that contained iron, and accept this origin, l^encki and Berdez"^ do not, because they failed to find this metal in the pigment isolated derivatives. it

from a melanotic sarcoma. These discordant opinions are harmonized, hoM’6ver, by the newer conception I submit: The first-

named authors

dealt with whole luemoglobin, containing, there-

fore, its iron; while

Xencki and Berdez dealt quite as surely its albuminous constituent.

with luemoglobin, but only with

Having traced

to the adrenals the origin of the active agent

of this albuminous hamioglobin and this substance being melanin,

the presence of the adrenal

shown.

In the

first

principle

in

melanins should be

place these pigments were found by Walter

Jones"" insoluble in alcohol, ether, benzol, chloroform,

etc., i.e..

precisely as Vulpian, Moore,

and others had found

with the adrenal principle.

This applies as well to the action of

alkalies, to

which Jones,

and

Aliel

to be the case

and Davis"® found melanins very

In the second place direct evidence was afforded by Boinet,'® who found chemically that the bronze pigment of Addison’s disease was identical to melanin, and also sensitive,

to other tests.

by ]\Iuhlmann,'‘ who discovered independently that the Addison ian pigment was a product of the adrenals.

-

Finally, as the connection of the adrenal product with res-

piration and o.xygcnation I urge, suggests:

An

excess of adrenal secretion causes a nse of temperature. This action was first observed by Oliver and Schafer.'®

Keichert’" recorded a rise of 1° C. in the dog, having reached this

temperature “in

mental animals

it

less

than forty minutes.”

In three experi-

“continued hypernonnal for over two hours.”

•“Leonard Hill: “Text-book of Chemistry.” p. 374, 1903. ““Chittenden and Albro: Amer. Jour, of Physiol., 11, p. 291, »“ Morner, Brandi, and L. Pfeiffer, cited by Haramarsten: Physiological Chemistry," 5th American Ed., p. 688, 1908. Nenckl and Berdez: Ibid. Walter Jones: Amer. Jour, of Physiol., il, p. 380. 1899. ““ Abel and Davis: Jour, of Exper. Med., I, p. 381, 1879.

™

Boinet:

Marseille mOd., April

15,

1896.

Milhlmann: Deut. med. Woeh., No. 26, p. 409, 1896. Oliver and Sehilfer: Jour, of Physiol., xvlii, p. 2.30, ” Reichert: Unlv. of Penna. Med. Bull., April, 1901.

1895.

1899.

“Text-book of

THE!

ADRENAL SECRETION AS THE OXIDIZING AGENT.

MorcF* noted

67

a rise of 0.5° to 1° C. (0.9° to 1.8° F.) in guinea-

Lepine^® states that the increase of blood-pressure caused

pigs.

by adrenal extract This

is

is

always followed by a rise of temperature.

controlled by the familiar fact, first observed by

Sequard, that removal of the adrenals

is

Brown-

followed by a steady

decline of temperature and by the hypothermia which attends

Addison’s disease. Additional evidence on this particular feature of the gen-

problem will be found in Volume II. I studied, for example, the evolution of the red corpuscles throughout the animal scale'’“

eral

and learned that they were tardy additions to the blood

when the Inemoglobin

cells

many

invertebrates

as storage

diffused in the plasma, as

is

in

and in certain low vertebrates, failed

to

satisfy the needs of the vital process.

the conclusion that, contrary to what

it

Having been brought to now taught, it is the

is

plasmatic Inemoglobin which carries oxygen to the tissues and not the red cells (though these act as storage cells for it as a constituent of their albuminous Inemoglobin),

stance in

various tissues and organs,

I traced this

sub-

including the nervous

system, the guaiac and methylene-blue tests being those most frequently employed. reactions

term to

of

the

Again,

I

found that the oxidases gave the

oxygen-laden adrenal

secretion.

Hence the

I applied to the latter: adrenoxidaseJ'^

On the whole, this evidence, considered collectivelj^, seems me to afford a solid foundation for the conclusion that It is the adrenal secretion which, after dhsorhing

from

the 'pulmonary air

and heing taken up hy the red

oxygen

corpuscles,

supplies the whole organism, including the hlood, with its oxygen. It

is,

as such, the oxidizing constituent of the hcemoglohin, which,

in turn, sustains tissue oxidation

and metaholism. This latter function is treated in detail in the second volume. “That the suprarenals are related in some way to metabolic changes in the tissues and organs,” says Schafer,'^® “there can be but little doubt. This is indicated by the symptoms of Addison’s disease.”

Additional evidence in favor of this conception of the role ’‘Morel: Le Progrfis medical, Aug. 3, 1903. ” LOpine: La Semaine mOdicale, Peb. 18, 1903. Sajous: The present work, p. 828.

”

™

Sajous: Ihid., p. 822. Schafer: British Med. Jour., June n

G,

1908.

FUNCTIONS AND DISEASES OF THE ADRENALS.

()S

of the adrenal secretion

is

all'orded

by the fact that

it

accounts,

shown by a few examples, for the properties of the adrenal secretion and preparations that the prevailing restricted as will he

view

fails to explain.

Increased oxidation clearly accounts, for instance, for the observations of Reichert, Morel, Lepine and others, referred to above, that even non-toxic doses of adrenal extractives produce a rise of temperature, or those of Israel'® which showed the great frequency of fever in tumors of the adrenals, or those of Courinont"® in which adrenal grafts produced without the least

evidence of infection what he characterized as a “formidable hyperthermia.” In the latter cases it persisted until death oc-

Xor

curred.

with the

rise

is

an ephemeral phenomenon,

it

blood-pressure,

of

in

the

as

is

adrenal preparations, for, as Reichert observed in

ments, the high temperature persisted as

the case

experimental use of

much

as

liis

experi-

two hours in

some of the animals. Again, adrenal preparations are familiarly known to raise the blood-pressure; but, obviously this

but not how they do adrenal secretion

as

it.

tells

This becomes

us only what they do,

clear,

the active constituent

however, when the of hiemoglobin

is

regarded as the oxidizing agent of the tissues, and, as such, an active factor in metabolism.

The muscular elements

of the arter-

being themselves the seat of increased metabolic activity, they

ies

are

caused to contract, thus raising the blood-pressure.

shown by Oliver and Schafer, however, there is action on the arterioles, and by Meltzer®^ a similar

also a

As

direct

action on the

capillaries. This local effect is due also to enhanced metabolic activity of the adrenal product, its identity as catalyzer enabling it to activate oxidation in any

endothelium of the the

tissue with

The

which

it

comes into contact.

hypernephroma the inordinate oxidation, due

excessive growth of children caused by

also finds its

normal explanation

in

to the overproduction of adrenal secretion.

The

resulting surplus

activity, with alinormnl appetite and thirst as accompaniment, clearly accounts for the excess of nutriwhich the jihenomenal overgrowth is due.

of metabolic logical

tion to

cUtd by Moffltt: Boston Med. and Surg. Jour., Oct. S. Courmont: Congrfis de M^declne Interne, Montpellier, 1898. Meltzer; Amer. Jour. -Med. Sel., Jan., 190:".

^•Israel,

1908.

69

THE ADRENAL SECRETION AS THE OXIDIZING AGENT. 111

its

relations

general diseases,

to

tlie

adrenals as

of

identity

the

accounts for

the eontrolling agents of oxidation

that ubiquitous syiuptoiii, fever, the inechanisin of which has also remained obscure. This gives these organs a prominent place in

Indeed,

pathology. certain limit

is

if

the

modern doctrine that

fever

up

to a

the outward expression of an auto-protective or

sound—and the bulk of evidence strongly become factors in —the adrenals,

immunizing process sustains this view

is

fever,

as direct

Their also direct factors in protecting the body against disease. role in the economy thus assumes noble proportions in the extreme, since by their influence on tissue oxidation the adrenals sustain

life,

defend

life.

while through their participation in immunity they

Addison’s disease

may

be due, as

is

well known, to tuber-

and other organic disorders of the changes in the solar plexus and semiadrenals, or to pathologic lunar ganglia. But how do these lesions cause the Addisonian Many theories have been sjmdrome iii all its complexity? culosis,

cancer,

cirrhosis,

vouchsafed, but, in truth, as Anders'*- puts

it,

“the pathologic

connection between the sj^mptomatic phenomena of Addison’s disease

and the anatomic

lesions has not

been made out.”

jSTow,

consider the disease with the adrenals as governing oxidation and

metabolism these

:

three

The

adrenals being the seat of destructive lesions,

conjoined

functions

deficient oxidation

;

show signs of and clamminess due to

increasingly

deterioration; hence the low temperature

the marked and progressive asthenia, with

great lassitude, due to inadequate metabolism in

all

muscles ; the

small and feeble pulse and weak heart action and steady lowering of the blood-pressure due also to inadequate

metabolism in the

cardiac and vascular muscles; the tendency to vertigo and the

mental torpor due to ischagmia of the cerebrum, the turn, of the general vasodilation

result, in

and of the resulting withdrawal

of blood into the deep vessels, and, finally, the bronzing,

due

like-

wise to vaso-relaxation and circulatory torpor, the latter entailing the deposition in the epidermis of what has been found chemically to be the oxidized adrenal product,

i.e.,

melanin.

The experimental production of glycosuria by injections of adrenalin reported by Blum, Croftan, TTerter, and others is nowAnders:

“Practice of Medicine,”

p.

489,

OtU cd., 1909.

FUNCTIONS AND DISEASES OP THE ADRENALS.

70

familiar to every one.

The

labors of rollak'‘“ have

shown that, this form of glycosuria was due to some relationship between the adrenal product and the hepatic glycogen. But what is this relationship ? Here, again, the role had previously suggested,

as I

of the adrenals in oxidation tion

:

By

and metabolism supplies the explana-

raising the blood’s asset in o.xygen, the adrenal active

principle injected raises the rate of metabolic activity throughout

the entire organism, including, of course, the pancreas.

This organ being caused to secrete an excess of amylopsin, which in turn converts an excess of glycogen into sugar, the proportion of the latter in the blood soon exceeds the needs of the body, and the

surplus

is

The

eliminated in the urine.

adrenals themselves in the process

is

participation of the

controlled by various facts.

when the

Herter, for example, found that glycosuria was caused adrenals were compressed in such a

way

as to increase the outflow

of secretion, while, conversely, ligation of the adrenal veins which

transfer the secretion to the inferior vena cava caused the sugar to

diminish rapidly, both in the blood and in

our resources in the treatment of diabetes are

That enhanced by due

tlie

urine.

consideration of the part played by the adrenals in one of

forms

its

soon shown by therapeutic results obtained.

is

Many

other disorders the pathogenesis of which

and the treatment of which

is

obscured

is

unsatisfactory, mainly

owing to

the fact that the adrenals are overlooked in their pathogenesis, are described in detail in the second volume.

mitted in the foregoing pages will that the

function now

suffice,

The

facts sub-

however, to suggest

attributed to the adrenals,

i.e.,

that of

sustaining the tone of the vascular system, is hut an epiphenomenon of its true function: that of sustaining pulmonary and tissue respiration.

ntE GOVERNING CENTER OF THE ADRENALS. THE PITUIT.ARO-ADRENAL NERVE. such important duties in the organism as the above should be governed by some nerve-center almost

That organs

imposes tively

itself

fulfilling

when we

minor importance

"•’Poliak:

Arch.

f.

consider that

—

many

functions of rela-

color vision, coughing, sweating, ear

exper. Path. u. Pharm., Bd.

1x1,

S.

1-19.

— THE GOVERNING CENTER OF THE ADRENALS. movements, connection

etc.

—are supplied with showed that

first

The governing

one.

71

My

researches in this

is

neither located in

:

center of the adrenals

the cerehrum nor in the medulla oblongata, hut in

some organ

at the base of the brain.

Eemoval of both hemispheres does not influence temperaGorin and ture, as shown by Fredericq,®^ Goltz, and others. van Beneden*® found in fact that, in decerebrated pigeons, the oxygen intake and the carbonic acid output did not differ from Pembrey®” states moreover that “the that of normal pigeons. rapid rise in temperature which occurs when a hibernating mannot awakens is not prevented by removal of the cerebral This applies as well to so high a

hemispheres.”

dog, in which, as

shown by

Goltz,®'^

mammal

as the

removal of the hemispheres,

including a part of the optic thalami and corpora striata (whose

by removal of the cortex, the impulses of which they transform and transmit), did' not interfere with any purely vegetative fimction. Evidently, therefore, functions

are

also

annulled

although the hemispheres and the basal ganglia can,

when

the

seat of lesions, cause a rise of temperature, the heat center is not

located in these organs.

The

base of the brain, however, asserts itself as a pathway

thermogenic

for

Schreiber,®®

impulses.

While

Tschetschichin,

in

1866,

and Eeichert®® located a thermoaugmentor center in

the pontobulbar region, Ott,®“ Tangl,®^ and Sakowitsch®- obtained

a marked rise of temperature by jiroducing lesions higher up, i.e.,

in the floor of the third ventricle

and the tuber cinereum.

But, as Eichet has long held, and as Schiifer®® states, examination of such experiments shows that “the results are

closely

dependent upon the establishment of an irritative lesion in parts which are either directly in or in close proximity to the path taken by motor impulses.” On the whole, the thermogenic lesions in the basal tissues

must have

irritated nerve-paths

some structure beneath the hemispheres. Fr6d«ricq: Arch, de biol., ill, p. 747, 4882. Gorin and van Beneden: Ibid., vil, p. 265, 1889. Schafer’s “Text-book of Physiology,” Goltz: Arch. f. d. ges. Physiol., li, p. 670, 1892.

“Pembrey:

“Schrelber: Ibid., viii, p. 576. “Reichert: Jour. Amer. Med. Assoc., January 18, “ Ott: Therap. Gaz., June 15, 1903. '^Tangl, cited by Ott: Ibid. “Sakowitsch: Neurol. Centralbl., xvl, p. 520, 1897.

“

Schafer;

Loc.

cit.,

il,

p.

717.

i,

p.

1902.

864,

1898.

from

— FUNCTIONS AND DISEASES OF THE ADRENALS.

72

Further study of the question then showed 'that The pituitary body se7ids nerve-fibers upward to the tuber cinereum and the walls of the third ventricle, and thence to the :

pontobulbar region and spinal cord.

As

just shown, the heat center can only be located beneath

the brain and basal ganglia.

Now,

anterior to the optic tlialami,

the corpora striata, and the scat of the thermogenic lesions pro-

duced by Ott and others, there

no organ capable of generating nerve impulses by way of the tuber cinereum other than the pituitary body.

exists

Tlie labors of

many

investigators in recent

years have overthrown the view that any part of

man

body of

is

vestigial.

histological grounds, “it is

tlie

As Herring®^ concluded

pituitary

recently on

an organ of physiological importance.”

The

various kinds of nerve-cells, neuroglia-cells, and ependyma-

cells

described by Berkley in the posterior lobe are of as great

physiological importance, from

my

viewpoint, as any in the body

at large.

Cushing"® recently confirmed by a large number of experiments the fact previously emphasized by many investigators, that complete removal of the pituitary invariably pro-

duced death. Sappey, Luschka, Muller, and others of the older anatomists refer to the presence of nerve-fibers passing from the pitui-

up to the third ventricle. But it was the Golgi method had been introduced that this fact

tary body along

only after

its

pedicle,

could be placed on a solid basis. that the fibers passed

thalami.

Joris"^ also

upward

Bamon y

Cajal"“ then found

to a large nucleus

behind the optic

found histologically that “numerous

descend in parallel lines along the pedicle of the

fibers

])ituitary.

They do not all come from the retro-optic nucleus,” he writes; “some come from regions posterior to the infundibulum”. .

.

Bearing directly upon the production of thermogenic impulses is the discovery by Gentes"" of fibers which pass from the pituitary to the tuber cinereum.

Andriezen"" had also traced, in the

white mouse, fibers from the pituitary to the pons.

We

thus have a direct nerve path from the pituitary to

tlie

“

Herring: Quarterly Jour, of Exp. Physiol., I, No. 2, 1908. “‘Cushing: Jour. Amer. Med. Assoc., p. 249, 1909. “> Ramon y Cajal: Anales dc la Soc. espaflola de hist, nat., 2a Scrla, p.

214,

1894.

« Joris: Mgm.

Couron. de I’Acad. Roy de Belgique, xlx, part “Gentfis: C. r. de la Soc. de blol., Iv, p. 1500, 1903. Audriezen: British Medical Journal, January 13, 1891.

10,

1908.

xxlll,

THE GOVERNING CENTER pontobulbar region

—

points, the lesions

tlie

OF.

73

THE ADRENALS.

identical tract along which, at various

produced by Ott, Tangl, Sakowitsch, and

Eeichert provoked a marked rise of temperature. We will see presently that this path is continued down the cord, and that it eventually reaches the adrenals.

determined was a striking functional Schafer and correlation between the pituitary and the adrenals. Ilerring'®” recently emphasized this parallelism not only as to their function, but also as to their development and structure.

The next

feature

I asceidained, for example, that

tion

The pituitary, like the adrenals, influenced general oxidaand the temperature, and also general metabolism and

nutrition.

Although removal of the hemispheres does not influence the temperature, as we have seen, removal of tlie pituitary deeply Marinesco'”^ and Yassale and Sacchi“affects this process. observed that it was followed by increasing hypothermia. This cannot be ascribed to operative shock, for Masay^"‘‘

trephined

first

the sella turcica to expose the pituitary, and allowed the animal to recover after

The

this—the most violent step of the experiment. was the same. Andriezen^"*

result of subsequent removal

and other authors

also refer to a steady decline of temperature.

Paulesco^“° noted that this decline was progressive until death

occurred.

ture.”

main symptoms are referand respiratory systems and the tempera-

Pirrone^®® states that the

able to the "vascular

The

relationship with the respiratory process

is

further

shown by the .marked disturbances of this class, dyspnoea, polypnoea, etc., noted by Cyon, Andriezen, Masay, and other experimenters.

The impairment of general metabolism through deficient oxygenation must necessarily inhibit nutrition. Practically all investigators refer to rapid emaciation

and cachexia as prominent

symptoms.

In a dog which survived si.xteen days’ removal of the organ, Thaon’®^ observed “a progressive emaciation, followed Herring: in..

Philos. Transactions, cxcix, p.

Sacchi: Arch. Iniy/®®®'® Masay: “I** Arch, de la Soc. part 3, p. 1, 1903.

Andriezen

:

1906.

29,

biol., p. 509, June 4, 1892. de biol., xxil, p. 123, 189,5. roy. de sci. mOd. et nat. do

ital.

Lor. elf. Jour, de physiol, et de path. g6n., No.

loopirronc: Riforma medlca, February ^‘‘^Thaon: L’Hypophyse, p. 90, 1907.

25,

1903.

3,

p.

Bru.xellcs,

441,

1907.

xil,

— FUNCTIONS AND DISEASES OF THE ADRENALS.

74

by death in extreme cachexia.”

Masay“®

Pirroiied"® and phenomenon. Fuehs'“ and many though obscure relationship be-

also allude to this

Caselli/®®

—

other authors urge the close

—

tween the pituitary and bodily metabolism.

Striking evidence

of the influence of the pituitary on .metabolism and nutrition

is

afforded by its role in gigantism and acromegaly, the excessive growth during the period of hyperplasia of the organ, and the

steady decline from the time degeneration of

A

begins.

relationship with the adrenals

is

its

anterior lobe

suggested, moreover,

by a familiar symptom of the cachectic stage of acromegaly, of which Harlow Brooks^*- saj-s: “A general brownish pigmentation

present in the average case, which at times strongly

is

resembles that found in Addison’s disease.”

Another feature attesting to the parallelism between the pituitary and the adrenals is that

The

pituitary,

adrenals,

the

like

influences

the

blood-

pressure.

Cyon^'® and subsequently Masay“^ found that excitation of

marked

the exposed pituitary caused a

from 81

to

200

mm. Hg.

rise of blood-pressure

Masay

in one instance.

attributed this

action to the presence in the organ of a secretion which the

and accompanying pressure forced into the circulation. While no one can assert today that such a secretion is not produced by the pituitary body, the actual existence of such a excitation

secretion or its functions has not so far been demonstrated.

The

substance considered as such

globin,

and

is

rich in albuminous basmo-

the adrenal principle

it is

it

contains which, in

my

opinion, causes the rise of blood-pressure obtained by injections

of the extract.

When

the pressure

is

marked, the kidneys, being

passively congested, dilate, and diuresis

is

caused.

Tbe

effects

observed experimentally are tbus accounted for without the need of a secretion to do so. several

so-called

This applies

“internal

orchitic extract, for instance,

108

Casein;

Studl anat.

also,

from

secretions.”

e sperim.

is

my

viewpoint, to

Testicular

juice

an oxidizing ferment and cata-

sulla flsio-pat.

della glandula pltuitaria,

1900. log pii-j-one:

no Masay: 1*1 Fuchs: 1*8

11*

Loc. cit. tor. rlt.

Wiener med. Woch., February 8, 1903. Harlow Brooks; Archives of Neurol, and Psychol.,

ii*Cyon:

Masay:

Arch, de physiol., Loc,

cit.

x,

p.

or

618,

1898.

I.

p.

435,

1898.

— 75

THE GOVERNING CENTER OF THE ADRENALS. lyzer; it is

male;

found in

all tissues,

in the female as well as in the

gives crystals of luBmin with Florence’s test, etc.,

it

and

other reactions peculiar to the adrenal and thyroid principles

both of which are also found in all tissues. A close examination of Masay’s report, moreover, does not sustain his opinion that the rise of blood-pressure

is

to be ascribed to a secretion

produced

The rise of pressure was instantaneous and which points either to vasoconstriction through nerves or to the action of some intensely active and evanescent Both these factors are available. Not only is the principle.

by the

pituitary.

general

—a

pituitary

fact

known

to be related

with the sympathetic system, but

Langley^^® has called attention to the remarkable fact that “the

produced by adrenalin ujion any tissue are such as follow excitation of the sympathetic nerve which supplies the tissue,” effects

a conclusion confirmed

fact

is

clearly explained

in the hasmoglobin.

by the presence of the adrenal principle

When Cyon and Masay

therefore, they merely caused

excited the pituitary,

sympathetic constriction of

arterioles, including their offshoots the vasa

of

vessels

all

(adrenoxidase)

This paradoxical

by several observers.

receiving an

excess

of

all

vasorum; the walls

albuminous haemoglobin

they contracted, thus causing a rise of blood-

pressure.

Again, as

is

well Imown, the adrenals ara intimately con-

nected with the abdominal ganglia and

sympathetic structures.

are,

embryologically,

Their vessels being likewise influenced,

a sudden excess of secretion furnished a second cause for the

ephemeral

rise of blood-pressure

observed by Masay.

of the adrenal secretion to cause such a rise nized.

effects

generally recog-

Schafer^^® characterizes as “astounding” the minuteness

the dose of adrenal

of

is

The power

;

extract that will excite physiological

5.7 millionths of a

gramme

of Abel’s epinephrin sulphate

body weight was found by Eeid Hunt“^ to cause a rise of blood-pressure of 66 ,mm. Hg. As to the action on the heart, Oliver and Schiifer^^® found, as is well known, that adrenal

to each kilo of

products not only acted directly on the muscular walls of bloodvessels, causing them to contract (which accounts for the rise of Langley: !

Hill s Recent Advances in Physiology, Textbook of Physiology, I, p. 957, 1898. Amer. Jour, of Physiol., v, p. 7, 1901. Oliver and Schafer: Jour, of Physiol., xvi, p. 1,

p.

58-1,

1906.

Reid Hunt:

1894;

xvii, p. 9, 1896.

FUNCTIONS AND DISEASES OF THE ADRENALS.

7(5

blood-pressure), but also

upon the muscular wall of the

Finally, the rise of pressure

adrenalin extract

itself,

heart.

undoubtedly produced by the for Strehl and Weiss”" found that is

clamping of the adrenal veins lowered the blood-pressure, while release of these vessels restored

Another suggestive parallelism

The

is

it

to its previous level.

fact attesting to the pituitaro-adrenal

that

pituitary, in beeping with the adrenals, gives rise to

glycosuria.

Adrenal extractives,

as

observed by Blum,”"

Metzger,^-- Herter, and others, cause glycosuria. secretion evidently provokes the

phenomenon

Croftan,^"^

The adrenal

also,

for Herter

and AVakeman^"® found that compression of the adrenals, by increasing the outflow of secretion into the adrenal veins, caused glycosuria, while, conversely, adrenalectomy

marked diminution

was followed by a

of the sugar in the blood.

Again, we have

seen that the adrenal secretion passes from the adrenal veins into

the inferior vena cava vessel

Kauffmann'-'* found that Avhen this great was ligated the sugar diminished rapidly, both in the blood

and in the

Now,

;

urine.

the influence of the pituitary over glycosuria

as marked.

]\1.

is

quite

Loeb”“ urged, over twenty years ago, that the

glycosuria which accompanies so often tumors of the pituitary

should not be ascribed to mere coincidence.

had

five

with this disease, 71 of

organ.

whom had

years earlier,”^ he ascribes this

of the pituitary,

In

Ifi

and

its

it

in

Borchardt”" tabulated

over one-half of his cases of acromegaly. 17() patients

Slarie observed

glycosuria; as I

symptom

to overactivity

cessation to final degeneration of this

reported cases studied by Launois and Boy'"® each

That the glvTcosuria is not due to pressure of the enlarged organ upon the basal or bulbar tissues is shown by the fact that it can be produced in a normal organ. Thus, F. W. Pavy”" found that, subject presented at the autojisy a

tumor

of the pituitary.

strehl and Weiss: PHUger’s Archly, Ixxxvl, p. 107, 1901. Dcut. Archly f. Med., Ixxl, Nos. 2 u. 3, p. 146, 1901. Croftan: American Medicine, January 18, 1902. Metzger: Miinch. med. Woch., xllx, p. 478, 1902. ’^Herter and IVakeman: Araer. Jour. Med. Sci., January, 1903.

’“Dlutn:

'2* Kauffmann: Arch, de physiol., yiil, p. 150, 1896. ’“Loeb: Centralbl. f. inn. Med., September 3, 1898.

Borchardt: Zeit. Sajous: Lor. pit.,

f.

Launois and Roy: '-“Payy: Proc. Royal

Med., Ixyi, No.

4, 1908. 1st edition, 1903. C. r. de la Soc. de blol., ly, p. 382, 1903. Soc. of London, x, p. 27, 1859.

1.

klin. p.

366,

THE GOVERNING CENTER OF THE ADRENALS. ‘'of all

77

the operations on the sympathetic of the dog that have

yet been performed, removal of the superior cervical ganglion tlie

This enig-

most rapidly and strongly produces diabetes.”

matic result finds

known,

explanation in the light of the conclusions I

its

The

have submitted:

superior

cervical

filaments

vasoconstrictor

supplies

ganglion,

as

pituitary;

the

to

removal of this ganglion by causing relaxation of

well-

is

its

arteries

causes the organ to

become hyperaemic and therefore overactive,

with glycosuria as a

result.

by the fact the

Control of this conclusion

is

afforded

that, as in all exacerbations of activity thus induced,

symptom was

shown by Pavy’s statement that

fleeting, as

the glycosuria was “only of a temporary nature.”

Having now ascertained

1,

that the pituitary could alone

be the source of impulses to the adrenals; 2, that this organ projected fibers toward the bulb, and, 3, that the pituitary and rise to similar experimental and clinical became a question 'whether a nerve-path actually united these organs. Study of this question showed that

the

adrenals

phenomena,

gave

it

The phenomena

pi'ovolied

hy both the p-ituitary and the

adrenals can he traced Uy irritation or sections along a continuous

path leading from the pituitary to the adrenals. The tuber cinereum, which, we have seen, receives

from the

fibers

backward toward the bulb. Puncand others not only raised the temperature and quickened the respiration, but a section below the same region by Sawadowsky’^® and Ott and ScotP®^ rendered impossible the production of fever by pituitary, extends

tures along the upper part of this path by Ott, Tangl,

agents

known

to produce

iri’itation of tlie

same

Caselli,*®-

it.

tissues

moreover, found that

produced glycosuria.

The nerve-path continuing downward, we meet

in

the

pontobulbar region the thermogenic center of Tscheschichin, Schreiber, and Eeichert.

Suggestive in this connection

is

the

Bruck and ,Gunther‘®® found that simple puncture with a probe between the pons and medulla not only caused a marked

fact that

rise of

temperature, but that this rise was general.

tory center

is

Sawadowski: Centralbl. f. d. med. Wissen., xxvi, pp. U5, Ott and Scott; Jour, of Exper. Med., November. 1907. Caselli

:

The

a familiar classic feature of the medulla

Lof.

161,

;

1888.

cit.

Bruck and GUnthcr:

Arch.

f.

d.

ges.

Physiol., Hi,

p.

578,

respira-

we have

1870.

FUNCTIONS AND DISEASES OF THE ADRENALS.

78

how

seen

all

the

phcuomeua evoked by

the adrenals are linked

M'ith the res 2 )iratory jirocess.

All this applies as well to Claude Bernard’s jnmcture in the same region as a cause of glycosuria,

and due in the light of all this evidence from the pituitary to the adrenals. In

the

upper

Tscheschichin,^*^

portion

Bernard,^““

of

the

and

to irritation of the path

spinal

down

various animals sent the temperature

division

by

respectively,

in

cord,

rochoy,^®“

7° to 16° C. in

from

four to twenty-four hours, death following in Pochoy’s animals.

found that production of heat was diminished. That glycosuria is produced through efferent fibers passing downward in the upper cord is shown by the well-known fact, mentioned BiegeP^'^

by Stewart,^^* that puncture of the bulb does not cause glycosuria if

“the spinal cord above the third or fourth dorsal vertebra be

cut before the puncture

This

level of the

is

made.”

cord

is

of special interest, since

Here

that the nerve-path to the adrenals leaves the spinal cord.

can be evoked a

due

to

rise of blood-pressure

vasomotor nerves.

occurring in excess of that

Thus, Frangois-Franck and Hallion^®*

obtained a rise of pressure by exciting the

and

also

here

it is

five

upper dorsal rami,

by stimulating the corresponding segment of the sympa-

thetic chain, although the vasoconstrictor nerves to the organ

studied, the liver,

was known to reach

lower ramus, the sixth

—a

organ through a

this

limit confirmed by Langley.^'*'*

But

they could not account for this phenomenon. Bulgak, Bunch,^*^ Jacobi,^"'- and others also obtained marked vasoconstrictor effects by e.xciting these upper rami, although the vasomotor nerves to the organs influenced were known to leave the cord- lower down.

In other words, a duplicate source of vasoconstriction, as it were, was present whose nature remained obscure. It was brought to light, however, by the fact that Jacobi*'*® found that excessive inhihitorij consirictwn of the intestinal vessels ceased, and was replaced by normal vasoconstriction

when he

Tscheschlchln: Arch. f. Anat., Physiol., Bernard: Lemons sur la chaleur animale, i5**Pochoy: Th^se de Paris, 1870.

IS*

5»TRiegel:

Archlv

f.

d.

severed the nerves

u. wissensch. p. 161, 1876.

Med.,

p.

Jacobi: Jacobi

I

Arch. Ibid.

f.

1866.

ges. Physiol., v. p. 629, 1872.

Manual of Physiology, p. -152, 1900. >»» Frangois-Franck and Hallion; Arch, de physiol., vlil. No. 5, ’"Langley; Sehafer's Textbook of Physiology. 11, p. 644, 1900. ’“Bunch: Jour, of Physiol., xxlv, p. 72, 1899. Stewart:

’*”

151,

exper.

Path. u. Pharmakol., xxix,

p.

lil,

p.

936, 1SJ6.

1892

— 79

THE GOVERNING CENTER OF THE ADRENALS.

The

to tlie adrenals.

blood-pressure

clearly

intense action ot their secretion on the

my

from

accounts,

the

for

viewpoint,

excessive constriction observed. Briefly, these facts indicate jointly that

The

pituitaro-adrenal path leaves the spinal cord through the

upper four or

five

rami, to enter the sympathetic chain, and

then the great splanchnic, which, through the intermediary of the

semilunar ganglia, supplies nerves to the adrenals.

That

this path is the true

Thus, Goltz and

one

is

shown by additional

spinal cord from the bulb do\vn could live a long time

even

—but

—years

that they showed a striking peculiarity, even after

their vessels cold.

data.

EwakV'*'* found that animals deprived of their

had resumed their normal

OtT'*“

dying of

caliber, that of

found, however, that the animals were able to

generate their usual heat fifth dorsal vertebra.

when the

This

is

section

was made

heloiv the

evidently because the pituitaro-

adrenal nerve-paths had left the cord above this level to pass over to the sympathetic chain and the splanchnic, for, although

had failed to increase the secretory activity of the adrenals by exciting electrically all the median and lower dorsal rami, both he and DreyeE^^ had succeeded in doing so by stimuBiedP'*”

lating the great splanchnic nerve.

Proof of this

is

aiforded

by the fact that the greater splanchnic also transmits the impula to the adrenals Avhich provokes glycosuria, for Laffont^'*® cause(

by stimulating

Moreover,

it is evidently through medulla that glycosuria is caused; for Eckhard, Kauffmann,^*® and others found that even the glycosurja caused by Bernard’s puncture ceased vdien the greater splanchnic. was severed. There can be no doubt that it is through the adrenals that the glycosuria is caused, for, besides

it

this nerve.

a nerve-path starting at least in the

the evidence I have already adduced to this effect, A. Mayer^®®

found that Bernard’s puncture failed to produce this symptom after removal of the adrenals.

On

the whole, all the evidence, of which the foregoing

part, seems to

me

to

have shown

is

:

Goltz and Ewald; Archiv f. d. ges. Physiol., 1x111, pp. Ott: Textbook of Physiology, p. 348, 1904. “"niedl: Arch. f. d. ges. Physiol., Ixvii, No. 9-10, p. 44.3, Dreyer: Amer. Jour, of Physiol., 11, p. 203, 1899. d'ted by Laulanld: Eldments de physiologic, 2d Kauffmann: C. r. de la Soc. de biol., p. 284, 1894. Mayer: Arch. gOn. de mCd., July 17, 1906.

362,

400,

1836.

1897. ed., p. 943, 1903.

a

80

FUNCTIONS AND DISEASES OF THE ADRENALS. 1 hal

1,

the

pilmUwy

direct nerve-paths ; 2, that

connected with the adrenals by

is it

thus yoverns, throuyh the adrenals,

general oxidation, inctaholism, and nutrition.

HYPOADRENIA. This designation

is

submitted as a more exact one than

now

the tenn “liypoadrenalism”

increasinglj’- used.

Uggesting to the uninitiated that the condition

ne of liabitual insufficiency of the adrenals the secretory activity of these organs

even where advanced lesions

and “adrenal

more acceptably the true condition

obviously cumbersome and as

ill

The

latter

describes

is

misleading, since

subject at all times,

is

The phrases

exist, to fluctuations.

“insufficiency of the adrenal”

tray

is

it

insufficiency” por-

present, but they are

calculated to designate this

condition from a scientific standpoint as would “deficiency of red corpuscles” for anemia.

While wo owe to Addison, a clinician, the first observations (1855) which indicated that the adrenals were of signal importance to the welfare of the organism,

it

was Brown-Sequard,

who (1856), we have seen, first demonstrated importance to life. The symptoms caused by a

a physiologist,

their

true

deficient

production of adrenal secretion Avere not, hou'ever,

erected to the rank of a special syndrome quite independent of,

and capable and as

disease,

of occurring Avithout tbe presence of, Addison’s a manifestation of other diseases, until Sergent

and Bernard*"' did so in 1899. YieAved from my standpoint, plex of this condition

is

hoAvever, the

symptom-com-

subject to quite a different interpreta-

tion than the prevailing one, all the labors anterior to

having taken

as

foundation only tAvo functions:

my

OAvn

that of sus-

taining the cardio-vascular tone (OlWer and Schafer), and that of producing an antitoxic substance capable of neutralizing toxic

products of muscular activity, and other undetermined poisons

(Abelous and Langlois). effects are

The

processes through AA’hich these

brought about having remained obscure, hoAvever, more

or less empirical conceptions have had to be employed to gaps.

Thus, the muscular asthenia in Addison’s disease

is

fill

the

attrib-

uted to the toxic effects of tbe muscular poisons that tbe adrenals Sergent and Bernard:

Archives

gfin.

do m^d., July,

1899.

81

HYPOADRENIA.

while, to explair. in their normal state should have destroyed, the bronzing, irritation of the sympathetic plexuses around

other

are indifferently attributed to the low blood-

symptoms

pressure or to the intoxication. tation

of

the

dyspnoea, and

The hypothermia,

adrenals has to be invoked.

If

we

ask, however, hoio irri-

sympathetic plexus produces bronzing, or why

after adrenalectomy the temperature, both rectal

and peripheral,

fathom to any depth the explanations that soon becomes apparent that some important

steadily declines, or

are furnished, it

factor

is

missing.

my

me

have supThey afford an explanation of all the symptoms brought plied. Being on by inadequate functional activity of the adrenals. submitted experimental data based primarily upon the array of

which

It is this factor

labors seem to

to

in the earlier portion of this chapter, they also

constitute a

foundation for a more exact conception of the various disorders of the adrenals than the prevailing teachings afford.

my

Another feature which

me

of the adrenals seems to a

special

chapter,

is

interpretation of the functions

to elucidate, as will be

shown in

the process through which these organs

carry on antitoxic functions other than those concerned with

muscular origin.

toxic wastes of

Albanese,^“-

who noted

frogs to neurine as

This property, observed by

a decreased resistance of decapsulated

compared

to

normal

frogs,

was

first

placed

on a solid footing by the researches of Abelous^’'^ and Langlois, which showed similar results with atropine in the frog, and strychnine and' curare in the rablnt, though less marked. Charrin

and

Langlois^®^

then

found

that

the

addition

of

adrenal extract to nicotine in vitro reduced the toxic activity of the latter,

when adrenal

and that injected nicotine was also extract was

added to

it.

less

poisonous

Oppenheim^^”^

then

obtained uncertain results with potassium arsenate and atropine, but

marked

results with phosphorus, guinea-pigs in

which

was followed by that of adrenal extract surviving from two to four times longer in some inthe injection

of

this

toxic

Albanese: Arch. Itallennes de Biol., pp. 49 and 338, 1892. Abelous; Rev. Gdndrale des Sciences, May 15, p. 273, 1893, and Bull, de la Soc. de Biol., April 2, 1898. Charrin and Langlois: Bull, de la Soc. de Biol., p. 708, 1896. Oppenheim: Bull, de la Soc. de Biol., March 22, 1901; also “Les Capsules Surrdnales. Leur fonction antltoxique,” Paris, 1902.

—

;

FUNCTIONS AND DISEASES OF TllE ADRENALS.

82

and altogether

Strychnine, Vgo whieh and four minutes, produced but few spasms and proved harmless as to life when its injection was followed a minute later by one of 2 e.c. of adrenal extract. A

staucos,

in others.

killed guinea-pigs in three

larger dose of strychnine

(V 48

grain)

proved

fatal,

however.

These and other experiments with various toxins led Oppen-

heim

conclude that “the adrenals, which normally destroy

to

poisons elaborated during muscular work, assume great impor-

tance during pathological states and must be classed

among

the

most useful of protective organs.”

On

the whole, in the light of the personal views submitted,

hypoadrenia or insufficiency of the adrenals means far more

than the

lowered blood-pressure and the adequate

of

effects

destruction of muscular wastes;

it

means

besides:

inadequate

oxidation and therefore imperfect tissue metabolism and nutri-

and

tion,

also

impairment of the auto-protective functions

of

the body at large.

The bearing

of this conclusion will be gradually developed

while analyzing the three clinical forms into which

—

divided hypoadrenia, essarj" to

a classification

whieh appears

to

I

have

me

nec-

enable us to apply prophylactic and remedial measures

These three forms are the following: Functional hypoadrenia, a form in which the adrenals,

judiciously. 1.

though not the

seat of organic lesions, are functionally deficient

because of tardy development, debilitating influences such as fatigue, starvation, etc., 2.

and old age;

Progressive hypoadrenia, or Addison’s disease, a form

in which the functions of the adrenals or of their secretory nerves are progressively impaired by organic lesions, tuberculosis,

cancer, fibrosis, etc. 3.

or less

Terminal hypoadrenia, a form which occurs as a more tardy complication of infectious diseases and toxemias,

owing to e.xhaustion of the secretory activity of the adrenals during the earlier and febrile stage of the causative disease.

FUNCTIONAL HYPOADRENIA. adrenals playing so important a role in the maintenance of the life process itself, it is obvious that, apart from any organic lesion in these organs, any marked depression of

The

83

FUNCTIONAL -HYPOADRENIA. their functional activity should manifest itself

To the name of

responding with this depression. this

have given the

condition I

by symptoms cor-

symptom-complex “functional

of

hypo-

from the forms due to destructive disorders of the adrenals, which constitute Addison’s disease, and offer, of course, a far graver prognosis. As a definition of tliis condition, I would submit that Functional hypoadrenia is the symptom-complex of deficient activity of the adrenals duo to inadequate development, adrenia” to distinguish

it

'

exhaustion hy fatigue, senile degeneration, or any other factor ivhich, without

nerve-paths,

provoking organic lesions in the organs or their

is

capable

of

reducing

their

secretory

activity.

Asthenia, sensitiveness to cold and cold extremities, hypoten-

weak cardiac action and pulse, anorexia, anannia, slow metabolism, constipation, and psychasthenia are the main symptoms of this condition. The field covered by functional hypoadrenia is necessarily a vast one, since it includes the asthenias so often met with in the four main stages of life: infancy, childhood, adult, and old age, usually attributed to “weakness” or “exhaustion,” and often “neurasthenia,” which have been traced to no tangible cause. All I can submit herein, therefore, is a cursory analysis

sion,

of the subject.

Functional Hypoadrenia of Infancy and Childhood.

—Although the adrenals third the

size

of

the

are relatively large in the infant (one-

kidney at birth), their functions are

limited to the carrying on of the vital process, at least during tlie first

year of

life,

the mother’s milk supplying the antitoxic

products capable of protecting

it

against the destructive action

of poisons of endogenous and exogenous origin. influence of maternal milk

is

This protective

clearly defined in the following

quotation from Prof. William Welch’s

Harvey Lecture: “It is an important function of the mother to transfer to the suckling, through her milk, immunizing bodies, and the infant’s stomach has the capacity, which ing these substances in active

is

state.

afterward

Tbe

lost,

of absorb-

relative richness of

suckling’s blood in protective antibodies as contrasted with the artificially fed infant explains the greater freedom of the tlie

former from infectious diseases.” 0

Striking proof of this

is

FUNCTIONS AND DISEASES OF THE ADRENALS.

84 afforded

fact that during the siege of I’aris

l)y tlie

according to

-I.

1870-71,

in.

E. Winters,*”® “while the general mortality was

doubled, that of infants was lowered 40

jDer

owing to

eent.

mothers being driven to suckle their infants.”

The

predilection of children to certain infectious diseases

obviously indicates that

it is

not only in infancy that vulner-

ability to these disorders e.xists;

exposes life during the

it

decade, and more, of the child’s existence.

If,

first

then, in the

infant the maternal milk, as Welch says, protects the suckling

we must

against such diseases, at least to a c-onsiderable extent,

conclude that the same underlying cause of ^^llne^ability persists several j'ears, i.e., until it

How

this

we have

occurs

we

other organs,

has in some

The

seen.

shall see, the

power

way been overcome.

adrenals acquire, with

to supplant the

mother in

contributing antitoxic bodies to the blood; they supply internal

which fulfill this role. These facts point to the adrenals as at least prominent organs among those whose inadequate development explain the

secretions

special

\mlnerability

of

children

certain

to

the

infections,

It becomes a question now whether there are degrees of this hypoadrenia which render the child more

“children’s diseases.”

or less liable to infection.

That degrees

of hypoadrenia exist in children

a familiar fact to every physician

when

is

in reality

the signs of this con-

dition are placed before him. The ruddy, warm, hard-muscled, heavy, out-of-door, romping child with keen appetite and normal functions, is one in, whom the adrenals are as active as the

development commensurate with

its

age will permit.

ruddy and warm because oxidation and

He

is

metabolism are perfeet

and' the blood-pressure sufficiently high to keep the peripheral tissues well filled

with blood

;

his muscles, skeletal, cardiac,

and

vascular, are strong because, in addition to being well nour-

they are exercised and well supplied with the adrenalsecretion, which, as shown by Oliver and Schafer, sustains musished,

cular tone.

As normal outcome

of this state,

we have

constant

The stimulation of the functional activity of the adrenals. muscular exercise and maximum food intake involve a demand for

increased Winters:

metabolism

and

oxidation,

"Practical Infant Feeding,”

p.

6.

and the resulting

— 85

FUNCTIONAL HYPOADRENIA.

pargreater output of -wastes imposes upon the adrenals, as greater ticipants in the oxidation and auto-protective processes,

work, more active growth and development, with increase of defensive efficiency as normal result.. The pale, emaciated, or pasty child with cold hands feet, flabby

the

muscles, whose appetite

pampered house-plant

so

is

often

and

capricious or deficient

met among the

rich

rejiresents the converse of the healthful child described, just as The does the ill-fed, perhaps overworked child of the slums.

the cold extremities,

emaciation,

deficient

indicate

oxidation,

metabolism and nutrition owing to the torpor of the adrenal functions; the pallor is mainly due to a deficiency of the adrenal principle in the blood and to the resulting low bloodpressure,

which

This child

face.

is

not

ill,

abnormally low, and all

it is

adrenals,

its

is

conditions which in the adult tend to produce

self-evident.

FunctioNxIl Hypox\.deenia in the Adult.

circulation

show other signs of hypoadrenia.

As

I have witnessed suggestive

a rule, however, the development

—

an accomplished fact

of the adrenals in adults

is

of their coworkers in the

immunizing

we

oxidation

—

As in the do Such subjects may hypotbyroidia, show signs of myxoedema; but their and heart action are feeble, they tend to adiposis, and

bronze spots in such cases.

pituitaiy,

same

be inherently weak.

child, the adrenals

not, as in

is

TOlnerable to infection.

functional hypoadrenia affect the child at least to the extent

sur-

but the h}'poadrenia which prevails

normally, owing to the undeveloped state of

That

from the

entails retrocession of the blood

shall see.

The

as also that

process, the thyroid

and

adrenals, fully capable of sustaining

and metabolism, are able to defend tbe organism

adequately; indeed, they do more: by sustaining oxidation and

metabolism up to

its

highest standard in

all

organs, they also

preserve the efficiency of all other defensive resources, including phagocytosis, with which the body level.

On

is

endowed to

their highest

the whole, the normal adult whose adrenals func-

tionate normally is relatively resistant to infection. The infrequency with which the physician is infected, notwithstanding

daily exposure in his professional work, attests to this fact.

Functional hypoadrenia appears, however, when, irrespective

FUNCTIONS AND DISEASE'S OF THE ADRENALS.

8 () of

disease,

ail}'

the

ence,

ami

as a result of tlie vicissitudes of our exist-

adrenals

are

exhausted by the excessive

Fatigue

is

a

prominent factor in

ergograph shows clearly the functional If by

means of

this

secretory

upon them.

activity that exaggerated labor or exercise imposes

Mosso’s

this connection.

efficiency of the forearm.

instrument we compare the muscular power

of a case of Addison’s disease with that of any other kind of sufferer

whose muscles are organically normal,

ference will be noticed

;

muscular impotence asserts tuberculosis,

for

striking dif-

itself

and

where an advanced case of able to show appreciable

example, will be

Intense asthenia

strength.

a

signs of fatigue appear very soon,

symptom

in fact, a

is,

of Addison’s

disease almost as characteristic as the bronze spots.

It is as

pre-eminent after experimental removal of both adrenals.

harmonizes with Oliver and

This

demonstration of the

Schafer’s

influence of the adrenal secretion over muscular tone.

other proofs could be adduced to show that there

is

Many a close

and the functions of the adrenals. The pale and drawn face of an exhausted man, the readiness with which he suffers from the effects of cold and exposure,

relationship between fatigue

especially in the intestines, are familiar features of daily

The unusual prevalence field is of

campaign

life.

soldiers in the

course partly due to the defective sanitation that a

—

entails; but fatigue

particularly that due to heavy

marching, carrying heavy accoutrements important predisposing cause, through

Not only

adrenals.

among

of disease

—

in

is,

its

my

opinion, an

influence

are these organs called

upon

upon the to

sustain

general oxidation and metabolism at a rate exceeding by far that which amply suffices for nonnal avocations, but the fact that, as

destroy

shown by Abelous and the

toxic

products

of

Langlois,’®'^ they also sen*e to

muscular activity

constitutes

another cause of drain upon their secretory resources. “Fatigue,” write Morat and Doyon,^®® referring to experimental fatigue in

animals deprived of their adrenals, “has an aggravating influence, as first indicated by Abelous and Langlois, and confirmed by Albanese and

all

authors.

Hultgrcn and Andersson have even

Abelous and Langlois; Loc. rit. iM Moral and Dovon: "Traite de Physlologle, p.

441,

1904.

’

Art.

Secretions Internes,

„

;

87

FUNCTIONAL HYPOADRENIA.

observed sudden death as a result of powerful movements of the body.” Debility from any source as efficiently renders the

starvation, loss of blood, etp.,

:

body vulnerable to disease:

“Combine

Prof. and antitoxin, and inject “no haim will follow. But weaken the animal by Charrin starvation or slight bleeding and administer the same injection death will follow with all the signs of poisoning by the toxin,

the mixture,”

toxin

with congested adrenals.”

.

.

.

“That

writes

relations

exist

be-

tween the adrenals and infection,” urges the same authority, “is It follows, therefore, that an incontrovertible fact.” hypoadrenia from any source should render the body vulnerable Deficient food, excessive work, that of the sweatto disease. shops for example, account for much of the predilection of our

today

slums’ inhabitants to disease, their filth nurturing the appropriate

germs.

Masturbation and excessive venery are important morbid factors in this connection.

The

and asthenia witnessed

pallor

in these cases, so far unexplained, can readily be accounted for if,

as I believe, the liquid portion of the

This

principle.

is

as does the adrenal principle.

absolute

alcohol,

is

hffimin tests.

;

The

same

and

acts precisely

an oxidizing body

in ether

Xow, speimin not only and produces

all

raises the blood-pressure,

other

peculiar to the adrenal principles, but

same ;

tests

latter is

temperatures up

it resists all

insoluble

slows the heart

rich in adrenal

to, and even, and practically insoluble in and gives the guaiac, Florence, and other

acting catalytically it

is

suggested by the fact that spermin, the purest

of testicular preparations, gives the

boiling;

semen

its

physiological

effects

solubilities are the

same tests it resists boiling. Moreover, it is regarded in Europe as a powerful “oxidizing tonic” and has been found equally useful in disorders in which adrenal preparations had given good results. The inference that spermin consists mainly of the adrenal product suggests that it should it

gives the

not be regarded

;

af?

specific to

the testes, but, instead, a con-

stituent of the l)lood at large; not only did this prove to be the case,

but

it

was found

in the blood of females as well as in that

of males. ic®Charrin:

“Les Defenses Naturelles de rOrganisme,”

p. 63, Paris, 1898.

FUNCTIONS AND DISEASES OF THE ADRENALS.

88

Functional Hypoadrenia of Old Age.

— Perpetual

life

would doubtless be ours were it not that all living organic matter is subjected, after more or less precarious periods of growth and adult existence, to one of decline and final disintegration.

This applies particularly to the adrenals,

if

their

functions are, as I hold, to sustain oxidation and metabolism,

fundamental processes of the living

the

senile state is

may

state.

Indeed, the

be said to be as evident in these organs as

it

in the features of the aged.

According to Landau,'*“* Ecker, Henie, and von Kblliker found that fat occurred in increasing quantities in the adrenal cortex as age advanced, while Hultgren and Andersson found fibrous tissue between the cortex and medulla in Very old animals. Minervini'"‘ found a similar condition in the medulla of aged individuals.

—

Dostojewski, moreover, observed a marked

occasionally very great

Landau studied the adrenals,

—reduction

in the size of the adrenals

Polleston*®- has also called attention to this fact.

in the aged.

influence

of

age on

the

vessels

of

the

adopting for the purpose a process introduced by

Pauber and applied by many others, including Bezold, Hyrtl, and Lieberkiihn, to the study of other organs, viz., injection of the vessels with some hardening substance, and the subsequent The use of a corrosion method to destroy the parenchyma. adrenals

receiving, their

blood

through

a

number

of

small

which contains no valves, was used The annexed plate shows the result. The for the injection. vessels, and therefore the adrenals, are w'ell developed and in arteries, the adrenal vein,

were, in the adrenals of the three young adults, while those of the aged are shrunken and correspondingly defia certain index of the lowered activity cient as blood-channels full

bloom, as

it

—

of the adrenal functions, and, through these, of the vital process

they sustain. asthenia of old age thus finds a normal explanation in precisely as it does defective supply of adrenal secretion

The

the

—

in Addison’s disease.

the glands in the ’“Landau: ’“Lorand:

fact, Polleston states that

young may produce

this disease.

atrophy of

Lorand,^®^ in

Pctcrsb. med. Woch., .lunp 14, 1908. Jour, d'annt. et de physiol., pp. 449 and 8u9, 1904. Lancet, Mar. 2,1, 1895. ‘‘Old Age Deferred," Am. cd., p. Ill, URI.

St

”” Mlncrvini; Rollcston:

In

THE ADRENAL RESSELS IN THE YDHNG- AND 1,

Man

S2 years

22 years

old,

4,

old,

2,

Woman

Man BU years

33 years

old.

S,

Woman

LLD,

3, Pregnant woman B2 years old, (Landau.)

old,

— 89

FUNCTIONAL HYPOADRBNIA. liis

recently published book

on old

age, urges in fact that

old

ductless glands, and t a caused by degeneration of the quite autointoxication in old age there exists a condition of power with a decline of the antitoxic in keeping, I may add, in others Ixirand, who has antedated shoMTi hy the adrenals. glands upon old age, has showincr the influence of the ductless Pineles, Sir Herman found his views confirmed by Campbell,-relationship between old Weber and also—tbough he denies a a succeedWe shall see age and myxcedema— Metchnikoff. a close connection between ing chapter, however, that there exists genesis of old age, in the the adrenals and the thyroid in the acre is

m

form

of a functional relationship.

remarks on the causation of old age, Loranc considerations that all remarks; “It is evident from the above any kind of excess, hygienic errors, be they errors of diet or and that premature old will bring about tbeir own punishment, In fact it is mainly life, will be the result.

In

his closing

age, or a shortened

and die before our fault if we become senile at 60 or 70, page: 90 or 100.” Hence the motto of his title

“Man He

does not die,

kills himself.”

—Seneca.

however, it is In the light of the data I have submitted, subjected during clear that the lesions to which the adrenals are

and autointoxication, from birth to the last day of fimctional area of life, do greatly to shorten it by limiting the It is quite the organs through the local fibrosis they entail. probable, in fact, that centenarians owe their prolonged longevity

infections

mainly to integrity of their adrenals. Hygiene, and particularly those of directly itself as

its divisions

which bear

upon the prevention of infectious diseases, thus asserts direcone of the most useful of our sciences in another

organism against those diseases which, seemingly benign because they are recovered from, measles for example, in the end shorten our existence by compromising

tion, viz., that of preserving of

the integrity of the organs which sustain the vital process itself. PnoPTiTLAxiR AND TREATMENT. Though we are dealing

—

with depraved states of a physiological condition, we cannot JO*

Campbell:

Lancet, July, 1905,

FUNCTIONS AND DISEASES OF THE ADRENALS.

90

but regard them as abnormal in the sense that we deem adynamia abnormal and, therefore, susceptible to remedial measures. Indeed, there is mueh that can be done in each of the three

forms of functional hypoadrenia described. In

infants,

or

infection

adrenals and

we should by every

intoxication

to

other auto-protective

whole situation

lies in

possible

preserve

the

means prevent

integrity

of

The key

organs.

the

the fact that, as Ruhriih states, “nearly

the cases and nearly

all

all

the deaths are in bottle-fed babies.”

Physicians are, as a rule, entirely too ready to yield

demands

their

of

to‘ the'

of social and other claims put forth by mothers

who

do not wish to nurse their offsprings.

The responsibility assumed by both mother and physician under these circumstances is

I cannot but hope that if this continues,

overlooked.

sacrifice of countless infants proceeds, laws

may

and the

be enacted to

by imposing upon the physician the duty of submitting

prevent

it

to the

State authorities a certificate in M'hich sound reasons

from Nature’s Lewis Smith states

shall alone account for his consent to a departure

methods Avhich

entails deaths untold.

that the death rate

among foundlings

J.

in

New York

City reached

almost 100 per cent, until wet-nurses were provided. ]\Ien such as Jacobi, Winters, and many French authorities have written

upon

forcibly

this subject,

but seemingly to no

avail.

The

holo-

caust continues.

Experimental research in the same direction has only served to emphasize the all-importent prophylactic value of maternal

milk.

As

L. T. de

M.

Sajous^®® states

:

“That milk

is

capable

of conveying antitoxic substances after these have been injected into the

mother has been known for

a

number

of years.

In

1892 Ehrlich and Brieger demonstrated this fact in their experiments on mice. The offspring of non-iiumune mice were suckled

by other mice which had been immunized against the actions of certain poisons. It was found that the young were thereby rendered immune to the poisons employed, viz., ricin, abrin, and Tins im.munity steadily increased during the period of lactation, persisted for some time after, and then Ehrlich thus showed that a passive gradually disappeared. immunity was created in the young hy the absorption of milk tetanus toxin.

1“L.

T. da M. Sajous:

Univ. of Peuua. Med. Bull., June,

1909.

FUNCTIONAL HYPOADRENIA.

91

from an immune adult^ and even went so far as to assert that all so-called hereditary immunity was in reality of the passive variet}"^, being transmitted during lactation and not inherent in the offspring

itself.

“This transmitted immunity has been shown to occur in Thus, in 1893, Popoff showed that various other animals.

immunity against cholera could be transmitted through cows’ milk.

He

injected bouillon cultures into the peritoneal cavity

from 2 to 10 c.c. The guinea-pigs became immime against of the cow’s milk. The same observer noted also that when the milk cholera. was boiled before injecting it no immunity was produced. Kraus showed that the milk of goats immunized by injections of “t}'phus-coli bacilli” and cholera organisms had protective and agglutinating properties. He also ascertained that the relative proportion of agglutinating substance present in milk of a

cow and

later injected into guinea-pigs

Taking to that contained in tlie serum was as 1 is to 10. up the subject from the standpoint of tuberculosis, Figari showed in 1905 that the agglutinins and antitoxins of this disease appeared in the milk of cows and goats that had been actively immunized against it. In another series of experiments he fed the milk of immune cows to a number of rabbits, and in others injected it subcutaneously. In both cases these animals, thus passively immunized, were found to transmit to their young, by their milk, the agglutinins and antitoxins of tuberculosis.

“Evidence

is

not lacking of the transmission of antitoxic

substances through

human

milk.

It

has long been

known

that infants below one year of age were but slightly susceptible

and in particular scarlet fever, diphtheria, measles, and mumps. In fact, it was in an attempt to throw some light on this subject that Ehrlich performed his classic experiments on mice in 1893. Four years later Schmid and Pflanz performed some interesting experiments on guinea-pigs. Into some of the animals they injected bloodserum derived from human blood which was taken, at the to certain infectious diseases,

time of delivery of her child, from a woman to whom had been administered dipbtheria antitoxin. Into other guinea-pigs thej'’ injected milk from the same woman. The animals were then

FUNCTIONS AND DISEASES OF THE ADRENALS.

92

given injections of the

From

toxin.

ordinarily

fatal -dose

diphtheria

of

the results obtained the investigators concluded

that antitoxic substances found in the blood of parturient

(1)

women

milk; (2) that the quantity of antitoxic substances excreted with the milk is much less than that found exist also in the

Similarly, in 1905, la Torre injected diphtheria

in the blood.

antitoxin in several wet-nurses, and noted the antitoxic power resulting in the blood of the nurslings by injecting measured

amounts of pigs.

He

this blood Avas

mixed with diphtheria toxin

able to satisfy himself

antibodies occurred

in small

into guinea-

that a passage of the

amounts into the blood

the

of

infants.

“These experiments show, then, that antibodies injected This being into the mother are transmitted to the offspring. protective of the the case, it is but reasonable to expect that some substances ordinarily present in the normal mother’s blood should likewise reach the child through tlie milk. Experiments have shoAvn this also to occur. ]\toro found that the bactericidal power of the blood-serum in breast-fed cbildren Avas distinctly greater than in those artificially fed. Further confirmation Avas afforded by the fact that this difference rapidly disappeared

Avhen the bottle-fed infants Avere put back to the breast.” The prevention of disease in the infant is raised to

its

Tlie organisms of its highest standard by maternal lactation. gastrointestinal canal are kept under control ; the barriers to

infection that the respiratory tract and

are

AA^ell

armed

Avith antitoxic bodies; the

pulmonary blood

ive to pathogenic organisms, and the infant

against those diseases Avhich, CA'en seen, leaA'e enfeebling lesions, fatty

those organs upon

AAdiich his

if

alveoli offer

itself is destructis

thus protected

recoA'ered from, Ave

and

have

fibrous degeneration, in

health in after years and the dura-

tion of his life depend. is In the child beyond the nursling period the problem more difficult. Tlie fatal “second summer” recalls the sins of

and of the vessels in enough which the milk is transported and kept— amply long virulent the bacillus, to favor the groAvth of the oft-present Shiga the milkman, the

bacillus

c-oli,

filth

of the cowshed,

and even at times the streptococcus.

rection of these

and many

The

cor-

other factors replete Avith danger

93

FUNCTIONAL HYPOADRBNIA. to

and which surround

the child,

on

it

offers

sides,

all

the

children s only resources to diminish not only the mortality of health diseases, but also their occurrence, besides safeguard. ng

and longevity in after years. profession in this direction

is

already done by our

The good

incalculable.

Briefly, public,

home,

school hygiene, in the light of the facts I have submitted,

and

not only serves to protect concerned, but

its

enhancing greatly It

life

for the

moment when

the child

is

entire career as a healthful individual, while its

chances for a long

life.

question whether our resources are such

now becomes a

where functional hypoadrenia

as to enable us to raise,

e.xists,

the

autoprotective resources of the child, sufficiently, perhaps, to

enable

The

infection successfully.

it to resist

influence of

many

toxins and drugs on the adrenals points clearly to overactivity under their influence. In the first edition of this book, I referred to mercury as occupying “a high position among the stimulants Now, C. R. Illingworth^'’^® and others of the adrenal system.”

have found the binioclide of mercury e.xtremely

efficient

in

aborting scarlatina, diphtheria, measles, variola, varicella, per-

and many other

tussis, parotitis,

of calomel

found

its

among

The

infections.

great vogue

the physicians of the past generation

raison d’Ure precisely in just such

have myself observed.

Arsenic

is

an action

may have

—which

I

a familiar agent in the abortive

treatment of malaria in Africa, and, as Surgeon-General Boudin states, in

many

The remarkable results of Petresco infusion of digitalis in pneumonia have explained. But if ive realize that division

other diseases.

with large doses of only been tentatively

of the path to the adrenals arrests digitalis, as

we

and prevents the effects of good ground for the

shall see elsewhere, there is

belief that the prevailing conception of the action of this is

erroneous, and that

acts, at least in part.

adrenals, therefore, in this infectious

drug by stimulating the adrenals that it In view of the immunizing action of the it is

we can

realize

how

and how

digitalis could be of use

might prove useful in aborting any pulmonary disorder due to pathogenic organisms. disease,

it

Tliese few examples are submitted merely to

show that there is ground for the elaboration of a system of immunizing medication.

Its use

has served

‘"“Illingworth; etc.,

London,

1888.

me

well.

“The Abortive Treatment

of

Specific

Febrile

Disorders,”

FUNCTIONS AND DISEASES OF THE ADRENALS.

94

‘

Very remarkable in this connection is tlie action of thyroid 1 grain (0.06 Gm.), adrenal gland 2 grains (0.12 Gin.), and Bland’s pill 1 grain (0.06 Gm.) in a capsule three times

gland

daily, previously referred to.

tated child of 10 or 12 years

machinery on a new

it

Given during meals to a debiliseems promptly to start the vital

lease of life

—where,

of hygiene are adequately met.

milk,

Meat

demands

of course, the

of value here, while

is

portion of which gives the test for oxidase, and

tile fluid

which, as shown in the second volume, depends upon the adrenal secretion for

its

ferment (adrenoxidase),

Digitalin or strychnine in small doses

weak

or to increase the oxygen intake.

also of great value.

is

added

is

if

the heart

is

All these agents tend, by

keeping up a slight hyperaemia of the adrenals (and of the other organs acting in conjunction with it), to augment the efficiency of the child’s defensive resources.

may

In the adult functional hypoadrenia

from childhood.

persisted

hax'e

Here the measures just suggested for children

apply as well not only as preventives where infection threatens, or as abortive treatment, but also to raise the efficiency of the

adrenals and the general health of the individual to the normal plane.

It

is

probable that most tonics exert their beneficial

influence through the adrenals. t'.e.,

it

minute

is

That “tonic” doses of mercurv, known; we have seen that

doses, are efficient is well

a powerful adrenal stimulant.

observed by Molinie,’'’^

it

In toxic doses in

fact, as

causes intense congestion and even

luemorrhage of the adrenals. AVhile there is no doubt that meat in e.xcess is harmful, as we shall see under Functional Hyperadrenia, it is no doubt true that,

through lack of the

as Ixirand'®* states, undernutrition

necessar)^ proteids in the diet increases the liability to infection,

Lorand

as I urged several years ago in this work.

refers

to

personal cases of tuberculosis arising from a purely vegetarian diet.

On

the other

hand, Eichet and

remarkable effects from a diet of

Hcricourt'®* obtained

raw meat

in enabling

to resist tubercle infection by inoculation, and

become an impoi'tant factor

’“^Molinifi:

in

7,

1911.

raw meat has

the treatment of this disease.

Bulletin gfiifral de tU6rapeutlque. Apr.

‘•^Lorand: Lo(\ Hf., p. 313. Lancet, Jan. H6ricourt:

animals

8,

1906.

95

FUNCTIONAL HYPOADRENIA.

predisposed Grawitz'"® also found tlmt a purely vegetarian diet We have seen that tlie adrenals supply the blood its to anieinia.

an important Did we live where pathogenic bacteria do feature of anaemia. not flourish, we might safely undertake to adopt vegetarian principles; but a reasonable amount of meat, by keeping our albuminous haemoglobin, a

organs,

autoprotective

deficiency, of

which

is

and particularly the adrenals,

active,

serves a very useful purpose.

influence of excessive fatigue on the adrenals,

The

seen, is such as to

weaken

we have

greatly their functional activity and,

and immunizing functions of the feature in this connection is the harmful The main deficiency of rest, which means, from my viewpoint,

therefore, their oxygenizing

blood. relative

inadequate

opportunity

afforded

the

adrenals

to

recuperate.

amount

This, of course, should be proportionate to the

of strain

imposed upon these organs, and the resistance of which they are capable. It is probably owing to lack of this that apparently strong men are often the first to “give out” in forced marches.

The

upon the status (for we are now

physical examination being based mainly

preesens,

and the adrenals being necessarily

dealing with a

new

line of thought) overlooked as factors, there

marked inequality

men

to strain.

This

applies as well to the pathogenesis of chronic disorders.

In a

is

in the resistance of the

personal analysis of 40 cases of hay fever, for instance, the severity of the disease

corresponded to a considerable degree

with the number of children’s diseases the patient had had, the worst cases having had six of these diseases in comparatively quick succession.

This suggests the need of ascertaining the number and severity of children’s

and other

diseases to

which the recruit has

been subjected and to add this factor to others in deciding upon

arm to which he is to be The mounted man suflFers less from actual fatigue than the infantryman who must carry his accoutrements, arms, cartridges, etc., aggregating in some armies as much as 70 his admission to the service or the

assigned.

pounds.

When,

exposure,

etc.,

”“Grawitz:

impure water, and other frequent accompaniments of a campaign besides, defective or poor food,

Klinische Pathologie des Blutes, 3d

ed.,

1906.

FUNCTIONS AND DISEASES OP THE ADRENALS.

9 ()

are taken into account, one need not wonder that disease

is

a

far greater factor as a cause of debility and death than wounds.

owing to its inhibiting immunizing process in which

Briefly, fatigue should be considered,

influence on the adrenals and the

they take part, as an important predisposing cause of disease.

The

periods of

rest

should be so adjusted, therefore, as to

counteract this by far the most destructive factor of active war-

In

fare.

civil

here likewise

life,

much

such hardships are seldom endured, but

could be done to prevent infection

liy

means

calculated to insure the functional integrity of the adrenals.

To

when marked fatigue would of course only aggravate the hypoadrenia after The powdered perhaps a period of temporary betterment. adrenal substance should, on the other hand, judging from the stimulate the adrenal functions

prevails

effects

of

injections

of

adrenal

experimentally

in

e.xtracts

fatigued animals, serve a useful purpose.

In old age the ductless glands assume such importance, that a valuable work has been written by Lorand‘^‘ to indicate

how

the functional activity of these organs could be preserved

in order to retard the ravages of age beyond the fifth decade,

while prolonging Ijorand’s

The

life.

reader

is

therefore referred to Dr.

volume for a mass of information which cannot be

considered here.

The

adrenals, as

shown by the

plate opposite page 88, are

deficient in circulatory activity, and, therefore, unable to sustain

functional activity of

all

organs -up to

becomes a question whether, realizing artificial

means

fonner standard.

In the

first

life

It

we should by That activity.

this fact,

excite the adrenals to greater

such a step might shorten probable.

its

instead

of

prolonging

it

is

place, the frequent presence of arterio-

aged counsels prudence; in the second place, to activate the adrenals would only hasten their degeneration by imposing a greater wear and tear upon them. Drugs capable of

sclerosis in the

enhancing adrenal activity had, therefore, better be avoided in the aged.

Far better is it to compensate for the loss of efficiency of the adrenals by supplying to the blood, through a suitable diet, substances which contain the adrenal principle. If my opinion A. Lorand:

“Old Age Deferred,” F. A. Davis

Co.,

Phila., 1910.

97

ADDISON’S DISEASE. that spcriiiin owes is

its

virtues to

tlie

warranted we can understand why

adrenal principle

it

contains

Brown-Sequard rejuvenated

himself by means of testicular juice injections (I saw liim at the time and can testify to its wonderful effects upon him), since

he enriched his blood with the iMhulwn of oxidation, metabolism, and general nutrition, without impairing his adrenals. With

We

advanced knowledge we need not follow his example. seen that milk contains the adrenal principle, and that

owe

tissues

their,

functional activity to

buttermilk especially (since

presence.

its

almost pure plasma),

it is

a ready and inexpensive means to

have

animal

all

In milk, we have

compensate for deficient

adrenal activity.' If debility and other signs of functional hypoadrenia prevail, I advocate the daily addition to the plain,

though varied diet to wliich

elderly

should

people

restrict

themselves of the expressed juice (uncooked) of one pound of fresh beef daily taken in salted to taste.

This

is

soup,

if

distasteful

otherwise,

and

a powerful agent for good which

is

by the stomach, and which more than compensates for it rapidly restores strength and vigor provided, of course, harmful influences in other directions are avoided, and a hygienic mode of life, with reasonable out-of-

well borne

the weakened adrenals, since

—

door exercise, prevails.

In matters sexual, aged

men

should be extremely reserved,

since the waste of seminal fluid to

them means waste

of life

substance replaced with difficulty and never in abundance.

ADDISON’S DISEASE, OR CHRONIC PROGRESSIVE

HYPOADRENIA. That new

lines of thought concerning this disease are not suggested by Anders’s previously quoted statement in a recent edition of liis textbook that “the pathologic connection between the symptomatic phenomena ofAddison’s disease and the anatomic lesions has not been made out.”

untimely

is

Of major importance in this conneetioii are the facts that advanced lesions have been found in the adrenals post-mortem, though the subject had during life presented no signs of the Addison syndrome, and that, as Davis”states, “in the majority of eases the patients have compkined of asthenia for a considerDavis:

Sajous’s Cyclopaedia of Prac. Med., vol.

i,

p.

133.

3d ed., 1900.

FUNCTIONS AND DISEASES OP THE ADRENALS.

9y

—the

the right and left lymphatic ducts

thoracic duct, according to Pembrey®®

—

into the subclavian veins,

and by way of the superior vena cava to the heart. Here they become merged with the venous blood of the entire organism, forming a single secreiion, which is then inevitably carried to the heart, and thence to the lungs. As the venous blood carrying the adrenal secretion passes from below to these organs to be oxygenized, so

above to the

is

the thyroparathjToid secretion carried from

air-cells.

All these facts tend to controvert the current view that the

The

thyroid and parathyroids are not functionally related. is

that the prevailing opinion, referred to on p. 147,

on a broad view sustains

of the evidence in the case.

l\Iy

fact

not based

is

own conception

and completes that of Gley, which admits a functional

association in the sense that one set of organs seiwes to complete

the

work of the

observation of

other.

This intimate connection

Edmunds

that,

is

shown by the

while extirpation of the para-

thyroids causes histological changes in the thyroid, removal of the latter also causes degeneration of the parathyroids.

^lore-

and Generali®® found that after death from removal no colloid. Lusena®' noted the same fact, thus showing that the formation of the thyroid secretion depends in some way upon the functions of the paraEdmunds emphasized this fact by shoAving that thyroids. over, Vassale

of the latter the thyroid contained

hypertrophy of the thyroid followed parathyroidectomy, both embryonic tissue and vessels showing development. This survival kiln. Woch., Bd. xxv, S. 954, 1888. Virchow’s Archiv, Bd. cxxxvl, S. 170, 1894. “Vassale and de Brazza: Arch. ital. di blol., vol. xxiil, p. 292, 1895. “Welsh: Jour, of Anat. and Physiol., Apr., 1898. « Capobianco and Mazziato: Giorn. Int. de Scl., Nos. 8. 9, and 10, 1899. “Pembrey: Hill’s ’’Recent Advances In Physiology." p. 579. “Vassale and Generali: Riv. dl Patol. Nerv. et Ment., vol. 1, pp. 95 and

“Biondl:

Berl.

Zielinska:

Lusena:

Fislo-patologla

dcll’Appar.

Tlro-parat.

Florence.

1899.

— thyroparathyroid secretion as oxidation activator. suggests that removal of the parathyroids

is

159

not as fatal as

Indeed, Gley-'® had two dogs survive removal of the thyroid; the of all the parathyroids leaving only one lobe same operation in two other dogs and in a cat was followed

generally believed.

by disturbances which became fatal on removing tlie remaining In another dog parathyroidectomy caused only thyroid lobe. trophic disturbances and death in one month. The same thing was observed in rabbits when two parathyroids only were left. sinwivals in dogs after parathyroidec-

Edmunds-'’'' also

had two

tomy and deems

this operation less grave

opinion which

also Gley’s.

is

than thyroidectomy, an

Again, Halpenny,'“’ after a comprehensive series of experiments in the same direction, writes: ‘T have been unable to confirm the statement that complete parathyroidectomy invariaIn dogs 3 and 7, bly proves fatal, and that in a short time.

where

serial sections of the

thyroid removed post-mortem showed

no parathyroid, the animals lived 30 and 27 days, respectively, without symptoms and were killed. In dog 1, symptoms did not occur, and at the post-mortem no parathyroids were found, although serial sections were not cut.

In cats

1,

6,

and

8, in

which at the operation the thyroid lobe with the parathyroids on one side, and the parathyroids alone on the other side, were removed, the animals lived, without symptoms, 23 days, 25 days,

and 30 days, respectively, and were then killed. In all three cases a careful post-mortem search was made, and the remaining lobe of the thyroid was cut in serial sections, and no traces of parathyroid was found. exceptions

There

is

a tendency to disregard these

—MacCallum and Davidson,

Berkeley and Beebe^"

and explain them by supposing that parathyroids have remained behind unobserved.” This explanation is hardly tenable in view of the numerous examples presented. As to accessory glands, as Vincent'*'’ states,

“If accessory glands be so usually present, the

question as to the importance to life of these glands ceases to

have the value hitherto attached to

penny

it.”

Although

I believe

killed his animals too soon after the operation,

^Gley; Brit. Med. Jour., Sept. 21, 1901. Edmunds: Jour, of Pathol, and Bacteriol., Jan., 1896. ^•’Halpenny: Surgery, Gynecology, and Obstetrics, May, 1910. MacCallum and Davidson: Medical News, Apr. 8, 1905. ‘‘J;

Berkeley and Beebe: Journal of Medical Research, Peb., Lancet, Aug. 11 and 18, 1906.

« Vincent: London

1909.

Hal-

Parhon

THVROr'ARATIIYROin APPARATUS.

k;o

and

having observed postoperative death

Golstcin''*

witlioiit tetanic

phenomena)

as

thyroparatliyroideetoniy in the cat, to the data recorded

view

that

tlie

(though and OG days after the fact remains tliat added

much

as 30

by Gley his evidence tends

parathyroids

endowed

are

to Aveaken tlie

independent

Avith

functions. Finally,

and pointedly suggesting a combined function,

aa'C

have seen that a transplanted or grafted piece of thyroid tissue, free of all parathyroid tissue, assumes the functions of both sets of organ.s, arrests the convulsive disorders due to e.xtirpation of

the parathyroids alone, and prevents death.

All this clearly ])oints to a functional connection (probably a nci’A'ous one to co-ordinate the relative proportions of their secretions)

betAveen these tAvo sets of organs,

and thus insures

the ultimate formation in the lungs of a perfect,

i.e.,

jihysio-

logical, thyroparathyroidal product.

The purpose that, as stated

of this itinerary suggests itself AAdien Ave recall

by Xothnagel and

large quantities of iodine.

llossbach,"'"

It accounts

hasmoglobin can

fi.\

also for the fact that

and Bourcet found iodine in the red corpuscles. Being a component of the albAiminous hamioglobin of these cells Avith adrenoxidase, hoAA-eA’er, iodine should be found in all tissues. Gley^®

While Bourcet'" ascertained that such found

it

in

all

cellular nuclei,

so

the case, Justus'*®

Avas

rich as

Avell

is

knoA\-n

in

This simultaneous presence of iodine and phos-

])hosphorus.

])horus in the nuclei, coiqded Avith the presence of iodine in the

red cor])uscles, suggests the nature of process carried on in the cells

:

Auz.,

of the lupmogJohm enthe viilnerahitity of ferment, increasiny, as a oxidation hy hances the phosphorus, u'hicli all cells, particularly their nuclei, contain,

The iliyropamthyroid comtUuent

to oxidation

hy the adrenoxidase in the blood.

This action aetiA'e

is

strikingly shoAvn by the fact that iodine, the

constituent of the thyroid secretion, and

by ITenrijcan and “ Parhon and

Corin,'"’ ITandfield Jones,®®

Golstein:

its salts, as shoAAui

others, cause

and

"Sderdtions Internes," pp. 607 and

Nothnagel and Rossbach:

“Therapeutlque/’

p.

261,

609,

Paris, 1899.

1889.

La Seinaine ra^dlcale. May 25, 1898. lOAi is.a , Cited by Moral and Doyon: Traits de physiologic, i, p. 4

are resorted to

etc.,

This ultimately leads the

periodically.

patients to realize that semifluid or fluid food l)orne

by the

child,

which has

mouth

alimentary canal from condition as the fluids

—

skin

i.e.,

to be fed

is

alone well

with a spoon, the whole

much in the same much of its normal

anus being

to

deprived of

another source of constipation.

The

genital

organs, both the ovaries

and

remain

testes,

imperfectly developed, though not necessarily infantile. sionally the genital organs

are

instincts

Occa-

and the sexual

are hypertrophied

Their offspring tend to be feeble-

enhanced.

minded, however, and are liable to excessive mortality. struation often fails to

appear,

or

is

scanty;

and even hsemorrhagie, owing,

profuse,

deficiency of adrenoxidase in the blood

coagulating power this entails.

as

and

in to

Men-

may

be

myxcedema,

to

or it

the imperfect

Epistaxis and bleeding at the

gums are also commonly obseiwed. The urine shows but little change, though the urea excreted is below normal. In very marked cases, albumin and hyaline casts have been found periodically, doubtless owing to the

autointoxication

intestinal

seem

to

resulting

The

canal.

from retained excreta in the

thoracic and abdominal organs do not

be involved in the morbid process.

The mental the case.

state of the child

In some

it is

depends upon the severity of

not far removed from what Eoesch has

termed a ‘diuman plant,” even the intelligence common to the higher animals being wanting. The child fails to recognize its parents or any person about it, or even a person from an object, and nothing, even toys, interests it in the least. It neither weeps

n

THYROPAUATHYROID DISEASES.

196 nor laughs.

It

is

absolutely

manifesting any special wants.

apathetic,

sits

quietly

without

may, however, show signs of hunger or thirst, either by crying like an infant or by grunts or inarticulate sounds. In a higher grade, a few words may be spoken, there

is

It

recognition of parents and familiar faces and

even a show of affection for them, but beyond the limited vocabulary no progress can be made, even the alphabet being

beyond them. Still higher grades may speak fairly well, be free, though slow and deliberate, in their movements, etc., but fail to develop thereafter, even

if

they attain old age, which

is

not often

the case.

The classes

:

brothers Wenzel have divided these cases into three

the cretins,

who

are unable to speak, and lead a purely

vegetative life; the semi-cretins,

whose language

who

are simple-minded, but

limited and imperfect; and the cretinoids,

is

who

are endowed with some intelligence, but show the physical signs of cretinism.

There

is

another type, the mongolian, called thus

because of their slanting eyes, which closely resembles the cretin of a higher order, but this type shows

more intelligence and seldom

yields to the effects of thyroid preparations.

The

thyroid, in about two-thirds of the cases,

is

more

or less

atrophied, to such a degree in some that

it cannot be detected by In the remaining third, and usually in the endemic there exists a more or less developed (sometimes volumi-

palpation. cases,

nous) goiter. Etiot.ociv.

—

It liecomes necessary in this connection to dis-

tinguish between the two general classes, endemic and sporadic cretinism.

Endemic cretinism, often a family disease, and observed in number a of cases in special localities, is believed to be due to some chemical substance or micro-organism peculiar to the waters available in those regions.

This type has been connected with special proofs from various directions. in these regions,

Not only

is

by

localities

cretinism

common

but normal individuals may, on moving

to

them, have cretinic children therein, and normal children in healthy regions. Again, animals from the latter were found to develop goiters (the preliminary cause of endemic cretinism) in the contaminating districts

by drinking their water, while

this

197

•

CRETINISM.

water carried afar to healthy localities and given to dogs as sole Whether it is a beverage also caused goiter in these animals. mineral salt, a vegetable mold or some other pathogenic micro-

organism

is

not established, but for the time being the germ

theory seems to prevail.

The question

We

of heredity in these cases is a debated one.

have seen under “hypothyroidia” that syphilis and alcohol-

ism tend to leave their imprint upon the thyroids of descendants. Some oppose this view in respect to cretinism on the ground that the positive signs of cretinism only appear

weaned, and contaminating water obviously wrong:

given

is

when the child But this to it.

who

are thoroughly

familiar with the morbid effects of hypothyroidia.

condition in the mother

is

—a

alcoholism,

inherited,

knovm

also well

thyroidia in her offspring defect

is

Cretinism can readily be detected in a child

one month old and earlier by observers

maternal

is

fact

such

The

which brings ns back as

latter

to result in hypo-

hypothyroidia,

to

any

syphilis,

may

be present as the origin of the hypoIn other words, there is at present no sound foundation for antagonism to the prevailing view that endemic cretinism may be congenital in a certain jiroportion of etc.,

that

thyroidia in the child.

cases.

Sporadic cretinism,

has also been termed “cretinoid,” and “cretinoid pachydermia” occurs in any country, in localities that are entirely free from cretinism, and in healthy families. It is mainly due to some lesion of the thyroid caused by an acute febrile disease or some intoxication ivliich

or “myxadematotis, idiocy/^

capable of inhibiting or arresting

its

functions, either before or

after birth.

How

a general infection can produce such lesions in the

From my viewpoint, it finds its explanation in an autodigestive process similar to that which occum in the pancreas under certain conditions. As previouslj'^ thyroid

is

admittedly unknown.

stated,

I have attributed to the thyroid secretion properties similar to those of Wright’s opsonins, a view recently sustained

by Marbe and Stepanoff, at the Pasteur Institute. The antitoxic and antigeiTn constituents of the blood circulating in the thju’oid (and parathyroids, which may also he the seat of similar lesions), it is obvious that undue accumulation of thyroid secretion in the

—

THYROPARATHYROID DISEASES.

198 organ

own parenchyma

itself will oversensitize its

or its vascular

elements or both, and render them vulnerable to proteolysis along with any germ or toxin that

The

may

be present in the organ.

autodigested areas are replaced by fibrous tissue, and a

process of cirrhotic atrophy

which sooner or

started

is

later

annuls the functions of the organ.

The

which have shown themselves

diseases

most

to be the

frequent causes of sporadic cretinism are typhoid fever, scarla-

pneumonia,

tina,

and

pertussis

—the

identical

series

which

proves most prolific in the genesis of the infantile encephalopathies,

another source

of

idiocy,

but in which the cerebral

lesions are the direct pathogenic factors.

Pathology.

—The end

growth of

interstitial

enlargement of the gland ular tissue.

Some

remnant, however,

lesions are the

same in both forms.

a marked proliferation and overtissue or connective tissue, causing both

In the endemic form there

—

is

goiter

—and

obliteration of the gland-

glandular tissue usually persists; even this slioivs

evidences of degenerative change.

The symptomatology of both forms indicates clearly, we have seen, that deficient oxidation, metabolism, and nutrition This apunderlie the resulting general physical phenomena. plies as well to the

development

mental phenomena, symmetrical arrest of

affecting

more or

less

all

the

elements of the

There are occasionally found localized lesions of the nature of infantile cerehropathies, porencephaly, etc., but it is probable that these are concomitant changes rather than com-

brain.

])onents of the tyjiical jneture of cretinism per se.

Briefly,

we

of the brain

are dealing with arrested nutrition and development as a result of the absence of the secretion which sustains these

fundamental processes.

Treatjiext.

—Before

the introduction of thyroid gland in

the treatment of this distressing condition, there was practically nothing to he done. While its use must be continued, relapse

(excepting the body growth)

though, as a rule, with

much

that the changes produced

occurring invariably without less

it,

intensity, the fact remains

in the child, particularly in sporadic

early development of the disease childinhibits the mental development accordingly, the later in far in so treatment, of it appears, the better are the results cases, are truly marvelous.

hood

As

199

CRETINISM. as

tlie

intelligence

concerned.

is

The

jiliysical

restoration

not

is

materially iiiHuenced by the age at which the disease first apChildren grow with surprising rapidity in some peared. instances, over one inch per month in some cases, until the normal stature of the corresponding age is reached. The brain responds more slowly; but considerable intelligence is gained, though it does not reach, as a rule, that of normal children.

They learn slowly and develop only very gradually their vocabulary. They should be gently assisted in this direction.

When

the thyroid treatment

is

instituted the ease should be

carefully watched, as the tolerance varies greatly in different children.

They should be kept from any

Another important reason for

heart-failure occur. tion

is

violent e.xercise lest

the bones tend to soften, and, therefore, to yield tibia

this precau-

the fact that the growth of the skeleton is so rapid that

and

and bend.

to offset this

tendency

if it

shows

itself,

until the

normal height

of a child of a corresponding age has been attained.

calcium lactophosphate of the U. less,

The

fibula are especially exposed; braces should be apjfiied

according to the age,

This

this connection.

and Papinian^^ and

is

is

S.

P.,

Syrup of

one teaspoonful or

a useful adjuvant to thyroid gland in

accounted for in the opinion of Parhon

others, based

on

many

published facts, that

the thyroid gland plays an important role in the assimilation of

calcium.

Large doses are not only dangerous, but they inhibit the beneficial process. Again, it must be remembered that the thyroid cumulative in the sense that the organism will utilize a certain quantity ^which varies with each case and. that any excess may prove toxic. This stage may be reached active principle

is

—

—

early in one instance

and late in another. I have seen it produced in three weeks with 2-grain (0.132 Gm.) doses; conversely, in a case reported

grains (0.396

Gm.)

by Freund in a

girl of

14 years, 6

daily in divided doses caused a sudden rise

of temperature to 104° P., a pulse of 160, rapid breathing,

and

death the next day, though she had been taking the same agent nineteen months. The danger signals are rapid pulse, vertigo, general weakness, pains in the back and limbs, syncope, and,

Internes/ ’°p.

“edicala,

1904,

cited

in

if

“Secretions

200

THYROPARATHYROID DISEASES.

the intoxication be severe, nausea and vomiting, a

temperature, and collapse.

When

marked

any untoward

rise of

effect occurs,

remedy a few days suffices. They are more likely appear when the preparation used is old, a fact which suggests that it may have undergone putrefactive changes when cessation of the to

long kept.

An

infant can be given

grain

1/2

(0.033

Gm.)

dally of

desiccated thyroid, and a child of 2 years, twice daily, and older children thrice daily, or 1 grain (O.OGG Gm.) can be given at

dinner and another on retiring.

untoward

produce

effects,

the

have never seen such doses recumbent position after the I

second dose, as urged by Murray, preventing them. When it is necessary to increase the dose, the patient should be seen fre-

As much

Gm.) have been given three times daily with safety; but it must be remembered that the preparations now available are better and more efficacious. The preparation I now use is Burroughs, Wellcome & Co.’s standardquently.

as 5 grains (0.33

ized desiccated gland substance (in tabloids),

which contains 0.2

per cent, of iodine in organic combination.

stand larger doses than others.

A

Cretins usually

good guide in them

the

is

temperature, which tends to rise to normal; as a rule, the dose that will

When

do this

this is

suffices

to bring about the

to prevent recurrence.

But

it

desired

Gm.) on must not be neglected;

attained, 1 grain (O.OGG

results.

retiring suffices

otherwise,

the disease will certainly return.

The younger as a rule.

are

the patient, the

more marked the improvement,

In adult cretins, the results are meager

obtained.

The improvement

is

any at

all

much more marked

in

if

sporadic than in endemic cases, owing probably to the fact that

up

to the onset of the causative disease physical

growth had proceeded normally. thyroid treatment

is

and mental

In the Mongolian type, the

useless.

Grafting of thyroid tissue to render the constant use of thyroid

preparations

investigators.

unnecessary has

It is only in recent years,

been

tried

by various

however, that a promis-

ing method has been introduced by Cbristiani,'- of Geneva. conditions are that only normal and living tissues be used the grafts be small *-

Chrlstiani:

The ;

that

(about the size of a grain of wheat), but

Semalnc m^dicale, March

16,

1904.

1

Fiu.

Fiu.

1

THYRQin EXTRACT IN CRETINISM, Fig.

1.

E. MnDes.'}

Cretinic idiot 7 yoars old wtLBn thyroid treatment

begun. Fig. 2,

-

[J,

Had

Changes

ceased

after

to

develop

when

3 years

one year's treatment, G-rowth,

[Cleveland Medical Gazette.]

was

old.

inches,

]

J

201

MYXaSDBMATOUS INFANTILISM. very luuuerous

taneous

vascular subcuthat they he inserted in very

;

tissue,

cellular

employed.

and

only

that

human

thyroid

he

grafts from This makes it possible to obtain small to containing areas of normal tissue, and

a removed goiter

The

transplant tliem into the cretinous subject. saline kept alive an hour in physiological

tissue can be

solution.

grafts

A to

very avoid

the sharp instrument should be used to cut in sUu, where they introduced then crushing them. They are

parenchyma. gain a perfect foothold, becoming perfect thyroid obtained good results Jitore recently, Charrin and Christiani^ Six months after the operation, the with sheep’s thyroid.

myxoedema) became pregnant, and it with the was found that each graft became enlarged, in keeping proper physiological process which occurs normally in the gland patient (a case of operative

under similar circumstances. improvement in 60 per cent,

myxoedema, cretinism, dwarfism,

reported

Christiani^^ of

his

distinct

which included

cases,

remarkable results in 34

etc,,

The most

per cent., and no result in 6 per cent.

striking results

were in the various types of cretinism.

MYXCEDEMATOUS INPAOTILISM. This disorder,

first

attributed to the thyroid

resembles cretinism very closely, but class is

by Brissaud,

retention as a separate

warranted by the fact that the arrest of development

manifests of

its

itself

mainly by the persistence of the characteristics

childhood, physical and mental, without

true idiocy, and often without dwarfism. tus, either

the evidences of

The

thyroid, appara-

through inadequate development of congenital origin,

organic lesions, especially sclerosis, acquired in the course of acute infections during infancy, or from some other cause,

unable to supply enough of

its

is

secretion to subserve the needs

metabolism and growth (which involves an excess of metabolic activity), and the latter ceases, while normal metaboof both

lism,

enough

to sustain the vital process, continues.

Symptomatology and Pathogenesis. in

—The

worst cases,

which myxcedema predominates, are virtually instances of ’’Charrin and Christlanl; Le bulletin medical, July 11, Christlanl: Bull, de I’Acad. de mOd., vol. Iviil, 1907.

1906.

202

THYROPARATHYROID DISEASES.

cretinism of a mild type. obese,

Tlie patient

though child-like in shape, and

is

short, thick set,

may

and

look old for his age.

The face appears bloated, rounded, pale, and wa.x-like, a reddish patch being sometimes present below the cheek bones. The nose squatty and pugged, and the mouth large; the latter is usually open, a fact accounted for by the almost invariable presence of adenoids, hypertroi)hy, and infiltration of the nasal mucosa and tonsils. The tongue, as in the cretin, may be thickened and the lingual tonsil likewise, rendering speech thick and difficult. ihe hair may be profuse, though coarse and lusterless, but about the eighteenth year

begins to

it

fall

in

patches,

leading, in most instances, to alopecia.

In most cases hair fails grow on other parts of the body. The skin is tense, owing to infiltration, and is also dry, because of deficient action of the cutaneous glands, and it feels rough and scaly to the touch. to

Pruritus

often complained

is

of.

The teeth remain infantile, as a rule, and decay The abdomen is unusually prominent and hard in all

early. cases,

owing, mainly, to the stubborn constipation which causes retention of gas and fajces, the latter being only voided in some cases

by engorgement and to relaxation of the abdominal muscle. The constipation is also mainly due to' the loss of tone of the intestinal muscular fibers and the paucity of succus entcricus. Enuresis

is

commonly

Although the respiration

observed.

apparently nonnal there

is

deficient oxidation; the e.xtremities

is

are cold and are readily affected with chilblains in cold weather.

The

and extremities may even be cyanotic and the patient

face

complain of constantly feeling

common in this

phenomenon

is

well

Actual hypothermia

cold.

The

feature of these cases.

is

a

part played by the thyroid

shown by the

fact that Beebe'®

found

that “by the administration of thyroid to a cretin or patient

with myxoedema

oxygen from 20

The

it

is

possible

to

increase

the

absorption

of

to 75 per cent.”

between this form and true cretinism

diffei’cnee

as stated, in the fact that idiocy does not occur.

The

child

lies,

may

not be bright or oven nonnally intelligent, having been slow to

and shown deficiency at grammar, and arithmetic, but

talk

15

Beebe:

Loc.

clt.,

p.

659.

school, it

is,

particularly in spelling,

nevertheless, quite able to

203

MYXOiDEMATOUS INFANTILISM. hold

its

that for all ordinary needs; the face, in fact, unlike Yet the bears an expression of intelligence.

own

of the cretin, intellect retains the characteristics of childhood,

both as to ideas,

judgment, and emotions, a patient of twenty years, for example, preferring the company of children below ten to that of young

men

own

of his

lie, steal,

These patients

age.

start fires, etc., especially

may show

a proclivity to

when under the

evil influence

normal individuals. Any unlawful act they may commit is due, in most eases, more to lack of judgment and inability to resist suggestion and a desire to please others than of designing

an

to

proclivity

inherent

Others

crime.

to

excitable,

are

turbulent, and rough, and frequently break anything that again, the element of willful

all fragile; here,

harm

is at

absent,

is

muscular tremor and inability to prevent movements of the hands or fingers ^s in athetosis being the underlying cause

—

—

of the defect.

The heart

is

excitable, a slight

violent “palpitations”

is

This

and tachycardia.

a deficiency of adrenal secretion.

the same cause marked tendency

emotion sufficing to cause is

mainly due to

Dilatation of the heart from

often witnessed.

The

veins

also

to dilate, the veins of the extremities

hremorrhoidal veins particularly.

Varicocele

In a case seen through the kindness of Dr. a sprig of thick veins spread

upward over

may

show a and the

also

exist.

W. Egbert Eobertson, the mons veneris and

coincided with undeveloped testicles and total absence of hair

man

over the genitalia, in a young philia

is

frequently

hypothyroidia,

haemophilia

since

noted,

thyroid

an

Haemo-

twenty years.

indirect

gland

by increasing the

of

result

given

coagulation

also

of

the

orally

counteracts

time.

Epistaxis,

menorrhagia, and metrorrhagia are also ohseiwed in some cases, the two latter all,

which

is

phenomena where menstruation has developed

at

often not the case, coinciding with non-development

and pubic hair. The penis and testicles often remain rudimentary even when the male reaches full adult age, and his general shape and high-pitched voice recalling those of of the breasts

a

woman. In a

still

higher type of infantilism the signs of myxoedema

are hardly discernible.

the average individual.

The growth may even exceed that of Such cases are usually plump and even

204

THYROPARATHYROID DISEASES.

portly; as in the preceding form, the

abdomen tends to be large, but the limbs are well rounded, recalling those of a woman, with fair skin, a high-pitched, or infantile, voice to complete the

The

resemblance.

face, axillaa,

and pubis are free of hair;

tlie

penis and testicles small

and rudimentary. Mentally “he is simply an overgrown child,” wrote Meige,^'’ who gave us a close analysis

of

these

“These children, who should long

cases.

before have reached the reasoning period of their lives, play with

laugh at a childish prank, cry for practically nothing, become angry as readily, are subject to ridiculous frights, and toys,

call

their

mamma

In the average

under the influence of the

case,

emotion.”

least

— years—

however, this truly infantile type

the behavior of a child of but two or three

recalling better

is

exemplified by one of seven or eight years, though he be perhaps actually beyond his twentieth year.

The feminine

marked

attributes are sometimes very

in the

male, the breasts, thighs, and general conformation resembling closely those of the female, constituting the “feminine” type.

In the female, in

whom

infantilism occurs less frequently, the

body preserves the attributes of childhood, i.e., it fails to undergo the normal changes of puberty. Though tall, perhaps, the body shows no development on sexual lines: the breasts

remain small and

flat,

no hair grows in the

axillie or

over the

and the hips and nates flat. The uterus and its adnexa also fail to develop, and menstruation Some cases tend even toward the male sex, fails to appear.

pubis, the trunk remains cylindrical,

constituting

“masculinism,”

the

voice,

the

physical

assuming a masculine type. Diagnosis. From this type, which belongs

—

outline,

essentially to

the domain of the thyroparathyroid apparatus, must be distin-

guished several types

Lorain

Type

ivliich

of

do not.

Infantilism

.

— In

a

type

symmetrical in

Lorain, in 1870, tbc dwarfism is the ultimate products are symmetrical,

described tlie

miniature

form being practically always observed in the male.

by

sense that

men

No

—

this

myxoe-

dematous symptoms are present; the genitalia are usually normal, though the pubic and axillary hair is wanting, and notwithstanding their diminutive stature and their slender physique, «

Malge;

Revua

Intern,

de Mdd. et de Chlr., Mar.

25.

1896.

205

MYXaSDEMATOUS INFANTILISM. tlieir

facial

appearance and expression, and

are usually quite

from

They depart

to the average.

up

their fully developed fellow-inen, in

thyroid insufflcieney, but to anangioplasia,

ment

and premature

of the arteries

i.e.,

no way

in

except in the

fact,

this type is

As shown mainly by Meige,”

stature.

intelligence

tlieir

not due to

defective developIt is usually

ossification.

alcohoHsm, ascribed to parental hereditary syphilis, tuberculosis, Thyroid preparations in this other debilitating disorders.

and form are of no value. This type is characterized by Mongolian Infaniilism Mongolian features, and particularly the slanting eyes. These .

features occur at birth, culosis,

alcoholism,

prolonged deliveries

and are not traceable

account in some cases, at

^ivhich

—

the flat skull or bulging forehead

They

during pregnancy.

to syphilis, tuber-

as in the Lorain type, but rather to

etc.,

—

—

or to strong mental emotions

not morose

are

least, for

or

torpid like the

myxoedematous cases and are usually amiable and well behaved. Curiously! enough, all show a marked predilection for music and signs of unusual development of the musical sense. is

The tongue and

usually quite thick and heavy, and the hands square

the latter

flat,

accounting for the clumsiness which characterizes

these cases.

They usually

and are apt Their undeveloped

suffer

all

from some chronic respiratory some intercurrent infection. Mongolian facies, the bulging

to die early of

trouble,

size,

their

forehead, and their feeble-mindedness render the recognition of

Thyroid preparations are of no

these cases quite easy.

Achondroplasia,

or Foetal Riclcets

.

—

^This

avail.

typo of dwarf,

unlike the ni3'xoedematous type, does not show mental deficiency,

but

many

of the charaeteristics of cretinism

:

the relatively large

head, the saddle nose, the short and bowed limbs, the prominent

abdomen, and the marked

But the arms and legs are, show some degree of symmetry,

lordosis.

unlike the other types, which

all

entirely too short for the body, the finger-tips never reaching

the level of the hips.

and deformed.

The

Again, the long bones are usually bent skull is

unduly developed and

proportion with the face, which

The

eyes, lids,

eretin,

and tongue

but the hair

” Melge and

Allard;

is

may

is

then

made

to

is

out of

appear small.

resemble greatly those of the

normal and usually abundant, and the

Nouvelle^ Iconog.

de la Salp6tri6re,

No.

2,

1898.

206

TIIYROPARATHYROID DISKASES.

skin soft and well nourislied.

These characteristics, the fact

that the mental faculties are quite normal, and the inelTectivencss of thyroid treatment render the identification of achon-

droplasia quite easy.

Tkeatment.

—

filie

dematous infantilism

is

only measure of any value in myxoethe use of thyroid preparations.

'J’he

treatment recomniended for cretinism being as applicable here, the reader is referred to page 198. The younger the ])atient, the greater arc the chances of im])rovcmcnt. l)cen rcacheil, the results, in so far as the

After puberty has

mental status

is

con-

cerned, are seldom satisfactory.

THYROID HYPER.EMIA AND THYROIDITIS. This

a very important disorder mainly because of

is

its

upon the conditions just reviewed, e.g., hypoparathyroidia, myxoedema, and cretinism, and the whole gamut of morbid effects of deficient functional activity of the causative

influence

thyroparathyroid apparatus. acute"

when

form

the

It

is

generally recognized in

inflammatory

marked, but, unfortunately,

it is

phenomena

is

is

The

structure of the

and the quantity of blood circulating through it that a high blood-pressure, such as that which occurs

such,

so great,

during high interstitial

febrile processes, is sufficient to

produce areas of

interlobar

connective-tissue

haemorrhage

spaces, Avhich

form

done has been

as

in

many

the

sclerotic areas

sufficiently great.

of thyroid tissue over

limit the result

is

if

a

excess

and above the needs of the organism, how-

prove harmless, but

hypoparathyroidia

wherever the damage

As nature provides an

ever, inhibition of a proportion of the

may

very

not only in this class of cases

that lesions in the organ are provoked.

thyroid

are

its

if

more

gland below this limit

the sclerosis happens to e.xceed this or less marked hypothyroidia (or

the parathyroids are involved, which

is at

least sometimes the case) corresponding in severity with the Indeed, we have seen proportion of thyroid tissue sacrificed.

the disorders treated so far in the present chapter far sclerosis of the thyroid, with its resulting atrophy, was by

that in

all

the most prominent pathogenic lesion.

The graver paratively rare.

condition, acute thyroiditis,

is

fortunately com-

Moreover, while simple hypcraiinia, even vhen

—

207

THYROID HYPERyEMIA AND THYROIDITIS. attoruled

by

thyroiditis

interstitial haemoiTliagc, is

which make

seldom recognized, acute

attended by severe local and general phenomena,

is

it

possible to identify

early, to

it

meet

it

therapeu-

and avoid disastrous results. Acute inflammation of the thyroid apart from that due to the presence therein of goiter, is usually provoked by invading bacteria in the cancer, etc. tieally

—

—

notably

course of infeetion.s,

diphtheria, typhoid fever, scarla-

:

tina, measles, parotitis, tonsillitis,

rheumatic

dysenter}',

tussis,

orchitis,

and

influenza.

of poisons, constituting

It

pneumonia, per-

puerperal

fever

has also been attributed to the action

with other signs of iodism. the glandular tissues undergo

also

been known to cause

met with

area thus affected

become

sufficiently

is

along

it

In these inflammatory disorders

marked changes, including desqua-

mation and degeneration of the epithelium, besides the tial sclerosis

sepsis,

what has been termed “toxic thyroiditis”;

and the iodides have

iodine

erysipelas,

fever,

in the

form previously described.

large,

the

intersti-

If the

may

functions of the gland

impaired to constitute marked hypoth}'roidia,

which, we have seen, ma}q in children, arrest general develop-

ment

of

both

the

body and mind.

Shields^®

instance in which thyroiditis lasting one

week

witnessed

an

led to complete

atrophy of the organ and to typical cretinism.

In a case reported by Bonney^'*'^ the left lobe was converted into an abscess cavity. Symptojiatoi.ociy. Though capable of doing considerable injury to the gland, the acute hyperamiia attending infectious diseases gives rise to few tangible iihenomena,

i.e.,

slight swell-

ing of the neck, sensitiveness to pressure, and, perhaps, slight pain during deglutition. ITnless looked for, they will seldom bo discerned, as they do not cause sufficient discomfort to attract the attention of the patient.

fn acute thyroiditis the onset, usually ushered in by a chill, the most marked symptom is difficult}' in ; swallowing with, sometimes, neuralgic pain udiich radiates

is

generally sudden

Avidely in various directions, the ears

and occiput;

and neck, even

to the

arms

sometimes very severe, particularly during deglutition and on moving the head from side to side. If the whole gland is involved and the swelling, which is often the this is

size of a hen’s egg, is '“Shields:

marked, severe dyspnoea and even cyanosis

N. Y. Med. Jonr., Oet., 1898. Bonney: London Lancet, July Ifi, 1911.

208

THYROPARATHYROID DISEASES.

may

occur,

owing

to pressure of

tlie

inflamed organ upon the

may

Paralysis of the recurrent laryngeal

trachea.

produce

and

hoarseness

paro.xysms

of

occur and

but

sulfocation,

the

hoarseness and cough are more likely to be due to involvement of the

larynx in the inflammatory process.

glottis

may

occur,

also

as

in

(Edema

the

Lewis and

by

reported

cases

of

O’Neill.’®

The identity of the inflamed organ is readily established by causing the patient to swallow, when the tumor will rise, provided the head is not bent backward, which will immobilize Headache is often present and epistaxis occurs someowing to pressure of the enlarged thyroid upon the

the organ. times,

cervical veins

and the passive cerebral congestion

this produces.

The

Carotid pulsation has also been observed by Broca. of the organ

is

sometimes quite congested.

fever during the acute stage;

less

it

is

There

is

surface

more or

sometimes quite high

notwithstanding the absence of suppuration

—a

fact

which

cardia

independent of temperature

has

been

also

is

Tachy-

ascribable to the excessive production of thyroiodase.

noted by

As observed by Jeanselme, the coagulating power of blood is greatly increased. The morbid process lasts, as a

Parisot.®®

the

but a few days, the swelling subsiding completely in most (Occasionally a certain amount of enlargement may instances. rule,

persist. i.e.,

Forty per cent, of the cases terminate in resolution,

without suppuration.

OVhen an abscess

is

formed the course

of the

morbid process

more jirotracted. A single abscess rarely occurs, the glandular mass being studded with numerous purulent foci, which, if Each abscess tends close one to the other, tend to nin together. is

to break through the adjacent soft tissues, including the skin.

The trachea and oesophagus may therefore be invaded by a purulent stream when rupture occurs. iMctastatic abscesses may also appear in the cervical cellular tissue.

hen spontaneous

rupture occurs through the skin, or when the abscess cally evacuated, the inflammatory process recedes

When, however,

it

surrounding parts ’» 20

is

may

Lewis and O’Neill: Parlsot:

left to .itself, the

is

surgi-

rapidly.

purulent infiltration of

give rise to serious complications, by

.lour.

Presse MC’dicalc,

Amcr. Med. Assoc., Nov.

May

7,

1910.

12,

1910.

—

209

THYROID HYPER.15MIA AND THYROIDITIS.

referred to above, involving, besides the trachea and oesophagus, causing septic the mediastinum, the pleura, and the lungs propet,

pneumonia, and

also the large vessels of the

neck and chest and

Thyroid abscesses bleed readily and are

thus causing pyiemia.

sometimes the source of severe capillary haemorrhages. Chronic thyroiditis

may

follow the acute type, either through

perpetuation of the infection in some small portion of the gland or the formation of a sinus which fails to heal. In the majority of

instances,

however,

it

chronic

with

concomitantly

occurs

processes, such as syphilis, tuberculosis, echinococcus cysts, acti-

nomycosis,

etc.

in these cases is less favorable

The prognosis

than in the acute form, since more or less impairment of the functions of the organ follow the destructive action of the

owing mainly to the fibrous Both the induration it -entails in various parts of the organ. acute and chronic types are prominent causes of hypothyroidia with its long train of morbid results, ranging from cretinism abscess

through

upon the glandular

its

many

tissues

modalities to the milder types of

myxcedema

described.

—

In the acute form, the increased volume of the which sometimes becomes greatly enlarged in a few

Diagnosis. gland,

hours, the sensitiveness to pressure,

and the radiating pain,

all

located in the region of the thyroid, coupled with the fact that,

on swallowing, this organ,

i.e.,

the scat of

all

these acute

symp-

toms, moves up and down, render the diagnosis quite easy in

well-marked is

eases.

When,

as is often the ease, the

inflammation

unilateral, especially if oedema, of the tissues prevails,

it

may

resemble mastoiditis or parotitis and has, in fact, often been

taken up for the latter disease.

Its connection

with a mobile

structure on the other side of the neck, however, renders the differentiation possible.

times discernible.

If abscesses form, fluctuation

is

some-

CEsophageal abscess in the neighborhood of

the thyroid furnishes

much

the same symptoms, but the mobility

of the gland during deglutition

makes

it

possible to identify

it

as the seat of abscess.

Treatment. its

milder forms,

The prevention is

of acute thyroiditis, even in an important feature in this connection,

when wo consider its pernicious effects upon development of the child and upon the general welfare of the individual at all ages.

—

THYROPAnATHYROID DISEASES.

210

As previously

main cause

stated, the

of the lesions

is

the excess-

ive pi-oteolytic activity of the intrathyroidal plasma,

owing

to

the identity of the organ as the source of the substance which, as I have pointed out,

opsonin

i.e.,

the homologue at least of Wright’s

is

The

the thyroiodase.

thyroid brings to

it,

presence of bacteria in the

as elsewhere, all the defensive constituents

of the blood, both fluid

and

cellular.

The

excess of opsonius

increasing the vulnerability of the thyroidal tissues to the proteolytic activity of these antibodies, however, these tissues yield

readily to the destinctive action of the latter. fore,

The aim,

there-

should be to prevent this complication in the course of

febrile infections.

Two

measures of value are at our disposal in this connec-

The

tion.

these

first of

is

The

the local application of cold.

thyroid should be carefully watched for any complication, and if it

becomes sensitive or swollen, or the patient complains of

pain in the thyroidal area, cold compresses should be applied over

it.

The

effect of cold is to

reduce local temperature and

through this the activity of the proteolytic enzymes which the antibodies

of

the blood

In other words,

contain.

is

it

not

bacteria which do the damage, but the excessively active germicidal substances they invite into the gland,

and by reducing this

activity with the aid of cold the excess of digestive

tagonized.

That the bacteria

these conditions

is

obvious, but

power

is

an-

are less violently attacked under it is

far better to allow the blood-

stream to transfer the germs elsewhere in the body for destruction, i.e., to the general circulation, where their destruction can proceed

without compromising the integrity of any tissue so

vital to the welfare of the

The second measure solution,

either by

body as the thyroid. is

the free use of physiological saline

tbe mouth, rectum, or subcutaneously, to

reduce the viscidity of the blood.

Not only does

this counteract

excessive proteolytic activity of the antibodies which underlies

and other tissues and cells the underlying causes of liEEUiolysis and autolysis but it facilitates osmosis and therefore the circulation through the thyroid, which has been fittingly compared by Berard to a Another advantage of the sponge, so replete is it with blood. use of saline solution is that, as shown elsewhere (see page 13^7),

their destructive action on the thyroid

—

—

211

THYROID HYPER-^DMIA AND THYROIDITIS.

enhances the activity of the autoprotective process Avhile facilitating tlie renal elimination of toxins or the end-products. The treatment of acute thyroiditis likewise includes the it

use of the above measures besides the remedies the causative One feature of importance in this connection disease wamints. is

that a high blood-pressure

orders

;

a pernicious feature of the dis-

is

vascular depressants, such as chloral hydrate and veratrum

viride, preferably the former, therefore, are of considerable value.

Wilson has shown that chloral hydrate can be used advan-

J. C.

tageously to reduce the peripheral congestion and general distress in

As

scarlatina.

and other exanthemata are

this

frequent causes of acute thyroiditis,

it

may

safely be

relatively

employed

to counteract this condition.

Surgical measures often become necessary.

Kocher-^

:

“The presence

of pus is difficult to demonstrate

premature incision must be avoided. itself

should be exposed.

According to

and

If necessary, the gland

If incision of the abscess is not fol-

lowed by rapid recovery, the presence of multiple abscesses should be suspected.

Fistula points to extensive necrosis.

such a case the affected Pai-tial

tliyroidectomy

thyroiditis thyroiditis.”

that

have

of

lialf

may

also

become

In the chronic

the gland

be

chronic

eased paid removed surgically, especially Kocher;

Keen's “Surgery,”

and

vol.

14

iii,

p.

380,

in

in

excised.

cases

hy hypo-

and the actually if

dyspnoea

1908.

of

chemicotoxic

attended

tliyroiditis

thyroid ia, thyroid gland should be given,

=1

must be

considered

In

is

dis-

present.

CHAPTEK

Y.

DISEASES OF THE TIlYPOrAKATHYROID

APPAPATUS

{Continued).

DISORDERS DUE TO EXCESSIVE ACTIVITY OF THE THYROPARATHYROID APPARATUS. OvEiiACTiviTY of the thyroparatlij’Toid apparatus, in keeptlie opposite state, described in the preceding chapter,

ing with

has been identified by numerous terms, the most used of which pseudo-Graves’s

are

aberrant

disease,

or

larval

de Basedow, hyperthyroidism, and thyroidism. these were based

exophthalmic

Basedow’s disease, forme fruste de

goiter, incomplete

upon the fact that

all of

the

la

maladie

The first five of phenomena were

reproduced in exophthalmic goiter, of which the disorder truth,

The

mild type.

a

absence

the

of

erroneous

into

diagnoses

that the

in

major sjTuptoms:

exojihthalmus and goiter, however, so readily misleads the cian

is,

tendency of

clini-

modem

from true exophthalmic goiter, i.e., to regard it as an autonomous syndrome, in which the cardinal s3'inptoms mentioned above are not sugHence the terms “hyperthyroidism” and “thyroidism.” gested. As stated in the preceding chapters, however, the temiinal “ism”

observers

is

appears to

to distinguish this milder type

me

to suggest the presence of a habit rather than a

morbid process subject

to treatment.

I prefer the

tenn “hyper-

covering

this

feature,

harmonizes with the terminals previously used.

To

simplify

thyroid ia,”

the term,

it is

not

in hypothyroidia,

are

which,

therefore,

made it

besides

to include the parathyroids, though, as

must be understood that these glandules

deemed functionally

associated with the thyroid proper in the

process to be described.

IIYPERTHYROIDIA. “aberrant” or “laiTal” Exoplitlialmie Goiter; forme fruste Vou Schrbtter: MediziniscUe Klinlk, April S, 1908. "

—

THYKOPAKATIIYUOID DISEASES.

21G

Thus, Wasliburn," in a

superior.

test of iiiy contention tliat tlie

“Then we should

adrenals take part in the process, writes:

expect high blood-pressure during a considerable part of the clinical course, that

and he gives

during the period of adrenal

is,

overactivity,'’

170, 1(50, and 200 nun. Ilg observed by him in four cases as proof of the correctness of this postulate. While 1(50,

this is perfectly true, and, as observed

by SpietholV ^lorris and

Edmunds,** and others, there

is

rise of blood-pressure, the fact

remains that

cases, contrary to

marked

a tendency toward a moderate

what we should expect under the arteries of the entire

pulsation in the liver, spleen, capillaries, ?

advanced

influence of a

excess of adrenal secretion in the blood, there

markable dilatation of the occur

in severe or

As we

shall see presently, this

is

etc.

a re-

is

organism with

Why

due to the

should this

specific action

of the thyroid secretion, which, exaggerated, offsets that of the

adrenal secretion.

And

it is

between the two functions of these organs that the

symptomatology finds

its

elements.

The

activity of both organs being synchronous,

exaggerated, secretory

we have merely

a cor-

respondingly’ exaggerated expression of their normal functions.

Thus,

if

the thyroid functions exceed those of the adrenals,

have vasodilation and a more or blood-pressure, while

if

less

marked depression

the adrenals predominate there

of blood- pressure such as that observed by

Washburn

we

of the

a rise

is

—though

in

advanced cases the accumulation of intennediate wastes in the

may cause it by exciting the vasomotor center. The following definition summarizes my conception

blood

pathogenesis of the disease

of the

:

a constitutional disease due to excessive functional activity of the thyroparathgroid apparatus, and to the resulting dilatation of ail arteries which the excess

Exophthalmic goiter

is

phosof thgro parathyroid secretion causes by producing excessive intissues, all in as P^O-,) elimination phorus oxidation {and

cluding the vascular muscles, the nervous system, and the general vasodilator:

the depressor nerve.

1’atiiooexesis

AND SYMPTOMATOLOGY.

—While,

as stated

above, the disease was divided in the earlier editions of this “Washburn: Spiethoft:

Wisconsin Medical Journal. March, Zentralblalt

“Morris and Edmunds:

1907.

innere Med., Bd. xxili, S. 819, Medical News, vol. Ixxxvi, p. 62, f.

190.. 190».

work

—

— ;

217

EXOPHTHALMIC GOITER.

two clearly delhied periods, further development of the of (piestions has rendered it advantageous, from tlie standpoint into

therapeutics, to recognize three stages

:

1,

the sthenic or erethic

during whicli the overactive thyroparathyroid apparatus causes excessive sensitization of the phosphorus of all tissues to oxidation, and, therefore, abnonnally active cellular metabolism stage,

2,

the transitional stage, during which the overworked thyroid

is

beginning to be restrained by the gradual formation of sclerotic areas and atrophy and, 3, the asthenic or niyxoedematous stage,

during which progressive

and atrophy increasingly inhibit

fibrosis

the functions of the organ and finally cause the patient’s death.

The

general vasodilation, though an important feature of the

process,

is

and,

incidental,

as

previously

subject

stated,

to

fluctuations.

Under “hyperthyroidia” we

Sthekic on FinsT Stage.

have seen how clearly the excess of thyroiodase enhances cellular activities

— driving

the thyroid secretion

the cell to death, as

and extracts increase

it

were.

all

That

tissue oxidation is

generally recognized, but unlike the oxidation produced by an excess of adrenal secretion or extract there occurs,

under the

influence of the thyroid secretion, phosphoric acid metabolism

and excretion, upon which Chittenden® had

laid stress.

This

is

a feature of the action of thyroid products upon all phosphorus-

containing structures, which stand out even more prominently in the clinical history of

hvperthyroidia. rich, as well

exophthalmic goiter than in the milder

'The brain

known, in

and nervous system are especially

this element.

ive thyroid activity, therefore, is

restlessness

of sight

sthenic

The

influence of the excess-

shown by the greater

agitation,

(children being unusually irritable), hallucinations

and hearing, capriciousness or unusual gayety in the which not infrequently includes also pseudodelirium, and even mania. Nervous disorders are so

stage,

hysteria,

evident in the disease that the latter has been considered by manj'" excellent autborities, including

Putnam, as a neurosis. Tremors, upper extremities, but not infrequently involving even the muscles of the back and of tbe whole body felt, as indicated by Maude, by placing the hands on tbe patient’s especially

marked

in the

shoulders while he “Chittenden:

is

standing

—are

practically ubiquitous in

Trans. Cong. Amer. Phys. and Surg., vol.

Iv, p.

87, 1897.

218

THYROPARATHYUOID DISEASES.

Even

these eases.

tlie

voiee

Choreic movements (which

may become strident and may replace tremors in

tremulous. children),

muscular spasms, and even epileptic convulsions and by no means rare, symptoms of tlie disease. They

local cramiis,

are classic,

denote undue erethism in the cerebrospinal axis and the peripheral nerves, and explain the excessive excretion of P-.Oj. The

undue carbohydrate metabolism noted by Kraus, Ludwig, Chvostek, and others are but additional expressions of the same factor.

We cannot ascribe to tlie thyroid secretion per se any more than to the thyroid preparations in common use the powerful oxidizing power this denotes. It is here that “oxidizing ferment”

of the blood,

i.e.,

the adrenal secretion converted into

adrenoxidase, comes into play.

Indeed, concomitantly, we find

the evidences of increased oxidation. ture to 1UU° or 101°

an acute febrile

is

While

a rise of tempera-

the rule, some cases show a tendenc}' to

observed by Gilman Thompson in a 70 cases, the fever reaching 104° F. and continuing

series of

state, as

sometimes several weeks, and recurring every now and then. Few diseases, in fact, furnish examples of such temperatures. In a case observed by Eendu,^®

it

reached in the course of one

of these exacerbations 110° F., remaining two days between 107°

and 110° F. The patients often complain bitterly of a sensawarmth, of “burning flushes,” especially when pruritus and sweating, both due to excessive metabolism in the skin and sweat-glands, are present. The increased demand for food and fluids betokens the intense rate of metabolism to which the

tion of

tissues

subjected;

are

common.

indeed,

polydipsia

and

boulimia

Yet, emaciation proceeds; the thyroiodase,

are

by in-

creasing the vulnerability of the nucleus— also rich in phos-

phorus

—

of all fat cells to oxidation

consumes cell

all

by the adrenoxidase,

finally

reserve fats; then folloiv nitrogenous tissues, whose

nuclei are likewise rich in phosphorus.

The

vascular phenomena, referred to above, and others they

entail, are due, as stated in

my

definition, to this excessive oxida-

and breaking down of all organic phosphorus, including that of vascular and nerve cells, and particularly Ludwig and Cyon’s depressor nerve, which, as is well known, causes general vasodilation and a fall of the blood-pressure. Cyon found, nioreover.

tion

Rendu

:

Lyon radical, March

11,

1900.

yASCULilR SUPPLY DP THE THYRDIU ELRUU.

219

exophthalmic goiter.

nerve, an clTect wliicli that thyroid extracts excite the depressor phosphorus of all cells explains. tlic action of thyroid on the arteries of the The vascular dilatation may affect all the marked to cause pulsation of all the laige

body and be artei-ial

sufficiently

trunks, most

and transmitted explains many, now obscure, phenom-

marked It

to the capillary system.

ena that attend the disease.

at the carotids

The tendency

to hajmorrhages in

the fact that the mucous membranes and skin is doubtless due to in excess the dilated arterioles admit blood into the capillaries the Hence, of the volume the venules can readily carry off. memffushing of the skin, the hajmorrhagic areas in the mucous branes, the ejiistaxis, the coffee-ground emesis, the subcutaneous extravasations of blood which, as in Popoff’s case,^^ ™^y attain

huge dimensions, the

telangiectasis, and, indeed, the

To

occasionally witnessed.

the vasodilation

may

gangrene

also be ascribed

and legs, the fugitive the mdemas swellings of the face, neck, arms, and joints, none of which are, A disof course, beneficially influenced by thyroid treatment. vessels, as a large tinct “wilin’” may be heard in some cases over result of the unusual volume of blood circulating through them. The thyroid is, as a rule, only moderately enlarged, and its greatly dilated vessels likewise give rise to a distinct whirr under often observed in the eyelids

During the first under pressure.

auscultation, while palpation elicits a thrill.

stage the goiter

is relatively soft,

and

Exophthalmos, commonly the eral), belongs,

}delds

sign (sometimes unilat-

first

when not merely apparent,

of the eye-lids, to the

i.e., due to retraction same vasodilation of depressor origin, the

vessels behind the eye-ball, especially of the retro-bulbar

plexus, becoming greatly engorged. of the arterioles,

Here

we have

dilatation

which admits an excess of blood into the tissues

drained by this venous plexus.

At

fluctuates with the vascular dilatation, to

also

venous

first the exophthalmos and may even be caused

disappear temporarily by pushing gently on the eye-balls.

Later, no recession occurs

and connective

owing

to the local deposition of fat

tissue.

8tellwag’s sign (in reality Dalrymple’s,^"

twenty years

earlier),

retraction

who

described

it

of the lids, also finds its explanation in this vascular dilatation; the palpebral muscle "Popoft: Neurol. Centralblatt, April 15, 1900. Dairy tuple: London Lancet. May 26, 1849.

220

THYKOPAKATHYHOID DISEASES.

receiving un excess ol' arterial blood, it is unduly spastic, in keeping with other muscles oi the body. This applies also to Uraefe’s sign: lagging of the upper lid when the eye-ball moves

downward ; movements

its

muscle being

spastic,

it

cannot carry on

its

physiologically, that is to say, synchronously with

those of the eye-ball.

This spastic state may, in fact, be discerned by means of L. Napoleon Boston’s sign‘=> The head being firmly braced, the patient is directed to follow as high as :

possible with his eyes the operator’s hand, raised upward, start-

ing from the level of the patient’s chin about three from his face, then brought down again. The upper noticed to follow the pujjil

downward

feet

away

lid will

be

a short distance, then to

when what the author terms a “spasm” occurs before it resumes its downward course. The dependence of both Stellwag’s and von Graefe’s signs upon so fluctuating a factor as the circulation is shown by the fact that they may vary from day to stop,

day and that they are not constant.

The

tachycardia, one of the cardinal signs of the disease,

in the light of these facts,

but only in part, for practically nonnal.

it

an expression of

is

persists even

The erethism

when

tjie febrile

process,

the temperature

is

of the central nervous system

and of the nerves themselves, including the accelerator nerve, provoked by excessive oxidation in them, being taken into account, however, the abnormal pulse-rate finds its normal explanation even without the presence of a febrile state.

must itself

this be the case in view of the fact that the is

Especially

myocardium

rendered hyperexcitable by the blood overladen with

thyroiodase and adrenoxidase

it receives.

The

cardiac

symptoms

of the disease, extreme irritability, distressing violent palpitations,

with loud valvular sounds, especially marked at night, and

even endocarditis, betoken the presence of such a condition of the entire cardiac mechanism.

In children, in

whom

the disease

develops rapidly, as a rule, the cardiac signs are often the

first

to appear.

The

respiratory

phenomena

are closely allied to the cardiac,

in that the respiratory muscles, including the diaphragm, are also rendered supersensitive

b}'^

the excessive oxidation to which

they are subjected by the blood, and the irritability of the nerves: 13

Boston:

New York

Medical Journal, August

17,

1907.

;

221

EXOPHTHALMIC GOITBU. the plirenic, the respiratory nerve of Bell, the vagus,

The

receive.

restricted,

chest muscles being crampetl,

and the

air intake is

tlieir

tliey

etc.,

excursions are

correspondingly reduced.

That

the bronchial muscles are likewise contracted, abnormally reducing the caliber of the air channels, is probable. These two

sources of diminished respiratory capacity suffice, to

it

seems to me,

explain the sensations of suffocation or dyspnoea so often

As

observed in these cases.

is

the case with the tachycardia,

this dyspnoea is subject to crises,

during which the respirations

become extremely rapid, sixty a minute, sometimes, as observed in two cases by Sharp.^'* This observer noted that “opium had a marvelous action in slowing the respirations.” As shown in the second volume, page 1272 of this work, opium,

viewpoint, produces arterioles

which

—thus

its

effects

I ascribe the

process, congestion

by causing constriction of the

abnormal- effects.

and

is

morbidly influenced by the same

irritability of the gastric

muscular coat predisposing to emesis. is

hypercemia of

all

A

are

often

mucosa and

similar condition of

the underlying cause of diarrhoea.

and lymph-glands

spleen,

my

opposing precisely the muscular hyperasmia to

The alimentary canal

the intestine

from

found

The

liver,

enlarged.

The

organs moreover gives rise to a general malaise

or sensation of discomfort, the sensory terminals of all nerves

being rendered irritable.

Various

which

is

may

complications

occur,

most

distressing

of

ulceration of the cornea and loss of vision, through loss

of protection of the lids

and imperfect lachrymation and

lubrica-

tion of the ocular surface.

Some cases of exophthalmic goiter recover spontaneous!}^, though very gradually ; others suddenly enter into a rapid downward course, whieh W. G. Thompson has compared to malignant endocarditis, for

which disease it is frequently taken. A very and irregular heart action hyperpyrexia

rapid, tumultuous,

;

dyspnoea with labored breathing; vomiting; diarrhoea; haemorrhages and ecchymoses ; marked congestion and enlargement of the liver; delirium; stupor, the typical of

symptoms

and coma.

In most

cases, however,

of hyperthyroidia are replaced

by a period apparent quiescence—the transition stage— and then lapse

“Sharp:

London Lancet, June

27.

1903.

— 222

THYHOPAKATHYUOII) DISEASES.

into Hiosc of liypotliyroitlia, the

normal

toniiinal niorhicl jn-ocess

of projrressive exoplitlialinic goiter.

'TransUion Slaije

.

— Wliat

me

api)ears to

to be entitled to

this designation is a ])eriod in the course of the disease

there occurs apparently considerable improvement.

The

when skin

ceases to be abnormally moist, the heat flushes, the sensation of

heat and the fever disappear, and the skin loses pearance, and

may

its

suffused ap-

The tremors and nervous

even become pale.

and even the mental aberrations and emotionalism, arc replaced by a gratifying placidity; the tachycardia greatly lessens, though reawakened by exertion. The emaciation tends also to disappear, and the patient, though weak, may even show a tendency to corpulence. On the whole, he appears to his surroundings greatly improved and even on a fair way to recovery. If the goiter be examined with due care at this time, it will be found, at least in most insttinces, to have receded, and to have lost somewhat of its rounded shape. Its former softness still remains in some places, but in others nodular masses or bosses can readily be detected by passing a linger over the mass, and exerting slight pressure. The meaning of this is selfevident the goiter is undergoing atrophy owing to the sclerotic areas with which it is now studded, and the transition stage is that period of the process during which the normal tissues, i.e., what remains of them, are just able to sustain the metabolic equilibrium although the latter is further compromised by the irritability,

:

—

deficiency of cellular phosphonis following

The time

finally arrives

when

its

excessive oxidation.

the thyroid secretion produced

longer sufficient and the case then enters into the

is

no

:

—

Asthenic or 21 yxccdcmatoiis State In this stage, reached, as previously stated, if cure or death does not occur early in the course of the disease, we witness the results of exhaustion of both .

the thyroid and the adrenals with fihrosis of the former. recognition of this fact

is

The

important, for, while thyroid prepara-

tions are very harmful in the

first stage, a.s

many

reported cases

show, they may be useful when myxoedema has appeared. During the transition period the change is so rapid in some cases that certain symptoms of both exophthalmic goiter and myxoedema

may In

occur together, the case lapsing ultimately into myxoedema. its symptoms, unrecognized, are promiscuously

textbooks

—

:

223

EXOPHTHALMIC GOITER.

In a case M’itlabor, premature nessed by de Smet,^° the transition followed Tlie exophthe goiter alone remaining of the first disease.

merged in with those

thalmiis

may

of exophthalmic goiter.

also persist.

The myxocdeinatons phenomena include most of those reviewed under Myxoedema, thyroidia

and

symptoms

of impaired oxidation

tions

hypoadrenia,

They

entail.

are

the manifestations of hypo-

i.e.,

and,

the

shown,

previously

as

and metabolism these condihypothermia,

briefly:

coldness, obesity with a non-pitting,

sensation

of

rough, dry skin; supra-

scapular swellings or pads, loss and coarseness of hair, brittleness

and ridging of the

nails,

cutaneous disorders,

leucoderma,

pigmentation,

There

is

etc.

;

predisposition to

onychia; various

scleroderma,

vitiligo,

mental tor 2ior, depression, and

brown

irritability.

intense weakness, especially of the legs, with occasionally

a tendency

to

tabes-like

paralysis,

hemiplegia,

or muscular

which may begin during the sthenic stage. There is a heart weakness and dilatation than in ordinary eases of myxoedema, owing probably to exhaustion of atrojihy,

tendency to greater

the cardiac muscle during the sthenic stage.

If the patient

is

not carried off by some intercurrent disease, cachexia supervenes

with a tendency to fainting spells and heart-failure, the usual cause of death.

Etiology.

In the

first

edition of this

work (1903)’“

I

traced the iirimary cause of exophthalmic goiter to the pituitary

body (the neural lobe), a nervous connection having been shown by Cyon, a physiologist, to exist between this organ and the thyroid, similar to that traced by myself between the pituitary

body and the adrenals.

The following year Salmon” also concluded that the pituitary body was the seat of primary irrita:-

tion,

though his explanation of the process differed from mine. from my viewpoint, the pituitary body contains the

Briefly,

center of the thyroid

and adrenals, and when certain toxics capable of irritating this center, such as the toxic wastes of pregnancy and menopause, various toxins, toxins of intestinal origin,

endotoxins,

auto-

occur in the blood during a prolonged period both these organs are unduly excited, and. De Smet Sajous:

Salmon

Lc

:

etc.,

bulletin mfidlcal, Oct.

24,

190G.

‘Unternal Secretions," etc., 1st ed., p. 514, 1903, and Clinique Moderne (or Clinical Med.), Aug. 3, 1904.

p.

1861, 1907

224

THYROPARATHYROID DISEASES. socrotions being iiroduced in exuessiYe quantities,

tlioir

ease

That it

dis-

tlie

awakened.

is

e.xophtlialmie goiter occurs in persons predisposed to

by supersensitiYeness of the central nervous system, as in

and other neurotic subjects, is suggested by the frequency with udiicli such disorders proceed or occur with the disease. Eobinson^'* and others have even gone so far as to hysterical, epileptic,

consider of 32

it as

cases,

a form of hysteria.

Grandmaison,’® in a study found hysteria in 19. Abadie ascribes the di.s-

ease to irritation of whichever center governs the svmpathetic

vasodilator branches of the thyroidal vessels.

safed a similar opinion.

Von

Dana®® vouch-

Griife, Ivober, Charcot,

and many

other authorities have directed attention to the sympathetic in this connection, while

and others have found not

necessarily

Virchow, Trousseau, von Eecklinghausen, lesions (which,

occur)

of

the

Now,

branches supply the thyroid. thetic that

posterior

from

cervical it

is

C'yon traced nerve-paths from

lobe

of

which

is

a

my

viewpoint, need

whose through the sympaS)'mpathetic,

the pituitary

(the

sympathetic structure, rich in

chromaflin substance) to the thyroid, and, as I show in the second

volume (pp. 982

ct seq.),

the pituitary contains, in

all likelihood,

the previously unidentified center of the sympathetic system.

One

most evident indications of the influence of the waste accumulation on the genesis of the disease is shown in of the

pregnancy.

Eichardson®' states that "in southern Italy

it

has

long been the custom for the parent to measure the circumference of the daughter’s neck before size

and

after marriage, an increase in

being considered as an evidence of conception.”

Time

has

sanctioned this popular custom, various observers having shown that the thyroid

becomes temporarily congested and enlarged

under the influence of what Audebert®® tenns, in describing a case in which exophthalmic goiter developed during the seventh month the "usual symptoms of hepatic toxiemia.” While :

exophthalmic goiter occurs rarely, the fact remains that

it

is

but the exaggerated expression of a physiological process.

Thus,

’"Robinson: “Etudo sur les syndrome de Graves-Basedow consIddrC manifestation de I'hystfrie,” Paris, 1899. Grandmalson Medeclno moderne, July 7, 1897. ** Dana: New York Medical Journal, June 14, 1902. *’ Richardson: “The Thyroid and Parathyroid Glands,” p. 20, 1905. Audebert: Annales de gyn. et d'obstOtrlque, Sept., 1906.

comme

:

225

EXOPHTHALMIC GOITER.

133 cases of pregnancy, found the thyroid fifth enlarged in 108, the enlargement beginning about the month. The thyroid ceased to increase in volume when thyroid Lang,-'® in a series of

gland was administered, remedy was withdrawn.

and resumed

its

growth when the

That we are dealing with an antitoxic function having for purpose the destruction of wastes of foetal and maternal

its

origin,

is

suggested by the fact that the thyroid gland has long

We

been credited with such a function.

have seen that

my

view

that it increased the opsonic power of the blood has been sus-

Eeid Hunt-'* found, moreover, that when mice were fed on small amounts of thyroid they showed marked resistance tained.

to poisoning

by

acetonitrile.

The

relationship of the pituitary

body with the toxsemia of pregnancy is also shown by the observations of Comte,^® that during pregnancy the pituitary body is also markedly enlarged, a fact confirmed by Launois and ]\Iulon.2“ more recent paper Launois” reaffirms his former conclusion, stating that the anterior lobe (which, as I will show,

page 1072, receives the toxics that awaken the impulses transmitted by the posterior lobe to the thyroid and adrenals) is, during pregnancy, “in a state of marked hyperactivity.”

Another feature which points to the pathogenic role of is that, as stated by Ord and Mackenzie: “In diswhere ordinary goiter prevails, the exophthalmic form is

intoxication tricts

also

met with.”

Grasset observed

France, and Carter,^® in England.

a

similar

The

coincidence

latter

author

in

states,

moreover, that, while, in a certain valley in the West Riding, the

who drink water from hills from goiter, those on the other side of the river, who drink water from hills to the north, suffer a good deal from this growth. Moreover, it is from the latter, or goiter side, that cases of exophthalmic goiter are derived. This clearly suggests that the exophthalmic form is hut a development of inhabitants on one side of the river,

to the south, do not suffer

simple goiter.

“Lang: ^Hunt: -

p.

2,

Indeed, referring to. 3 eases of this “secondary”

Zeitseh.

f.

Geburta.

u.

Gyn., Bd.

xl,

S.

34,

1889.

Jour. Amer. Med. Assoc., July 20, 1907. Comte: ThSse de Doctorat; Lausanne, 1898. Launois and Mulon: Ann. de Gyn#coI. et d’Obst6t.,

2d

1904.

^Launois: Carter:

Th^se de la Faculty des Sciences de Paris, Edinburgh Medical Journal. Oct., 1899.

1904.

s6rle,

vol.

i,

THYROPARATHYROID DISEASES.

22G

Dean D. Lewis-”

type.

some

goiter of

writes

“In

:

these cases a history of

all

Two

years’ standing could be elicited.

goiters were of the diffuse, colloid type,

of these

and one of the mixed So far as I was able histologically, from the

type, partly parenchymatous, partly colloid. to determine, these goiters do not differ,

simple

colloid

or

parenchymatous

Basedow’s symptom-complex.”

unassociated

goiter,

with

Goiter being due, according to

prevailing views, to a telluric poison,

its exophthalmic fonn must likewise be due to such a poison. The relations between bacterial toxins, endotoxins and autotoxins and the thyroid (with the latter organ considered as the

source of one of the antitoxic constituents of the blood) afford

evidence

considerable

in

this

also

Boger and

connection.

Gamier’’® examined the thyroids of 33 cases which had died from scarlet fever, measles, diphtheria, small-pox, typhoid fever, cere-

brospinal meningitis, and septic peritonitis, and found in

all

congestion and hypertrophy with increased secretion, and in two instances

(variola

ha?morrhage.

typhoid

fever,

and.

diphtheria)

^Marine and Lenhart’’^ influenza,

foci

of

also

parench 3unatous

state

that syphilis,

and articular rheumatism are

fre-

quently associated with or followed by thyroid hyperplasia.

B.

Abrahams®” reported 3 cases which developed in the course of active syphilis.

Closely associated with this class of causes

is

that described

by W. H. Thomson,®® i.e., auto-intoxication from the alimentary canal due to imperfect gastro-intestinal digestion of nitrogenous Treatment based on this view, in which meat was foods. banished from the

diet,

gave satisfactory results. is

evident that, from

my

and

intestinal

antiseptics .were used,

^Yhile this view has been eriticised,

it

viewpoint, such poisons can, as well as

any of the others referred to above, bring about the disease in predisposed subjects, by exciting the thyro-adrenal center, and thus cause an excessive production of thyroiodase and adrenoxidase. In a case reported by Aiken,®'* the disease began under ether anaesthesia and persisted six

j^ears.

Surgery, Gynecology and Obstetrics, Oct., 1906. Roger and Gamier: La presse mddlcale, April 19, 1899. Marine and Lenhart: Archives of Internal Medicine, Nov.,

““Lewis:

Philadelphia Medical Journal, Feb. “'Thomson: Medical Record. Jan. 13. 1900. “ Aiken: Trans. Amer. Ophthal. Soc., 1897.

“•'Abrahams:

9,

1901.

1909.

'227

EXOPHTHALMIC GOITER,

Excessive and jirolonged exertion lias also been known to produce the disease. Overwork is a generally recognized factor. reported a case which came on after climbing rapidly which had a steep mountain.- Harland observed two instances appeared suddenly in soldiers who had been in action in the Daiischer'''''

Boer War.

Potain^® called attention to the fact that violent

formed the starting point of exophthalmic awakens symptoms quite similar to this disease, procidence

anger, which has goiter,

of the eye-balls, trembling, violent palpitations, sweating, diaiv

psychical

rhoea,

disturbances,

accumulate in the organism

In

etc.

all

such cases wastes

more rapidly than they can be

hydrolyzed into eliminable products, and the disease is brought about precisely as in all the forms of toxremia previously reviewed.

Fright and other violent emotions, which are relatively frequent causes of the disease, bring

though kindred, process.

and Sir Charles

Bell, accord-

person in intense terror in the fol-

“The heart

lowing words: it

Damdn

Carter,®'^ describe a

ing to

on through a different,

it

beats quickly

and

violently, so that

palpitates or knocks 'against the ribs; there is trembling of all

muscles

the

of

the

body; the eyes

start

forward,

and the

uncovered and protimding eye-balls are fixed on the object of

and clammy sweat, and

terror; the skin breaks out into a cold

tbe face and neck are flushed or jiallid fected.”

The resemblance

of these

;

the intestines are af-

phenomena

of exophthalmic goiter is obvious.

refer,

I

to the

sjnnptoms

elsewhere in this

volume, to the sympathetic center as the sensoriwn commune, in the sense that it bears the brunt of violent emotions, shocks, etc., as

one of the most sensitive of

Carter correctly says, intense terror

all is

somatic centers.

I7ow, as

“a condition in which the

somatic nervous system

is, for the time being, almost paralyzed.” Traumatic shock, blows upon the head, etc., may produce the

disease in a similar way, the violent concussion to

sympathetic center basal

centers,

is

which the and

subjected, along with the other cerebral

being tbe cause of tbe molecular

disturbance.

Delorme and Leniez,®® for examjile, reported 2 cases in “

Dauscher; Wiener med. Presse, Feb. 17, 1899. “Potain; Revue Intern, de mfid. et de chir., Oct. 10, Carter: Edinburgh Medical Journal, Oct., 1899. ™ Delorme and Leniez: Le bulletin mddical, July 20, 15

1895.

1910.

officers

THYROPARATHYROID DISEASES.

228 had been

ivlio

from their

tliroivn

pavement on their heads. two months

in the other,

by c.xophthalmie

though

etc.,

and one montli

later

They report a similar who had fallen from a roof,

goiter.

morbid

If the

tlie

in botli cerebral concus-

later in the one,

less severe case in a soldier

striking his head. shock,

was

Tliere

sion, followed

and had struck

liorses

effects of emotions,

traumatic

are attributed to a molecular disturbance of the

sympathetic center,

—

—which governs the

caliber of the arterioles,

it will become apparent that the morbid process that prevails under the influence of toxics likewise applies here.

We

have seen that poisons, by exciting tbe syunpathetic

thyro-adrenal center, so exaggerate the functional activity of the thyroid and adrenals that the characteristic action of an excess of thyroid secretion on phosphorus oxidation manifests

general

With

vasodilation.

fright

it«elf, viz.,

any violent emotion

or

capable of jiaralyzing the functions of the same center, we have general relaxation of

all arterioles

symptoms

governs, the acute

temporary exacerbation of the thijroid

which the sympathetic center

of fear being the expression of a

this vasodilation, including those of

and adrenals, and,

arterial blood in these organs.

therefore, 'an

abnormal influx of

This moans for them, as shown

in the salivary gland, a corresponding increase

by Claude Bernard

In the majority of such cases the result-

of functional activity.

ing disturbances, though sometimes severe, are either recovered

from

as soon as the central molecular equililirium is restored or,

if this restoration

docs not occur,

it

may

manifest

itself 1)V

other

however, heredity happens to predispose the victim of fright, shock, etc., to e.xophthalmic goiter, tliis disease is the one which develops; the circulation receiving an excess of thyroid disorders.

If,

becomes excessive, and the general vasodilation, the dcus ex niachina of the morbid

secretion, the oxidation of cellular phosphorus

process,

is

perpetuated.

prevailing view that heredity influences greatly the development of the disease is based on a sound foundation.

The

Among

the examples

Oesterreicher,*®

in

may

which

be cited the family referred tn by an hysterical woman’s 10 children

included 8 cases of exophthalmic goiter.

™

Oesterreiehor:

Paris, 1894.

cited

by

Chamberlain:

Ono

"Maladle

do

of these had 4 nasedow,"

p.

13,

229

EXOPHTHALMIC GOITER.

orandchildren, 3 of which suffered from the disease, while the Hare'*“ reported a case in a girl,

fourth was hysterical.

whose

great-grandmother and grandmother suffered from exophthalmic goiter, and whose great-aunt, aunt, and mother suffered from goiter, which increased with each pregnancy in the mother’s

exophthalmic goiter in the

Grober^’- reported 4 eases of

case.

same family, a brother, two

sisters,

and a

E. G. Curtin^"

niece.

collected 40 cases of the disease in 15 families.

Treatment.

—The

great value of thyroid preparations in

hypothyroidia suggests that they should prove harmful in the opposite condition, hyperthyroidia, and particularly in its most

marked

type,

exophthalmic

record suggest that such

is

Indeed,

goiter.

many

cases

on

But, in the light of the

the case.

views submitted in the foregoing pages, the reason for these

untoward

effects, is

plain:

they were due to the empirical use of

these powerful agents and regardless of the stage of the disease

and of dosage.

We

have seem that exophthalmic goiter

three stages

:

is

divisible

the erethic, that during which there

is

sensitization of the phosphorus of all tissues to oxidation

abnormally rapid cellular metabolism

into

excessive

and

the transitional, during

;

which the overactive thyroid has rmdergone sufficient fibrosis to produce only such secretion as is needed by the body, to carry

on

its

functions,

and the m,yxcedematous, during which advanc-

ing sclerosis of the gland

is

increasingly inhibiting

until these cease

and death oecurs.

the erethic stage

tlie

It

is

its

functions

apparent that during

use of thyroid could but add fuel to the

fire; that in the transitional it

might prove useful to arrest the which is inducing sclerosis, by work, and finally that in the myxoedema-

excessive activity of the thyroid, relieving it of part of its

tous

it

should prove invaluable, as

life-saving measure.

An

it

does in myxoedema, as a

even finer subdivision

is

necessary,

however, one in which the primary cause of the disorder is taken into account, if satisfactory results are to bo obtained. During the erethic stage, as a general rule, thyroid and iodine preparations are productive of serious harm. They enhance inordinately the oxidation of cellular phosphorus in all tissues

“

Hare;

^Grober: Curtin;

Intern. Medical Magazine, April, 1898. Medizinische Klinik, Aug. Jfi, 1908. Trans. Amer. Climatol. Assoc., Sept., 1888.

and

THYROPARATHYROID DISEASES.

230

the general vaso-dilation, n-hieh, as 1 have

increase, tliereby,

shown, underlies

the major phenomena of the disease.

all

In

certain mild cases that are clearly due to a to.xajinia of ovarian, uterine, or intestinal origin, thyroid is valuable (I have seen

cause comjilete retrogression of the goiter) 1

in small doses,

it

i.e.,

grain (O.OGG Gm.) of the desiccated gland during each meal,

with abstention from meats wastes

;

in its entirety, the

aim should be

to

and particularly of the

arteries,

volume of thyroid

to decrease the

formation of

but wdiere the symptom-comple.x of the disease

to.xic

present

promote constriction of the which control the

arterioles

admitted into the organs, including the

arterial blood

itself,

is

the post-orbital vessels, and the cardiac muscle.

my opinion,

Huchard obtained good results from ergot and hydrobromate of quinine. The latter drug has also been highly recommended in this country by Forchheimer. It may be given in 3-grain doses (0.198 Gm.) It is because of this action, in

that

3 times daily in capsules, increasing the dose until 5-grain doses

(0.33

Gm.)

To prevent

are given.

unpleasant

its

effects,

which

often occur promptly, and reduce the erethism of the cerebral centers

(those of the pituitary in particular)

Gm.) grains (0.99 Gm.)

grains

(1.32

of

sodium bromide on

of chloral hydrate

if

I

also give

retiring,

20

ndding 15

the bromides do not

counteract the insomnia.

Some

highly nervous women, especially those

who

suffer

from pseudo-liysteria, any preparation of quinine seems to increase discomfort. In these, tlie bromides at night, with chloral if necessarj' to counteract insomnia, should be supplemented by the u.se of phenacetin in the daytime, 5 grains (0.33 Gm.), gradually increasing the dose until 15 grains (0.99 Gm.) are taken three times daily. As stated above, the bromide reduces tbe pathogenic hypersensitiv-eness of the cerebral centers; the phenacetin maintains this action by causing constriction of the

—

which supply them with blood a common action of the coal-tar products (of which phenacetin is the safest), as I arterioles

point out in the second volume.'*®

The

favorable effects obtained by

pituitary gland are explainable in

« See vol. « Renon and

li,

p.

128.1

Delille:

to 1291. Hull. gfn.

Fenon and

Delille'*'*

much the same manner.

do Thfirap.,

May

„ 8,

190(.

with

In

231

EXOPHTHALMIC GOITER.

Gm.) of the whole gland (ox), which they subsequently deemed advisable to increase to 71/2 grains improve(0.5 Gm.) in divided doses daily, they obtained marked

doses of -JV2 gi’ains (0.3

Hallion and Carrion''® then found experimentally that pituitary extracts ‘‘'always produced their effects by raising the

ment.

arterial tension,”

constrictor action

producing at the same time “an intense vasoupon the thyroid body.” Briefly, we have

—the

here precisely the phj'siological action necessarj^ strictor

power of the adrenal component of

tlie

vasocon-

pituitary gland

superseding the vasodilator action of the thyroid, the underlying cause of the disease. 'The to

morbid

effects of

the excessive oxidation of phosphorus

which the cellular elements are subjected require attention. resulting exhaustion of the phosphorus in the muscular layer

The

of the. arteries aids powerfully the action of the depressor nerve ill

keeping the general vasodilation, including that of the thy-

roidal vessels, thus keeping

must, therefore, be replaced.

up the disease. This phosphorus Hence the value of sodium phos-

phate, noted long by ICocher, Trachewski, A^etlesen (40 cases),

and

others,

and of the glycero-phosphate of sodium in 20-grain M. Allen Starr though none of

—

doses three times daily, noted by

knew the modus operandi of these agents. Of great importance to enhance the curative process is the free use of saline solution by enteroclysis and hj^poderraoelysis. The fonner, given at 108° F., sometimes suffices when, after clearing out the intestines by means of an enema, the solution,

these autliors

using a quart at a time, considerable absorption.

is

retained sufficiently long to insure

If this

is

not the case, hj^podermoclysis

every other da}q regulating the quantity according to the case,

By

indicated.

is

increasing markedly the osmotic properties and

the viscidity of the blood,

its toxicity

and

its

exciting action on

the thyro-adrenal center are greatly reduced, and the elimination of is

tlie

pathogenic poisons by the kidneys and the intestinal tract

greatly enhanced.

The

must he carefully sought and, if removed. In cases due to pregnancy, menopause, and inadequate ovarian development, the disorder is mainly due to causative condition

possilile,

inability

of

the thyroparatliyroid

“Hallion and Carrion:

Soc. do Thdrap.,

apparatus to neutralize the March

13,

1907.

232

THYROPAUATHYROID DISEASES.

increasing tide of wastes

tlie blood eontains. The organ is abnormally stimulated, in the sense that its arterioles are widely opened to allow a vastly gi-eater volume of arterial blood than usual to enter it, and it heeomes enlarged. Here, thyroid

preparations, starting with 1 grain (0.006 Gm.) t.i.d. of the dried gland, are of great value by compensating for the organ’s If the toxasmia

deficiency.

he banished,

and free

is

of intestinal origin,

saline

purgation

—

in

meats should

addition

to

the

—

measures advocated in the preceding two paragraphs is indicated. Highly nervous or pseudo-hysteric cases are also helped

by the bromide, phcnacetin, and saline solution treatment, but rest in these cases and in those due to traumatic shock is of great importance. In fact, it must be borne in mind that exertion increases toxic waste formation, and, therefore, the asset of pathogenic poisons, and that rest

is

always indicated in these

cases.

from animals deprived of their thyroid Ballet and Enriquez’s dog serum, Mobius’s sheep serum, or “antithjToidin,” Eogers and Beebe’s serum, obtained from rabbits or sheep inoculated with extracts of exophthalmic Various

obtained

sera

:

goiter, are all of value in that they are all antitoxic substances

which aid the blood in neutralizing the pathogenic poisons. This applies also to Lanz’s results with the milk of thyroidectomized goats’ milk, which gives the same reactions as blood-

serum in so far as its antitoxic constituents are concerned. During the transitional stage the treatment depends entirely upon the progress made by the atrophic process. As a rule, howsigns

ever,

of

myxeedema

are

already present; in that case

thyroid preparations are indicated, as they are during the myxee-

dematous

stage.

The

latter is virtually a case of

mj'xiedema and

requires the measures enumerated under that heading in the

preceding chapter.

marked tendency

In both these stages, however, there

to cardiac failure,

and

is

a

digitalis or strophan-

thus are precious adjuvants.

When cated

:

medicinal treatment

fails,

surgical measures are indi-

partial thyroidectomy or, as frequently done hy the ttlayo

brothers, ligation of the thyroid arteries

—a

measure quite in

keeping with the aim of the treatment detailed above.

—

CriAPTEE

VI.

THE ADEEHAL SYSTEM AND FUNCTIONAL ACTIVITY. By

“adrenal system,” I

three organs studied so far,

mean a

viz.,

and the tliyroparathyi’oid apparatus, taining, as previously stated

center of the two others. assert itself

when we

functional union of the

the pituitary body, the adrenals, tlie

first-named organ con-

(see also p.

610), ihe governing

The importance of this union will

consider such diseases as acromegaly, which,

though due primarily to a lesion of the pituitary, manifest themselves through their influence upon the adrenals and the thyroparathyroid apparatus.

To make

this

and other questions

intelligible,

however,

necessary to show that what I have termed adrenoxidase

it is

(the

oxidizing substance of adrenal origin) circulates in all organs in conjunction, of course, with the thy ropara thyroid secretion,

though the

latter will

not be mentioned, to avoid confusion.

Even the nervous system, we dase,

by adrenoxi-

shall see, is traversed

thus bringing the neuron itself within the field of the

general circulation.

ADRENOXIDASE AND THE MOTOR NERVES IN THEIR RELATION TO MUSCULAR CONTRACTION. The functions.

skeletal muscles stand apart in respect to

The sympathetic system

striped muscular fibers elsewhere,

known

to

supplies

and yet

extend to the extremities.

vasomotor

nerves

this system

to is

unnot

Again, vasoconstrictors

and vasodilators are said

to accompany the larger nerve-bundles, the sciatic, for instance; but a survey of the field distinctly shows that the evidence as to the existence of separate vasoconstrictors is purely inferential. Since the sympathetic

nerve

does not appear to send subdivisions to this class of muscles, the association of constrictors of another source

introduces an ele-

ment

of confusion, not only as regards the peripheral structures themselves, but particularly in respect to the central origin of the two systems classed under the one single term of “vaso(

233 )

THE ADRENAL SYSTEM AND FUNCTIONAL

234

motors.” question,

ACTIVITY.

As it is imjiossible to proceed witliout clearing this we will first ascertain whether the prevailing views as

to the physiology of the circulation in the

my own

not, in the light of

Adrenoxidase AND

]\I

muscular system

may

conceptions, be subject to change.

YOSINOGEN.— In

the production of

muscular contraction a nerve-impulse is of course transmitted to the muscular elements; but how are this impulse and the resulting contraction related to the functions of the blood itself?

This question

is

suggested by the role I have assigned to the

oxidizing substance or adrenoxidase.

Stewart'

refers

to

contraction as follows:

the

thermal

“When

phenomena

perature rises; the jjroduction of heat in is

most distinct when the muscle

of

a muscle contracts,

is

proved for single contractions.

it is

muscular tem-

its

This

increased.

tetanized, but has also been

The change

can be detected by a delicate mercury- or

temperature

of

air-

thermometer;

and, indeed, a thermometer thrust among the thigh-muscles of a dog may rise as much as 1° to 2° C. when the muscles

phenomenon of hyperoxidation through suprarenal overactivity we have suggested when studying the action of drugs. This affords a are

thrown into tetanus.”

first clue:

If the

That tetanus

is

a

plasma contains an oxidizing substance, the

chemical changes in muscular tissue during contraction

—

i.c.,

absorption of oxygen, increased production of carbon dioxide,

change of reaction from neutral or alkaline to the

formation

of

sarcolactic

acid

—

clearly

acid,

and

suggest

finally

that

the

and the mechanical energy utilized may be due to an increased supply of oxygen through the agency Indeed, Ivronecker has shown of the oxidizing substance. that “the injection of arterial blood or even of an oxidizing contractile

process

agent like potassium permanganate into the vessels of an If an agency hausted muscle also causes restoration.”

remote in

composition from the

e.x-

so

normal organic fluids can power an exhausted mus-

restore merely through its oxidizing

eminently ph}'siologieal a fluid as the blood-plasma, charged with oxygen in loose comhination, must surely possess Indeed, the link seems to correspondingly active properties. cle,

1

so

Stewart:

“Manual

of Physiology,” p. R98.

—

235

ADRENOXIDASB AND MYOSINOGEN. be a strong one

if

the full

meaning

of the following sentence

from Foster’s “Physiology” (sixth edition) is gathered: “We might compare a living muscle to a number of fine, transIf we parent, membranous tubes containing Tjlood-pt'asma.” also recall the fact that capillaries do

not possess contractile .

and that arterioles represent the ultimate subdivision which vasomotor nerves are distributed, it becomes clear that we have all the mechanical elements necessary to account fibers

to

some unexplained phenomena that attend muscular contraction. An impulse capable of causing a change of caliber of a peripheral arteriole would thus suddenly admit more arterial for

—

more oxygen-laden plasma into the “fine, transparent, membranous tubes,” and contraction, an inherent property of muscular tissue, would follow. blood

i.e.,

The

prevailing

views

as

to

the

nature

of

the

j^roeess

through which the mechanical energy utilized during muscular activity cause contraction or retraction

from

selections

Professor

Foster’s

may

te.xt.

be illustrated by

Eeferring

to

the

chemical analogy between the axis-cylinder and .muscle-tissue,

“We

he says:

have no satisfactory evidence that in a nerve

even repeated nervous impulses can give

rise to an acid re“nor have we satisfactory evidence that the progress of a nervous impulse is accompanied by any setting

action”

.

.

.

form of heat.” In the summai’y, referring phenomena, he remarks: “This muscle-impulse, of which we know hardly more than that it is marked by a current of action, travels from each end-plate in both direcfree of energy in the to the terminal

tions to the end of the fiber, all events,

where

it

appears to be lost; at

we do not know what becomes

of it. As this impulse-wave, whose development takes place entirely within the latent period, leaves the end-plate, it is followed by an explosive

decomposition of material, leading to a discharge of carbonic acid, to the appearance of some substance or substances, with

an acid reaction, and probably of other unknown things, with a considerable development of heat. This explosive deconi]X)sition gives rise to the visible contraction-wave, which travels behind the invisible muscle-impulse at about the same rate, but with a vastly increased wave-length. The fiber, as the wave passes over it, swells and shortens, and thus brings its

two

THE ADRENAL SYSTEM AND FUNCTIONAL

236

When

ends nearer together.

ACTIVITY.

repeated shocks are given, wave

follows wave of nervous impulse, muscle-impulse, and visible

contraction; but the last do not keep distinct; they are fused into the continued shortening which

The

we

call tetanus.”

word, “tetanus,” stands as the highest expression

last

of a rapid succession of nervous impulses; hut, viewed

from

my

standpoint, this succession of impulses can as readily produce

and give

successive variations of vascular caliber,

rise to pre-

the phenomena, witnessed, by admitting the oxidizing sub-

cisely

“membranous

stance of the blood-plasma into the fine,

The shock experienced when

tubes.”

the current

is

turned “on” or “off”

further suggests that the latter process

is

the true one.

mere passage through

a

of

nerve

a

constant

does

not,

current

of

uniform

“The

intensity

under any circumstances,” says

Professor Foster, “act as a stimulus generating a nervous im-

only set up when the current either from the nerve. It is the entrance or the exit of the current, and not the continuance of the “It is the sudden current, which is the stimulus.” change from one condition to another, and not the condition

pulse; such an impulse

is

into or is shut off

falls

.

itself,

.

.

which causes the nervous impulse.”*

The confusion that attends manner in which muscular tissue contract

is

newer conceptions outlined in the the

various

causal

views

as

to

the

physiologically caused to

readily accounted for when,

is

dissociate

prevailing

in

the light of

last chapter,

elements

of

we

the

analytically

muscular

activity.

Indeed, we have seen that various phenomena ascribed to the sympathetic system belonged to the domain of the adrenals

have tenued the adrenal system; we are again brought to realize that in all organs certain functions must likewise, and for the same reasons, be disconnected from

i.e.,

to

what

I

immediate purpose in the tissues. Thus, the fact that the musc\o-iinpiilse, which “travels from each end-plate in both directions to the end of the fiber, where others

it

as

regards

their

appears to be lost,”

though

causal,

element

material, etc.,” through

*

All Italics are

is

my

own.

at present considered as an inherent, of the “explosive decomposition of

its activity as

a physiological stimulus.

—

—

ADRENOXIDASE AND MYOSINOGEN.

But

we can separate

if

237

these elements of the process into two

a nervous impulse to the muscular the elements themselves, and (2) a simultaneous change in impulse leaves caliber of the local arterioles, the fact that as the viz.:

distinct parts,

(1)

followed by an explosive decomposition of stand as material, leading a discharge of carbonic acid,” will necesbecomes Such a division the only result to be expected. sary in the light of my conception of the process.

tlie

end-plate “it

is

While the nerve-impulses only have for their purpose i.e., the bloodto excite and govern contraction, the blood becomes the substance oxidizing plasma mainly through its factor through which the chemical process to which contractile

—

—

work tion

due

is

suddenly awakened.

is

per se

feature of this concep-

—

must be laid since it applies organs is that it dissociates from the oxidation process a stimulus which does not belong to it and which, there-

upon which particular

to all

A

stress

—

“We

fore, introduces elements of confusion.

Stewart, “in what the

cannot

muscular contraction in the intact body really

how

differs

it

from

tell,” says

‘natural’ or ‘physiological’ stimulus to

artificial

stimuli.”

consists,

nor

Believed of this au-

tonomous agency the organic physico-chemical processes enter within the limits of exact investigation.

Oxygen

in

other fields of thermochemistry

is

kno'wm to

which “explosive deawakened and sustained. That it fulfills the same role in this connection, some complex organic compound in the muscular fibers constituting the primary source of en-

constitute the reactionary agent through

composition”

ergy

or

is

fuel,

is

Under

probable.

these

passive “irritability” of a living muscle

circumstances

the

would be maintained

by a continuous reaction in which the reagents would he these compounds i.e., hydrocar])ons and the oxygen held in loose

—

combination in the blood, particularly the hlood-plasma, which penetrates

the

contractile

elements

themselves.

This

irrita-

would then become abruptly converted into contractility when the blood-supply i.e., the plasma in the contractile fibers ^\vould be increased through the arrival of more oxygen. bility

—

Considerable

duced

is

familiar

evidence besides

that

already

ad-

available in support of this conception of the general

physiology

of

muscle-tissue.

Although continuous muscular

THE ADRENAL SYSTEM AND FUNCTIONAL

238

contractility

is

generally thought to be associated with nerve-

impulse, destruction of does not cause

ACTIVITY.

it

in this particular

all

nervous connection with a muscle

to lose its excitability. is

shown by the

Its inherent property

fact that, although the apex

of the heart contains no nerve or nerve-cells,

responds to stimulation.

nevertheless

it

Even when detached from the body,

muscles preserve their contractility for a time under suitable conditions. This would appear to eliminate the need of further energy to account for the phenomena witnessed; but the

contrary

is

the case, since

it

shows why .muscular

tissue,

owing

to its inherent irritability, responds to various stimuli: vital,

physico-chemical, and mechanical. Electricit}'^, we know, acts as a powerful stimulus, but heat alone acts in precisely the same manner if the temperature is adequate and is electrical,

marked contraction may thus be caused when reached, and violent activity induced before the mus-

raised rapidly;

30° C. cle is

same

is

Chemical stimuli

heated to 45 degrees. effect,

will

produce the

provided the reaction induced occurs with

suffi-

cient rapidity.

That the nervous impulse

is

not the source of mechanical

energy utilized under these circumstances,

is

shown by the

fact

that a chemical stimulus applied to a nerve, ammonia, for instance, will not stimulate

it

though

various acids, hydrochloric, acetic,

it

will excite the

etc.,

will

muscle;

give rise to the

same phenomena. “Certain poisons (curare) cause the motor nerves to become completely incapable of action,” says iM. Duval, “and, therefore, incapable of transmitting irritation to a muscle; nevertheless, under these circumstances, the excited

muscle can directly pass from the state of rest to that of activity (Claude Bernard, Kolliker) ; the ultimate and fine nervous ramifications that they contain take no part in this irritability, since the poisons referred to kill .mainly the intra-

A motor nerve muscular endings of the nerves (Vulpian). separated from the cerebro-spinal axis loses, after four days, inall excitability; the muscle, on the contrary, previously than more excitable nervated by this nerve remains directly months (Longet).” That muscle is directly and independently excitable by a large number of stimuli is evident; that oxygen should. three

—

239

ADRENOXIDASE AND MYOSINOOEN. exacerbations

through

of

physico-chemical

continuous

a

action of which its tissues are the scat while state,

the passive

in

he able suddenly to awaken the active state

AVhen the muscle

is

re-

as clear.

is

in the passive state, the transformation

upon the continuous reaction manifests heat; while, when it is active, it manifests itself

of energy incident self

as

Armand

greater heat plus mechanical work.

it-

as

Gautier has as-

certained that a working muscle took up nine times more blood than a resting one, and that the ratio of carbonic acid given

by it or transmitted to the venous blood was nearly one hundred times greater. This raises the question as to whether off

tl:e

work

conversion of chemical energy into the mechanical

upon which contraction depends must

A

heat energy. based on voltaic

showed

Carnot’s investigations,

cell

in

be transformed into

that,

just

in

as

a

which the chemical potential at once appears

under the form, of intermediate

first

study of this question by Professor Gautier,

state

without

electricity

of

heat,

can

so

passing

through

intramuscular

tlie

chemical

energy become directly transformed into work. Indeed, he found that 65° C. (149° F.) would represent the final temperature of an active muscle, were

conclusion that “a mistake direct

transformation

tension,

of

it

otherwise, and reached the

contracts

the

and works owing

chemical

potential

into

to

a

elastic

without ever requiring the intervention of the heat

which theoretically accounts for internal co.mbustions.” These facts seem to me to warrant the deductions 1. That the mechanical energy utilized by living voluntary :

muscles in the passive state

is converted chemical energy, the a reaction in the muscular contractile elements during which various compounds, mainly hydrocarbons, are oxidized. 2. That active muscular worh is the result of an exacerba-

result of

tion of the activity of this mechanical process, attended with a direct transformation of the passive potential: i.e., irritability, into the active potential:

i.e.,

contractility.

The

suggestion that the reaction occurs in the living contractile elements themselves cannot, for obvious reasons, be demonstrated experimentally. But if we associate Foster’s

comparison of a living .muscle to parent,

‘ka number of fine, transmembranous tubes containing blood-plasma” with my

—

—

THE ADRENAL SYSTEM AND FUNCTIONAL

240

ACTIVITY.

conception of the nature of blood-plasma as an excipient for an oxidizing agent of adreno-pulmonary origin, on the one side, and, on the otlier, recall the view of Eugleniann, that a

from the bright bands of the

Iluid substance passes

the interstitial disks

—

into the dark bands

i.c.,

— the intimate process would be as follows

fiber

i.e.,

the contractile

The hydrocarhon compounds would occupy the contractile dishs, while the oxidizing substance would fill the interstitial disks, and on the proportion of the latter entering the contractile disks would depend the activity of the oxidation process and the degree of contraction.

d isks,

:

Further evidence that the general process outlined prevails

may

substance

be obtained by tracing the identity of myosin

found in the muscles after death.

:

the

“While dead

muscle contains myosin, albumin and other proteids, extractives,

and certain insoluble matters, together with gelatinous and other substances not referable to the muscle-substance itself,” says Professor Foster, “living muscle contains no myosin,^ but

some substance or substances which bear somewhat the same relation to myosin that the antecedents of fibrin do to fibrin, and which give rise to myosin upon the death of the muscle. There are, indeed, reasons for thinking that the myosin arises from the conversion of a previously existing body which may be called myosinogen, and that the conversion takes place, or may take place, by the action of a special ferment, the conversion of myosinogen into myosin being very analogous to We may, in fact, the conversion of fibrinogen info fibrin. speak of rigor mortis as characterized by a coagulation of the

muscle-plasma comparable to the coagulation of blood-plasma, hut differing from it inasmuch as the product is not fibrin, but myosin.

The

rigidity,

the

loss

of

suppleness,

and the

diminished translucency appear to be, at all events, largely, though probably not wholly, due to the change from the fluid plasma to the solid myosin. We might eompare a living muscle to a

number

blood-plasma.

of fine transparent

When

membranous tubes containing

this blood-plasma entered into the ‘jelly’

many much of

stage of coagidation, the system of tubes would present

of the

“

phenomena

of rigor mortis.

All italics arc our own.

They would

lose

241

ADRENOXIDASE AND MYOSINOGEN.

amount suppleness and transhicenc)', and acquire a certain imporand marked very one There is, however, of. rigidity. the and muscle tant difference between the rigor mortis of

tlieir

coagidation of blood. a

slight

Blood during

change only in

its

its

coagulation undergoes

reaction; but muscle during the

onset of rigor mortis becomes distinctly acid.” of rigot If .myosinogen were the precursor of the myosin

what would its composition probably be and how would become metamorphosed into myosin ?

mortis, it

I

my

have submitted the data sustaining

existence of the oxidizing principle,

view as to the

and have referred

to

it

body derived from the suprarenal glands, which, in passing through the lungs, entered into loose combination with as a

The

oxygen.

labors

Jaquet,

Salkowsky,

Schmiedeberg,

of

Abelous and Biarnes were quoted to show that such a principle had also been found by chemical methods, though its origin remained

unknomi

to them.

If combustion of products of nuclein metabolism in the

blood-plasma, through the presence therein of oxidizing substance, can produce uric acid, it seems reasonable to conclude

same substance

that, if this

is

also present in

should find evidence of a similar action.

myosinogen, we

Not only

this the

is

musportion of muscle-plasma obtained by

case, but the same products of metabolism are found in

cle-serum;

the liquid

Though obtained

rubbing up and expressing fresh muscle.

only in very small quantities, the purin bases, creatin, xanthin,

hypoxanthin, and creatinin, are always found in addition to their end-product, uric acid.

Phosphoric acid

—

a waste-product

derived mainly from the catabolism of nerve tissues

—

is

an-

other link between muscular plasma and that of the general

Of

bodies

should

not

be considered as elements of muscular activity.

Their

his-

blood-stream.

course,

these

various

tory indicates that, along with other albuminoids found, they are

mere passive hosts

of

the

muscular plasma

products of muscular fisstTupathetic nerve, the character of the cells is changed to such a degree that one thinks he has to deal with a completely new organ.” They also refer to tlie experiments of von Wittich. which showed that “excitation of the cervical sympathetic nerve remained without effect of saliva

.

ADRENOXIDASE AND THE LACRYMAL GLANDS.

upon the the same

271

secretion of the parotid gland, if the facial nerve of side

had been torn out from the cranial cavity either All this suggests that the

immediately or some days before.” sympathetic

fibers,

as disconnected

which are

from the

also distributed to the vessels, are

active function as in the lacrymals:

a view strongly sustained by

tlie

experimental observations of

Heidenhain, which showed that the secretion obtained by exciwas very

tation of the sympathetic nerve (in dogs or rabbits)

That similar experiments in the submaxillary gland have given corresponding results is well kno^vn. But the S3unscarce.

pathetic cannot be regarded as a secretory nerve on this account since the secretion is merely the result of a

blood pumped,

as

were,

it

into

the gland

slight excess of

bj'’

the increased

propulsive activity which the stimulated fibers provoked in the spiral muscular, coat of the arterioles.

from Professor Foster’s also be found to show that

If the annexed engraving, taken

work,

is

carefully examined,

the circulation

of

the

intimately associated. of

the

carotid,

while

will

it

organ and the sympathetic

The

arteries

the

veins

ultimately lead to the jugular:

fibers

are

are terminal subdivisions

are

primary channels that

features which emphasize their

Over these are entwined sympathetic from the superior cervical ganglion, which fibers are

functional importance. fibers

inclosed

in

present,

the

a

common

vagus:

sheath

further

with the main

evidence

sensory nerve

that they must,

in

a

measure, govern the quantity of blood distributed to the organ. In fact, this association with the vagus, sufficiently intimate “to form udiat appears to be a single trunk,” almost imposes the deduction that the arterial branches of the latter nerve transmit the afferent or sensory impulses in the reflex arc upon

which the “nervousness” of speakers, actors, etc., depends as “dry-mouth,” or temporary xerostomia, so

to the condition of

frequently observed.

hazard;

it

Such an inosculation

is

not due to mere

strongly suggests that the s}Tnpathetic fibers form

part of the mechanism through which the intraglandular bloodpressure of the organ is governed. All this shows clearly that the influx of blood regulates the secretory activity of the gland', and that we are dealing with

a vasomotor phenomenon.

This idea would seem to be opposed

THE ADRENAL SYSTEM AND FUNCTIONAL

- ST ss

Centralbl.

f.

d.

med. Wissensch., Dd.

d.

xvlil. S. 945,

ges. Physiol., Bd. xxll, S. 12G, 1880.

Luchsinger: Archly Langley: Lor. rit., p. 061. Ostroumoff: PflUger’s Archly., Dd. f.

xll,

S.

219,

1876.

1880.

277

ADRENOXIDASE AND THE SWEAT-GLANDS. of sympathetic origin

is

to observe the effects of stimulating

the abdominal sympathetic,” he refers to the experiments of Gaskell-® who found “ a slight decrease of the blood-flow

through the muscles,”

who observed

and lleidenhain*® “Neither found on

vasoconstriction,

i.c.,

a slight fall of temperature.

direct stimulation,” says Langley, “evidence of the presence of

Bayliss^^ recently reviewed

vasodilator fibers.”

had been recorded on the

cpiestion,

what evidence “It seems

and remarks:

have been almost taken for granted, up to the present time, that the dilators must run in the abdominal sympathetic, but to

the actual evidence for this

that the sympathetic,

t.e.,

is

It is clear

very unsatisfactory.”

the vasomotor system, takes no part

in the process.

Conversely, there

is

evidence to show that the skeletal mus-

contain vasodilator nerves and that the fifth pair presents

cles

which ]3oint to it as their motor nerve. Thus Dastre and Morat^^ obtained dilator effects by stimulating this nerve in attributes

the cranium

and

also

by exciting the Gasserian ganglion, while

Laffont®* caused flushing by stimulating the fifth nerve after the sympathetic fibers anastomosing with to degenerate.

had been allowed

it

GaskelP'* also observed that the branch of the

fifth

distributed

Such

effects

to

the

mylo-hyoid

contained

vasodilators.

cannot be attributed to excessive vasoconstriction when a cranial nerve is the source of dilation, since the only

—in

the light of

views, with the vasa-vasorum of those arteries.

They cause

connection of the latter with the arteries

my

is

dilation or nothing.

Moreover, the manner in which its influence on the muscle manifests itself points to a pure motor

Thus the mylo-hyoid takes part

action. less

says

by transmitting efferent impulses. :

“The

efferent impulses

in deglutition, doubt-

Starling,^® for instance,

from the center pass by the hypo-

glossal nerve to the muscles of the tongue,

by the

“Gaskell: Jour, of Anat. and Physiol., vol. xl, p. 3G0, 1877. Heidenhain; Heidenhain, Alexander u. Gottstoln, Archly t.

fifth to the

»>

Bd. xvl.

S.

1,

Bayllss:

“

ges. Physiol.

Jour, of Physiol., vol. xxvl, p. 173, 1901.

Dastre and Moral:

““Laffont; “ Gaskell:

d.

1878.

"Recherches sur

le Syst.

Nerv.,”

1884.

Cited by Vulplan: C. R. de I’Acad. d. Scl., T. li, p. 981, 1885. Jour, of Anat. and Physiol., vol. xl, p. 720, 1877. “Starling: Schafer’s “T. B. of Physiol.,” vol. li, p. 320, 1900.

THE ADRENAL SYSTEM AND FUNCTIONAL

278

muscle, by

iiiylo-liyoid

glosso-pliaryngeal,

llie

branches of the vagus, the

the pharyngeal

and the spinal accessory nerves

fifth,

to the muscles of the fauces

ACTIVITY.

and pharynx.^’

Conversely, Charles

Bell obtained paralysis of the facial muscles on cutting the

(Quoted by Schafer.^”)

fifth nerve.

When

these observations are supplemented in the light of

the experimental facts previously adduced, and the aggregate is

taken as the basis of analysis, a close functional relationship

between the muscles of the sweat glands and the skeletal muscles not only suggests itself, but the fifth nerve stands out

prominently as the motor nerve of both. Sherrington*^ states that “the nerves of muscles derive

numbers of

from the spinal ganglia.” In the limb muscles of the monkey and cat he** found “from a half

large

their fibers

He

to a quarter of all the nerve fibers to be sensory.”

—muscle

says tliat “these sensory fibers end in end-organs

modified

Golgi-organs,

dles,

bodies.”

As

is

Pacini-organs,

and

in

also

spin-

Pacini

well knouTi, anassthesia of the surface prevents

the development of convulsions:

it is

therefore by paralyzing

the cutaneous sensory end-organs, of nerves connected with the

muscular nerve-supply that these abnormal muscular contracAgain, while Binswanger obtained spasm tions are prevented. reflexly

—

are

the

—

efferent

motor impulses being necessary

factors of the

in various parts of the body by stimulating branches of

fifth

pair,

Sherrington as interpreter of the prevailing

knowledge, states that the gelatinosa which caps the posterior horns and receives all the fibers from the sense organs of the

body surface and muscles extends “without break from the cranial fifth to the lowest coccygeal, inclusive”

The

vasodilator

observed

effects

by Dastre

and

Moral,

Laffont, Gaskell point to the presence in the sweat and skeletal muscles of the head and neck of stricto-dilator nerves belonging

In the light of the above data, it seems probable that this applies to the trunk and extremities as well. What experimental evidence there is to show that an influx to

the fifth pair.

of blood into a gland *>

cited by Schafer:

3"^

Sherrington: Sherrington

***

:

is

not the factor which incites function

Ibid, vol.

Ibid, vol.

ii,

p.

il,

p.

726.

1007.

Jour, of Physiol., vol. xvii, p. 211, 1894.

—

279

ADRENOXIDASE AND THE SWEAT-GLANDS.

views I have submitted are “The action of the Howell/® for instance, writes: sound. nerve-fibers upon the sweat glands cannot be explained as an loses considerable of

—

indirect effect

M^eiglit if the

for instance,

a result of variation in the

as

Experiments have repeatedly shown that, in

blood-flow. eat,

its.

stimulation of the sciatic

still

tlie

calls forth a secretion after

the blood has been shut off from the leg by ligation of the aorta, or indeed after the leg has been amputated for as long as twenty

An

important feature of these experiments, however, is that the secretory activity is of very short duration and that the relaxation of the arterioles and the sudden influx of blood

minutes.”

among nerve

the epithelial cells induced by stimulation of the sciatic

is sufficient

human

beings

accompany a

it

to accoimt for

known

is

it.

Howell

also states that “in

that profuse sweating

may

often

In all of shown in the second volume, there is gen-

pallid skin, as in terror or nausea.”

these conditions, as

eral vasodilation, including of course relaxation of the arterioles,

which

also increases the

lial cells.

M. DuvaE®

growing weaker, sweating of the toe-pads occurs; these are not pigmented they become pale and exsanguine.

heart-action

and

if

volume of blood admitted to the epithemoribund cats, while the

states that in

is

This corresponds with the profuse sweating of death-agony in

human

beings, which is also attended, of course, with pallor an obvious sign that the vascular arterioles are relaxed allowing a temporary influx of blood into the sweat-glands. Finally, as I will show on page 1380, pilocarpine as well as other drugs, nicotine, for

example

—owes

—

its sudorific

properties to the fact that it depresses the sympathetic center, thus causing relaxation of the arterioles. A et, division of the sciatic nerve, through

which the S3Tnpathetic

fibers reach the arterioles of the lower not prevent sweating in the corresponding But we must not lose sight of the fact that the relaxation

e.xtremities,

limb.

does

of all the arterioles of the

body by the drug produces a conmoribimd animals, and that

dition akin to that observed in

under such conditions division of the sciatic would not prevent an influ.x of blood into the gland and cause sweating. The process through which the functions of a sweat-gland Howell: hoc. cit., p. 790. ‘“Duval: “Cours de physiologic, ”

1892.

—

.

THE ADRENAL SYSTEM AND FUNCTIONAL

280

ACTIVITY.

are influenced by variations of blood-flow becomes all the more evident when we take into account its histology and especially

the

manner

in which the muscular elements are disposed. In the light of all this evidence, the following conclusions seem warranted :

The

secretory activity of a sweat-gland is increased hy the circulation of an excess of adrenoxidase-laden plasma in its epithelial and muscular elements. 1.

2. All the intrinsic structures of the gland being thus rendered hyperactive, the secreting activity of the glandular elements is enhanced and the spiral muscles around the coiled and

straight tubes are caused to contract periodically, each contraction causing an outflow of sweat. 3.

The increased supply

of blood

due to dilation of the glandular arterioles by vasodilator impulses received through the secreto-motor nerve of the gland (probably an extension of the fifth including 4.

The

its

is

spinal extension)

secretory activity of a sweat-gland

the volume of blood circulating through

contraction of

through

its

its arterioles

it is

is

reduced when

decreased owing to

by vasoconstrictor impulses, received

sympathetic terminals.

The

capillaries form a close net-work around the coiled and reach down to an extremely thin basement membrane, which, in turn, surrounds the layer of muscular fibers that coil around these tubes. An important feature of this muscular layer, ^^vhich is only separated from the cavity or lumen of the tube by the secreting epithelial cells and their

tubes,

—

endothelial lining,

—

^however,

is

tliat

its

ribbon-like fibers are

wrapped round the tube, and in such a manner as to a gap between their border, throughout their whole length.

spirally

leave

Not

only, therefore,

is

the thin basement

to reach the secreting cells

membrane thus enabled

through the gaps, but the former

actually project through the latter so as to touch the

brane.

Furthermore, the projecting

mem-

cells are so related to

one

another as to form canaliculi-like spaces, which extend from the capillary-covered

membrane completely through

to the

lumen

of the tube (Itanvier).

and Sebaceous Glands. influence of

— Foster

refers to the

the nervous system upon the mammary glands

in

ADRENOXIDASE AND THE MAMMARY AND SEBACEOUS GLANDS.

281

“That both the secretion and ejection the following words: system is shown by of milk are under the control of the nervous but the exact nervous mechanism has not ^Yhile the erection of the nipple 3^t been fully worked out. breast are ceases when the spinal nerves which supply the

common

exjjerience,

divided, the secretion continues,

and

is

not arrested even

when

the sympathetic as well as the spinal nerves are cut.” The nerves that supply these organs and the skin cover-

ing them are the intercostals from the second to the sixth, inclusive ; the thoracic branches of the brachial plexus ; and the descending branches of the cervical plexus, while thetic filaments

accompany

we

In this analysis since the to

mammary

sympa-

all blood-vessels.

will, in

secretion

is

a measure, cover two subjects, carried on in a

that which prevails in sebaceous glands.

manner similar The functional

and the similarity referred to are well the following quotations from the work of W.

process in the latter illustrated in

Eoger

autlior says:

part cells,

we

glands,

the

sebaceous

“Within the membrana

propria of

Williams.'*^

Eeferring to

its

this

secretory

find a stratum of small, irregularly-shaped epithelial

each with a large nucleus (Fig.

1, &).

The

cells of this

region are constantly proliferating, and, as the products of the

become changed and gradually form the secretion.” If the words that we have italicized are placed in immediate sequence, they will be found to describe exactly the histological arrangement of the sweattubes from the delicate membrane to the lumen. “The steps of the process are as follows The cells next the marginal cells (Fig. 1, b) inerease in size and their nuclei duundle. As they approach the center of the acinus their nuclei disappear, and the cells become distended with granules and oil-globules. Finally they burst and their debris forms the secretion, which is discharged.” This also coincides with the manner in which

process gradually shift toward the duct, they

:

sudoriferous glands produce their secretion.

“Lactation

Mr. Williams.

is the outcome of a similar process,” continues “Milk must, therefore, Ije regarded as the prod-

uct of the deliquescence of successive degenerations of epithe-

W. Roger Williams:

“Diseases of the Breast,” London.

1894.

THE ADRENAL SYSTEM AND FUNCTIONAL ACTIVITY.

282

cells 'which

licil

relays of

new

are destroy eel in this process and replaeed by derived by division from other still active

cells

epithelial eells of the part.

Thus we

see that growth, devel-

opment, and seeretion are but slightly varied manifestations of .

eellular .

aetivity

finding

eventuates in lactation process

is alwa3’s

is

gradual.

Creighton’s deseription of

hand

e.xpression

“The complete degree

.

in

funetion

in

different

function that only attained periodically, and the

The it

:

hand with imdoing

following

a brief aeeount of

is

Subsidence of the funetion goes of structure,

and

revival of the

with the building up of strueture.

Variations

intensity in the seeretory foree are measured by

Fig. 1.— Histologicai. Section

Cyst. a,

Fibrous

stratum

stratum,

which correspond

The beginning

c,

to

ways.”

mammary

of

of the

its

of

produets

Wall of a Sebaceous

(Cornil and Rani

ier.)

with connective tissue corpuscles. 6, Hornlfying cells, d, Sebaceous cells.

Marginal

changing aspects of the secreting

aeini.

of the rising function coincides with the be-

and the process occupies the entire During the intervals between its periods

ginning of pregnancy, period of gestation.

of functional activity the breast remains in a quieseent funetionless state: is

the resting stage.

shrunken and surrounded by

fibro-fatty

tissue.

The

acini

are

In this condition the gland a

considerable shriveled

up.

quantity

On

of

miero-

examination of sections of the gland in this stage (Fig. 2) each acinus appears as an alveolar space bounded by a thin layer of fibrous tissue, denuded of epithelium.' Its eonscopical

ADRENOXIDASE AND THE MAMMARY AND SEBACEOUS GLANDS. tents

irregularly-arranged,

are

polymorphic,

epithelial

with large nuclei and scanty surrounding protoplasm.

283 cells, .

.

.

“During the rising function the size of the acini gradThe cells inually increases from that of the resting stage. crease in number and size and acquire more protoplasm. They gradually arrange themselves so as to form a lining membrane for the wall of the acinus

proaches,

is

(Fig. 3), which, as lactation ap-

converted into a regular mosaic.

The

cells

become

granular, irregularly shaped, excavated, and vacuolated, secret-

ing granular and is

mucous

fluids.

always somewhat cnide,

The milk

of the first few days

containing colostrum-cells,

Pig.

2.

Fig.

3.

which

The Mammary Lobule Near the Restino Stage (Upper) and During Functional Activity.

(Creighton.)

are the last of the long series of secretory products during the period of rising fimction.

thrown

off

“The fully-expanded acinus secretion stage.

is

(Fig. 4) in a state of active at least four times as large as that of the resting

contained cells are much more numerous than at any other period, and they form a perfect mosaic, lining the membrana propria. Each cell is flattened and of polyhedric sliape, and has a large nucleus surrounded by a broad zone of Its

protoplasm.

“During the period of subsiding function the organ gradually reveits to the resting stage through the converse series

ADKBNAL SYSTEM AND FUNCTIONAL

284 of changes.

In

ACTIVITY.

this process the cells pass through a succession

of transiormations,

from the forms

characteristic of the per-

mosaic of lactation to those peculiar to the various stages of the subsiding process. These changes are accompanied by fect

constant destruction and renewal of the participating cells. ‘‘With regard to the influence of the nervous system on the mammary secretion, most of those who have studied the subject are agreed that the secretion of milk

is

not directly

under its control. LaflFont,'*however, maintains that the niamnuE possess vasodilutor nerves which, when stimulated, cause augmentation of the quantity of milk secreted; but de Sinet)',''^ who has repeated his experiments, is unable to accept his conclusions.”

Fig

4.

—Expanded

Mammary Acinus, Showing the Arrangement OF Epithelial Mosaic. {Creighton.)

The foregoing

review

not only indicates

the

important

part cellular metabolism plays in the functions of the

mary

glands, but also that the blood

of active functional work.

“The blood

is is

mam-

an important source the ultimate source

it becomes milk only through the and that activity consists largely in a metabolic manufacture by the cell, and in the cell, of the common things brought by the blood into the special things ])resent in the milk. Experimental results tell the same tale.” Another feature which it places on a solid footing when asso-

of milk,” says Foster, “but activity-

of the

cell,

“ Laflont: Comptes-Rendus de I’Acad6inle des Sciences, “ De Slndty: Mdmolrcs de la Socldtd de Dlologle, vol.

1,

vol. jxxxlx, 1879. 1879.

—

—

—

glands. adrbnoxidase and the mammary and sebaceous

285

and one whidi I wish dated with Professor Fosters remark, emphasize, is the identity of the liquid which particularly to

in solution, viz.: hloodholds the various constituents of milk of M. Duval’s, plasma. This is also suggested by a statement “The transsays: who, referring to the formation of cream, reprevessel the of parent portion that remains at the bottom

plasma of the milk that is to say, the milk without We employ the word ‘plasma’ here to establish a globules. the blood. parallelism between the analysis of milk and that of sents the

:

corresponds to the liquor of the blood.” In another chapter the true identity of blood-plasma, owing its antitoxin, to its inherent oxidizing substance or adrenoxidase, will be connection, this as a prophylactic, and its role in

Skimmed milk

etc.,

But, bearing directly upon the question in the presence of plasma i.e., the functional mechanism, point, in the milk forcibly indicates that an important vasoconstrictor In fact, that so system must exist in the mam.mary gland. further studied.

—

careful an investigator as Laffont should have observed vasodilation further emphasizes this, and tends to indicate that a

process similar to that described

by

maxillary functions must prevail,

me i.e.,

in

my

analysis of sub-

indirect vasodilation,

a fact sustained by the counter-experiments of an equally competent physiologist, de Sinety, who was unable to find vasodilators per se. Laffont reached his deduction that vasodilation

occurred by measuring the

blood-pressure

in

the

mammary

artery of a bitch, during lactation, after severing the mamma,ry nerve and stimulating the peripheral segment of the latter. Congestion of the gland and increase of milk-flow followed,

but after cessation of the

artifieial

not arrested, was greatly reduced. clude inferentially that the

stimulation the flow, though

This led Laffont to con-

mammary

gland possessed typical

submaxhave shown that the phenomena upon which

vasodilators similar to those thought to exist in the illary gland.

I

such a deduction could be based, in respect to the latter organ, could be accounted for without vasodilators and dilation

was a mechanical impossibility.

testimony to this

is

that active

Claude Bernard’s own

indirectly afforded by the fact that the

“interference” or “inhibition” theory was introduced by to

account for vasodilation:

him

the existence of which he was

THE ADRENAL SYSTEM AND FUNCTIONAL ACTIVITY.

286

—

first

as lie

had been

in the case of vasoconstriction

—

to

dem-

onstrate.

The

various data reviewed seem to me,

when considered

col-

lectively, to suggest modifications of generally accepted views.

mammary

In the

have seen,

first

second, by latter

a

gland the secreting apparatus is formed, we by an extremely thin basement membrane, and,

single

layer

of

epithelial

secretory

The

cells.

supply the milk-forming elements other than the liquid

which liquid responds to various tests of blood-plasma (Duval) and seems to replace the water secreted by the sweat, salivary, and lacrymal glands. In all three of the latter organs, however, the secreting structures are surrounded by a net-work of cajiillaries. That such is also the case in' the mammary

per

se,

gland

is

evident,

vessels, says:

since

“From

referring to

Piersol,'*^

the glandular

these vessels on the anterior surface of

organ branches penetrate into the glandular mass and

the

pass between the lobules, giving off twigs which break capillaries

inclosing the

A

alveoli.”

up

into

nCt-work of nerve-fila-

ments are also traced to the glandular elements of salivary' and sudoriferous glands a feature also reproduced in the mammiB. Thus, Bohm and von Davidoff,'*® alluding to the :

terminations of the nerves in the

mammary

glands, recall that

they have been studied by means of the methylene-blue method by Dmitrewsky, who found that “the terminal branches form epilamellar

plexuses

outside

the basement

membrane

of

the

from which fine nerve-branches pass through the basement membrane and end on the gland-cells in clusters of alveoli,

They

terminal granules united by fine filaments.”

also state

form capillary net-works surrounding the that “the alveoli.” The ducts when nearing the nipple have an outer vessels

layer of cellular tissue containing a large fibers

and smooth muscular

fibers

which

number

the axial line in direction, though insufficiently so to “spiral” as in the case of the sweat-gland muscles. the

mammary

of elastic

from be termed

depart slightly

gland, suckling, by creating a

But, in

vacuum and

caus-

ing elongation of the nipple, fulfills the function of the latter. “Plersol:

"Normal Histology,”

« Bohm and von p.

361, 1900.

Davldotf:

p.

241,

seventh edition,

1900.

“Text-book of Histology.” translated by Huber,

ADRENOXIDASE AND THE MAMMARY AND SEBACEOUS GLANDS.

We

thus have

all

287

the structural elements of the j^reviously

studied glands present in these.

should also correspond, however’.

Their peripheral mechanisms As to the nervous supjrly,

seen that dilation of arteries was found to be con-

we have

by motor nerves, by Laffont, and that the presence of vasomotors was denied by de Sinety. Hence, the vasodilation must be due to indirect action, especially since Laffont caused it by stimulating these nerves, precisely as Claude Bernard had trolled

The stimulation

done in the case of the submaxillary glands. must, therefore, have caused this

dilation

manner described when the chorda tympani was

the

in

vascular

indirect

question:

i.e.,

That

vessels.

by causing this

stricto-dilation

the

of

conception of the process

is

in

glandular justified

is

further sustained by the experiments of Eohrig,^" Mdio found that a motor nerve, the external spermatic, supplied constrictor fibers

the

to

glandular blood-vessels

in

the

goat,

division of one hrancli of this nerve, the lower,

tion

and that

enhanced secre-

(evidently due to relaxation of the vessels through loss

of their

normal stimulus), while stimulation of the peripheral

end of this subdivision of the nerve decreased the secretion. This clearly suggests that, just as is the case in the submaxillary and other glands, the secretory activity of the organ should be attributed to an increase of the blood coursing through

its

secretory elements.

As to the sympathetic fibers, they are also stated by Roger Williams to “accompany the mammary blood-vessels”; and, as section of a sympathetic nerve is always followed by dilation of the arteries, they can only act as vasoconstrictors here as elsewhere. That all efferent fibers distributed to the gland-

ular elements and to the blood-vessels originate tral

nervous sj'stem

from the cen-

evident when their relationship with the cord, and particularly the results of section immediately below the medulla, are recalled. That a single stream of imis

from the cerebral centers can sustain the entire function that is to say, that part of it under nervous control scarcely needs, under these conditions, to be emphasized. pulses

—

An *“

important characteristic of the functions of the

Rohrlg:

Virchow’s Archiv,

vol.

Ixvii,

187G.

mam-

THE ADRENAL. SYSTEM AND FUNCTIONAL ACTIVITY.

288

mary

however,

glands,

nervous supply

This

is

is

it

is

its

dependence upon their

their is

the case with other organs.

when the

conversion into milk-plasma;

probably merely filtered through

is

propria and the epithelial layer of

cells in

becomes charged with their products. source of the latter; lial

identity of the liquid

The blood-plasma must undergo

realized.

change during

little

deed,

not as great as

readily accounted for

portion of milk

but

that

is

cavities,

in-

membrana

the lobules and thus

Leucocytes are the main

them both

Kadkin'*^ found

and alveolar

lining

the

“wherein

in the epithe-

disintegration

of

their nuclei supplies the milk with a proportion of its nuclein,

amount

the remaining

of the latter being furnished by the These bodies and the oxidizing substance of the blood-plasma not only transfer to the milk their immunizing qualities, but the oxidizing substance is itself a source of

epithelial cells.”

functional energy through which leucocytes and' epithelial cells are

caused to endow the milk with

^luch of the organ’s work “\i\diile

its

experiments

is

not arrested even

as well as the spinal nerves are cut,”

soon

Laffont’s animal, the flow,

when only one

nutritive principles,

therefore automatic.

“the secretion continues and

when the sympathetic control

is

show that, though not

set of nerves is cut.

as

was the case with

arrested, is reduced even

This indicates, when con-

sidered along with the fact that stimulation of the

mammary

end of the nerve increases the gland’s activity, that the nervous supply must not be disregarded, and it also suggests that the sharp line drawn between “active” and “passive” activity, in the case of other organs, and which mainly depends upon nerve-impulses to secreting structures and vascular walls, is Indeed, we are doubtless dealing scarcely applicable here.

with mere fluctuations of activity, called forth, during lactaa feature tion, by afferent impulses to the motor centers: the inand nursing which the rapid formation of milk after In framing our fluence of emotions upon its flow suggest.

summary

of the functional

mechanism

of the

mammary

gland,

not the difference between active and passive activity that we have in mind, but the manner in which fluct-

therefore, it

«Kadkln;

is

Inaugural Dissertation,

1890.

—

289

THE ADRENAL SYSTEM AND THE KIDNEYS. activity

of

nations

The

brought about.

are

actual

process

one, even here, however, is' primarily a mechanical elements secreting since filtration of the blood-plasma into the As blood-pressure torepresents no mean expense of force.

involved,

tally

independent of the normal systemic pressure must account we are relegated to the vessel-walls and their nerve-

for this,

out. supply as the intermediaries through which this is carried mammary of a On the whole, the functional mechanism gland may, in the light of the foregoing facts, be interpieted

as follows

:

The formation

1.

of milk is due to

an exacerbation of

secretory activity, the nutrient fluid being held in reseive by the organ until withdrawn mechanically by the suckling.

Blood-plasma, including

2.

oxidase),

is

the

main

plied to the secretory cells by the

fourth, fifth,

and sixth

When

3.

and is supglandular arterioles when these

constituent of milk,

fluid

vessels are dilated by their

oxidizing substance (adren-

its

motor nerves, the terminals of the

int'ercostais.

the formation of milk is to cease, the arterioles

referred to resume their normal caliber, the result of constrictor

impulses received through the intermediary of their sympathetic nerves.

Kidneys.

—HowelP®

states that “the kidneys receive a rich

supply of nerve-fibers,” but that

“most

histologists have

been

unable to trace any connection between these fibers and the epithelial cells of the

kidney tubules.”

standpoint such a connection as 'I have

now shown

is

Interpreted from

my

not in the least necessar)', since

repeatedly, the function of an organ is

dependent upon the volume of arterial blood circulating through it.

as

My view is fully sustained by tbe prevailing doctrine, since, Howell says, the marked effects obtained during purely physi-

ological experiments are “all explicable

in the blood-flow through the organ.” ,

by the changes produced It becomes a question,

therefore, as to how, lated,

for

and by what nerves this blood-flow is reguas stated by Stewart’*® “increased blood-flow entails

increased secretion.”

‘“Howell: T. B. of Physiol., second edition,' ‘“Stewart: Loc. cit., p. 419.

p. 763,

1907.

— THE ADRENAL SYSTEM AND FUNCTIONAL

290

ACTIVITY.

Tliat the vasodilation necessary to the inception of an ex-

—

acerbation of function

as it

is

in the

subinaxillary gland

occurs in the kidney as well as in the organs previously reviewed,

shown by

is

tlie

experiments of Bradford®® who found that

vasodilator nerves entered the kidney with the vasoconstrictor fibers,

and that when the anterior roots of the eleventh,

twelfth,

and thirteenth dorsal nerve roots were stimulated with induction shocks one second apart, the organ swelled though no sufficiently marked rise of blood-pressure occurred to account for

it.

Stewart®’^ also states that the presence of dilator libers

for the kidney has been “demonstrated in the splanchnic nerves.”

That is

which enhance the flow of urine

these vasodilators

it is

sustained by the prevailing opinion that true secretory nerves,

nerves influencing directly the epithelial elements, are not

i.e.,

present in the kidnc3\

The

source of these renal vasodilator nerves

by the fact that

it

is

is

disclosed

only by stimulating the splanchnic that

the caliber of the renal arteries

is

Indeed, Eckhard®-

increased.

found that stimulation of the vagi below the diaphragm does not influence the flow of urine. This imposed the conclusion that even the vasodilators of the kidney belong to the sjin'

confirmed by the researches of Berkley®® which showed that “the innervation of the kidney is de-

pathetic system.

This

is

pendent directly upon the great svnnpathetic and histologically speaking, it is found that all the nerves of the glands belong to ;

the non-medullated type.”

Briefly,

the vasodilator nerves of

the kidney which promote the flow of urine belong to the sympathetic system.

How

are the arteries restored to their normal caliber

—

^that

compatible with the normal excretion of urine? In the light of the conclusions submitted in the foregoing pages the kidneys should receive filaments capable of causing

when the That such

constriction of the renal arteries

the organs

is

to be decreased.

shown experimentally by many “Bradford: '>

Stewart:

“Eckhard: “Berkley:

excretory activity of is

observers.

the case has been

In

the

dog,

Jour, of Physiol., vol. x, p. 358, 1889. Lor. cit., p. 152. Cited by Starling: Schafer’s “T. B. of Physiol.," vol. Jour, of Path, and Bact., vol. 1, p. 40G, 1893. ,

I,

the

p. 645.

THE ADRENAL SYSTEM AND THE KIDNEYS.

291

vasoconstrictor nerves leave the cord, according to Stewart, ‘diy

the anterior roots of the sixth thoracic to the second

nerves and especially the last three thoracic.”

lumbar

Langley®* ob-

and upper part lumbar nerve, and slower, though still great, pallor on stimulating the second lumbar in the eat. As stated by Starling®® a rise of the general bloodpressure coincides with marked shrinkage of the kidney, so that the effects observed by Langley must be of vasomotor origin. served prompt and great pallor of the kidney of the ureter on stimulating the first

Moreover various toxics known to raise the vascular pressure produce effects similar to stimulation of the renal vasomotor nerves. to

Thus Sakussow®®

recently found that digitalin in

1

1,000,000 solution caused contraction of the renal vessels.

The same

effect

adrenalin.

The

ford®^

was obtained from a 1

to 1,000,000 solution of

latter result accounts for the fact that

Brad-

obtained renal vasoconstriction by stimulating, besides

the nerves included within the above limits, the fourth fifth thoracic,

thus including

among

and

those stimulated, the fibers

which pass to the splanchnic and thence to the kidneys. He found, however, that the most active vasomotor nerves were those of eleventh, twelfth,

and thirteenth thoracic.

That

all

these

filaments are distributed, to the arterioles in the organs has not

only been established histologically, but as stated by Bohm, Davidoff, and Huber,®® “from the plexuses surrounding the vessels small cells of

branches are given

off

which end on the muscle-

the media.

As to the source of the vasoconstrictor fibers, it corresponds with that of the vasoconstrictors supplied to other abdominal organs, the splanchnic. Thus Hollner®® and others have traced from the sympathetic chain through the great and small splanchnics to the solar plexus, and thence to a network of fibers lying in the fat between the adrenal and the kidney. these nerves,

Several of the filaments were found by Nollner to enter the latter with the renal artery.

M Langley:

“ Starling: “ Sakussow '’'Bradford:

® Bohm,

:

Schafer's “T. B. of Physiol.,” vol. IhUl, vol. 1, p. 645. Vratch, April 10, 1904.

It,

p. 643.

Jour, of Physiol., vol. x, p. 358, 1896.

Davidoff and Huber: too. off., p. 335, 1905. “Nollner: Beitrage z. Anat. u. Physiol, v. Eckhard, Bd. 19

Iv,

S. 139, 1869.

THE ADRENAL SYSTEM AND FUNCTIONAL ACTIVITY.

292

We

thus find ourselves in the presence of the surprising

and vasoconstrictor nerves

fact that both the vasodilator

kidneys

—those which preside over the functions

are of s}Tupathetic origin. is

of tlie

of these organs,

Indeed, as will he shown later, this

a characteristic of the adrenals, these organs and the kidneys

working in harmony

:

the adrenals by supplying, as

we have

seen, the oxidizing substance of the blood,

which takes part,

among

or

other

functions,

the

disintegration

proteolysis

of

waste-products in order to convert them into eliminable end-

products;

the kidneys, by insuring the excretion of these end-

products from the system. Tliis accounts for various observations that present knowl-

edge

to

fails

concomitant

explain.

lesions,

Thus Aubertin and Ambert®“ found

both on naked eye and microscopical exami-

and kidneys in all cases of nephritis studied by them characterized by high-pulse tension. The latter phenomenon suggests that while an excess of adrenal secretion was being produced ^this product and adrenalin causing, ^the as is well known, a marked rise of the vascular tension kidneys had also been overworked in these cases, i.e., excessive In other words, excretor}'^ activity had brought on the nephritis. nation, in the adrenals

—

marked increased functional

—

activity of the kidneys, as repre-

sented by renal vasodilation,

—

should coincide

renals are simultaneously stimulated

—with

since

the

ad-

increased vascular

This has been actually observed experimentally by He found that urea

tension.

Cavazzani,®^ though unexplained by him.

—and

caused simultaneously expansion of the kidney

—

therefore

an increased production of urine and general vasoconstriction. Puncture of the floor of the fourth ventricle (Bernard’s piqure) produces glycosuria through the intermediary of the adrenals, as will be shown elsewhere; a similar puncture also produces, as stated

by Stewart, “a copious flow of urine.”

We

need not

And ani]fle proof of the fact that polyuria is a prominent symptom of diabetes, i.e., that the adrenals and the kidneys work in harmony. The importance of this relationship asserts itself when the obscurity surrounding Thus referring to polyuria, Ilensell, the question is recalled. go beyond

common

experience to

Aubertin and Ambert; Tribune m^dicale, o^Cavazzaul: Arch. Ital. de biol., vol. xvlii, 00

p. 119, 1904. p. 168.

——

293

the adrenal system and the kidneys. Well, and

Jelliffe'’-

common

state that “it is

two diseases— nephritis—but in to

diabies mellitus and chronic interstitial this symptom does not exist.” either case a clear explanation of following additional evidence to this effect the

Pending

conclusions as to the functions

warranted 1.

of

the kidney appear to

us

:

When

the flow

he increased, the renal

of urine is to

sympaare dilated hy vasodilator terminals of the splanchnic nerves thetic which reach the organ hy way of the thus and the semilunar ganglia. The glomerular tufts being

arterioles

urine traversed hy a greater volume of hlood the components of are thus filtered out into Bowmans capsule. 2.

When

the flow of urine

is to

he decreased the

same

arteri-

normal caliber hy the vasoconstrictor which reach the hidneys also hy sympathetic filaments of the way of the splanchnic nerves. reduced

oles are

J^.

to their

The adrenals and

the Tcidneys are functionally united,

the adrenals contributing hy their secretion to the conversion Icidneys excrete of waste-products into end-products which the

with the urine.

of

With the functions of the kidneys as complemental to those the adrenals, what we have termed the “adrenal system”

acquires greater importance in the vital functions of the organsupplies the body the substances which susand metabolism, but provides also for the elimination of end-products of catabolism and other wastes. By “substances” here, are meant both the adrenal and thyroid secretions. The former of these, by becoming oxygenized in the

ism as a whole

;

it

tain oxygenation

lungs, constitutes the oxidizing substance of the blood,

albuminous portion of

its

hsemoglobin

;

i.e.,

the

the thyroid secretion as

previously stated, and as will be shown, enhances the vulnerability of all tissues to oxidation,

including the adrenal center

in the pituitary body.

As they

to the functional relationship

may

evidence

The

between

all these

organs,

be briefly summarized as follows, pending additional

:

pituitary body contains a center which governs the

“Hensel, Well and

Jellifte:

“The Urine and Faeces,”

1905.

—A THE ADRENAL SYSTEM AND FUNCTIONAL

294

ACTIVITY.

functional activity of the adrenals and of the kidneys. Any excitation of this center by the thyroid secretion in the blood,

may

or certain toxics that

occur in the latter, increases the functional activity of both the adrenals and the kidneys, and therefore, general oxygenation and renal excretion.

Geneilvl Conclusions as to the Mechanism of Functional Activity. number of general questions have been referred to in this chapter the discussion of which has to be

—

continued in the next, but the following deductions regarding the several organs the physiology of which has been analyzed

appear warranted 1.

The

:

arterioles of the skeletal muscles

mal, salivary, sweat, and

mammary

of two kinds of nerves: plied by a cranial nerve;

a,

and

of the lacry-

glands receive the terminals

motor or secreto-motor

b, constrictor fibers

fibers sup-

supplied by the

sympathetic system. 2.

The terminals

of the cranial nerves cause the arterioles

of these organs to dilate

and

to

admit an excess of blood,

i.e.,

of

oxidizing substance (adrenoxidase) , into them, thus enhancing their functional activity. S.

When

this exacerbation of functional activity is to cease,

the sympathetic fibers cause the arterioles to contract until they

resume their normal

caliber.

of the kidney are carried on in the same roay, but this organ differs from those enumerated above in that both its vasodilator and vasoconstrictor nerves are supplied by Jf.

The functions

the sympathetic system.

Another important feature to be emphasized in this connection is the manner in which the epithelium of these various organs are enabled to carry on their functions by the blood. According to the prevailing view, the red corpuscles, as the

deemed necessary participants in functhe evidence we have submitted and which

carriers of oxygen, are tion.

In the light of

will be greatly amplified in the

second volume, the red cor-

oxipuscles are not distributors of oxygen, but the carriers of is It blood-plasma. dizing substance which they supply to the

plasma which, after traversing the walls of the capillaries tissues leaving behind it the red corpuscles penetrates to the oxidizing and activates their epithelial elements by means of its

this

—

CONCLUSIONS AS TO NATURE OP FUNCTIONAL ACTIVITY. substance.

On

295

the whole, the evidence referred to warrants the

conclusion that 5.

In

all

the above-mentioned

stance (adrenoxidase)

—a

organs the oxidizing sub-

combination of adrenal secretion and

oxygen formed in the lungs and of which the red corpuscles and the blood-plasma are the vehicles is the physico-chemical agency

—

through which cellular metabolism functional activity.

activity,

is

sustained during passive

and increased during active functional,

—

CI-IAPTEE VII.

THE ADRENAL SYSTEM IN THE FUNCTIONS OF THE DIGESTIVE ORGANS. THE ADRENOXIDASE AND THE DUAL NERVOUS SUPPLY OF THE ORGANS OF DIGESTION.

The shown

to subserve the needs of several sets of

to

find, it

now been organs; we will now

oxidizing substance, or adrenoxidase, has

assume similar functions in the stomach,

liver, heart,

lungs, etc., notwithstanding the dissimilarity of the functions of these organs. tions

I

Here, again, the uncomplicated nervous func-

have described

—

all

apparently carried on, as far as

efferent impulses are concerned, t.e.,

through the agency of a motor,

—

vasodilator and a sympathetic vasoconstrictor

suffice,

the

gastric vasodilator being, however, the pneumogastric or vagus.

The In

an

Stoh-vcii

able

review

and

its

Physico-Chemical Functions.

of

the

relationship

between the nervous

system and the production of gastric secretion HowelP introduces the following remarks:

“It has been very difficult to

obtain direct evidence of the existence of extrinsic secretory

In the hands of most experimenters stimulation of the vagi and of the sympatheties has given negative results, and, on the other hand, section of these nerves to the gastric glands.

nerves does not seem to prevent entirely the formation of the gastric secretion.

There are on record, however, a number

observations

point to

that

a

direct

influence

of

of

the control

Thus, Bidder and Schmidt found that in a hungry dog with a gastric fistula the mere sight of food caused a flow of gastric juice, and Richet reports nervous system on the secretion.

man in wliom tlie oesophagus was completely ocand in whom a gastric fistula was established liy sur-

the case of a

cluded

gical operation

*

Howell:

:

It ivas then

"American Text-book

( 296 )

found that savory foods chewed

of Physiology,” second edition, 1900.

:

297

ADRENOXIDASE AND THE STOMACH.

mouth produced a marked flow of gastric juice. There would seem to be no clear way of explaining the secretions in these cases except upon the supposition that they were caused by a reflex stimulation of the gastric mucous membrane through in the

the central nervous system.”

Nervous Supply and the Formation of Gastric When the nervous su23i3ly of the stomach is closely

The Juice.

—

Gastric

examined, a rather unusual state of affairs presents itself it contains no bona fide motor nerves, unless we grant the sympathetic fibers distributed to to

recognize

But,

if

we do

these,

it

motor

accept the vagus

this, to

as

:

i.e.,

many

qualities, or, refusing

the secretory nerve.

which nerve must we ascribe the afferent

imprdses, which the ingestion of various substances that cause

nausea and other manifestations udiich clinicians so often witness induces? as

The sympathetic has everywhere shoum

itself

an efferent nerve, and I

have already furnished consider-

my

view that sympathetic nerves serve

able evidence in favor of

to constrict the arterioles after these vessels have been dilated by vasodilator nerves. We can thus account for the phenomena witnessed and relegate also to the vagus the role of afferent

nerve;

thus construed,

its

impulses to the vagal center evokes

therefrom secretory impulses to the gastric mucosa. Howell,

continuing

the

remarks

quoted

above,

says

“These cases are strongly supported by some recent experimental work on dogs by Pawlow and Schumowa-Simanowskaja. These observers used dogs in which a gastric fistula had been established, and in which, moreover, the oesophagus had been divided in the neck and the upper and low'er cut surfaces brought to the skin and sutured so as to make two fistulous openings.

In these animals, therefore, food taken into the

mouth and subsequently swallowed escaped through the upper stomach.

oesophageal

Nevertheless, this

fistula

to

without

the

exterior

entering the

meal,’ as

the authors brought about a secretion of gastric juice. If in such animals the two vagi were cut, the ‘fictitious meal’ no longer caused a secretion of the gastric juice, and this fact may designate

‘fictitious

it,

be considered as showing that the secretion obtained when the vagi were intact was due to a reflex stimulation of the stomach

THE ADUENAL SYSTEM AND THE DIGESTIVE ORGANS.

298

In

througli these nerves.

later

experiments- from the same

laboratory the secretion caused in this is

way by

the act of eating

designated as a ‘psychical secretion/ on the assmnption, for

which considerable evidence

is

must insensations accompanying

given, that the reflex

volve psychical factors, such as

tlie

the provocation and gratiflcation of the appetite.

In favorable was continued for as long as five to

cases tlie fictitious feeding six hours,

with the production of a secretion of about 700 cubic of pure gastric Juice. Finally, these observers

centimeters

were able to show that direct stimulation of the vayi^ under proper conditions causes, after a long latent period (four and

marked

a half to ten minutes), a

The long

latent period

secretion of gastric Juice.

attributed to the simultaneous stim-

is

Howell closes his review of this “Taking these results together we

ulation of inhibitory fibers.”

subject by the

must

remark:

believe that the vagi send secretory fibers to the gastric

glands,

and that these

fibers

may

be stimulated reflexly through

the sensory nerves of the mouth, and probably also by psychical states.”

Indeed,

Pawlow

in collaboration with

Madame Schumow-

Simanowski’‘ demonstrated conclusively that the vagus was the secretory nerve of the stomach.

They obtained no

secretion by

exciting the splanchnics, while stimulation of the peripheral

ends of the cut vagi gave positive results, even twent 3'-four hours Schneyer® confirmed these after the nerves had been divided. observations.

a

secretion

Juice.

do

so.

Stimulation of the vagus in the neck produced chemically and physiologically similar to

Stimulation of any

The experiments

gastric

portion of the splanchnic failed to

of Eutherford® pointedly suggest the

Having cut both vagi during digestion he noted that the mucous membrane became paler;

stricto-dilator action of the vagus.

on stimulating the cut fibers connected with the organ the membrane became hyperaemic.

*

Pawlow and Schumowa-Simanowskaja:

“Die Arbeit der Verdauungsdril-

sen,” Wiesbaden, 1898. » All Italics are our own. *

Pawlow and Schumow-SImanowskl: “The W'ork of the Digestive Glands, St. Petersh., 1897; transl. by W. H. Thompson. 1902.

hy Pawlow, 6 «

Schneyer: Zelt. f. kiln. Med., Bd. xxxll. Nos. 1 and 2. S. 131, 1897. Rutherford: Trans, of Royal Soc. of Edinburgh, vol. xxvl, 1870.

ADRENOXinASE AND THE STOMACH.

The

of

identity

the

299

vagus as the gastric seereto-niotor

nerve being established, another feature of especial interest is its power to provoke the muscular contractions it governs. Moraf^ observed that the movements of the stomach could be arrested reflexly by stimulating the central end of the vagus.

WerKronecker and Meltzer® noted a similar phenomenon. end central theimer® reached the same results by stimulating the of the sciatic.

Openchowski,'^® however, obtained direct relaxa-

by stimulating a nerve formed by filaments derived from both vagi, and overlying this part of the organ. Langley^^ among other investigators, repeated Opention of the cardiac orifice

chowski’s experiments and confinned his results.

After “con-

necting the (Esophagus with a vertical tube containing fluid at

and stimulating the peripheral end of the vagus after curari and atropine had been given” he writes “the sphincter opens and fluid passes a pressure of 15 to 20 centimeters water pressure

He

into the stomach.”

also

ascertained experimentally that

the body of the stomach and the pylorus receive inhibitory as well as motor fibers

from the vagus.”

relax the gastric orifices

when

fibers

can

ingesta are to pass through them,

and, in the case of the pylorus, only

we

As the vagal

when they

are

fit

to pass,

are dealing, in vagal inhibition, with a physiological func-

tion,

whereas sympathetic “inhibition,” as

only be

we have

seen,

can

artificial.

Thus, besides

its

role as secretory nerve, the vagus also

governs the stomach’s motor functions, contractions during digestion.

i.e.,

its

This dual role

is

movements and well illustrated

by the observations of Eeynard and Loye^^ in a decapitated criminal. They stimulated the vagus forty-five minutes after the execution and not only obtained the characteristic movements of the stomach, but numerous drops of gastric juice appeared on the gastric mucous membrane.

On the other hand, P. May^® showed experimentally that “the splanchnic nerves

W. ’’

Moral:

Lyon medical,

T. xl, p. 289, 1882.

Kronecker and Meltzer: Archly f. Anat. "Wertheimer: Archives de physiol, norm, Openchowski: Loc. cit. «

“Langley:

Suppl. 1883.

et pathol., p. 379, 1892.

Jour, of Physiol., vol. xxlli, p. 407, 1898. la Soc. de biologle, p. 433, 1887. P. May: Jour, of Physiol., June 30, 1904.

“Reynard and Loye: Comptes-Rendus de

“W.

u. Physiol., S. 328,

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

300

no direct influence whatever, either motor or inhibitory on the muscular wall of the stomach” thus showing that the sympathetic was not the stomach’s motor nerve. liave

The sympathetic system it is

is

represented in the stom.aeh as

While Langley*'* includes both the glands and

elsewhere.

the muscular coat of this organ

with a double nerve supply,

t.e.,

among

the structures supplied

cranial

and sympatbetic, Ruth-

found that “normal secretion occurred after division of the splanchnics.” This points to the correctness of my view that in the stomach as elsewhere, the sympathetic terminals act as vasoconstrictors, since their division must under these circumstances produce exactly the effect noted, the resulting relaxaerford*®

tion

of

the

gastric

bringing

arterioles

about

the

condition

through which the secretory nerve, the vagus, incites nonnal secretion,

The

i.e.,

vasodilation.

arterial

distribution also

sustains

this view.

As

to

Auerbach’s plexus, we know that after piercing the external serous coat of the stomach

its

nerves pass between tbe circular

and longitudinal muscular layers, where they form a close network strewn with ganglia, the whole constituting the plexus.

The terminal

flbers of this plexus are distributed

as is usual

in the muscular coat of the stomach

they form an wiiramuscular plexus which entwines, as it were, the muscular fibers. Furthermore, this plexus gives off filaments which, entering deeper into the wall of the stomach, form another in muscles

:

plexus, also containing

many

ganglia:

i.e.,

Meissner’s plexus.

—

This net-work of sympathetic elements fibers, ganglia, cells, i.e., immediately under the lies in the submucous coat, etc. muscularis mucosae, which separates the latter from the secre-

—

tory glands.

Besides the

thin submucous muscular

many

filaments

layer, it

it

distributes to the

gives off a large

number

that

These, on reaching the glands, form a close net-work in the connective-tissue sheath surrounding them, which net-work gives off delicafe fibrils that enter into the penetrate this layer.

glandular elements themselves. They likewise supply terminal tlieir vasfibers to the neighboring muscular elements and to cular supply.

»

Langley: Schafer’s "T. B. of Physiol.,” '“Rutherford: Loc. clt.

yol.

II,

pp. 692

and

693, 1900.

ADRENOXIDASB AND THE STOMACH.

The

blood-vessels of the

301

stomach are distributed in a very as follows:

“The

larger arteries, after penetrating the outer coats, divide

within

similar manner.

PiersoP”

them

describes

the submucosa into smaller branches, one set of which pierces

mucous mem-

the muscularis mucosai, to be distributed to the brane, while the other enters the muscular

The

and serous

supplying the mucosa form a rich

vessels

tunics.

stib epithelial

capillary net-work as well as mesh-iuorks surrounding the gastric

glands, the capillaries lying immediately beneath the basement

membrane

in close proximity to the glandular epithelium.

branches

The

to the outer layers form long-meshed from which the muscle-bundle and fibrous

distributed

capillary net-works

tissue derive their supply.’’

A

feature that requires emphasis

manner in which the vessels are finally mucous membrane The small arteries or

in this connection is the

distributed to the

:

do not themselves ascend between the glands, but

arterioles

These, by anastomosing

give off fine capillaries that do so.

with one another, form a very rich plexus which surrounds each glandular tubule in a net-work of close hexagonal meshes.

The

secreting elements

cellular

of the glands

being covered

by a delicate basement membrane, the capillaries are thus related to the former precisely as we found them to be in the sweatglands.

Indeed,

the intrinsic structures of the stomach are compared with those of the organs reviewed, it soon becomes evident that the mechanism to which the production of secretions is due does not differ from them.

We

if

cannot, however, say the same in respect to the exand nerves, and to this feature of the process

trinsic vessels

we wish

to

call

especial

vascular supply of

the

attention.

stomach

is

As is well made up of

lenown,

the

the

gastric,

and right gastro-epiploic branches of the hepatic artery and the left gastro-epiploic and vasa brevia from the splenic. 1 he important feature referred to is this The gastric, hepatic, and splenic arteries arise from the cceliac axis, and, as shown pyloric,

:

in the earlier chapters, the cceliac axis is the first great arterial tiunk to receive the blood from the lungs: i.e., before the activity of the oxidizing substance in the downward

blood-stream has

“Plersol;

“Normal Histology,”

p.

166, 1900.

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

302 in any

way been reduced.

that the cceliac axis

Another very suggestive feature is surrounded by the cceliac plexus, a portion

is

of the solar plexus of the sympathetic, and that extensions of the cceliac plexus

and

—the

gastric,

hepatic,

gastro-epiploic plexuses

name

—

^follow

the walls of the stomach.

to

pyloric,

gastro-duodenal,

the arteries of the same

We

thus have as the co-

ordinators of gastric function, the two nerves which

elsewhere to

fulfill

similar roles,

viz.,

we found

the vagus, to carry on

the secretory and motor functions of the stomach, and sympathetic jilexuscs and nerve so distributed as to constrict the blood-vessels supplied to the organ

blood circulating in the digestive process

and

to reduce the

volume of

its

glands and muscular walls, when, after

is

ended, the stomach must be restored to

the passive state.

Another feature requiring our attention is the formation In the blood-plasma we have sodium and potassium chlorides; in the secretion of the stomach these represent the most important and abundant salts, and constiof the gastric secretion.

tute the source of the hydrochloric acid in the gastric juice,

according to prevailing views.

Has

the oxidizing substance of

the plasma any influence upon the formation of this acid?

marked want.

affinity of chlorine for

It takes it

up whether

combination extra corpore; gastric

it

hydrogen seems able

to

fill

The the

the gas be free or in vulnerable doubtless does the

same in the

But here conditions are especially well such a reaction, if we analyze the question with

structures.

adapted for

Equal volumes of chlorine and hydrogen can only be kept in an absolutely dark place; diffuse the aid of thermochemistry.

light causes

them

light, for instance

to slowly unite, while a bright light

—brings

—sun-

on such an instantaneous combina-

tion of the two elementary bodies that the flask containing

them

flies

into pieces.

The

fact that this

on with a n.agnesium light which, is

as is

rich in chemical rays, indicates that

may

also be

brought

the ease with sunlight,

we

are dealing with a

Precisely as process in which heat plays a predominant part. the sun sends radiations which the earth transfonns into heat, so does it, in the experiment mentioned, send radiations which the combined chlorine and hydrogen transform into heat; the mixture absorbs the undulations of the ether and transforms ^

303

adrenoxidase and the stomach.

moUcular energy, i.e., heat. But a multitude of increased molecular familiar every-day phenomena prove that

them

into

be procured without light-rays, etc.; the cause it to mere rubbing of a match against a dry surface will That this occurs without in the least inlight, for instance. energy, or heat,

may

against volving the need of a chemical body on the substance which the match is rubbed to start the reaction indicates that friction causes increased vibratory activity in the ingredients of the match-tip, and, these only

combining when a given tem-

perature is reached, heat must obviously be accepted as the Now, a very significant featcausative factor of the process.

ure in connection with the formation of the gastric hydrochloric acid is the fact that the combination temperature, when an im-

mediate reaction is obtained between chlorine and hydrogen, is SO. 5° C. (103.1° F.), while that of the gastric cavity is about S8° C. (100.1/° F.). The fact that the walls of the stomach,

must show a higher temperature

the seat of the blood-fiow,

than this (at least 2 degrees, that of the liver being 106 degrees) pointedly suggests that the formation of hydrochloric acid only occurs

when the stomach

is

brought up to the

re-

quired temperature.

Under

these conditions, the formation of hydrochloric acid

The volume of blood circulating in the would be as follows gastric mucosa being increased by vasodilation of its arterioles under the auspices of the vagus, the oxidizing plasma, by enhancing metabolism, raises the temperature of the stomach at :

least the 1.5° C. required to

render the formation of hydrochloric

acid possible.

The

acid would be

formed when needed:

in accord with experimental data.

The

a feature quite

parietal cells of the

glands, which are the seats of

its formation, are only active during digestion, and then increase in size; they continue in

this condition as long as the

stomach contains food, and then

return to their normal

The following

size.

also tend to indicate that

my

lines of Howell’s

conception of the process

may

be the right one:

“The chemistry of the production of free remains undetermined. No free acid occurs in the blood or the lymph, and it follows, therefore, that it is manu-

HCl

also

factured in the secreting

cells.

It is quite evident, too, that

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

304

the source of the acid is the neutral chlorides of the blood; these are in

hydrogen

to

some way decomposed, the chlorine uniting with form HCl, which is turned out upon the free

surface of the stomach, while the base remains behind

and

probably passes back into the blood.” Closely related with the formation of hj'drochloric acid that of pepsin.

Landois,'’ for example, writes:

is

“The glands

themselves contain no pepsin, but only a zymogen, namely, the jiepsinogenic substance or propepsin, which occurs in the gran-

The zymogen,

ules of the chief cells.

ence upon proteids. chloric acid or

If,

however,

sodium chloride,

The hydrochloric

acid

is

of itself, exerts no influ-

it

it is

be treated with hydro-

transformed into pepsin.”

formed by the parietal or

in the cardiac portion of the stomach, while pepsin

o.xyntic cells is

produced

in the peptic cells which occur both in the cardiac and pyloric regions.

The mutual

influence

of

these

products brings in

other factors, however, which are reviewed at length in the

second volume.

For the present,

mode

it

may

be said that

my

views as to the

of action of the vagus and sjunpathetic nerves upon the

cardiac arterioles elucidates several obscure points.

Thus, the

fact that the secretion of the gastric juice continues after diviis explained by the passive dilation and the admission of an excess of arterial blood

sion of the gastric nerves

of the arterioles

to the secreting elements.

This leaves to the vagus alone the

function of secretory nerve ings) since

it is

a vasodilator.

(in

accord with Pawlow’s teach-

The

sympatlietic has no function

other than to restore the arterioles to their normal caliber after On the whole, the functions of the digestive process ceases. the stomach, in the light of

lows

my

views, are carried on as fol-

:

During the phase of gastric inactivity, the arterioles distributed to the mucosa and muscles of the stomach are constricted sufficiently under impulses received through their sympathetic nerves, to admit only sufficient blood into the secretory and muscular elements to insure their nutrition and the forma1.

tion of the substances necessary for the digestive process,

”

Landols:

“Text-book of Physiol.,” tenth American

viz.,

edition, p. 293, 1905.

305

ADRENOXIDASB AND THE INTESTINES. pepsinogen in the pepiic

cells,

hydrochloric acid in the parietal

and myosinogen in the muscular

cells

-fibers.

begin the arterioles are dilated by terminals of the vagus, and an excess of arterial blood being thus caused to circulate in the peptic, parietal, and muscular 2.

^yhen digestion

gastric juice is

cells,

is to

formed and

secreted,

and muscular move-

ments of the gastric walls are incited. 3.

When

the digestive process

is to

cease the arterioles are

restored to their normal caliber by vasoconstrictor fibers of the

sympathetic nerve, and the stomach resumes the passive state described in the 1.

r

The

first

conclusion.

oxidizing substance (adrenoxidase) which circulates

the blood-plasma in the cellular elements, secretory

until

vruscular, sustains the functional activity

elements, both during the resting stage

4.

r

^ ^ *

B jp 5-

& I I >

Intestines.

We

find the

of all these cellular

and during

—The innervation of the

with that of the stomach.

and

digestion.

intestines corresponds

same secreto-motor nerve

the vagus, and, as constrictor of the arterioles, the sympathetic.

HowelP® refers to the extrinsic nerves of the intestines as fol“As in the case of the stomach, the small intestine and

lows:

the greater part of the large receive viscero-motor nerve-fibers

from the vagi and the sympathetic chain. The former, according to most observers, when artificially stimulated cause movements of the intestines, and are, therefore, regarded as the motor fibers.”

Among

the earlier writers to observe that this applied both stomach and intestines were Hemak,^® Weber, Pfiiiger, Budge and v. Braam Houckgeest, Ludwig and Kupffer,^® and Engelmann.^^ This was confinned by the more recent experi-

to the jr a;

A k

€

ments of Bechterew and Mislawskip^ Jacobi,^® Morat,^^ and Pohl.®® Pincus and Pannm both found that the intestinal movements persisted after section of both vagi, however, a feature wliich indicates that

'

an inherent contractile power

exists in the

’“Howell:

"Amer. T. B. of Physiol.,” p. 384. ’“Remak: MUller’s Archlv, 1858. Ludwig and Kupffer: Zeit. f. ration. Med., Bd. 11, S. 357, 1858. Englemann: Archly f. d. gea. Physiol., Bd. Iv, 1871. “Bechterew and Mlslawskl: Archlv f. Physiol., Suppl. Band, S. 243, “Jacobi:

Archlv f. exp. Pathol., Bd. xxlx, S. 171, 1891. “Morat: Archives de physiol, norm, et pathol., T. v, p. “ Pohl: Archlv f. exper. Pathol., Bd. xxxiv, S. 87, 1894.

142, 1893.

1889.

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

306

intestines as well as in the stomach.

Bunch,-® Courtade and Guyon,-^ contend that contraction of the circular coat was never obtained by them by stimulating either nerve. But Cash®*

noted that waves of constriction jiassed down the intestine when substances were placed in it after the splanchnic nerves had

been cut

—evidence

that the remaining nerve contained both

sensory and motor fibers.

ment

Starling emphasizes this by the state-

that “true peristaltic contraction

is

a coordinated reflex,

carried out by the local nervous centers in the walls of the gut.

He

also points to various disturbing factors

calculated to obviate them.

and

means

to the

“If these precautions are observed,”

he writes, “stimulation of the vagus in the neck, after paralysis

by means of atropin, will always movements.” Hallion and Frangois-Franck^® observing the same precautions, noted that stimulation of the peripheral end of the cut vagus caused of the cardio-inhibitory fibers

produce an

marked

effect

upon the

intestinal

vasodilation in the intestine.

dilator properties

An

This proves the

stricto-

of this nerve.

inhibitory action of the vagus

is

also generally recog-

Pfliiger, according to Bunch, “saw sometimes an insometimes a diminution of the intestinal movements on vagus stimulation.” Bechterew and ]\Iislawski concluded that while the vagus contained both motor and inhibitor nerves, the

nized.

crease,

former predominated.

Starling gives tracings in support of

and also states that “the vagus contains two sets of fibers to the muscular coat of the intestine,” one set inhibiting, Bunch also states that “the the other augmentor or motor. fibers for the musinhibitory vagi contain both augmentor and

.this view,

cular coat of the intestine.”

tion

The sympathetic fulfills in this connection the same “The that we found it to fulfill in other organs.

funcfibers

from the sjunpathetic chain, on the other hand,” as stated by Howell,*® “give mainly an inhibitory effect when stimulated.” We have seen that this is due to an exaggerated contraction of “Bunch:

^ “

Jour, of Physiol., vol. xxll, p.

25, 1898.

Courtade and Guyon: Archives de physiol, norm, et pathol., 1897. Cash; Proceedings Roy. Soc. of London, vol. xl, p. 469, 1886;

“ Halllon

and Prancols-Franck:

xll,

Archives de physiol, norm, et path., T.

vlll, p. 502, 1896.

"“Howell:

vol.

„

p. 213, 1886.

T. B. of Physiol., second edition, p. 669, 1907.

307

ADRENOXIDASE AND THE INTESTINES. the

arterioles

by the sympathetic terminals

—proof

that

the

Briefly as elsewhere, function is

latter act as vasoconstrictors.

and arrested by vasoconstriction. The kinship with the stomach applies also to the hitestinal lines of secretory organs. This is emphasized by the following follow the Piersol’s: “The blood-vessels supplying the intestines veslarger The general arrangement of those of the stomach. slendei sels pierce the serous and muscular coats, giving off the reaching upon tunics; the twigs to supply the tissues of incited by vasodilation,

submucosa the

vessels

Numer-

form a wide-meshed net-work.

ous branches then pass through the museularis mucosie, to be distributed to the deeper as well as to the more superficial parts of the mucosa;

narrow

form net-works which

capillaries

surround the tubular glands, while beneath the epithelium wider From this capillaries encircle the mouths of the follicles. superficial capillary

tween the

follicles,

net-work the veins arise and, passing bejoin the deeper venous plexus, which, in

turn, empties into the larger vein of the submucosa.

parts of the intestine where

villi exist

In those

special additional arteries

villi, when they expand into which run beneath the epithelium and around the central lacteal as far as the ends of the villi. These capillaries terminate in venous stems, which descend almost perpendicularly into the mucosa, in their course receiving the Brunsuperficial capillari'es encircling the glandular ducts. ner’s glands and the solitary and agminated follicles are supplied from the submucosa by vessels which terminate in capillary net-works distributed to the acini of the glands and to the

pass directly to the bases of the capillary

net-works,

interior of the lymph-follicles.”

.

.

.

“The nerves

distrib-

uted to the intestines are arranged almost identically to those of the stomach fibers,

tery

;

they are composed largely of non-medullated

derived from the trunks which pass within the mesen-

from the larger abdominal sympathetic plexuses.

After

giving off branches to the serous coat, the nerves pierce the

form the rich intramuscular composed of a rich net-work of delicate, pale libers, at the nodal points of which microscopical ganglia exist; after supplying the longitudinal and outer part of the circular muscular coats the fibers obliquely pierce the

longitudinal muscular tunic

plexus of Auerbach.

This

is

to

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

308

submucous tissue, vlicre they form the plexus of Meissner, which closely resembles Auerbach’s nervous net-work witliin the muscularis, jiossessing, however, smaller latter tunic to gain the

ganglia and somewhat closed meshes.

From

the plexus of the

submucous tunic

fibers pass into the mucosa, to form net-works about the glands and to send fibrillie into the villi.” In analyzing the functions of the intestinal tract it is im-

portant to note that two distinct sets of active structures are (1) the secreting glands of Lieberkiihn and of Brun-

present:

ner; (2) the villi of the agminated lymph-follicles patches) and the solitary lymph-follicles. Secreting Glands

found in

.

—The

(Peyer’s

glands, or crypts, of Lieberkiihn,

throughout the entire length of the

close array

intes-

including the colon, are present only in the upper, or

tine,

mucous,

They

layer.

are simple in construction

sweat-glands, minus the coils and muscles:

i.e.,

and

recall the

a net-work of

and probably nerve-fibrils overlying a delicate basement-membrane which in turn surrounds a single la}'er of columnar epithelial cells. These cells radiate toward a common center and thus form a minute tube which opens upon the mucous membrane between the villi. Their functional mechanism is doubtless that of all simple tubular glands. Howell refers to the crypts of Lieberkiihn as follows: “These structures resemble the gastric glands in general apcapillaries

pearance, but not in the character of the epithelium.

The

the goblet is of two varieties: form mucus, and columnar cells with Whether or not the border.

epithelium lining the crypts cells,

whose function

is

to

a characteristic striated crypts

form a

iologists are

definite secretion

.

.

.

has been

accustomed to speak of an

much

debated.

Phys-

intestinal juice, 'succns

formed by the glands of Lieberkiihn ; but practically nothing is knovoi as to the mechanism of the secreWe have seen that nerve-filaments are distributed to tion.” the secreting cells of the intestines, as stated by Piersol. The entericus,’ as being

functional needs of those stnictures seem, therefore, to be satisfied.

mucus seems evident if their histologcan be taken as guide. As we pointed out in this

That they

ical attributes

secrete

1903, however, the intestinal secretion serves also to protect the body against infection through foods^

work

in

ADRENOXIDASE AND THE INTESTINES.

309

—The

gastric juice

Intestinal Immunizing Functions.

not only concerned with digestion, bnt it is likewise a powerlul Howell refers to this property in the following antiseptic. is

“One

words;

It

in which it witlistands putrefaction.

way

tlie

of the interestmg facts about this secretion is

for a long time, for

with very

little

may

be kept

months even, without becoming putrid and

change,

if

any, in

its

digestive action or in its

This fact shows that the juice possesses antiseptic properties, and it is usually supposed that the presence This might serve of the free acid accounts for this quality.” acidity.

total

beyond the pylorus further protection of this unnecessary; but greater is the care with which Nature

as evidence that sort is

Every structural

protects her organic creations.

in any

cell

way

exposed seems to be surrounded not only with prophylactic weapons, but also with second and even third lines of defense to

cope with what the

line

first

may

have failed to disarm.

Eemoval of the stomach in animals has been followed with return to normal health;

it

seems plausible that the intestinal

tract should also be supplied its

with means for the protection of

organs.

The material formed first

in the living crypt of Lieberktilin

presents the form of granules, then becomes transformed

into a transparent substance

which accumulates in the spaces

This either constitutes the mucin found

of the cell-substance.

in the secretion or represents

The secretion proper That it may possess

is

clear,

to

labors of St. Clair

prove bactericidal.

“mucus”

nasal cilli

viscid, yellowish,

killed

—

and

staphylococci

nasal “mucus,”-

i.e.,

Thomson and

alkaline.

by the thanks to

—

Hewlett,®^ has been found

Page^^ experimentally ascertained that

anthrax

bacilli,

were almost actively destroyed

lence of

this material.

antiseptic properties is suggested

fact that a very similar fluid, tlie

an antecedent of

that

Klebs-Loffler

ba-

it, and that the viruand streptococci was reduced. Nasal largely made up of serum a feature

liy

“mucus,” however, is which also applies .to the secretion of the glands of Lieberkuhn. Brunner’s glands, which occur in the duodenum, at the :

St.

Clair

Thomson and Hewlett:

Medico-Chlrurgical Transactions, vol.

Ixxviii.

Paget:

Journal of Laryngology, Nov.,

1896.

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS

310

portal of the intestinal canal, would seem to suggest, by tlieir situation and their general conformation, just such a function.

While they resemble in general structure the pylorie glands, which most authors compare them, they also present many

to

characteristics of the

mammary

man-

lobules, especially in the

ner in which their interlobular ducts are disposed. The gland jiroper is situated beneath the smaller erypts just deseribed,

submucous

the

in

he.,

surface between the

tissues,

villi

—

or into

that

products.

Indeed, their secretion

plasma relieved of

The juiee,”

analogy

considerable

serous:

also

is

:

an

between their i.e.,

blood-

its fibrin, globulins, etc.

of these two glands

secretion

“suceus

or

is

erypts of Lieberkiihn

tlie

indication

tliere

ducts penetrating to tbe

its

entericus,”

and

is

termed “intestinal regarded by many as is

capable of acting on starch, proteids, fats,

with intestinal digestion:

in connection

etc.,

which could not conmight possess through the presence of oxidizing substance and alexins. Professor Poster, however, referring to this supposed action on foods, says: “Even Moreover, many obat its best its actions are slow and feeble. jiroperties

all

any antiseptic power

trovert

it

servers have obtained negative results

ments are

And

conflicting.”

conclude that at present, at

;

so that the various state-

he adds:

“We may,

we have no

all events,

therefore,

satisfaetorj'

reasons for supposing that the actual digestion of food in the intestine will- see

is,

to

any great extent, aided by such a juice.”

in the second volume, however, that such

is

We

the case.

These two glands are the only ones forming part of, the intestinal tissues per se to which the protective functions reHence, the facts that they both ferred to could be ascribed. produce a secretion so be

called

“serous,”

of serous

source Asiatic

cholera.

—

nearl}^ identical

for

the

diarrhoea, ]\Ioreover,

glands

and

of

to blood-plasma as to

Lieberkiihn

are

the

the rice-water discharges of

the

recognized

fact

that

blood-

plasma is the normal excipient for chemical protective agencies, suggests, as a working proposition, that the. glands of TAeherTciilin

and

having for

the duodenal glands of its object to asepticize,

Brunner supply a secretion and prevent the putrefaction,

digestive of, the intestinal contents, besides tahing part in the

process.

311

ADRBI^OXIDASE AND THE INTESTINES.

of a bactericidal fluid in the intestinal canal,

The presence

at least along its walls,

It is

now

suggested by various facts.

is

generally recognized that the nursing infant

receives through its mother certain substances which increase the bactericidal power of its blood-serum. Thus while Schmid

and Pflanz®* found experimentally that the antitoxic substances in the blood of parturient also

women

exist also in the milk, Figari®®“

noted that calves and young goats are not only capable of

absorbing agglutinins and antitoxins with the milk of

immu-

nized mothers, but that rabbits immunized by the administration

immunized milk taken by the mouth, are capable of transmitting to their young both agglutinins and antitoxins. This suggests that apart from the stomach general immunity may be conferred by fluids absorbed from the intestinal canal. This of

accounts for the fact that nursing babies are able to withstand

more

effectually than bottle babies

tions.

As

mechanism

will be

both local and general infec-

shown elsewhere in

this volume, the adrenal

not developed in the nursling sufficiently to pro-

is

tect the child against infection,

and Nature

insures,

through

the mother’s milk, not only the child’s nutrition, but its protection.

Welch, in his Harvey Lecture, said

:

“It

is

an impor-

tant function of the mother to transfer to the suckling through

her milk immunizing bodies, and the infant’s stomach has the capacity,

which

in active state.

is

afterward

The

lost,

of absorbing these substances

relative richness of the suckling’s blood in

protective antibodies, as contrasted with artiflcially-fed infant,

explains the greater freedom of the former

from infectious

dis-

eases.”

The importance

“Among

of this fact in practice, cannot be over-

who believe in the omnipotence of chemical formulae,” wrote Jacobi, recently, “there prevails the opinion that a baby deprived of mother’s milk may just as readily be brought up on cows’ milk that is easily disproved. ; In Berlin they found that among the cows’ milk-fed babies estimated.

those

under a year, the mortality was breast-fed infants. slightly smaller,

si.x

times as great as

Our own groat

cities gave us similar, or proportions, until the excessive mortality of

Schmid and Pflanz: Wiener klin. Woch., No. Rlforma Medlca, April 8, 1905.

““Figarl:

among

42, 1896..

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

312

the very young was somewhat reduced by the care bestowed on the milk introduced into both our iialaces and tenements. ]\Iilk

was examined for bacteria, cleanliness and chemical reaction. It was sterilized, Pasteurized, modified, cooled, but no cow’s milk was ever under the laws of Nature changed into human milk; and with better milk than the City of New York ever had, its infant mortality was greater this summer (1904) than it has been in many years. That hundreds of thousands of the newly-bom and small infants perish every year on account of the absence of their natural food, is a fact which is knoum and which should not exist.” Winters states that “during the siege

Paris

of

(1870-71), while

the

general

mortality was

doubled, that of infants was lowered 40 per cent, owing to

mothers being driven to suckle their infants!” This shows that the alimentary canal may be the seat of an immunizing process, and suggests that if the intestinal secretion of adult animals

is

bactericidal,

the intestinal im-

munizing process must prevail at all ages. That the intestinal secretion are endowed with immunizing properties is suggested by various facts. Pawlow found that the succus entericus increased strikingly the proteolytic activity of the pancreatic fer-

ments

—sometimes

to

an astonishing degree.

When we

con-

sider that jMetchnikoff’s “cytase,” the substance which enables

phagocytes to digest bacteria

is

mainly

a

pancreatic ferment,

same ferment should likewise digest bacteria in the intestine and thus protect the body This is further suggested by the fact that Wender at large. trypsin,

it

is

self-evident that the

found that milk contained a ferment to which he refers as “galactase or trypsin,” an observation confirmed by several inThe intestinal secretion can thus replace milk vestigators. obviously with greater activity as an immunizing agent, since

—

both fluids contain the same proteolytic and therefore cidal agents. We will see in the second volume that

bacteriall

the

agents concemed in the immunizing process are present in the intestinal

secretion as well

That the

as in milk.

bacteriolytic process occurs

the intestinal mucous

membrane

is

upon the surface of

rendered probable by the

by Howell, “extracts of the walls of the or the juice squeezed from these walls have been small intestine fact that, as stated

'

313

ADRENOXIDASE AND THE INTESTINES.

found to contain four or five different enzymes, and to exert a most important action upon intestinal digestion. Whether these enzymes are actually secreted into the lumen of the intestine,” continues the author, “is not satisfactorily shown, but since they are contained in the intestinal wall, as secretory products

and lonsider them

we must regard them a‘s

the important and

characteristic feature of the intestinal secretion.”

The most

direct evidence, however, is

that furnished by

Charrin and Levaditi, Zaremba, and others, who showed that the pancreatic juice could digest bacteria

and

their toxins.

The

and Morgenroth

investigations of Bordet, ]\Ietchnikoft, Ehrlich

having demonstrated that the distinction of bacteria in phagocytes

was due to the presence in these

pancreatic ferment, trypsin,

it

is

cells of the

difficult to

corresponding

conceive how, in

accord with the prevailing views on the subject, intestinal bacteria, especially those

ingested with foods, can escape digestion,

along with the food-stults. It is

now

the intestinal

believed that intestinal bacteria are necessary in digestive pirocess;

“By taking embryo

states:

but as

IsToel

Paton

(1905)

guinea-pigs at full time from the

uterus and keeping them with aseptic precautions,

it

has been

shown that the absence of micro-organisms from the intestine does not interfere with digestion.”

Por reasons that will be submitted in the second volume, immunizing process is carried on mainly, as far

the intestinal

as liquids are concerned,

by a recently discovered ferment (a compound containing trypsin and the oxidizing substance, as 1

IV ill

show) which has been found to act more vigorously than and termed “erepsin” by Cohnheim. It splits peptones

trypsin,

and many other

jiroteids into their

component

bodies, particu-

laily the is

As

di-amido and non-amido acids leucin and tyrosin. It thought to supplement the proteolysis begun by the trypsin. bacteria are proteids,

thus destroyed as living teids.

l

ienee

m this work

tlie

it

follows that they are digested— and

organisms— as w^ell as the other proimmunizing process urged by myself

intestinal

in 1903.

Ponding additional testimony

I may submit as a working proposition, the conclusion that intestinal digestion of proteids includes that of living proteids, viz., bacteria and that this

THE AUUENAL SYSTEM AND THE DIGESTIVE ORGANS.

314

bacteriolysis represents a function through which general infec-

tion is prevented, Villi

now

an immunizing process.

i.e.,

and Lymph-follicles.

conceived by physiologists,

—The

process of absorption, as

concisely described by Howell

is

in the second edition of his text-book (p. 733) takes place very readily in the small intestine. correctness of this statement

loops of the intestine.

may

:

“Absorption

The

general

be shown by the use of isolated

Salt solutions of varying strengths or

even blood-serum nearly identical in composition with the animals’

own

blood,

may

be absorbed completely from, these loops.

Examination of the contents of the intestine in the duodenum and at the ileocecal valve shows that the products formed in digestion have largely disappeared in traversing this distance.

All the information that

mucous membrane

we

possess indicates, in fact, that the

of the small intestine absorbs readily,

and

one of the problems of this part of physiology to explain Anatomically the means by which this absorption is effected. it is

two paths are open to the products absorbed. They may enter the blood directly by passing into the capillaries of the villi, or they may enter the laeteals of the villi, pass into the lymph

and through the thoracic duct

circulation

of the Ijunphatic sys-

tem eventually reach the blood vascular system. The older physiologists assumed that absorption takes place exclusively through the central laeteals of the were described as absorbents.

villi,

and hence these

We now know

vessels

that the digested

and res^mthesized fats are absorbed by wa^f of the laeteals, but that the other products of digestion are absorbed mainly through the blood-vessels, and therefore enter the portal system and pass through the liver before reaching the general circulation. Aca patient with a fistula at the end of the small intestine [Macfadyen, Nencki, and Sieber],

cording to observations

made upon

food begins to pass into the large intestine in from two to five and a quarter hours after eating, and it requires from nine to twenty-three hours before the last of a meal has passed the ileocecal valve; this estimate includes, of course, the time in the

stomach.

During

this passage absorption of the digested prod-

ucts takes place nearly completely.

In the

fistula case referred

was found that 85 per cent, of the protein had disappeared, and similar facts are known regarding the other foodto above, it

—

315

ADRENOXIDASE AND THE INTESTINES. stuffs.”

“The energy

.

•

.

that controls absorption recides,

presumably in the epiand constitutes a special form of imbibition which

therefore, in the wall of the intestine, thelial cells,

not yet understood.” Various facts tend also to suggest that the intestine is the seat of a protective process, where bacteria and poisons of all is

kinds are most likely to penetrate the blood-stream:

i.e.,

the

organs of the intestinal wall connected with absorption. Viewed from my standpoint the question embodies features

which seem

to

me

to have been overlooked, but

which require

a review of the functions of each organ involved in the process

and lymph-follicles. The villi, the and the agminated lymph-follicles, or

studied, especially the villi solitary Ijunph-follicles,

Peyer’s patches, are considered together, because they appear to represent parts of a single- system.

The

structural similarity between the walls of the stomach

and those of the intestine must be function referred

to,

in connection with

—

set

absorption,

i.e.,

the intestines,

aside here,

—a

since the

predominating one

can hardly be said to be

worth considering as a factor of gastric functions. Conversely, the villi distributed throughout the whole small intestine are adapted for this purpose.

especially

nerves, muscular tissue, basement

-

Besides the capillaries,

membrane, and epithelium,

these structures contain a lymph-trunk, or lacteal, the purpose of

which

is

to take

up nutritional agencies from the

intestinal

contents as they pass along.

Each gland, is

villus

may

be considered as a sort of “reversed”

a sweat-gland

if

outside

i.e.,

is

taken as standard.

The epithelium

exposed in the intestinal canal,

the epithelium lies the basement

membrane.

—

^while

under

Combined, these

two constitute a glove-finger-like projection inside of which are the structures that we found over the basement membrane

The capillaries form a close-meshed network not only in contact with the inside of the basement membrane, but entwined with considerable connective tissue in the sweat-gland.

strewn with leucocytes, the tissue and cells constituting “lymphoid tissues.” T said “connective tissue,” but at this point ve must emphasize the fact that it is not true connective tissue, as met with elsewhere, but a fenestrated membrane made

up

entirely

of

star-like

cells

that

give

oft

thin projections,

or

a

THE AUUENAL SYSTEM AND FUNCTIONAL ACTIVITY.

81 G

make np the tissue itself: The fenestra, or openings, cytogenous membrane is permeated accommo-

pseutlopodia, which by intermixing i.e.,

witli

Kblliker’s

which

cyiogenoiis iissue.

this

date the capillaries.

Another

histological

feature

of

interest

special

presence of smooth muscular fibers wliich stand upright

being horizontally capillaries

and

disposed

—and

are

interwoven

villus’s

delicate

among

We

cell-fibers previously referred to.

immediately under the

is

the

—a few the

thus have

basement membrane a

Intestinal Villus; Venous radicle shown at

a.

(Cadiat.)

though minute, suction-pump which by alternately contracting and relaxing causes the organ to absorb the pre-

perfect,

viously asepticized intestinal fluids. Xext in order inwardly are the venous steins (one or two) veins Avhich carry the blood from the villous capillaries to the caii} A\hicb These vascular channels, in the dee])or tissues.

end the bulk of intestinal foodstuffs to veins which ultimately and cut, annexed in the portal system, are well shown in the will again be referred to.

Last of

all,

in the

middle of the organ,

is

the lacteal,—

317

ADRENOXIDASE AND THE INTESTINES. thick,

club-like,

sometimes

double,

lymphatic

vessel,

which

the tip of stands upright and reaches almost to the inside of the former. the villus, its own blind apex almost touching This vessel. Each lacteal represents the origin of a lymphatic is illustrated

Lymph

in the second figure.

—derived

contains chyle

from the

intestines

—only

At other times the fluid found during intestinal digestion. that in the lacteal and neighboring structures is identical to

Intestinal Villi; Injected Lacteals in the Middle of each Villus. (Cadiat.)

found elsewhere in the organism. emphasize the fact that lymph

and

is

It is perhaps

advisable to

very similar to blood-plasma,

owing to the presence of leucocytes. Indeed, it only differs from blood in the absence of red corpuscles. It undergoes coagulation and separates, as does plasma, into serum and clot, the latter likewise containing fibrin-globulins. It contiiins serum-globulin and serum-albumin in relative proportions similar to those in blood, though in smaller quantity: a feature which accounts for its somewhat richer than this fluid,

THE ADRENAL SYSTEM AND THE DIGESTIVE' ORGANS.

318 lower

ipiantities,

counted

correspond

also

vehicle^ for

Inorganic

gravity.

siiecific

derating,

various

and the

those

to

substances,

it

plasma.

constituents

is,

Being a

are

variable

-conflicting analyses published are thus ac-

Stewart says, in this connection

for.

;

the chlorides prepon-

the

of

its

been defined as blood without j\Iuller)

salts,

red

its

“Lymph

:

has

(Johannes

corpuscles

in fact, a dilute blood-plasma, containing leu-

some of which (lymphocytes) are common

cocytes,

to lymph and blood, others (coarsely granular basophile cells) are absent from the blood. The reason for this similarity appears when

recognized that the plasma of lymph is derived from the plasma of blood by a process of physiological filtration (or osmosis) through the walls of the capillaries into the lymph-

it is

spaces that everywhere occupy the interstices of areolar tissue.

But, in addition to the constituents of the jjlasma, lymifii appears to contain certain toxic suhstances produced in the metabolism of the tissues and destroyed in the lymphatic glands.”

now seems

It

probable that the intestinal tract, being one

of the two regions

most exposed

to toxics, the villi not only

have for their function to absorb chyle, but to protect the orThe lacteal is the recognized absorption organ for

ganism.

emulsified fats.

As

I

view the process involved, the fat-con-

taining fluids, as soon as they reach the basement membrane, are

first

submitted to the asepticizing influence of

They

thelial cells.

epuration,

phoid

and probably chemically transformed

layer

endo-

its

are then submitted to the next process of

—Kolliker’s

cytogenous

layer

in

the

l3’m-

—immediately

be-

neath, in which leucocytes, and, therefore, antitoxic substances, are constantly being formed.

M'hen

it finally

reaches the lacteal,

it again meets endothelial walls, and when through these and in the lacteal, must run the gauntlet of an accumulated array

of

fresh

therefore,

leucocytes is

met

from the cytogenous

as soon as

latter’s protective resources:

tissue

cells,

endothelial

it

layer.

The

enters the organism by

chyle,

the

all

phagocytes, stellate or connective-

cells,

and

finally

the

oxidizing

sub-

stance, the latter probably serving here to convert products of local

metabolism and other toxic materials into inert bodies.

which thus absorb all nutrient substances assimilated by the organism whether by their venous stems or

The

villi,

319

ADRENOXIDASE AND THE INTESTINES. distributed

thickly

are

lacteals,

tlieir

throughout

the

entire

In the duodenum and jejunum

length of the small intestine.

they doubtless fully satisfy the needs of the organism, both In the lower part of the as to absorption and prophylaxis. canal,

intestinal

however, more protection

is

required,

owing

perhaps to continued exposure of the contents to a relatively high temperature during the time elapsed since this material has been submitted to powerful antiseptic

stomach

A

several hours to a day, according to the meal.

i.e.,

:

treatment in the

morning movement of the bowels, for instance, includes

products of the breakfast of the preceding day, thus representing twenty-four hours of exposure in the intestine to a This additional temperature averaging 39° C. (102.2° F.).

precaution

is

and While the

represented by the solitary lymph-follicles

the agminated lymph-follicles, or Peyer’s patches. solitary lymph-follicles are

found throughout the entire canal,

small and large, they are by far most numerous in the lower

part of the ileum and in the

first

part of the colon.

patches, or the agminated follicles, are likewise

duodenum and jejunum, though site of predilection is also in

Peyer’s

found in the

rarely in the former; but their

the ileum, and, inasmuch as they

vary from one-half inch to four inches in length and are oval or round, they cover to thirty in

number.

practically limited

to

an extensive area, though only twenty Especially

is

this the case since they are

one side of the intestine:

t.e.,

to

portion facing the latter’s attachment to the mesenter ^ 3 also frequently

the

They

form a continuous layer in the vermiform ap-

pendLx.

A

single “solitary follicle” is typical of

ing those in Peyer’s patches.

A

them

follicle consists,

all,

includ-

on the whole,

of a rounded mass lodged in the of its

submucous tissue, a small part upper portion appearing upon the free surface of the

though the epithelium of the intestine also covers it. 'I'he overlying layer of epitlielium, however, is separated from the follicle by a special delicate membrane perforated with a latter,

multitude of holes that surround communicate with the organ itself.

The

its

projecting portion

and

structure of the body of the follicle will perhaps he

best understood if

it

is

divided into three different parts, be-

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

320

from

ginuiiig

work of

tlie

A

inner portion of the organ.

capillary

blood-vessels

fine

net-

which acts as a supporting

fabric, furnished by underlying arterioles, is the central feat-

ure;

this,

fibrils,

turn,

in

is

surrounded with a close net-work of

in which “lymph-corpuscles, small round cells, with a

large nueleus

and very

little

perinuclear protoplasm” so com-

preponderate as to almost entirely obscure the net-

pletely

But there is a feature of special interest here which remind us of the cell-forming membrane of Kblliker foimd in villi i.e., a central nodule, described by Flemming, in which some cells undergo active karyokinetic division, while others, Ijunphocytes, are formed in continuous quantities. “In the center of the nodule,” say Bohni and von Davidoff,®'""' the cells often show numerous mitoses, and it is here that an active work.®'"'

will

:

The

proliferation of the cells takes place.

cells

may

either

remain in the lymph-follicle or the newly-formed cells are pushed to the periphery of the nodule and are then swept into the circulation by the slow lymph-current which circulates between the wide meshes of the reticular connective third portion

is

tissue.”

The

the interval referred to, a delieately partitioned

sinus which surrounds the

follicle.

To

this sinus the

lymph,

from the blood-capillaries, after it has permeated the meshes and cell-spaces of the adenoid tissue and became charged with the newly created cells, gravitates, finally to find its way into the lymph-vessels of the submucous tissues beoriginally

neath.

The

physiological functions of the follicle seem plain

when

anatomical relations

we consider two salient features of its with the mucous surface of the intestine and with the villi. As to the relationship between 'the interior of the follicle and the intestinal canal,

it is

suggested by the perforations to which

we have previously referred, but tliere seems to be no mechanism to insure absorption. The case is not the same, however, in respect to the connection with the

phatic vessels

villi.

which originate from the

Indeed, the lym-

lacteals of the latter

constitute the afferent supply of the sinus, while the lymphatic vessels of the submucous tissue represent its efferent system. Clarkson:

“Histology,** 1896. Davidoft: Loc.

Bobm and von

cit.

ADRENOXIDASE AND THE INTESTINES.

we

It is very evident, therefore, that

powerful adjunct to the overlying projibylactic villi

means

321

have, in each follicle, a

villi,

to

add

While the

those already enumerated.

to

do not occur upon

another

still

portion of the follicle that projects

tJie

into the intestinal free surface, they are nevertheless present

and their lacteals when below the level of the epithelium break up into vessels which find their way to the lympharound

it,

sinus.

“When

they reach the level of the closed follicles,” says

Berdal,®®^ “the chyliferous vessels

become united

to the sinuses

which they constitute the afferent

of these follicles, of

vessels.

Crossing the muscularis mucosie, they form part of a varicose

net-work

capillary

submucosa.

the

in

arise true l}'mphatic trunks Supplied

intestinal

From

net-work

this

with valves that cross the

and then reach the subperitoneal Ijunphatic

coats

net-work.”

The intimate phatic follicle their

is

relationships between the villus

and the lym-

further emphasized by the similarity which

mechanisms present.

If the l}Tnph-sinus of the latter

considered as functionally encircling

what in the

villus

is

has

been termed cytogenous tissue by Kolliker, including

its

work of

Indeed,

capillaries, this similarity

the fact that the sinus sue instead of in

becomes striking.

net-

situated around the l3unphoid tis-

is

as it is in the villus,

its center,

to indicate that the follicle does

would tend,

not absorb intestinal

fluids,

would merely, before reaching the sinus, be subwhat epuration the epithelium and the fenestrated

since these

jected to

memhrane

overlying the organ could afford. It is, therefore, probable that the solitary follicle or organ does not include absorption among its attributes. Indeed, unless possessed of a suction

mechanism such

surrounded, as its

is

its

as that of the villi, it is evident that,

projecting part, by these minute pumps,

usefulness would he

ver}!"

slight.

hat can be the use, therefore, of the minute apertures encircling the projecting part of the follicle and which constitute

the

“fenestrated”

subepithelial

orifices

memhrane?

“These

appear,” says Ecrdal, “to afford passage to lymphatic cells that emigrate from the follicle toward the cavity of the ““Beraal:

"Hlstologio Normale,”

p. 3C5, 1894.

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

322

intestine”

—and

to

assist,

considered from

if

ni)’

standpoint

in asepticizing the contents of the lower end of the small intestine

hy permeating

now connect

it

with mobile phagocytes and alexocytes.

If

we

this fact with the predilection of Peyer’s patches for

it would seem as if funcimpairment of these organs would render possible the

bacterial invasion in typhoid fever, tional

pnllulation of pathogenic organisms in the ileum.

This would normally lead to infection of the patches, and of the system at large through the apertures. Besides this

first,

and

I

may

tective function, the follicular sinus,

by serving as a secondary

for the chyle, appears to afford a supplemental pro-

jiassage

tection to the organism of no

that

add, very important pro-

mean power

Avhen

we

consider

serves not only as a channel for freshly-manufactured

it

leucocytes, but that the follicle simultaneously receives freshly-

oxidized blood directly from the great arterial trunks, through

the mesenteric arteries.

This blood, which reaches the lym-

phoid tissue through the rich intrinsic capillary net-work to

which

I

elements

have referred, doubtless furnishes

way

with the various

—

the metamorphoses retrogressive and by Flemming and others, then forces its

required

progressive

it

for

—

^noted

into the sinus, carrying with

it

not only the newly-created

but also serum supplied with all the defensive agencies which the blood affords. The accumulation of Peyer’s patches cells,

in the lower two-thirds of the ileum seems to point directly to

—

most toxic part of the canal and clinicians well know how frequently this region becomes the seat of intestinal

this as the

disease.

It

would thus appear

as if in the

duodenum, the jejunum,

and the upper part of the ileum, the gastric juice, the secretion of tlie crypts of Lieberkiihn and that of the glands of Brunner, would subserve the to the end of the and that beyond protective process ileum, the follicles, either solitary or agminated in patches, in

addition

the

to

ultravillous

process,

this,

;

the villous process plus the folliculous process, including the output of lymphocytes into the intestine, united to accomplish the same prophylactic purpose.

The

colon

is

deprived of

villi,

but plentifully supplied with

crypts of Lieberkiilin, while solitary glands, somewhat larger

323

ADRENOXIDASB AND THE INTESTINES.

than those in the ileum, are scattered throughout its entire The former doubtless furnish the mucus, while the extent. latter

probably contribute the asepticizing lymphocytes.

Here

as

in

other organs of the

alimentary system the

sympathetic system alone, through its vasoconstrictors, does not account

for

vasodilation.

the

This

phenomenon which is

function,

initiates

Disturbance of the functions of the adrenal lesions of their nerves seriously

ing process.

i.e.,

supplied, as in the stomach, by the vagus.

Onuf and

hampers the

intestinal

system by

immuniz-

Collins refer as follows to the disturb-

ances that result from extirpation of the stellate ganglion in

“They .consisted of diarrhoea and putrefaction of the The faecal matter was semiconsistent, of yellow or darkgrayish-brown color, and of exceedingly foul odor. This putrefaction of the faeces was observed in two of the three animals from which we removed the stellate ganglion. In the third cat they were not noted; but it should be added that this cat was killed before a time corresponding to that which had elapsed antecedent to the occurrence of putrefaction in the first two cats. The putrefactive symptoms made their appearance as late as two or three months after the operation, and it was noted that the digestive disturbances had a tendency to increase and persisted until the death of the animals, three and four and one-half months, respectively, after the operation. In one instance the autopsy revealed marked aniemia of the incats:

faeces.

testines.”

We

are dealing, in these experiments, less with the effects

of section of intestinal

nervous supply on the local vascular

walls than with those of impaired adrenal functions,

as

the

extirpated stellate ganglion contains fibers to the thyroid, whose secretion sustains the functional activity of the adrenal center.

Decrease of adrenal secretion, the plasma, was the

i.e.,

main morbid

of

o.xidizing

factor.

substance in

The functional

energy of the intestinal crypts, glands, and follicles being impaired through loss of part of their pabulum energeticum in the blood, the asepticizing secretion of the crypts of Lieberkiihn

and the glands of Brunner became reduced, the production of IjTuphocytes by the follicles likewise, wdiilc the reduction of oxidizing substance in the secretions per se contributed to fur21

—

o24

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

ther impair their prophylactic qualities. refer to

Onuf and

Collins also

one of their animals ope'rated in the same way, in

which diarrhoea developed in two weeks; the third week “the animal began to be uncertain in gait, which increased to wellmarked staggering” “within two da}’S it died in collapse.” That the functions of important organs the thyroid and adrenals had been impaired, is evident. The following deductions seem to me to be warranted by .

.

.

—

—

the analysis submitted:

The glands of LieberTcuhn and the duodenal glands of Brunner supply a secretion the purpose of which is to asepticize the intestinal contents.

The

villi,

through their venules and

and chyle-forming materials from

lacteals, absorb nutrient

the intestinal foodstuffs,

the contents of the lacteals are submitted to a

and

further asepticiz-

ing process, mainly in K'dllilcers cytogenic membrane.

The

solitary

and

agminated

lymph-follicles

(Beyer’s

patches) are cytogenic structures which further asepticize the materials absorbed by the surrounding villi, the efferent lymphvessels of the latter constituting the afferent lymph-vessels of the follicles, where both Icinds of organs occur together: i.e., in the

portion of the small intestine in which pullulation of pathogenic bacteria is most likely to occur, the ileum particularly.

The

solitary

and agminated lymph-follicles

also supply leu-

in cocytes to the intestinal canal, which leucocytes are formed out pass their- cytogenic area (Flemming’s central nodule) and

through the fenestrated membrane overlying each

follicle.

The

to insure the destruction

jmrpose of some of these leucocytes is result of putrefaction of the of pathogenic agents formed as a intestinal contents or introduced into the intestine. rich In the colon, the asepticizing process is fulfilled by a bathed walls its keep which supply (1 ) of Lieberkuhn’s crypts, irregularly scatwith their muco-serous secretions; and (2) of latter secretion tered solitary lymph-follicles, which supply the with bactericidal

cells

and

their antitoxic blood-scrum.

the The nervous supply of the intestines is derived from various the to vagal and sijm pathetic systems, the distribution to that similar being action mode of intestinal coats and their inifibers vagal the stomach: While of the same nerves in the

—

325

FUNCTIONS OF THE VERMIFORM APPENDIX.

causing vasodilation, the sympathetic fibers

Hate function

hi/

arrest function

by restoring the arteries

to their

normal

caliber..

—

Vermiforji Appendix. Solitary follicles being also very numerous in the cascuni, and the appendix so rich in agminated follicles as to have suggested to some anatomists that it was a large Peyer’s patch, I

was

led, in

view of the facts presented

in the foregoing pages, to the conclusion that

The ccecum, being

:

particularly exposed to the accumulation

of putrefactive materials, is supplied with

an organ in which

agminated lymph-follicles are particularly numerous,

The functions

vermiform appendix.

of this organ,

i.e.,

the

therefore,

be to supply the ccecum with bactericidal cells

and

phagocytic leucocytes and

alexocytes

(in

addition to those supplied by the ccecal agminated follicles)

and

appear

to

products,

their

i.e.,

antitoxic blood-serum.

Shortly after this conclusion had been published in the first

Prof.

edition of the present

MeAdam

work

(Januar}",

1903, page 323)

Eccles, of London,^®® stated, in his

Leetures, that practically

little

or nothing was

Hunterian

known concerning

the functions of the appendix, though he thought that

it

was

Favoring

probably “in part absorptive and in part excretive.”

the latter view he pointed out that the action of the muscular fibers in its

muscular coat tended “to force

its

contents toward

and into the cavity of the ciecum,” the caliber of the aperture, “while amply sufficient in its natural state to allow the free evaeuation of secretion from the itself.”

He

also

shows that in at

positions of the organ, its orifice

mucous membrane least

was

of the tube

two of the fairly

common

so situated as to facilitate

“the exit of the secretion.”

Corpe®^' in experiments on dogs found that the appendix secreted considerable fluid, estimating this at four ounees daily in these animals, and that the secretion was powerfully germicidal. Hoefer*®® noted, in the course of appendiceetomy, that the appendix secreted a light, strawcolored fluid, and refers to Macewen as having seen a stream of alkaline fluid poured

from the appendix just before the cscal contents passed into the colon. Each time a small quantity of

chyme passed the Eccles:

Corpe:

“eHoefer:

orifice

of

the

appendix

London Lancet, March 14, 1903. Medical Sentinel. May. 1903. St. Paul Med. Jour., Jan., 1907.

it

would become

—

— ;

THE ADRENAL. GENERAL MOTOR. AND VAGAL SYSTEMS.

326

smeared by the exudation therefrom.

Condi

is

referred to as

stating that six ounces of this fluid were secreted in the twenty-

Hoefer concludes with Bunge and others that the

four hours.

purpose of this fluid

is

to alkalinize the caecal contents before its

migration to the colon. London,®^''

Eecently, however, E.

M. Corner,

of

a comprehensive study of the subject, con-

after

cluded that the vermiform appendix was “a specialized part of the alimentary canal, nature having structure and endowed it

lymphoid

tissue

organisms of the

use of a disappearing

with a secondary function, by giving

it

to

made

protect

ileo-csecal

body against the micro-

the

The trend

region.”

of evidence,

toward the immunizing function I attribute to the organ, a role which the resemblance of the glandular elements of the appendix to the tonsils had led various observers, notably

therefore,

is

Kilbourn,®®' to suspect.

The

Liver and its Physico-Chemical Functions. There is considerable evidence available to show that oxidation is one of the most active factors of hepatic functions, and yet it must be admitted that, according to prevailing views, there is no blood-supply capable of accounting for this powerful

To

source of energy.

the portal vein, essentially a channel

for physiologically impotent blood,

blood replete with the

i.e.,

waste-products of four important organs and the oxygen of

which has been ponderating

utilized in these organs,

role.

On

thought to supply the

—

is

ascribed this pre-

the other hand, the hepatic arter}'

liver

“with the blood of nutrition.”

is

Text-

books on physiology, therefore, seldom refer to this vessel works on histolog}' hardly grant it more than two or three lines, In text-books on anatomy it receives if they refer to it at all. attention, but only in its general topographical bearing.

more

As viewed from

my

standpoint, the hepatic artery does not

only supply the liver with ously with the blood

upon

its

nutritional blood, but simultane-

tvhich all its functions depend.

develop this proposition a review of the histology of Clarkson®'* gives the following comthe lobule is necessary.

To

plete,

though succinct, description of

this

Corner; Annals of Surgery. Oct.. 1910. “‘Kllbourn: Philadelphia Med. Jour.. May 17. Clarkson: “Text-book of Histology.” 1896.

**

wonderful

1902.

little bod}'

327

FUNCTIONS OF THE LIVER.

—about

one-twentieth of an inch in diameter

—and

which in

has been termed a “miniature liver” “A lobule of the liver is polygonal in shape, and

itself

composed chiefly of a number of gland-tubes, which radiate from near the center of the lobule to the periphery, where they open is

Thus, the blind terminal end of the tube

into their ducts.

is

turned toward the center of the lobule; the ducts at the periphery lie in the interlobular connective tissue, which to the

naked eye marks the boundaries of the lobule. “The blood brought to the liver by the porUl vein^^ conveyed along

its

subdividing branches

which lie, surrounding the

divisions are reached,

connective tissue

till

ultimate sub-

tire

together with the lobules.

is

Here

bile,

in the

capillaries arc

which pierce the lobule and pass between the radiatgiven ing gland-tubes to reach the center, where they open into the off

intralobular radicle of the efferent vein of the liver, the hepatic vein.

—^the

These small hepatic radicles open into the larger vessel, and the sublobular veins unite to con-

—

sublohular vein,

tribute to the hepatic vein itself.

The

walls of the branches

of the hepatic vein are destitute of muscular fibers

adventitia

is

extremely thin.

and the

The radiating gland-tubes

tomose laterally with each other, as do the capillaries

The meshes

anasalso.

of the net-works are elongated in a radical direction.

is composed of a radiating system of gland-tubes and a corresponding radiating system of capillaries lying between them. A very minute quantity of connective tissue

Thus, a lobule

accompanies the capillaries as an adventitia and in this Ijunphatic channels are to be found separating the gland-tubule

from the blood-vessel.

“The

lobule

is

surrounded (in part or whole) with con-

nective tissue supporting branches of the afferent portal vein,

—the

feeder of the

capillary net-work,

—and

the

hile-ducts,

which receive the secretion of the gland-tubules. Thus, the blood flows from the periphery to the center of the lobule; the bile, from the center to the periphery.

“But in addition duets another vessel

The

italics

are

my

and the bilefound in the interlobular connective

to the afferent portal vein is

own.

THE A.DRENAL SYSTEM AND THE DIGESTIVE ORGANS.

328

This

tissue.

is

the lieixitic artery, which supplies blood for the

nutrition of the connective tissue of the organ, the vessel-walls, It ultimately terminates in the small portal veins,

etc.

and

perhaps partly in the capillaries in the periphery of the lobules.”

There

some uncertainty

exists

manner

as to the

in which

the subdivisions of the hepatic artery are related to the other perilobular

and intralobular

Pick and Howden®* refer

vessels.

to its terminal distribution as follows:

“Pinally,

it

gives off

form a plexus on the outer side and the accompanying bilelobular branches enter the lohule and end in

interlobular branches, which

of each lobule, to supply its wall ducts.

From

this

the capillary net-work between the

however, doubt whether

it

Harrison

capillary net-work.”

Some

cells.

anatomists,

transmits any blood directly to the

“Each

says:

Allen®'^

lobule

is

a miniature liver having at its periphery between the lobules

branches of the portal vein and hepatic artery

(interlobular

branches) which freely intercommunicate and form through the

and

lohule, betw'een its periphery

Directly at

the

center, a capillary net-work.

center the venules of this net-work

(intra-

lobular vessels) converge to form radicles of the hepatic vein.”

Labadie-Lagrave^® states that, “as regards the divisions (of the hepatic artery)

destined for the lobules, they penetrate con-

jointly with interlobular veins, hut without

communicating with

them, in the interior of the lobule, in the vergent views, which but exemplify

all

lies

capillaries

In the presence of these

distributed to the central vein.”

our only choice

form of

other

of

tliose

in the selection of the one region which

authors seem to consider as reached by the artery:

periphery of the lobule. arterial

capillaries

intralobular

But, as

penetrate in

supply,

we

Piersol,

“

all

is

who, in accord with

we

believe

that

—the

more conthe annexed engraving by

the true one

many

the

another to the

or

—though

indicated in

i.e.,

concede, also, that the

one way

adopt

will

Harrison Allen’s definition servative distribution

di-

authors,

describes the

histologists,

Pick and Howden: “Gray's Anatomy”: edition, 1901. Harrison Allen: “Human Anatomy,” 1884. Labadle-Lagrave: “TraitO des Maladies du Foie,” 1892.

,

329

FUNCTIONS OF THE LIVER. hepatic

artery

as

“supplying

to

nutrition

the

interlobular

capillary net-work. structures and terminating in the lobular envelopnoteworthy feature of the capillary net-work

A

ing the cellular bodies

one

cell,

but

is

that each

Indeed,

several.

mesh does not merely

cover

the

hile-

were

otherwise,

it

capillaries could not exist as individual channels

and give an

to their contents without allowing the To prevent this, and yet bile to penetrate the blood-stream. simultaneously insure perfect exposure to the blood and lymph,

uninterrupted free

a very simple

way

arrangement

exists

:

i.e.,

three or

more

of the

Section op Liver Showing the Lobules, Cells, and the Blood-supply. (Piersol.) H.A., Hepatic artery.

P.V., Portal vein.

cells

H.V., Hepatic vein.

(usually polyhedral) are joined longitudinally, and, while

the narrow passage serves as

the blood-

in the

a bile-channel,

and lymph-

center of the group thus fonned

the outside only capillaries.

When

is

in contact with

only two

cells

are

thus joined, the surfaces in contact have in their center a small

opening, which, being adjusted to that of the adjoining insures the continuity of the channel.

that the blood-plasma

may

cell,

It thus becomes clear

penetrate the

cell,

undergo or in-

duce metabolism therein, and the product pass out through the intercellular biliary passages or bile-capillaries.

The

cells

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

330

are so joined as to form continuous, tliough correlated, chan-

which radiate from the center of the lobule

nels,

ery,

The intimate possesses is

to its periph-

where they join the interlobular bile-channels. structure of the hepatic cell

no limiting membrane; but

more dense than that

is

peculiar.

It

peripheral protoplasm

its

of its other parts

and the pseudocov-

ering so formed serves as the outer wall for numerous cavities or vacuoles which inosculate irregularly throughout

more

All these vacuoles, however,

rior.

inte-

its

or less directly con-

verge toward the center, where they meet a protoplasmic mass,

which in turn contains one and sometimes two nuclei. The cell, apart from its nucleus, suggests a miniature sponge the become filled with (secretion vacuoles) cavities of which

Biliary Canaliculi. a,

A

{Mathias Duval.)

biliary canaliculus cut transversely,

glj'cogen.

This substance seems

b.

Intercellular capillary.

accumulate in the outer

to

which appear wider in this location than the inner when, by artificial means, the glycogen has been removed.

vacuoles, ones,

noteworthy that this substance accumulates in the part of the cell nearest the blood-vessels and that the droplets, or “granules,” considered as bile are most abundant It is perhaps

in the opposite direction

:

i.e.,

near the bile-capillaries.

These

“droplets” accumulate between periods of digestion and diminA delicate canaliculus connects this ish during this process.

part of the

cell witli

the biliary channel.

The

vacuoles in the

in paraplasm, according to ICupffer, ‘^play an important part of confluence the the secretion of the cell, and are due to As soon as the minute drops of bile into a large globule.

vacuole has attained a certain size

it

tends to empty

its

con-

FUNCTIONS OF THE LIVER.

331

tents into the bile-capillary through a small tubule connecting

Kupffer’s

the vacuole with the bile-capillary.”

main vacuole

thought by him to constitute an intracellular vesicle connected with the bile-capillaries by means of delicate tubes. is

The

nerves of the liver enter the organ at the transverse

and accompany the blood-vessels and lymph-vessels to the interlobular spaces. That the vagus causes vasodilation of the hepatic arterioles was first observed by Cavazzani and fissure

Manca.®”

.

Frangois-Franck and

Hallion'*'’

also witnessed vaso-

on stimulating the central segment of the divided vagus with a weak current. Bruno^^ has shown, moreover, that the flow of bile was increased concomitantly with the passage dilator effects

of food-products through the pylorus under the influence of

the vagus.

The

vasoconstrictor

action

of

the

sympathetic nerve on

who found that stimufrom the coeliac plexus caused anaemia which they were distributed. Haffter,

the liver was pointed out by Vulpian^^ lation of nerves derived

of the hepatic area to

Samuel and Frerichs

all

observed congestive coloration phe-

nomena on dividing the splanchnic nerve and the plexus, similar to those that follow, in the ear, face, tion of the sympathetic nerve in the neck.

coeliac

etc.,

sec-

MalP® showed that

the splanchnics also contained vasomotor fibers for the portal Bayliss

vein.

and

Starling^'*

then found a rise of the blood-

pressure in the portal vein occurred in the dog, racic nerves between the third

were stimulated, the

maximum

the fifth to the ninth inclusive.

when

the tho-

and eleventh thoracic inclusive effect

following excitation of

Cavazzani and Manca^"^ were

led to conclude that hepatic vessels were also

under the influence of such nerves by passing warm saline solution at a given pressure through these vessels and measuring the outflow in a given

time.

Hallion.^®

™ and

This

The

was

confirmed

latter physiologists

by Frangois-Franck

Cavazzani and Manca: Archives ital. de biol., T. xxiv, p. 33, 1895. Frangois-Franck and Hallion: Arch, de physiol, norm, et path., T. ,

ix, 1896.

" Bruno:

Archives des Sc. biol., T. vil, p. 87, 1899. “Vulpian: C. R. de la Soc. de biol., p. B. 1858. “Mall: Archiv f. Physiol.. S. 409, 1892. “ Bayliss and Starling: Jour, of Physiol., vol. xvil,

“Cavazzani and Manca: Loc. cit. “ Frangois-Franck and Hallion: Loc.

cit.

and

showed, moreover, that the

p. 120, 1894.

viii,,

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

332

true vasoconstrictor effects of the sympathetic were produced

by

from the cord on a level with the sixth thoand second lumbar inclusive, all passing to the splanchnic

fibers derived

racic

nerves.

On

the whole,

evident that the functions of the liver and inhibited by sym-

it is

are incited through vagal vasodilators

pathetic vasoconstrictors as in the stomach

Our inquiry

into

and

intestines.

the character and composition of the

substances that are transformed in the liver and of the secretions of this organ

must necessarily include the blood

portal vein, since

contains whatever products of metabolism

the organ

is

it

We

thought to transform.

shall, therefore,

of the

begin

with this channel, which brings to the liver essentially venous blood,

since

it

contains

— —

the by four organs the pancreas and the spleen in

that utilized

stomach and the intestines, which the metabolic products include, besides those incident

upon tissue-waste, food metabolites, physiological As is well known, there exist in the liver’s evidences

tinct

of

known

to

modify the com-

passes through

it,

but the purposes

The

position of the blood as

it

secretions dis-

with splenic haematopoietic or

association

haemolytic functions.

toxics, etc.

liver is

of the alterations involved are not established.

The Splenic Vein

.

—The path from the spleen

vein, through the splenic vein,

spleen sends to the liver

is

is

to the portal

a direct one, and the blood the

not, therefore, modified in transit

by any other organ, though the splenic vein receives a few Still, these are mere

branches from the pancreas and stomach. tributaries to a

common

comes directly from the

channel, and, as the arterial supply plexus,

coeliac

we can

say that the

spleen receives nothing but pure, freshty-oxygenated blood in

great

quantities.

Indeed,

the

splenic

artery

is

remarkably

and we can easily account for the so-called “ague-cake” and the temporary enlargement that occurs during malarial and other fevers when we include large for the dimensions of the organ,

suprarenal overactivity and excessive vascular tension in the pathogenesis of these phenomena.

To

this

we cannot

ascribe,

however,

the

post-prandial

splenic enlargement, which attains its maximum about five hours after an ordinary meal, since we now know, how inde-

333

THE LIVER AND THE SPLENIC VEIN.

pendently of suprarenal overactivity and merely through nervous influence an organ’s function can be excited and governed;

and pneumogastric again unite here to a passive period and for an active period: that

sympathetic

indeed,

account for

of gradual enlargement. to be

of the spleen seems

due to a relaxation both of the arteries and of the mus-

cular tissue of the capsule

Foster

evidence that

:

arterioles to areas,

“The turgescence

we

and of the trabeculae” says Professor are again dealing with dilation of the

increase the influx of blood into the functional

—the physiological process we have found

in other organs.

That the organ is concerned with some process incident upon blood-changes is evident. But what is this process? The various points that

may

afford a clue are these:

red blood-

corpuscles have been found in various stages of disorganization in the organ, but in the interior of amoeboid cells buried in the

The spleen-pulp

also contains an albuminoid proteid and a pigment which shows considerable carbon. That an active combustion process may go on in the organ is suggested not only by the latter, but also by the presence of various purin bases ; xanthin, hypoxanthin, and their end-

pulp.

rich in iron,

produet, uric acid. succinic, lactic, etc.

Various other acids

—

—

acetic, butyric, formic,

are also found in relatively large quan-

This appears suggestive when we consider the large

tities.

quantity of oxidizing substance that must course through the

organ especially during post-prandial activity.

The

spleen also seems to be a leucocytogenic center, since

the splenic vein contains a

much

cytes than the splenic artery.

larger proportion of leuco-

But

as these leucocytes leave

the organ through the splenic vein, and ultimately, therefore,

reach the liver through the portal, they must either be connected with some function in the liver or be destroyed there. Again, the arterial blood has been found to lose one-half of its

red corpuscles; half

of

those

from the spleen contains onefound in the blood of the splenic arteries. at least, blood

Coupled with the finding of disorganized remnants of these bodies in the splenic pulp, this certainly suggests, as

is

erally believed, that red blood-disks are disintegrated arid

corpuscles created in the spleen.

poor in red disks.

gen-

white

Indeed, the portal blood

Yet, the hepatic vein

is still

is

poorer in them

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

334

in the sense that the proportion of red to white cells

is

as

four in the subhepatic vein is to one in the portal vein, after the blood has been submitted to the elfects of hepatic functions.

seems

It

clear,

therefore, that red corpuscles

are de-

stroyed both in the spleen and in the liver, and that, since the spleen

possessed of no external duct,

is

secretions that

we should

corpuscular elements.

find proofs

Indeed,

it is

in the liver’s

of this dissociation of

we have

in bilirubin,

a bile-

pigment derived from hiemoglobin, direct evidence of this fact. The Hepatic Blood-pigments We have already analyzed .

the second

(in

chapter)

—

the process through Avhich

We

blood-pigments are transformed one into another.

now only

refer, therefore, to the relations

various will

between these bodies

and the spleno-hepatic functions.

We

ascertained that the changes undergone in the liver

represented but a portion of a cycle of which the intestines were the starting-point, bilirubin (excepting that transformed

and stercorin) being reabsorbed from the intesand again used in the building up of ha?moglobin. Experimental evidence was adduced to show (Macallum) that in an animal fed on albuminate of iron free leucocytes crowded into urobilin

tine

with iron-pigment could be traced in transit through the in-

mucous membrane in the villi, and that similar leuhad cocytes been found in the spleen and in the liver. But can we conclude from this that the iron-laden leucocytes find their way to the spleen and that this organ constitutes a part testinal

of the cycle?

The anatomical

volved show that, even

if

relations of the structures in-

such an arrangement did

exist,

it

could serve no useful purpose, since the leucocytes would but penetrate the splenic structures to again enter the portal circulation. is

the

Obviously, the only pathway available anatomically

venous

one,

since

Macallum

found

the

‘fieucocytes

crowded with granules of iron-pigments” in the venules of the villi.

The

single venous channel

that of the distribution of the

mainly,

i.e.,

at our villi,

disposal, therefore,

is

the ileum and jejunum

the superior mesenteric veins,

—which

again lead

This probably means that the iron thus taken from the intestine is not ready for the circulation, and

us to the portal vein.

— 335

THE LIVER AND BLOOD PIGMENTS. that it

must undergo a secondary process

it

can serve

pliysiological

its

tion.

This

tions

of the

is

in the liver before

purpose in the arterial circula-

sustained by the prevailing view as to the funcspleen,

i.e.,

that

it

disintegrates

worn-out red

by the great increase of leucocytes observed in the splenic vein as compared to the proportion of these cells in the artery. It seems logical, therefore, to conclude corpuscles,

and

also

that both in the lymphatic structures of the intestine

and in those

formed which carry iron-pigments to from the intestine reach the latter by the superior mesenteric vein, and those from the spleen by the splenic vein. As Macallum observed iron-pigment leucocytes in the spleen similar to those witnessed in the intestinal villi, and the of the spleen leucocytes are

the portal vein; those

venules of the latter and the splenic vein ultimately transmitting their blood to the portal vein, no other conclusion seems possible.

The

similarity of the general

mechanism involved suggests

the presence of correlated functions. leucocytes are

formed in

situ,

Thus, in the spleen the

pass out into the pulp-channels,

and take up the iron-pigment and carry it out to the liver; in the follicle, the intestine they are formed in a similar structure,

—

—

pass out into the intestinal channel, take on a similar supply

blood-pigment, re-enter through the

of

system, and also proceed to the

liver.

villi

into

the

ascribed bactericidal properties to the leucocytes produced intestinal follicles;

which

is

shown by

their ability to take

the pigments, serves but to demonstrate that they

It

was

least

also

by the

but the chemotaetic property of the leuco-

cytes, the existence of

endowed at

venous

True, I have previously

must

up

also be

with phagocytic attributes.

shown, in the earlier editions of this work, that,

while the adrenals supply an o.xidizing substance to the blood, insufficiency of the

pound inferior

to

adrenals leads to the formation of a com-

haemoglobin in oxygen-absorbing powers,

methacmoglobin ; and, furthermore, that haematoporphyrin formed when the suprarenal insufficiency is still further ad-

i.e.,

is

vanced, hae,moglobin being unable to hold itself together, as it were, and to absorb oxygen. Again, we saw that haemoglobin

reduced to haematin when the reaction with the reducing agent occurs in the presence of oxj'gen. In tlie absence of oxj^gen

is

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

336 a

hiemochromogen

is

formed which slowly

loses its

the

iron,

end-product being also hiematoporphyrin.

hemoglobin mole-

It is evident that the integrity of the

cule

dependent upon the quantity of secretion that the ad-

is

and

renals supply to the blood,

molecule at a given time.

may

also

upon the condition of that

In other words, while the adrenals

be supplying their normal proportion of secretion, the

hemoglobin molecule in the red corpuscles of venous blood blood about to return to the vena cava for

i.e.,

pty—may

a

fresh sup-

be compared to that of blood during insufficiency.

Even as hemoglobin, the blood-pigment is when approaching the end of its systemic

loosely combined; circle,

nearer the state of disintegration

—according

the oxidation processes which

has subserved.

it

is

it

still

to the activity of

Starting fro.m

it returns promptly to the heart as hemoglobin or reduced hemoglobin, ready to absorb at once

the lungs as oxyhemoglobin,

another supply of suprarenal secretion and, once in the lungs, take

up

its

oxygen.

Blood from the head, extremities, and other structures which the drain upon ^its resources has not been excessive

re-

turns such a molecule to the heart;

an

oxygen-carrier.

But not

so

it

is

efficient

As

is

pancreas, and spleen

—

is

known,

well

the blood from the organs of the alimentary tract

intestine,

as

with the hlood from any organ

directly connected with the digestive system. all

still

in

—stomach,

not returned to the heart

has been submitted to whatever action the liver may have upon it; then only can it re-enter the circulation through the hepatic veins, which carry the blood to the vena cava. But before

it

thus be rejuvenated; some has gone beyond ; it has, indeed, almost readied the state of ha?matoporphyrin, the last on the list of pigments, that which appears in the e have seen most advanced stages of suprarenal insufficiency.

not

all

the blood

may

that luematoporphyrin and bilirubin are similar ; and, as known, it is bilirubin which passes out with the bile.

A

salient feature of the hiemoglobin molecule

here, however,

namely; the

iron.

As

is

is

well

missing

stated, a reducing agent,

luemoglobin in if used in the presence of oxygen, will reduce the absence of oxygen; the primary' product is a lucmochromogen which gradually parts with its iron, leaving as end-

337

THE LIVER AND BLOOD PIGMENTS.

As

product hcEmatoporphyrin.

bilirubin

and liannatoporphyrin

are fundamentally identical, the presence of the former in the bile

such

is

first

of

the case

which

That

result of a similar process in the liver.

must be the

is

sustained by considerable collateral evidence, the invulnerability of the hannoglobin mole-

is

cule.

Paradoxical as this statement appears,

it

nevertheless con-

stitutes the key-stone of the entire edifice, since

it is

when

only

vulnerable that the molecule becomes the prey of disintegrating influences.

have used the words “reducing agents” several

I

times; but the haemoglobin molecule does not yield to even

moderately-strong

powerful it:

agent

reagents

—

of

nature ;

this

sulphuric acid,

for

only

indeed,

—

instance

a

dissociate

^will

an exemplification of the wonderful binding power which

the suprarenal parts.

secretion

must

exert

we must not overlook

Still,

substance in the blood-plasma

is

all

its

constituent

the fact that the oxidizing

identical to this binding

Indeed, I have accumulated so

pound.

upon

the fact that the plasma per se

much testimony

com-

affirming

a potent source of energy,

is

while the red corpuscles always played so secondary a role in the various intrinsic functional mechanisms, especially those con-

cerned with muscular and glandular elements, that I have been led to conclude that the red disks are, after

the blood-plasma

pack-mules, as

it

:

all,

but servants of

were, from which

draw, as needed, enough oxidizing substance to maintain

it

can

its

own

functional potentiality as previously stated.

Under

we can

see how the haemoglobin molecule, gradually deprived of its binding oxidizing substance during the inordinate metabolism which the tis-

these

circumstances

sues of the digestive organs activity,

It is

readily

undergo during their periods of

should yield more readily to dissociating influences.

evident that a molecule so weakened, thrust in blood

such as that of the portal vein, physiological

waste-products

—a

and

vast

sewer replete with

deoxidized

blood-cells,

all

bathing in a plasma itself despoiled of its oxidizing substance, should soon become dissociated. Transported through gradually narrowing channels, the walls of which, like all tissues, eagerly absorb any loose oxygen that it may contain, it must

mevitably undergo the transformation of haemoglobin referred

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

338 to,

drops

leaving as end-product bilirubin.

its iron,

We or

the primary haemocliromogen, which soon

into

i.e.,

have here the identical process that occurs in the brain

other

when

structures

haimatoidin

preparatory

from

originate

“The

absorption.

haemoglobin,”

disorganized

are

blood-clots

to

Professor

says

into

bile-pigments

Howell

“this

;

origin was first indicated by the fact that in old blood-clots

or in extravasations there was found a crystalline product, the

which was undoubtedly derived from haemoglobin, and \vhich, upon more careful examination, was proved to be identical with bilirubin. This origin, which has so-called

fiiaematoidin,’

since been

upon

as

made

probable by other reactions,

That the infiuence

adopted.”

solid a foundation

of Boinet,

is

who found the blood

is

now

universally

of the suprarenal secretion rests illustrated

of a large

by the experiments

number

from

of rats

which he had removed the adrenals replete with “liasmatoidin.” To trace the itinerary of the two products, iron and bilirubin,

through the

liver,

naturally

brings

the

hepatic

cell

within the scope of our inquiry, since we have to account for the transfer of the former to the bile and the return of the iron to the general circulation.

The

importance

functional

molecule

is

generally

separated from

it,

recognized.

of

iron

Yet,

are not unable to take

we have ample evidence

in the

the

hiemoglobin

pigments,

up oxygen.

when

Indeed,

of this in the formulae of the very

products of which bilirubin is the primary compound. Thus, while bilirubin is CigHigNjOa, biliverdin is CiaH,gN204, and the latter can readily be prepared artificially from the former

supposed that, when the blood-corpuscles go to pieces in the circulation,” says Howell, “the haemoglobin of the is brought to the liver, and then, under the influence

by oxidation.

“It

is

converted into an iron-free compound: bilirubin It is very significant to find that the iron sepaor biliverdin. rated by this means from the haimoglobin is, for the .most part, retained in the liver, a small portion only being secreted in the liver-cells,

.

bile.

It

is

seems probable that the iron held back in the

again used in some

way

topoietic organs.”

We

fluence ofihe

to

make new Immoglohm

have seen that

liver-cells, as

now

it

is

believed, that

liver is

in the luema-

not uniter the in-

hwmoglobin

is

dis-

— 339

THE LIVER AND BLOOD PIGMENTS.

an important feature, since it removes the main element of confusion from our path. Indeed, we can now easil}" sociated:

account for the retention of the greater part of bilirubin in the liver, since

we have

at our disposal all the constituents for the

synthetic production within the portal capillaries of the hepatic

new lupmoglobin, and

lobule of

particularly oxidizing substance,

brought there by the terminals of the hepatic artery.

On

examining, on page 329, the illustration from Piersol’s

work, the distribution of the hepatic artery’s terminal arterioles or capillaries will be found to be unusual.

margin

the

vein breaks

of the lobule

up

into the capillary net-work of the lobule

may

hepatic arteriole

The

inference

from the

Immediately above where the portal or interlobular

i.e.,

is

obvious.

coeliac axis,

—the

be seen to open into the portal capillary.

The hepatic artery coming

brings freshly oxidized blood,

—which, mixing

—

directly

i.e.,

oxidiz-

narrow channels of the lobule with the portal blood, at once groups bilirubin and iron, and builds up all the hwmoglobin that the constituents ing substance,

freely in the

present (including what iron the splenic leucocytes

from the

intestinal follicles have brought)

and those

What

allow.

bili-

rubin cannot, owing to deficiency of either of the other constituents, be utilized, becomes an excretory product; and with many others

it

and

enters the hepatic cell

That

passed out with the bile. (adrenoxidase) can

is

deficiency of oxidizing substance

increase the excretion of bilirubin has been repeatedly herein.

I

may

refer,

for

example, to the

shown

many forms

of

acute poisoning and to the diseases attended with suprarenal insufficiency in

which there

is

increased excretion, either in the

urine or faices, of hiematoporphyrin, methiemoglobin, urobilin, stercobilin, etc. I

:

i.e.,

of

some derivative

have referred to the hepatic

This comparison, due to Berdal, Schafer^’ noted the existence,

is

of hiemoglobin.

a miniature sponge.

cell as

especially warranted, since

within this

cell,

of

canaliculi

which are in direct co.mmunication with the blood-capillaries. Having injected carmine gelatin into the portal vein, the colored substance

filled

this

vessel

and

"

Schater;

Journal of Physiology, Jan. 22

31,

subdivisions,

its

the canaliculi, but no other structure.

It

1902.

besides

may, therefore, be

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

340

inferred, says Professor Schafer, “that the injection has passed directly from the blood-vessels into the liver-cells; indeed, here

and there one can see what appear to be such direct commuThese can readily be seen in the annexed illustra-

nications.”

He

tion.

on

refers to the conclusion reached by Browicz,-** based

normal and pathological, “that there must

appearances,

exist a net-work of nutritive canals within the hepatic cells which are in direct communication with lobular capillaries”; this he had not as yet, however, verified by injections.

Schafer’s observation probably accounts for the direct transfer of the bilirubin to the biliary capillaries, along with other

Liver of Rabbit Injected from the Portal Vein. The Injection has Passed into Canaliculi within the Livercells.

(A’.

A

.

Hchafer .)

products of oxidation, to which we will refer later on. J.

W. and E. H.

Fraser"*® are also stated to

Indeed,

have found intra-

communicating with the blood-vessels in the For the present it seems logical to conclude that one or more of the canaliculi may lead to the vacuole previously referred to as nearest the bile-capillaries, and that That even it is in this vacuole that bilirubin joins the bile.

cellular passages

hepatic cells of frogs.

this

vacuole Browicz: J.

W. and

p. 240, 1895.

is

supplied with a canaliculus

we have already

Bulletin de I’Acadfimle des Sciences de Cracovie, 1899. B. H. Fraser; Journal of Anatomy and Physiology, vol.

xxlx,.

A

THE LIVER seen; Kupffer found

341

IN ITS RELATIONS TO BACTERIA.

afford a direct channel between this

it to

and the bile-capillaries per se. The Hepatic Tissues in their Relations prominent feature of the work so far done

to

Bacteria

is

the

furnished that several physiological processes

now

bile-reservoir

the hepatic

cell

and

—

evidence

ascribed to

and that the

in no lyay involve this stnicture,

portal vein itself

.

the intercellular^^ capillaries are the seat

of several of these processes.

must be the connection between bacteria and the normal liver. proceeding

Before

made

to

however,

further,

reference

emphasize “normal” here, because I can thus simultaneous!}^ lay stress upon a feature which plays a predominating role in I

disease:

t.e.,

the fact that anatomically, as far as bacteria go,

no direct normal connection between the digestive The liver, in fact, is essentially a system and this organ. physiological organ in the sense that it is mainly intended to there

is

rid the system of waste-products

may

again

and

to

economize others that

by preparing them for reabsorption

prove useful,

in the intestine.

We

have seen that the venules of the

pigment leucocytes

to enter the mesenteric

A

their blood to the portal.

digestive structures

instance

—can

—such

allow

villi

veins which carry

depraved condition of

as that

iron-

all

the

induced by alcoholism, for

so lower the functional activity of these struct-

ures as to cause these venules to lose their normal turgescence

and afford passage to bacteria, alcohol in large doses being known to impair metabolism. The intestinal venules under

weakened protective

these circumstances, surrounded by ures, can well

instance, or

conditions to

struct-

give passage to Adami’s cirrhosis bacillus, for

any other capable of coping with what prophylactic

may

still

prevail.

Labadie-Lagrave.

“One

connections of this kind

of is

“The

portal vein can transport

from the

the liver morbid germs

the

best

intestinal

surface,”

established

the influence exerted

says

pathogenic

upon the

de-

velopment of hepatitis by dysentery; although this relationship is not constant, all observers have noted it. Phlebitis

GO

necessary to give the terminals of the portal this name in order they contain blood from both the portal and hepatic chanform part of both as extensions. S.

to avoid confusion; nels, and in reality

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

342

from an ulcerated area and directed toward an hepatic focus has also been observed. When the primary portal strucstarting

tures are normal, transmission of the putrid material

through the lymphatics.

While

may

occur

this fact seems admissible, it

has not been verified.”

Again, pathological conditions of the stomach, pancreas, or spleen may supply the portal vein with

In the normal subject, however, the liverper tissues se are totally isolated anatomically from any of the

pathogenic elements. structures that

come into contact with exogenous

cisely as they are in other organs:

That

bacteria, pre-

the muscles, the heart, etc.

blood-stream affords protection from disease

its

is

un-

doubted, however, judging from the leucocytes that are con-

and the perivascular lymphatic is also an important field for of toxalbumins and their reduction to harmless

entering the

stantly

That the

channels.

the splitting

bodies itself

we is

organ,

portal vein

shall also see.

But

it

seems quite clear that the liver

not primarily a germ-killing organ, and that are

cell still

further from the functions

suggests

that

vessels

may

essentially

the

oxidizing

to

now

substance

be the main source of the

This brings us

its

at-

This removes the hepatic

chemical.

tributes

attributed to

in

liver’s

the

lobular

it,

and

blood-

functional activity.

the consideration of the functions in

which the oxidizing substance in the blood-plasma acts as a We have already reviewed, in this connection, the reagent. synthesis of haimoglobin; we will now take up and consider two equally important subjects i.e., the origin of urea and the :

conversion of sugar into glycogen.

—

Urea and its Formation. We will first analyze an experiment by Schroder®^ in which the liver was taken from a freshlykilled dog and irrigated through its blood-vessels by a supply Howell refers to this of blood taken from another animal. “If the supply of blood e.xperiment in the following words: was taken from a fasting animal, then circulating it through the isolated liver was not accompanied by any increase in the amount of urea contained in it. If, on the contrary, the blood was obtained from a well-fed dog, the amount of urea con-

Schroder; 1886.

Archlv

flir

exper. Pathol,

und Pharm., Bd. xv and

xlx, 1882

and

UREA AND tained in

it

ITS

343

FORMATION.

was distinctly increased by

jiassing

throngh

it

the liver, thus indicating that the blood of an animal after diffestion contains so,mething that the liver can convert to

urea.”

Considered from

my

During

other meaning.

standpoint, this experiment has an-

digestion, especially after copious feed-

organism

ing, as stated above, the entire

to a certain degree,

is,

involved in the digestive process, as shown by the general sensation of heat often experienced

and spleen, even after

pancreas,

intestines,

has passed, are

all

contains either in

its

In other words,

ing dog’s blood

is

—

corpuscles or in

its

serum a more or

less

Conversely, the

fast-,

especially if the fasting has been prolonged

unusually low, since suprarenal activity

We

that of the rest of the tissues. these their

liver,

digestion

abnormal blood, in which the oxidizing substance

really

is

As

at such times the blood

marked increase of oxidizing substance.

—

gastric

operating together, the suprarenal activity

doubtless enhanced.

is

after such a meal.

conditions,

the tissues

have

depressed with

is

also seen that,

under

continue to

absorb

nevertheless

normal supply of oxygen, the blood being thus actively It seems clear, there-

depleted while insufficiently oxygenated. fore, that the blood of the well-fed

dog contained more oxidiz-

ing substance than that of the fasting one.

That the injected blood taken from the well-fed animal should have been the source of the urea-forming substance Since

unlikely.

products,

it is

substances

the

liver

alone

receives

alimentary

is

waste-

only with blood from the portal vein that such

could have been obtained.

The urea-forming agent must, excised liver’s portal channels,

This

is

not specified.

therefore, have been in the and the only available agency

capable of inducing the reactions involved appears to be the oxidizing substance. Experimental evidence may be adduced

show that such is the case. I consider the blood of the hepatic artery, as previously stated, as the source of supply of the oxidizing substance, since it is directly derived from the to

coeliac

Stewart states that, “although the portal vein much greater supply of blood than the hepatic artery,

axis.

carries a

ligation of the latter causes a greater diminution in the ratio of the amount of urea to the total nitrogen in the urine than

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

344

ligation of the former.

This seems to indicate that oxidation plays an important part in the formation of urea in the liver

(Doyon and Diifourt).” That the substances thus oxidized reach the liver by the portal vein needs hardly to be emphasized. But Foster says: “The introduction of even a small quantity of proteid material into the-

urine,

and

alimentary canal at once increases the urea in the

in the curve of the discharge of urea in the twent}'-

four hours each meal

is

We

to tliink that the proteids of a

have seen reason

followed

a conspicuous rise.

meal are

absorbed not by the lacteals, but by the portal blood-vessels, and such bodies as leucin probably take the same course. This being so, all these bodies pass through the liver and are subjected

to

may

such influences as

be exerted by the hepatic

cells.”

—one

Such bodies of leucin enous dissociation sel

has

main products of nitrognaturally follow the same course. Drech-

—

suggested that

tyrosin, glycocoll, etc.

all

—

first

of the

bodies

of

this

—

i.e.,

leucin,

undergo oxidation in the

tissues,

class

and that their ammonia and carbonic acid then combine synthetically, forming ammonium carbamate, this, in turn, being carried to the liver and there transformed into urea. It is clear that these

outlined by Foster: veins,

and

i.e.,

ammonia compounds

the venules of the

finally the portal vein.

villi,

take the course the mesenteric

That they undergo oxida-

tion in the blood of these vessels, however,

is

not

likely,

for

they contain probably the most watery blood of the organism,

and that most depleted of Quite anotlier the hepatic lobule

field is

its

oxygen.

when ammonia compounds

of activity is afforded, however,

reached

;

here

the

meet the oxidizing substance brought by the hepatic capillaries.

Taking the

ammonium compound

artery’s

referred to by

Drechsel, for example, the series of reactions outlined by

seem

to follow in normal sequence:

1.

him

In the portal vein:

hydrol 3dic cleavage with the formation of amido-bodies, such as 2. In the hepaticleucin, tyrosin, aspartic acid, glj’cocoll, etc. lobule

capillaries

and

their

oxidizing

substance:

oxidation,

with the formation of ammonia, carbonic acid, and water,

lowed by the synthetic union of ammonia and carbonic

fol-

acid.

—

—

UREA AND

ITS

345

FORMATION.

forming the carbamate of ammonium. urea

;

This being dehydrated,

formed, as shown in the following equation

is

NIL

CO< ONH^ — ILO = CO < That the conversion

ammonia compounds

of

into urea does

by experimental physiology. the experiments of Schroder, in which this

the

occur in

NH,

liver

is

sustained

Howell refers to demonstrated as follows:

“As further proof

is

forming power of the

liver,

Schroder found that

the urea-

of if

ammonium

carbonate was added to the blood circulating through the liver

—

to that

animal

—

from the fasting

It follows,

from the

last

from the well-nourished

experiment, that the liver-cells are

convert carbonate of

able to

actions

as well as

a very decided increase in the urea always followed.

may

ammonium

be expressed by the equation

The

into urea.

re-

:

(NH J 2CO3 — 2H3O = COM,.” The foregoing

facts,

considered collectively, indicate that

the formation of urea in the liver is probably accomplished in

the following manner, taking Drechsel’s series of reactions as

standard of the numerous ones of the same class that must occur in this organ

:

Granting that the nitrogenous bodies are absorbed by the A'enules of the

and transmitted by the mesenwhich would the hepatic lobules, the first reaction would

intestinal villi

teric veins to the portal vein, the ramifications of

then carry them to

occur in the prelobular portal vessels:

i.e,,

the nitrogenous bodies

would undergo hydrolysis, with the formation of amides, leucin, aspartic acid, tyrosin, etc. The second reaction would follow as

soon

owing

as

these

bodies

reached

the

pericellular

capillaries,

to the presence therein of the oxidizing substance sup-

by the terminal branches of the hepatic artery; in other words, further reduction of these bodies by. oxidation to aininonia, carbonic acid, and loater would occur in the pericellular capilplied

laries of the first,

lobule.

The

third reaction would seem, like the

to require comparatively inert suiToundings

not charged with oxidizing substance as cellular capillaries.

is

:

i.e.,

a fluid

the blood of the peri-

Such a medium we have, in

all likelihood.

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

346

in the aHerent venous

channels, since

it is very improbable that any oxidizing substance, so precious in all physiological functions as I have now shown should be wasted in vessels

—

—

ultimately ending, via the hepatic veins, in the inferior vena

Hence, whether

cava.

it

involved a preliminary formation of

an ammonic carbamate or proceed

to

immediate synthesis,

it

appears as

if the terminal reaction ending in the formation of urea occurred in the efferent venous hepatic channels.

The

salient point of this

of reactions

series

the fact

is

that, contrary to the general belief, they all occur, not in the

hepatic

The

cells, hxit

in the bloodstream of the lobular capillaries.

following facts show this to be the case:

formed in transit through the

if

urea

it

should appear as soon

is

It

or at least soon after,

as,

is

clear that,

vessels of the organ, its

We

agencies are introduced in the portal system.

causative

will recall

from Professor Foster’s text, in which he says: “The introduction of even a small quantity of proteid matethe quotation

rial

into the alimentary canal at once increases the urea in

the urine, and in the curve of the discharge of urea in the

twenty-four hours each meal etc.”

When we

is

followed by a conspicuous

consider that the

entire

circulatory

rise,

circuit

occupies but twenty-six seconds, the cause of the rapid appear-

ance of urea

When

—heretofore

unexplained

—^becomes

apparent.

the role of the oxidizing substance in the produc-

tion of uric acid

from the alloxuric bases was analyzed in the

third chapter, uric acid was considered as the end-product of

a series of reactions in which, according to modern views, these toxic nuclein derivatives were converted into benign ones. All

nitrogenous products being transferred to the portal system, it now seems clear that normally the reaction must occur iu the intercellular capillaries of the hepatic lobules, and that is

when

this oxidation process in the liver is inadequate that

the so-called “uric-acid diathesis” acid

it

leaves

evident that

the

we

organism,

symptoms

occur.

As

as does urea, by the urine,

uric it

is

are again dealing with a function totally dis-

connected from the hepatic

cell

per

se.

Again, we have re-

peatedly seen, in the preceding chapters, that the elimination of phosphoric acid was increased by the administration of suprarenal, pituitary, and other organic extracts and by various

glycogen and

its

347

formation.

by the kidneys due to drugs always coincides with suprarenal overactivity, hence with enhanced oxidation. It thus becomes apparent that many

As we have

drugs.

seen, increased excretion

and abnormal,

constituents of the urine, normal

which

is

the origin of

obscure, are connected with variations in the oxidation

processes in the intercellular capillaries of the liver, caused by

corresponding

fluctuations

the

in

functional

activity

of

the

adrenals.

Glycogen and

its

Formation.

—Glycogen

obviously removes

our inquiry from the arteriole to the hepatic

organ

is

that in which

it

sight of the important fact that

the analysis, version

—

into

since this

two processes are involved in

(1) the formation of the glycogen and (2) its condextrose, and that the latter reactions must

—

occur in the vascular channels. sc

cell,

accumulates; but we must not lose

Again, the

bound up with the formation of the

first

process seems

bile that it

becomes

necessary to consider this subject simultaneously to avoid repetition.

The

sponge-like construction of the hepatic cell due to its

vacuoles, the

delicate

perilobular

room

bile-capillaries,

W. and E. H.

described by J.

canals

and Schafer, and, vacuole, or vesicle, leading through Fraser, Bro-wicz,

does

finally, its

not

own

the bile-collecting canaliculi to the

appear

to

afford

much

for protoplasm capable of undergoing functional metabo-

lism, since this

separating

all

would have to be embodied in the partitions these

cavities.

Yet,

ivere

—often duplicated, particularly almost one-third in that of the —^would represent a

nucleus

size

entire cell,

nucleoli

dent, judging

useless

which, as

otherwise,

the

and containing

structure.

by the appearance of the

fore, that the nucleus,

it

in herbivorous animals,

cell as a

we have

It

seems

evi-

whole, .there-

surrounded by a thin limiting layer of protoplasm, must impart its energy to this layer. This, in turn, being the central terminal of all seen, is

the partitions, which, along with the cell’s own pseudocovering, are protoplasmic, the vacuoles become receptacles, as it were, of the products of their walls.

Again, when we behold the minute canals so clearlj' shown Schafer’s illustration (shown on page 340) a direct communication with parts e.xternal to the cell is evident in several

m

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

o48

and

it seems clear that, if his carmine gelatin could through these, so could an equally viscid substance, penetrate

places,

and with

As “no

greater ease, the blood-plasma.

still

injection

in the intercellular bile-canaliculi nor in the perivascular lym-

phatics nor between the cells” could be detected, the penetrathe gelatin can hardly be ascribed

tion of

to undue stress. “no diffusion of carmine nor any staining or nuclei by carmine,” the nucleo-mural net-work to

“There being,” of the cells

also,

must be an independent structure, circumscribthe canals and the vacuoles. The canals communicating with the exterior of the cell, they are probwhich

I

refer

ing two kinds of cavities

:

ably the receiving cavities, while the vacuoles, their neighbors, are the spaces in which the useful products of metabolism are

The

accumulated.

reached, would thus pour their excretory conand its various constituents into this cavity, and in turn, would convey them to the intercellular bile-capilvesicle is

fer’s

tents

canals themselves, -continuing until Kupf-

—

this,

laries

—

bile

through

its

own

canals.

W'hether so direct a connection between the intercellular

and the bile-channels through the cell exists is a be determined. Bile and the various bodies excreted

capillaries

point to

would be voided as are the intestinal contents, the canalicular walls taking up certain elements, while physiological substances would be mixed with the substances in transit

with

it

for definite purposes.

The

question that suggests itself

first

Is glycogen

formed

is

the following:

during the active functional activitj' of the

(during digestion) or during its passive state (between meals) ? We have seen that the production of urea is increased immediately after a meal ; we have evidence, therefore, that an liver

active

state

based

upon increased oxidation

processes

.must

and that it of which glycogen

is

during digestion that the substances out

is

formed reach the

oxidizing substance

is

prevail,

liver,

i.e.,

while the

This suggests take part in the forma-

present in the capillaries.

that the oxidizing substance

must

itself

tion of glycogen, though perhaps indirectly, and also in the elaboration of

bile.

coloring constituent of bile, bilirujjin, I have previously considered as the product of a reaction in the inter-

The main

GLYCOGEN AND

As such

cellular capillaries.

349

FORMATION.

ITS

probably eliminated with the

it. is

high oxygen constituent places it beyond the limits of further oxidation. Yet we have in another merely because

bile

component of

bile,

occurs

process

its

evidence

biliverdin,

during the passage of

some oxidizing bilirubin through the that

—

under certain circumstances, perhaps when more oxidizing substance is present, for Howell says “Biliverdin is supposed to stand to bilirubin in the relation of an oxidation cell,

—

Bilirubin

product.

is

:

given

CioHigNoOg, and

formula,

the

biliverdin, CioHigNaO^, the latter being prepared readily from pure specimens of the former by oxidation.”

With

this

evidence that oxidation does play

of the processes involved, it will facilitate

main

review the mutual relations of

my

role

task to briefly

By

biliary constituents.

made up

far the larger proportion of these is

some

of the bile acids,

—

namely: the sodium salts of cholic acid, i.e., glycocholic and These are obtained from cholic acid derived taurocholic acid. Now, Tappeiner"’" found iiself from sugars and fats (Voit). that cholic acid yielded fatty

on oxidation, and, since

acids

taurocholic and glycocholic acids are fatty acids, this suggests

that they become such during their passage through the hepatic cells

and

as the result of

The become of

various

when

clear

the intrinsic

portal vein

an oxidation process.

phases of the process in the hepatic the oxidizing substance

factors

included as one

is

The blood-plasma

involved.

cells

contributes the sugars and fats

of the

(along with the

waste-products to be excreted), ‘while the hepatic artery sup-

plasma containing the oxidizing substance.

plies

active

All

three

agents meeting in the canaliculi, a part of the sugar

(according to the proportion of oxidizing substance present)

and

all

the fat (if the proportion of oxidizing substance

abnormally reduced by suprarenal insufficiency) into

cholic

(probably

acid.

But, as the blood

collagen-cartilage,

gelatin-waste),

glycocholic

mucin,

acid

is

also

contains

connective

formed.

is

not

are oxidized glycocoll

tissue,

and

Again, since the

blood likewise contains taurin (probably muscle and pulmonarytissue waste), taurocholic acid is formed.

oxidizing substance “Tappeiner:

Just the amount of

necessary being supplied

Zeitschrlft fur Blologie,

Bd.

xll,

S.

60,

by the hepatic 1876.

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

860

artery to each lobule, to properly regulate the functions involved, only the required sugar is burnt by the oxidizing substance. The rest, under the influence of the nuclei of the hepatic cells and the mural protoplasm of the latter, is converted into glycogen and collected in the adjoining alveoli.

But we must

also account for the elimination of the

waste-products that are found in

connected

with

these

fatty

acids

An

bile. is

m an y

interesting feature

that they

combine

can

synthetically with other bodies, even with proteids, while they

are simultaneously able to emulsify the

more insoluble soaps and other fatty acids and thus insure their elimination. Again, cholesterin, mainly derived from the white matter of the cerebro-spinal axis and nerves

(Flint), in which it occurs in abundance (Foster), was formerly considered as a fatty substance capable of undergoing saponiflcation, but it is now classed

among

the only alcohol that occurs in the

alcohols:

organism in a free

This body

state.

solutions of the biliary acids also, but

it is

connection

not only soluble in comhines with acids,

The importance

including glycocholic acid.

when

is it

of this fact appears

recalled that insufficiency of glycocholic acid in this

—and

main source

perhaps, of oxidizing substance

also,

The

of gall-stones.

constituent of bile,

present to take

it

when

up,

there

it is

is

—

is

the

cholesterin being a constant

not enough glycocholic acid

precipitated in the gall-bladder and

calculi of which it is the main component.Another body derived from nervous structures, but which, like cholesterin, is to be found in other fluids, especially bloodserum, is lecithin. This body, besides others not mentioned,

there forms the

only occurs, however, in very limited proportions. It

is

now

evident that glycocholic acid

acid should be looked

that

the}'^

upon

as functional

and taurocholic

acids, in tbe

sense

are not only vehicles for waste-products ‘of metabo-

lism, but are also capable of submitting

them

to

dissociating

reactions under the influence of the oxidizing substance.

They

are sources of energy precisely as myosinogen appears to be a

source of energ}% and capable of becoming factors of combustion

They to

phenomena when

in

contact

with

the latter substance.

are also truly physiological in the sense that they serve

recover or economize those

products which can

again be

GLYCOGEN AND

ITS

o51

FORMATION.

used by the organism. Indeed, they (or at least a part of their decomposition products) are again absorbed by the intestinal mucous membrane, and, passing through the venous channels, probably take up therein and transfer to the hepatic cells what waste-matter they are to carry to the intestinal tract.

We

thus have in the cellular canaliculi two acids endowed with powerful affinities and an active reagent, the oxidizing substance, to account for the processes of a chemical nature connected with the functions of the hepatic

Of

cell.

course, all this involves the necessity of showing, as a

controlling factor, that products of combustion are also present.

following lines by Professor Howell give this feature

The

“The secretion condue emphasis ; referring to bile, he says quantity variable, considerable, though tains also a of CO2 ga^, held in such loose combination that it can be extracted with a :

gas-pump without the addition of acid. The presence of this constituent serves as an indication of the extensive metabolic changes occurring in the liver-cells.”

Again, the element of nervous control implied when T referred to the oxidizing substance contributed artery

We

must be shown.

active nerve during functional activity of the

should likewise govern hepatic functions is

the case

Bernard, to his

greatest

almost

He

all

is

by the, hepatic

have seen that the vagus was the is

stomach; that

obvious.

it

That such

sustained by no less an authority than Claude

whom we owe achievements

sustained by

the discovery of glycogen

—and

all

—one

of

whose conceptions have been

the labor bestowed

upon them

since.

not only found that the vagus was the predominating nerve

in the liver, but that its section also suppressed its glycogenic

function.

The of

fate of glycogen, its conversion into sugar for the use

muscular and other

tissues,

may now

be

analyzed

with

greater facility.

My analysis of muscular functions led me to the deduction that the contractile elements contained a substance, myosinowhen brought into contact with the oxidizing substance of the plasma, became the source of the muscle’s work-

gen, which,

Ample evidence was afforded to show that we were dealing with an oxidation process, the intensity of which ing energy.

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

352

was commensurate with the amount of blood that the arterioles suiiplied to the contractile tubular elements. There seems to be considerable analogy between tliis process and that which prevails in the hepatic lobule. Howell alludes to this in the following Avords, which well recall the fact that we referred to glycogen as the main constituent of myosinogen “The history :

of glycogen

not complete without some reference to its occurrence in the muscles. Glycogen is, in fact, found in various places in the body, and is widely distributed throughout the animal kingdom. It occurs, for example, in leucocytes, in the is

placenta, in the rapidly-growing tissues of the embrj-o, and in

considerable abundance in the oyster and other mollusks. in our bodies

But and in those of the mammals generally the most

significant occurrence of glycogen, outside the liver,

is

in the

voluntary muscles, of which glycogen forms a normal constituent.”

The energ}'

is

similarity between muscular

and hepatic sources of

further emphasized when, in the following paragraph,

Howell says: “In accordance with the view given above of the

—namely:

general' value of glycogen

that

is

it

a temporary

may

reserve-supply of carbohydrate material that

be rapidly

converted into sugar and oxidized,^^ with the liberation of en-

—

ergy

it is

found that the supply of glycogen

is

greatly affected

by conditions calling for increased metabolism in the body, kluscular exercise will quickly exliaust the supply of muscle and liver glycogen provided it is

not renewed

bj^

new

food.

In a

starving animal glycogen will finally disappear, except perhaps in traces; but this disappearance wilt occur much sooner if the animal

is

made

has been shown also has been

made

more sugar

to

to use its muscles at the

by Morat and Dufourt

contract vigorously,

"from an artificial

it

same time.

that, if a

will

take

It

muscle

up much

supply of blood sent through

it

than a similar muscle which has been resting; on the other hand, it has been found that, if the nerve of one leg is cut so as to paralyze the muscles of that side of the body, the

amount

of glycogen will increase rapidly in these muscles as compared

“ The

Italics are

our own.

GLYCOGEN AND with those of

tlie

353

FORMATION.

ITS

other leg, that have been contracting

mean-

time and using up their glycogen.^’

These facts clearly indicate that oxidation processes are not in order here, since glycogen

is

a source of energy, intended,

therefore, for subsequent oxidation wherever

it

is

distributed.

“It was

Indeed, Professor. Foster remarks, in this connection:

formerly believed that this sugar underwent an immediate and

...

It was circulating in the blood. is sufficient for us at the present to admit that the sugar is made use of in some way or other.” Peferring to the physiodirect oxidation as

it

logical uses of glycogen,

he also says:

“The main purpose

of

the deposition of glycogen is to afford a store, either general or local, of carbohydrate material, which can be packed

without

much

trouble so long as

it

away

remains glycogen, but which

can be drawn upon as a source of soluble circulating sugar

whenever the needs of

this or that tissue

demand

it.”

That

the oxidizing substance has nothing to do with the process

is

clear.

The conversion as

of glycogen into sugar in the liver appears

a wasted function, the carbohydrates having been

split into dextrose or

Why

tem.

already

dextrose and levulose in the portal sys-

they do not merely pass on to the several tissues

But it soon becomes evident that, were it sugar would accumulate, then be excreted by the kidneys, and lost, since there can only be a fixed and limited seems

strange.

otherwise,

(0.1 or 0.2 per cent.)

given time.

So useful

amount

of sugar in the circulation at a

a substance

is,

therefore, stored, after

dehydration, in the hepatic cell as glycogen, and converted into sugar according to the needs of the organism.

Conversion of the liver glycogen into dextrose is generally ascribed to a special ferment, thought to originate in the liver, but the nature of which has remained undetennined.

The

experiment of Claude Bernard, upon which this view based,

is

mainly

the following, as related by Stewart “A rabbit, after a large carbohydrate meal of carrots, for instance is killed is

:

—

and

—

rapidly excised, cut into small pieces, and thrown into acidulated boiling water. After being boiled for a few minutes the. pieces of liver are ruhbed up in a mortar and again boiled in the same water. The opalescent aqueous extract its liver

is

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

Oo4 filtered

traces

—

from the coagulated proteids. No sugar, or only of it, is found in the extract, but another carbohydrate off

an isomer of starch, giving a port-wine color with

^glycogen,

iodine and capable of ready conversion into sugar by amylolytie

ferments

—

present in large amount.

is

Again, the

liver, after

the death of the animal, is

is left for a time in situ, or, if excised, kept at a temperature of 30° to 40° C. or for a longer period

at a lower temperature;

it

then treated exactly as before,

is

but no glycogen, or comparatively

from

it,

although sugar

ence plainly

is

little,

(dextrose)

is

now

can

The

abundant.

that after death the hepatic glycogen

verted into dextrose by some influence which

destroyed by boiling.

This influence

formed ferment or to the unformed ferments and at the

be obtained

may

inferis

con-

restrained or

is

be due to an un-

direct action of the liver-cells, for both

living

tissue-elements

destroyed

are

temperature of boiling water.”

Another explanation suggests

itself to

me

if,

instead of a

ferment of hepatic origin, we hypothetically use one of ex-

In the

ternal origin:

first

procedure immediate immersion in

boiling water destroyed the ferment which happened to be in

the blood-vessels, while, in the “second, the ferment was given

time to

act.

The

difference in the conclusions vouchsafed

is

no thought being given to the blood-vessels, the ferment could only be considered as of cellular origin. We simply this:

have seen how really

many

functions ascribed to the hepatic

cells

belonged to the intercellular blood-stream; this seems

an additional one. Admitting that we are dealing with a ferment of external origin, from which organ could we expect it to be derived? Can we attribute the process to ferments from the salivaiy

to be

glands or pancreas?

If it

is

produced only by digestive

fer-

amylolytie ferments poured out during digestion,

ments,

i.e.,

—why

does

glycosuria

process

when

the floor of the fourth ventricle

appear

irrespective

of is

any

digestive

punctured, as

shown by Claude Bernard ? He also found that conversion of glycogen into sugar was a continuous process, carried on to subserve the needs of the organism clusion

if

the liver

is

:

a perfectly logical con-

really a storehouse for this substance.

Again, the quantity of sugar in the blood, as

ive

have seen.

—

—

GLYCOGEN AND is

How

small, but constant.

ITS

:

355

FORMATION.

could

we account

for these feat-

ures of the problem with ferments transmitted digestive tract

thiough the

?

Finally, sugars thus produced

i.e.,

from amylolytic ferdo not seem to be

—

ments secreted by the digestive tract dextrose, the sugar produced by the supposed hepatic ferment. Thus, Professor Foster says: “In the case of the amylolytic saliva,

deed, of

other amylolytic animal

all

starch or glj'cogen

converted

is

is

fluids, the

dextrose.”

It is

is

and that

it

the intestinal

the sugar

dextrose, identical,

can at present be made out, with ordinary evident that a ferment other than the amy-

lopsin connected with the digestive process one,

sugar into which

Now,

maltose.

which appears in the liver after death as far at least as

and, in-

pancreatic juice, inte?:tinal juice,

ferment of

must reach the

tract,

the

liver etc.

villi,

must be the

active

by a channel other than Again,

it

must be very

nearly similar to the salivary and pancreatic amylolytic fer-

ments.

The

salivary glands are so remote anatomically that

they can hardly he considered;

we

are brought, therefore, to

the pancreas as the only organ which could act as source of a

ferment or diastase having for

its

main function

to

convert

glycogen into dextrin.

As shown by von Mehring, Minkowski, and de Dominicis, removal of the pancreas causes marked glycosuria, and this persists

whether the animal be given carbohydrates or not.

All the other

symptoms

of diabetes mellitus appear,

—namely

increased flow of urine, considerable urea, acetone, etc.

;

great

and hunger, emaciation, marked muscular weakness, followed by death in two to four weeks. Indeed, we are vividly reminded of the suprarenal glands, on ascertaining that graftthirst

ing of a piece of pancreas in the abdomen or sldn will arrest the glycosuria, and that, if a small portion of the organ is left, the

symptoms

will

are given as food

Again, whether carbohydrates

disappear.

or not, the glycogen

disappears from the from these experiments,” saj^s Howell, “that the pancreas produces a substance of some kind that is given off to the blood or lymph, and is either necessary for the normal consumption of sugar in the body or else, as is

liver.

“We may

believe,

held by some, normally restrains the output of sugar from the 23

—

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

356

and other

liver

sugar-iirodiicing

satisfactorily.”

tion

is

tissues

What

the body.

of

and how it acts has not yet been determined That we are dealing with an internal secre-

this material is

clear, and,

such being the

case, the secretion

probably

passes out into the blood by the pancreatic vein, which “opens into the splenic

and mesenteric

veins.”

As

these open, in turn,

in the portal vein, the pancreas would then supply a special ferment for the conversion of glycogen into a functional sugar.

If the foregoing sjTnptoms are closely scrutinized, becomes apparent that the functions of the pancreas

it

—

be shown in the next chapter

For the

generally believed.

soon

as will

—are far more important than

present, however,

we

is

will limit our

inquiry to the subject in point.

The

fact

notwithstanding the ingestion of carbo-

that,

hydrates, the glycogen will totally disappear from the liver easily accounted for.

A

prominent fimction of the pancreas

during intestinal digestion

is

to transform starches into malt-

to insure absorption of this sugar.

ose,

removed, therefore, intestinal

its

contents,

amylopsin

starches

is

When

the organ

no longer furnished

are not properly converted,

production of glycogen, therefore, ceases.

we can

that

so easily account for this

is

to the

the portal vein carries no maltose to the hepatic lobule.

that

is

and

The

The fact, however, phenomenon suggests

:

is the organ upon which all the preliminary with the formation of glycogen depend. connected functions

1.

The pancreas

2. Its amrjlopsin converts starches in the intestine to pre-

pare them for the elaboration of glycogen in the hepatic cell. 3. Its internal secretion, supplied to the portal system hy

way

of the splenic vein, converts glycogen into dextrose. That we are on the right path is suggested by a series of

experiments by Croftan,”^ in which the conversion of glyc-

ogen into sugar was obtained by means of injections of supra“Incomplete as these experiments are,” says renal extract: the author, “they reveal the fact that the injection of suprarenal extract can cause the excretion of dextrose provided the

quantity injected

w

Croftan:

is sufficiently

American Medicine, Jan.

large.

18, 1902

Why

in the case of

one

GLYCOGEN AND

357

FORMATION.

ITS

animal more must be given than in the case of another to produce approximately the same excretion is undecided and remains to be determined.” Dwelling upon the presence in the adrenals of a diastatic ferment, he states that “two possibilities

may

present themselves, viz.

:

the

either

suprarenals

manu-

facture a diastatic ferment or they retain the diastatic ferment that is formed elsewhere in the body (pancreas, salivary glands)

when it is The author

in the blood- or lymjih- stream.”

them

carried to

also refers to the investigations of F.

Blum,°® who,

“testing the effects of suprarenal extract empirically,” discov-

ered “glycosuria in 22 out of 25 animals that he operated on.”

My

manner

interpretation of the

reached their results

is,

in which these investigators

of course, not that of Croftan, since,

as I view the process, the oxidizing substance constitutes the

compound

active suprarenal agency as a

of suprarenal secretion

and oxygen.

We where.

are dealing with enhanced physiological activity some-

Indeed, Croftan says:

“In order that hyperglycosuria

amount of sugar normally poured into the blood must be increased, or the amount nonnally destroyed must be decreased.” That excessive activity was either probe produced the

cured by the injected

by overstimulation of the insufficiency, is shown by the

extract or

adrenals, both leading to total

brief history of one of the animals

:

“The second

rabbit died

in one hour and ten minutes; here some spasmodic symptoms,

involving chiefly the posterior extremities, preceded the coma.”

Eeferring to two rabbits, including the latter, the

first

having

died in two hours and forty minutes and to “all others to be

spoken of presently”

(six,

all

told), he says;

“Dextrose was

by its cupric-reducing powers and the phenylhydrazin test; in one of the dogs in addition by circum-

identified in the urine

and yeast fermentation. The substance excreted was undoubtedly dextrose. The amount excreted would be far polarization

too large to be explainalile by a

substance mentioned sible for

above

;

it

splitting of the jecorin-like

would

not,

moreover, be pos-

consideralile f|uantities of dextrose derived

from

this

source to appear in the urine for several days after the injec-

,

“F. Blum:

Deutsche Archiv

f.

hlin. Med., Oct. 31, 1901.

;

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

358 lion.”

Excessive stiiniilaiion hy a great increase of oxidizing the blood evidently occurred. As soon as the

substance in

extract was injected

individuality

it was carried to the lungs, and lost immediately therein by taking up oxygen.

its

It

could no longer, therefore, act as a diastase.

The

cjuestion

now

to decide is this

General stimulation

;

enhanced the production of an amylolytic ferment either by To which organ can we ascribe

the liver or by the pancreas. this function?

Since oxidation destroys sugar, a great excess

would burn sugar actively and produce the opposite of glycosuria i.e., excessive combustion and rapid disappearance of the liver glycogen through abnormal use of it in the other organs. But of oxidizing substance in the blood

on

all

here

sides

we

stance

:

have, as a result of a great increase of oxidizing

the

in

marked

blood,

without preliminary feeding, since this

As the oxidizing substance does not

by Croftan.

suli-

and that evidently fact is not mentioned

glycosuria,

cogen, that of the liver could not be converted by

it

affect gly-

into sugar

hence the excessive production of the latter can only be

ac-

counted for by an equally excessive j^roduetion of amylolytic ferment.

Claude Bernard showed that conversion of glj'cogen into sugar took place more rapidly when the blood was made to

Yet he attributed the it from pulp rubbed up and treated with glycerin, after the liver had been washed out so as to remove the vascular contents. But it traverse the liver with unusual speed.

formation of the ferment to the

liver,

having obtained

seems clear that injections by the portal vein will hardly deplete the liver of every particle of the ferment in its minute lobular pulp and a three

capillaries, while reduction of its substance to

days’ immersion in glycerin will dissolve

the latter.

When we

—even by — evident that

produced, Seegen,

consider

traces

it

is

of

how

all

that contained in

readily conversion can be

soluble

albumin,

upon the addition

glycerin solution the very small proportion that

mained imprisoned

in

some of the lobules

according to

of water to the

may

have

re-

will suffice for the

conversion of glycogen.

One

of Claude Bernard’s experiments seems to

me

to afford

proof that the amylolytic ferment reaches the liver through

—

—

FUNCTIONS OF THE LIVER, SPLEEN AND PANCREAS.

o59

he created a collateral circulation, and shifted the portal-blood stream into Ten or 12 grammes of sugar were the general circulation. then given to the animal, and sugar was soon found in the the portal vein.

By

ligating

tlie

vessel

latter

In a normal dog, on the other hand, 50 to 80 grammes had to be administered before this result was obtained (M. DuvaP®). The absence of sugar in the latter animal’s urine until a very large quantity of sugar had been ingested distinctly show's that conversion of its glycogen only occurred

uriue.

because

its

portal vein

was open; in the other dog urine,

converted gl3"cogen that passed into the intestinal starch

i.e.,

it

was not

but maltose,

which had been submitted to the action

of the pancreas’s intestinal ferment,

i.e.,

amylopsin.

we

If

now

couple the fact that conversion of liver-glycogen only oc-

curs

when

the portal vein

Claude Bernard’s ob-

free with

is

servation that increased speed of the portal blood through the liver causes the glycogen to

be converted more rapidly,

clear that the conversion process is not

ment, and that the pancreas

due

s^ipplies, as

to

it seems an hepatic fer-

an internal

secretion,

the ferment which converts glycogen into dextrose.

A ever.

perplexing feature of If,

as

we have

oxidizing substance,

why

all this

stated, is

of

Jaquet,

requires elucidation, how-

Armand Gautier”

which

an

blood-plasma contains

the sugar not oxidized on its

to the tissues of distribution?

investigations

the

demonstrated

way

refers to the

that

sugars

mixed with blood containing the oxidation ferment previously referred to, and which we found to be of suprarenal origin, did not become oxidized. He ascertained, however, that upon adding to the blood a small quantity of fine pulp of muscle, lung, or of any other organ, the oxygen

was absorbed.

This

obviously indicates that dextrose passes through the hlood with-

and it can only become oxidized after combining ivith bodies produced by the organs to which it is dis-

out being destroyed,

tributed.

—

General Functions of the Liver, Spleen, and Pancreas All the facts reviewed in this chapter suggest the following conclu.

sions as to the functions of the liver, spleen,

“ M. Duval: Loc, cit., p. 378. Armand Gautier: “La Chimle

de la Cellule Vivante,”

and pancreas

p. 98.

:

THE ADRENAL SYSTEM AND THE DIGESTIVE ORGANS.

3()0

1.

The hepatic

(adrenoxidase) that tribution

of

its

owing

artery,

to

oxidizing substance

the

plasma contains and the mode of

its

terminal

capillaries,

supplies

chemical energy which initiates and sustains hepatic lobule that require oxygen. 2.

The nervous supply

of the liver

is

dis-

exogenous

the

all reactions in the

composed,

first,

of

terminal subdivisions of the vagus, which enhance the activity of all its functions by causing dilation of the hepatic arterioles; and, second, of terminal subdivisions of the sympathetic,

which, by causing constriction of these arterioles, reduce the functional activity of the organ.

In the normal subject the liver from structures that come into contact 3.

is

anatomically isolated

luith bacteria,

and pro-

tected against their intrusion by the bactericidal products of the intestinal glands If.

The

mixture

and

follicles.

capillaries of the hepatic lobules,

therein

of

the

hepatic

artery’s

owing

to the

ad-

substance

oxidizing

(adrenoxidase) with the portal vein’s ivaste-ladcn blood, are the seat of several functions

now

ascribed to the hepatic

cell.

Blood-pigments and iron, derived from the intestine and spleen, simidtaneously penetrate the hepatic lobule, and com5.

bine with the adrenoxidase therein to form hccmoglobin.

v.ncombined pigment

is

The

eliminated with the bile as bilirubin.

end-product of three successive reactions, 6. viz., (1) nitrogenous bodies are reduced to amides in the afferent mesenteric and portal; (2) the amides are dissociated veins, into ammonia, carbonic acid, and water by the oxidizing sub-

Urea

is

the

—

stance (adrenoxidase) in the hepatic lobule; (3) urea

by synthesis in the efferent veins,

—

hepatic,

and vena

is

formed

cava.

The hepatic cell contains, besides its vacuoles and nuclei, numerous canaliculi (Schafer) and a vesicular vacuole which 7.

the opens into the hile-capinaries by a canaliculus (Kupffer); connected. canaliculi and the vesicular vacuole are probably 8.

and taurocholic acid arc functional acids, and, they dissociate and appropriate waste-products,

Glycocholic acid

inasmuch as into under the influence of the oxidizing substance, convert them

cells. excrementiiious products in the canaliculi of the hepatic and acids biliary the by 9. The waste-products so converted along themselves, constituting bile, arc transferred,

the latter

—

FUNCTIONS OF THE LIVER, SPLEEN AND PANCREAS. ivith other

products for which the latter

hilirubin, earthy salts, etc.,

—

may

361

serve as vehicle ,

to the vesicular vacuole of the cell

and eliminated by the canaliculus that opens into the

bile-

capillaries.

10.

The

biliary acids^, blood-pigments, iron,

or any of their components, that

may

ganism

are,

venules

and returned to the portal The sugars converted from

11.

entirely

and other bodies

prove useful to the or-

or in part, reabsorbed by the intestinal circulation.

intestinal foodstuffs in the

intestines are brought to the hepatic lobule with the portal blood,

and penetrate the dizing substance.

and with the oxiDuring the bile-forming reaction the sugars canaliculi with the latter

are dehydrated, and, probably with the assistance of the cellular

protoplasm, converted into glycogen. 12.

The

liver

glycogen

is

converted into dextrose by an

ferment supplied by the pancreas as an internal which enters the portal circulation by the splenic vein. 13. Dextrose is distributed to the organs in which it is

arnylolytic secretion,

used as a source of energy by the blood, and only becomes vulnerable to oxidation

when combined with products

lism furnished by those organs.

of metabo-

—

CHAPTEE

VIII.

THE INTERNAL SECRETIONS OF THE PANCREAS AND SPLEEN. Glycosuria and Overactivity of the Adrenal System. pancreas and spleen are considered together because

—The there

is

considerable evidence in favor of the view that they

are functionally associated; this question

and

and

it

is

to give the analysis of

relationship with the ferments furnished

its

by the pancreas to the portal blood due prominence that we

f:

V •

have, under other headings, considered the better-known functions of both organs.

To

sustain our belief that liver glycogen

dextrose by an

is

converted into

amylolytic ferment supplied by the pancreas

which penetrates the portal vein directly, i.e., by way of the splenic vein, we were fortunate in having at our disposal the experiments of Croftan, which showed that suprarenal over-

—

activity could so

augment the functional

activity of the fer-

i |

ment-producing organ as to induce a very great increase in

{

This feature requires further study,

t

will tend to elucidate other functions of the pancreas.

t

sugar eliminated.

the since

it

We

believe that

we

have conclusively

shown that

certain |

drugs and poisons increase the functional activity of the ad-

The uniformity

renal s.

of the

phenomena

traceable to these ^

glands under the influence of such agents seems to us to warrant the conclusion that,

if

we can demonstrate

t

that glycosuria

^

is j

also

subject to the latter,

its

fluctuations following those of

induced by them, a suprarenal overand direct connection between A^et we must bear in mind, in activity will have been shown. this connection, that all active drugs may have a primary the

suprarenal

activity

or

insufficiency

glycosuria

action upon tissues for which they possess a specific affinity before the suprarenal protective functions are fully awakened.

We

have seen that even

nic

is

wall

electrieal

stimulation of the splanch-

only followed by vermicular motions of the intestinal some time elapsed. But too much weight must

after (

362 )

363

GLYCOSURIA AND ADRENAL OVERACTIVITY.

not be given this feature, inasmuch as I have personally seen the typical symptoms of total suprarenal insufficiency occur

dog within twenty seconds after a fatal dose of hydrocyanide of potassium had been administered. Large quantities in a

of the less active drugs

which

for

potassium,

they

are

more

a

special

possess instance,

for

likely to

bromide

predilection,

such

than

reach the tissues

an

agent

While, therefore, .we cannot say that ex-

viously mentioned.

formation of sugar, when drugs are given,

cessive

pre-

that

as

of

is

due only

to overstimulation of the adrenals, we- can say that all drugs

can produce it when they stimulate suprarenal activity. Furthermore, if seems probable that some drugs not only do this, but they likewise, owing to their affinity for certain tissues, enhance the production of sugar by increasing the functional activity of the intimate structures of the organs concerned in its

—

production from ingested substances

different

organs

of

sets

stimulating two Such an agent we

^thus

simultaneously.

probably have in phloridzin.

In an able and exhaustive review of the subject of toxic glycosuria, F. Cartier,^ of Paris, says

phloridzin

is

...

true intoxication.

In

on glycosuria, and maintain to

it

man

“The symptomatology

:

very limited, seeing that

it

it is

even possible to bring

a long time, without giving rise

general disorders, provided a copious

We

sured.”

of

does not give rise to a

alimentation

is

in-

have evidence in the last sentence that the main

an excessive formation of sugar, and, more carbohydrates being required, it is to an excessive production

general result

is

we

of the converting agent that Still,

if

general

symptoms

suprarenal overactivity?

he says

“Yet

:

all

.must ascribe this phenomenon.

are absent,

authors

who have

if

tion

is

not overfed, rapidly wastes. insufficient,

grave

of

the

when

studied phloridzin unite

in saying that the animal experimented

and,

what becomes

Cartier answers this question

upon becomes

...

When

phenomena appear.

voracious,

alimenta-

Phloridzinic

glycosuria has been obtained in animals entirely deprived of

hydrocarbons; analogous

*

under

these

to those of diabetic

F. Cartier:

Th6se de Paris,

1891,

circumstances

general

s}'mptoms

coma have been observed.”

J INTERNAL SECRETIONS OE PANCREAS AND SPLEEN.

o()4

Osier-

states

that

Frerichs

recognized

three

groups

of

two of these are of special interest to us: (a) Those in which after exertion the patients were suddenly attacked with weakness, syncope, somnolence, and gradually deepencases;

ing unconsciousness, Cases

with

death

preliminary

occurring

gastric

few hours,

a

in.

disturbance,

such

as

(b)

nausea

and vomiting, or some local affection, as pharyngitis, phlegmon, or a pulmonary complication. In such cases the attack begins with headache, delirium, great distress, and dyspnoea, affecting both inspiration and expiration: a condition called by Kusamaul air-h unger. Cyanosis may or may not be present. If

it

is,

the pulse becomes rapid and weak and the patient

gradually sinks into coma, the attack lasting from one to

The need

days.

viously points

to

of

a

supply

copious

increased

of

carbohydrates

Indeed,

oxidation.

ob-

complete ab-

sence of glycogen in the liver and muscles has been

The

five

noted.

voracious appetite and rapid wasting further sustain this

—and

simultaneously,

therefore,

tlie

presence

of

suprarenal

The italicized words in the list of terminal symptoms, on the other hand, as prominently point to the gradually deepening suprarenal exhaustion. Alluding to the effects of acids in the production of overactivity.

the experiments

of Pavy® with was noted in twenty .minutes; fifteen minutes later a large quantity was present. In another strong, but fasting, dog the sugar was markedly Ilasmorrhagic infiltration of the reduced by a smaller dose. gastric and intestinal tissues and hivmaturia were also noted. These are all familiar landmarks of suprarenal origin. Strik-

glycosuria,

Cartier

phosphoric acid.

ing,

refers

An

to

increase of sugar

in this connection, arc the observations of

who found

that the production of

CO„ decreased

Stadelmann,^ in the rabbit

during acid intoxications as it does in diabetic coma. In a “Voit and Pettenkofer and Gaethgens

foot-note Cartier says:

have peremptorily shown, by means of most precise experiments, that (1) the oxygen absorbed by a diabetic is much less than by a normal man, and that

it

decreases progressively until

“Practice of Medicine,” third edition.

“

Osier:

’

Pavy: Guy's Hospital Reports, vol. of 1861. Stadelmann: Deutsche med. Wochenschrift, Nov.

*

4,

1890.

—

366

GLYCOSURIA AND ADRENAL OVBRACTIVITY. the end of the disease,

when

hardly equal to half of the exhaled is likewise reduced.”

it is

normal quantity; (3) that the CO 2 That this is essentially due to suprarenal insufficiency i.e., reduced oxidation is shown by the fact that, in a case of coma due to meningitis witnessed by Stadelmann, the proportion of

—

was 28.3 per cent.; while in diabetic coma the gradual decline is that observed in Minkowski’s rabbits, which, from the

CO 2

dropped to 16, 8.8, then 3.9 per cent. have seen that tetanus was partly due to adrenal overCartier refers to the experiments of Claude Bernard,

normal 25 per

We activity.

cent., steadily

which showed that strychnine produced glycosuria in dogs. “It is unnecessary to reproduce here,” says Cartier, “the symp.

toms of poisoning produced by say that nothing recalls tetanus intoxication by it.”

We

this alkaloid;

we

will simply

such a high degree as does

to

have another proof that

is

it

due to

an excessive production of a ferment or some other agency possessed of converting powers since Langendorll found that

“glycosuria only occurs in frogs

...

cogen.

when

the liver contains gly-

In the summer, when their

liver contains none,

strychnine does not cause diabetes in these animals.”

We are reminded of the disorganization of haemoglobin produced by advanced suprarenal insufficieney when, referring to

curare glycosuria, Cartier says

:

“Others account for this

glycosuria by an insufficiency of the respiration and by slowing of combustions. cates

The dark coloration of curarized blood Even tlie nervous distribution,

asphyxia.”

this

indi-

as

I

including the basospinal conneetion between the body and the adrenals, finds itself sustained in a

interpret

it,

pituitary

remarkable manner by the following lines of Cartier’s in referenee fact

to

that

morphine glycosuria: all

these

investigations

“An

extremely

indicate

interesting

one can produce with a toxic substance exactly similar phenomena to those recorded by Claude Bernard in his lessons at the College is

that

of France,

and obtained by puncture of the medulla, and that in most cases be arrested, as are glycosurias of nervous origin, by severing the centrifugal nervethese toxic glycosurias can

impulse

conductors.

Indeed, section of the pneumogastric does not prevent glycosuria caused either by Bernard s puncture or by morphine but, on the contrary. ; (centripetal nerve)

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

366

section of the splanchnic nerves (centrifugal nerves)

and

of the

medulla above the origin of these nerves prevents both the experimental diabetes of Claude Bernard and the toxic diabetes caused by morjdiine.”

The

of drugs that are able to produce glycosuria could

list

be indefinitely prolonged:

suprarenal overactivity.

includes all those that produce

it

But

this does not

mean

that the fer-

ment-producing organ is alone stimulated; glycosuria is but one of the manifestations of the exaggerated general metabolism

induced,

and oxidation processes are enhanced accord-

Toxic glycosuria, therefore,

ingly.

the

repre.sents

onl}'

sur-

plus of sugar which oxidation processes have not consumed; excess of sugar actually produced

tlie

is

proliably far greater

which the urine shows. Again, certain drugs phosphorus, for instance do not produce glycosuria to any

tlian the surplus

—

—

marked degree;

as soon as the dose capable of causing

reached, the adrenals lapse into insufficiency, and,

it

is

the dose

if

pushed to any extent, even tlie normal ratio is reduced. Antipyrin is now considerably employed in diabetes; we have seen that this drug and acetanilid readily produced suprarenal is

and

insufficiency

This

dissociation

sufficiently

is

methaemoglobinuria

seem

facts

due

to

me

of

the

luemoglobin

extensive sometimes to or

molecule.

manifest

even ha'inatoporphyrinuria.

to indicate that toxic glycosuria

itself

as

All these is

primarily

to overstimulation of the adrenal system, the excessive func-

tional activity ivhich increased oxidation produces giving rise to

an inordinate production of an agency that converts glycogen All these features will again be reviewed.

into sugar.

That the agency which converts glycogen

into

sugar

is

the amylolytic ferment produced by the pancreas to which I

have referred cially

is

further sustained by the foregoing facts, espe-

in view of the

secretion

in

the

amylolytic properties of the pancreatic

intestine.

Since the conversion

into

sugar

occurs during fasting as well as during digestion under the effects

of

toxics,

the

reaction

can

only

include

the

hepatic

glycogen and pancreatic ferment; and, there being nothing in the intestine to convert during fasting, the ferment must necessarily reach the glycogen

he the

more

by another channel,

d/ay this not

direct route afforded hy the splenic vein?

367

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS.

Yet there is a possibility that the flow of amylopsin in the intestine, which the enhanced activity of the pancreas must undoubtedly increase, may he reabsorbed by the venules, and, being carried into the portal system, produce conversion of the glycogen precisely as if it had entered the portal vein by the

way

But we have seen

of the splenic vein.

of the pancreas

is

tions of the gland can be safely removed.

while removal

Admitting that the the pan-

may have left the portions related with duct, how could we account for the effects

operators creatic

that,-

rapidly followed by death, very large por-

of trans-

planted fragments in arresting the glycosuria caused by re-

moval of the pancreas, recorded by Minkowski® and Hedon?" As long as fragments transplanted subcutaneously remained normal no glycosuria occurred; it reappeared, however, when these fragments tJiat

became histologically impaired.

could be the blood. trated the liver by

Thus way of

intercellular capillaries

penetrated the organ by

was evidently

to

convert

the

amount

the normal blood,

of

of

previously shown.

as

liver, it

glycogen

Croftan’s animals

Again, we have is

maltose, while

when stimulated with

renal extract gave dextrose in very great quantities:

denoting successive processes.

duced appear to

then pene-

up the very limited proportion of sugar found

seen that the product of intestinal reduction the urine

it

ferment could thus reach the

sufficient

required to build

carried to the heart,

the hepatic artery, and reached the

and the glycogen precisely as if it had way of the portal vein. Although but

a small quantity of the

in

It is evident

the only channel here for the amjdolytic ferment produced

me

to

supra-

a feature

This and the other facts ad-

contribute additional evidence to

my

view that the dextrose-forming ferment enters the portal system

hy

way

of the splenic vein.

THE FUNCTIOXAL RELATIONSHIP BETWEEN THE PANCREAS

AND SPLEEN. The

internal

secretion of the pancreas and that of the perhaps be best studied by submitting to a careful analysis the hypothesis advanced b}^ Schiff, sustained by

spleen

may

Iledon.

Congr. far Inn. Medicin, Wiesbaden. Archives do Physiologic norm, et path., vol. iv, 1900.

1892.

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

3fi8

Ilerzon/ and defended by Lepine’* and others that the spleen supplies a ferment which, when added to pancreatie juice, greatly increases

its digestive energy. JSchilf believed that the splenic snhstance played an important part in the genesis of the pancreatic proteolytic ferment, but Herzen attributed to

function

the

it

converting trypsinogen

of

albumin-solving

constituent

of

the

into

pancreatic

trypsin, juice.

the

This

subject was

more recently studied e.xperimentally by Gachet and Pachon,® who were led to conclude, as previously suggested by Laguesse (1893) and Schiifer (1895), that the spleen furnishes

true

a

internal

affinity for the pancreas,

secretion

udiich

into trypsin, as suggested by Herzen.

properties at the boiling-point; solution,

by alcohol

;

and

possesses

the protrypsin of which

is,

is

it

a

This substance

precipitated,

when

special

transfonns loses its

in aqueous

therefore, of the nature of a fer-

ment.

Lepine

also

confirmed Schifi’s and Herzen’s view by ex-

He found that a mixture of pancreas and spleen-pulp in glycerin possessed far periments in vitro and by blood-analyses.

more

On

active properties than pancreas alone similarly prepared.

the other hand, the blood of an animal deprived of

its

spleen proved almost inert as a tryptic, while the blood of a

normal dog possessed

digestive

distinct

Analysis of

powers.

experiments of these various authors distinctly indicates

the

that

some function

tomical

relations

The anahowever, make it

of the kind mentioned exists.

of the

organs

involved,

impossible for the internal secretion referred to to jienetrate the circulation without

first

passing through the liver with

the blood of the splenic vein, which collects the jjancreatic inter-

nal secretion

suggest

to

and that,

carries it to the portal vein.

besides

the

amylolytic

This fact seems

ferment,

the

portal

carries a ferment to the liver calculated to insure the trvjitic If we consider that action u])on albumins and kindred bodies.

we have

in

of digestion

tbe blood of tbe portal channels

and that trypsin

is

“ajiplied

all

the products

solely to

albuminoid

Revue G6n6rale dcs Sciences pures et appl., vol., 1S95. Lupine: Soci6t6 des Sciences Medicates dc Lyon, July, 1895. ‘'Gachet and Pachon: Archives de Physiologic, April, 1898. *

®

Herzen:

SHO

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. conversions

cliangos’’

iiml

(Charles),

the

importance

the

of

spleen’s internal secretion will appear.

Albuminoids, especially those ingested with food, are not the inoffensive bodies that they appear to be; indeed, they constitute the foundation of some of the most dangerous sub-

when

stances that enter the organism

undergoes certain

changes.

their molecular structure

Apart from any function of the

spleen in the direction mentioned, the pancreatic trypsin sup-

we can judge by

plied to the intestine— if a

small

remnant

manner

in a state of

is

in which

prevent glycosuria

will

when the pancreas

persist even

—^must

advanced

dis-

area

saw that one-eleventh of the functional

^Ye

ease.

pancreas

of

the

of

the adrenals sufficed to sustain the general oxidation processes.

That the pancreas area than strated.

it

absolutely

With proper

mal organism armed against .

ingesta

may

more functional needs has been experimentally demon-

possesses at least four times

is

—

—

uneontaminated

fresh,

practically invulnerable,

an}^

ehemico-physical

But

undergo.

so

food,

a

splendidly

decomposition

these physiological

noi’is

that

defenses

it

the

may

be weakened through general or local adynamia, he., lowered oxidation processes,

and peptones, capable of )delding toxal-

—

humins, leucomaincs, ptomaines,

all

albuminoids,

dergo further splitting in the intestinal

canal.

—

fail to

un-

Again, and

under the same circumstances, notwithstanding the destructive action of the gasti-ic and intestinal secretions, bacteria and their toxins circulation.

may

and the portal The blood-stream, furthermore, may be invaded penetrate the debilitated

villi

through

peripheral organs not only by baeteria and their but also by vegetable poisons and venoms all albuminoid substances, as previously emphasized. Even these do not reptoxins,

:

resent all the sources of danger that a protective function, such as that represented by the pancreatic and splenic secretions,

would have to meet, were they, as to fulfill such a mission. It toxic

I believe,

mainly intended

allmminoids reach the portal vein by way of the and the mesenteric veins, all conditions therein

intestinal villi

most advantageous for the action Avhich ti’ypsin is knoAvn to exercise upon tliem It acts with groat energy in alkaline media, and the presence of oxyg(>n does not iidiiliit its action;

are

:

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

370 if,

tlierefore, the

happen

venous blood of the alUerent channels should

to contain

an unusual amount of oxidizing substance

through suprarenal overactivity, the tryptic disruption of peptones would not, to say the least, be prevented; in laboratory

experiments the need of an antiseptic when pancreatic juice is

used

sels,

is

well

known; we have

seen that, in the afferent ves-

the fluids derived from the intestines had been saturated

therein with the antiseptic secretion of the glands of Brunner

and Lieberkiihn, and

it

is

evident that their influence would

normally continue in the venous channels; of trypsin does not cease it

when

finally,

the peptone stage

the action is

converts these into leucin, tyrosin, aspartic acid,

fate

which derivatives

of

I

reached; etc.,

the

have traced down to urea, the

end-product eliminated in the urine.

The

by the spleen in the pancreatic digestion of proteids, and to which I add a prophylactic function, has been so ably reviewed by H. F. Bellamy in a comparatively recent

role played

number

of the

London Lancei^^

that I will utilize the

greater part of his paper to illustrate the various features that appear to me to furnish a solid foundation, not only for the

views of

SchiflP

and Herzen, but

also for mjf

own.

The author reviews the history of the question as follows: “Corvisart found that in dogs in full digestion there was for a

certain time a constant rise to

power of the pancreatic fall

to

minimum.

maximum

juice, succeeded

in

the digestive

by an equally constant attained during the

The maximum was

eighth hour after the ingestion of a meal; the minimum from ]\Ieissner announced the thirteenth to the eighteenth hours. that in fasting animals the pancreatic juice possessed little or no peptonizing power. Schiff, after a number of experiments

on such animals as

rats, guinea-pigs, rabbits,

and young dogs

found that during fast the pancreas albumin really possessed almost no peptonizing power; the imprisoned in the duodenum remained there for whole hours

or dogs of small breed,

without dissolving, the infusion of the gland giving results On the other hand, in the case of ravens equally negative. and adult dogs of large breed the pancreas preserved during condition fast a certain digestive power, even in animals in a 10 II.

F. Bellamy:

London Lancet,

Oct. 27, 1900.

371

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS. of complete fast

which had digested a copious meal the day

before; under these circumstances, indeed, the infusion of the whole pancreas of a large dog was capable of digesting from

In such dogs this condition until toward the fourth hour maintained of weak digestion was after the meal, after which time digestion proceeded very much more rapidly, so that at the time of maximum the panDO to GO

grammes

of albumin.

was capable of digesting from 50 to 60 grammes As regard cats and small dogs, he was able to

creatic infusion

of albumin.

By

confirm the results of Corvisart.

above-mentioned

the

these experiments, then,

succeeded

observers

in

establishing

the

that the activity of the pancreatic

following two facts: (1) juice or of an infusion of the gland is not continuous,

but

in-

and (2) that maximal activity appears regularly during the culmen of gastric digestion (from six to eight hours after a meal), at which time it is very considerable.” Passing now, for the moment, from the pancreas to the spleen, he proceeds briefly to examine the behavior of this organ in relation to digestive phases. “Lauret and Lassaigne termittent,

in

1825 discovered that the spleen began to become congested

at the

mo.ment when the stomach discharged chyle abundantly

duodenum; that this is, however, merely a coincidence shown by the fact that the congestion also occurs after ligature of the pylorus. Dobson in 1847 discovered that in a dog three hours after a meal the spleen is still as small and as anaemic as during fast; that it commences to dilate in the fourth hour after a meal; that five hours after it has attained its maximal turgescence, decreasing afterward from the sevinto the is

enth hour to attain toward the twelfth

its

minimal volume.

Landois in the same year found that in the rabbit the relative weight of the spleen to the body-weight of the animal was the same two hours after a meal as after forty-eight hours of fast; that it increased considerably from the fifth hour, remaining high until the twelfth hour “The striking synchronism in the splenic congestion and

the

presence of trypsin

in

large

juice or in air infusion of the gland

quantity in the pancreatic

was observed by Schiff and former experiments on the tryptic digestion of albumins, this time on animals in wliieh tlie spleen

caused him to repeat

all his

24

—

—

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

372

had been for sonic time removed and on others in which it was prevented from dilating by ligature of its hilum at the

He

time of the e.xperiment.

number

a very large

experimented in this way upon

of dogs and cats

ments were double i.e., performed the same manner on two animals :

one another as the

much

all

his experi-

the same time and in

selected

so

as

to

resemble

and in only one of wbich had

as possible,

been extirpated

spleen

at

nearly

;

These experiments were of two kinds; (1) those conducted with pancreatic infusions, and (8) those carried out in the living duodenum, the or

ligatured.

following being typical examples “I. Infusions.

:

Ligature of the Ililvm of the Sj)leen.

—Two

much meat as they hour afterward they were etherized, and the spleens, which were found to be in a state of contraction, were brought out through a ivound in the abdomen and their hila were encircled by strong thread; in one of the animals the eats, after fasting for 19 h.ours, received as

would eat;

1

hilum was firmly tied, but in the other it was simply encircled and a knot was tied, leaving the splenic circulation perfectly free (this

was done in the endeavor

ditions as

much

in

as possible).

The

to equalize traumatic con-

spleens were then replaced

abdominal cavity and the wound was sutured.

the

On

recovering from the amesthesia the animals did not appear to suffer. They were killed G hours later. Gastric digestion was found to be more advanced in the animal in which the splenic

vessels

were

tied

;

the pancreas of both was cut

up

into small

fragments and infused with fOO cubic centimeters of Avater for an hour at 35° C. ; the liquid was afterward decanted and returned to the warm chamber together Avith cubes of albumin. “Result.

—In

7 hours the pancreatic infusion of the cat in

Avhich the hilum Avas not ligatured digested 17 grammes of albumin ; that of the other did not digest at all even at the end of 12 hours. “This experiment Avas performed on a large number of In spite, Iioaa"cats and dogs and ahvays gave the same result. ever,

of

of the perfection

animals,

it

gastric

digestion

Avas possible to lay at the

in

the

operated

door of traumatism the

absence of duodenal digestion; to correct this the experiment Avas repeated as folloAvs

:

373

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS.

“ExtirpalUm of the 5'pZeen.— Two dogs— one normal, the other having nndcrgonc splenectomy a month previously, but were operated at the time of the experiment in perfect health

—

ufion, while fasting, as follows

pylorus, injection into the

:

Etherization, ligature of the

stomach, per oesophagus laid bare

and opened, of 50 grammes of peptone and 2 grammes of dextrin; to allow drainage of swallowed saliva the oesophagus was Both animals were killed live ligatured below the opening.

and each pancreas was infused for three-fourths of an hour in 100 cubic centimeters of water at 35° C. Although death had occurred before the most favorable moment for the experiment,—i.e., in advance of the summit of the splenic curve, the infusion coming from the dog Avith the spleen intact digested 17 grammes of albumin in 17 hours, while the

hours

later,

—

iSTumerous experi-

other digested nothing even in 18 hours.

ments made in

this

manner ahvays gave the same

spleenless dogs

had

in

many

cases

result.

undergone splenectomy

The sca'-

eral months before the experiment, and the determination in them of perfect conditions of health was ahvays a matter of

great care. “II.

the

Experiments in the Living Duodenum. Ligature of ^Two dogs after fasting for 17 at Both Ends

Duodenum

.

hours received as

—

much meat

ately aftei'Avard were operated

would eat and immedi-

as they

upon

as folloAvs:

Etherization,

laparotomy, ligature of the pylorus and of the bile-duct, introduction into the

duodenum

of

from 30

min, and ligature of the jejunal end. the splenic hilum Avas also ligatured.

to 40

grammes

of albu-

In one of the animals Both were killed 7 hours

later.

“Besidt

min

Avas

.

—In the dog

Avitb the splenic

found to be intact;

it

hilum

tied the albu-

had, hoAvever, disappeared in the

other.

“This experiment was also several times repeated on animals Avhich had undergone splenectomy a long time previously, and ahvays yielded the same result; it is, of course, capable of being comliined Avith the preceding

by making an infusion

of the pancreas after the death of the animals. Such infusions give results in harmony Avith those furnished by tlie duodenum itself.

Further,

it

Avill

be remembered that in the pancreatic

:

INTERNAL SECRETIONS OE PANCREAS AND SPLEEN.

374

juice of dogs of large breed Sehiff generally found, even -while fasting,

a

quantity of trypsin;

certain

spleenless, however,

he was unahle to find any.

Duodenum Provided

“Digestion in the Normal

ula.

—A duodenal

jilote

when the same were

was established

fistula

with a FistAfter com-

in a dog.

recovery a measured and constant quantity of albumin

was introduced every day into the duodenum inclosed

in

membrane thread some centimeters long. The

by a

small envelope of fibrous

fixed to the cannula

progress of digestion was

then observed, the following results being obtained: the animal was fasting the albumin took from to

hecome

into the

dissolved.

2.

When

duodenum during the

the

3.

When

1.

When

G

hours

5 to

albumin was introduced

2 to 3 houi-s immediately fol-

lowing the ingestion of a meal hy the animal changed.

remained un-

it

introduced 4 hours after a meal

appeared very quickl}q

—

a

it

dis-

in about half the time, in fact, occu-

These facts having been duly noted, the spleen was then extirpated, and after complete recovery the same experiment was repeated; very different results were now obtained. Whether fasting or in full digestion the time

pied

during

fast.

taken for the digestion of the albumin was exactly the same, The acceleration in the peptonization viz.: from 5 to G hours.

which had formerly appeared after the fourth hour of digestion,

and Avhich coincided both with the appearance of trvpsin in the pancreatic juice and with the dilation of the spleen, was

now

absent.

The slow

(from 5

digestion

to 6 hours)

in this

experiment was probably entirely due to the secretion of the duodenal glands, which possess

power; the

onl}'

was due

active, rapid digestion

in large quantity, of trypsin

nomenon wanting

in

the

in

a ver}"

digestive

feeble

to the appearimce,

the pancreatic juice:

spleenless

animal;

.

.

a phe-

Schiff

.

by the following theory endeavored to interpret During the congestion of the spleen a substance is produced within it which, carried away hy the blood, gives to the panthe

creas the wherewithal to

facts

fonn

its

peptonizing ferment.

.

.

.

In 1872, however, the theory of Schiff received a rude shock through the great discovery of the zymogens by TTeidenhain

and

his pupils.

From

the researches of this observer

peared that, as the gastric

mucous membrane

fo'rms

it

ap-

at

the

0/5

relationship between spleen and pancreas.

outset hardly any active pepsin, but a zymogen accumulating does in its glands in the intervals of digestion, so the pancreas

not at once elaborate active trypsin but a substance destined certain to become trj'psin under certain conditions and in a

phase of the digestive act, this substance being, of course, the pancreatic zymogen trypsinogen, or protrypsin. The researches of Ileidenhain are well known, and it suffices to recall here

more

only one or

essential points

Thus from them we know

:

that the pancreas of a fasting dog contains little or no trypsin,

but

merely

trypsinogen;

consequently

infusion

glycerin

its

no digestive power; the infusion, howevei\ of a dog in full digestion digests rapidly and copiously, because If the pancreas of a fasting dog be divided it contains trypsin.

possesses little or

two equal portions, one of which is infused at once and the other only after an exposure of 24 hours to the air, the first is found to be inactive, while the other is immediately and into

from which it is clear that the inert trypcontains becomes spontaneously transformed

energetically active,

sinogen which into

active

it

trypsin; indeed,

suffices

it

to

pass

a

cuiwent of

oxygen through a pancreatic infusion, rich in trypsinogen and poor in trypsin (an active infusion), to transform infusion possessing

a

into an

This transformation,

power.

digestive

it

an oxidation, trypsin being oxidized trypsinogen. “The fact observed by Heidenhain of the continuous for-

then,

is

mation and storing up of trypsinogen in the pancreas and

its

subsequent transformation into trypsin during the culmen of gastric digestion proved that the

former substance at any rate

enjoyed an origin quite independent of the pancreas

itself,

all

influence

and the hypothesis of Schiff

outside

as to the inter-

vention of the spleen seemed, in consequence, to be at fault.

But new

it

was only the theory of Schiff which suffered by these

revelations; as far as the experimental results of the

two

observers were concerned, physiologists were face to face with

two

series

of

apparently

contradictory

facts

—apparently

be-

cause facts properly observed can never stand in contradiction

with one another, and

when they appear

beeause the interpretation of them plete.

It fell to the lot of

hypotheses.

It appeared to

l\f.

is

Herzen

him

that,

to do so it is

either

false

merely

or incom-

to unravel the tangled

by modifying the hy-

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

370

pothesis of Schiff as to the

manner

which the spleen

in

a tryptogcne, a fusion of the respective facts of

Heidenhain could be brought about, and antagonistic, they could be

lie argued thus

tive.

tomized animals,

is

:

shown

that, far

acts as

Schiff and from being

to be reciprocally corrobora-

since the zymogen, even in splenec-

being continuously elaborated, and there-

fore independently of the spleen and its periodical congestion,

and that it accumulates in the gland-cells during fast, but that it becomes rapidly and copiously transformed into trypsin only in the presence of the spleen and in direct proportion to its dilation, it would seem feasible that the spleen produces, by ‘internal secretion’ during its congestion, an unknown substance, which, carried away by the circulating blood, transforms the inert zymogen already deposited in the pancreas into active trypsin destined to pass into the secretion of the gland,

and that the influence exercised upon the zymogen by this product of the spleen seemed to be a condition sine qua non for the transformation of the former into trypsin, at least in the living pancreas, since in the dead organ or its infusion it is

so

transformed by

dii’ect

oxidation.

This hypothesis of

Herzen would seem to be further confirmed by the fact gleaned from the researches of both Schiff and Heidenhain, to wit: that the holding in zymogen of the pancreas at a given moment cither of fast or digestion is always in inverse ratio to its hold-

ing in trvpsin, and vice versa, while the latter

is

always in

direct proportion to the spleen dilation.

“So

far so good.

But Herzen reasoned

spleen really produces, during

its

further.

If the

congestion, a substance which

about the transformation of the pancreatic zymogen upon this subinto trypsin, it would then be possible to seize condition stance in the spleen itself while in its turgescent an making once by at and (from 6 to 7 hours after a meal),

brings

infusion of

it

and mixing a certain

infusion with pancreatic infusion a fasting animal (very rich in

.quantity of this .splenic

made from

the pancreas of

zymogen and very poor

in tnpsin,

in and consequently nearly inactive) there could be obtained recognizeasily vitro a rajiid and copious foniiation of trvpsin

Ihe by the amount of proteid digested in a given time. merely consisting simple, control experiment would also be very alile

—

377

RELATIONSHIP BETWEEN SPLEEN AND PANCREAS.

same pancreatic infusion that of a contracted and anemic spleen, in order to observe whether it would have the same effect as that of the spleen dilated and engorged with in mi.xing with tne

blood.

infusions

gave enormous differences

out with

carried

actually

digestions

Artificial

these

whereas the pancreatic

:

infusion alone, or that mixed with infusion of contracted spleen digested nothing or almost nothing, the same pancreatic in-

fusion to which had been added infusion of engorged spleen digested rapidly and copiously; indeed, digested

had often completely

it

dose of proteid by the time that the other two,

its

digesting at

all,

The mixed

had barely commenced.

thus behaved in the same

way

if

infusions

as a pancreatic infusion taken at

the culmen of digestion.

“A

large

number

of similar experiments were

made with

aqueous boric and glycerin infusions, each being double:

performed in two separate

series of vessels, the

i.e.,

one containing

and the other equal-sized cubes of coagu-

finely divided fibrin

The results were always the same. “At the German Congress of Medicine held at Strasburg

lated albumin.

.

.

.

in 1886 Herzen exhibited several graduated flasks containing the residua of fibrin

and albumin

in a

number

of his digestions,

and replaced by alcohol. The physiologists who examined them all recognized that the difference between the residua left by the pancreatic infusions alone and those of the mixture of the pancreatic and splenic infusions were very obvious. In a private conversation the

digesting

having been

liquid

decanted

with Herzen, however, Ileidenhain made the following criticism It is well Icnown that the pancreatic zymogen is very greedy of oxygen; on the other hand, the spleen during its :

dilation

is

engorged with blood.

hibited were intensely colored

the undoubted and

The

splenic

infusions ex-

by dissolved haemoglobin

considerable acceleration in

tained by adding such a liquid to

ergo,

digestion

ob-

another containing tryp-

sinogen could be quite simply explained by the rapid oxidation of the zymogen at the expense of the haemoglobin. This objection disconcerted Herzen in no inconsiderable degree,

he

lost

quiry.

no time

He

in

making

it

the subject of experimental in-

at length succeeded in disproving it

excellent experiment:

and

The pancreas

of a

by the following normal fasting dog

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

378

was infused in pure glycerin and the infusion was divided into eight equal portions. These eight portions were mixed with eight samples of, blood received directly into a double volume of glycerin, of which four came from a fasting dog and four from a dog in full digestion with the spleen greatly dilated.

The four samples were taken

in both animals from (1) the femoral artery, (2) the femoral vein, (3) the splenic artery, and (4) a large sjilenic vein. The eight portions were then given the usual dose of fibrin and placed at a temperature of

40° C. rial

Now,

it

is

evident that the femoral and splenic arte-

blood of the two animals contained more oxygen than

their venous blood; the former, then, according to Heidenhain,

should exercise a powerful influence on the digestion, equal

On

in the two dogs.

the other hand, according to Herzen, the

splenic venous blood alone should exercise this influence especially

that

of

the

digesting animal.

experiment was as follows

The

result

of

and the

After one hour there was still no trace of digestion under the influence of the femoral blood, arterial or venous, nor of the splenic arterial blood of the fasting dog; first traces of digestion were beginning to manifest :

themselves under the influence of the splenic venous blood of this animal.

Digestion was rather advanced in the case of the

femoral arterial and venous blood and splenic arterial blood of the digesting dog; the fibrin

had almost

entirely disappeared

under the influence of the splenic venous blood of the same animal.

“The answer could not be

clearer:

the product of the

internal secretion of the spleen, borne therefrom by the cir-

culating blood,

is

present during the period of the dilation

of the spleen in feeble, but appreciable, quantity in the blood

and abundantly in the splenic venous The venous blood returning from the contracted spleen blood. This experiment, only contains it in very small quantities. same result, showing gave the times repeated, always several of the general circulation

that

it

is

not the blood as such which favors the transformazymogen into trypsin, but that, by picking

tion of pancreatic

up from the spleen the unknown substance possessing this its vehicle and means of commu-

property, the blood becomes nication with the pancreas.

KELATIONSI-IIP

‘Trom

379

BETWEEN SPLEEN AND PANCREAS.

the bulk of evidence collected by Herzen there thus

seems to be very

little

room for doubt

that, apart

from hasma-

topoietic, and possibly allied, functions possessed by the spleen,

the

organ furnishes a product of ‘internal secretion’ which

zymogen

causes in the pancreas the transfoiTuation of its inert into active trypsin.”

Bellamy

closes his article

with a review of the criticisms

which the researches of Schiff and Herzen have been subIn the experiments of Lussana, in 1868, the spleens of three dogs were removed and the animals were subsequently killed to ascertain whether the extract of their pancreas would to

mitted.

coagulated

digest

The pancreatic

albumin.

glands of two of the dogs digested 0.25

infusion

gramme

of

the

of

albumin in

24 hours; that of the third digested 1.10 grammes in the same period of time.

“The

latter

three hours after a meal: it

been in possession of

its

animal had, however, been killed

i.e.,

at a

moment when, even had

spleen, that organ

have commenced to become congested.

would not yet

The experiment,

gave the result which might be expected,

—

there-

viz. no dinobody would accept seriously the digestion of 1.10 gi’ammes, knowing that the pancreas of a dog when digesting can dissolve from 50 to 60 grammes of albumin. .”

fore,

gestion,

—

:

^for

.

.

Indeed, the experiments of Lussana appear to ns to be confirmatory of Schiff’s and Herzen’s views. Carvallo and Pachon also reported negatively, but, errors in their experimental procedures having been brought to their

attention by

Herzen, subsequent experiments caused

Pachon

and a new collaborator, Gachet, to reach the conclusions sustaining the views of SchifE and Herzen to which we have referred on page 368. “Hay, they did more,” says Bellamy; “they invented an entirely new experiment, at once original and ingenious, which consisted in realizing in vivo what Herzen had hitherto only done in vitro. This experiment was as follows: A dog, which a long time previously had undergone splenectomy, was anesthetized and half its pancreas was removed and immediately infused; at the same time a normal dog, in the height of digestion, was killed and its congested spleen was infused in Avater, and this infusion AA'as injected into the venous system of the spleenless dog; from 15 to 20

—

—

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

O(S0

minutes afterward the remaining half of the pancreas of the latter dog was infused exactly like the first; of the two infusions udien given fibrin and albumin, the second only digested rapidly and copiously.” T1i 6

investigations

of

are next reviewed.

Popelski

‘‘In

both normal and splenectomized cats,” says Bellamy, “he lected the pancreatic juice by

means

col-

of a cannula introduced

into the duct of the gland, and was unable to find any differ-

ence

in

digestive

As, however, his cats had

activity.

side the

digestive period during which

congested, furnishes abundantly

its

been

made

fasting since the day before, his experiments were

out-

the spleen, becoming

product of internal secre-

zymogen into “But Popelski also performed some analogous experiments on a dog with a permanent pancreatic fistThe pancreatic ula, made according to the method of Pawloff. and examined collected juice of this animal was several times before and after splenectomy without any difference in activity tion which transforms rapidly and copiously the

trypsin.”

.

.

.

being demonstrable.

This

result,

however,

in view of the fact that in both instances collected immediately after a meal

i.e .,

no surprise

elicits

tlie

juice

—again

was always

to repeat it

advance of that digestive jieriod during which the spleen enters into function and the pancreas abounds in trypsin; so in

that as well in this experiment as in that with his cats, Popelski

was placed in that position in which the presence or absence .” of the spleen was a matter of perfect indifference. .

The

discussion

of the

.

various features in point have led to

considerable acrimony, but the impartial obseiwer cannot fail to consider that the position of Herzen, of those reviewed, is

the only tenable one. Bellamy’s review was published I’opelski“ reiterates his views, and states that since it has been demonstrated that there exist in the organism bodies in

In an

article written since

the nature of ferments possessing oxidizing properties, which he believes to be derived mainly from leucocytes, the results

obtained by Schiff,

Herzen, Pachon and

explained by their action.

Popelski:

Vratch, Feb.

3.

1901.

Gachet can

During the height

of

all

be

digestion

FUNCTIONAL MECHANISM OF THE PANCREAS.

381

an accompanying destrucmore oxidizing bodies, the latter,

digestive leucocytosis prevails, and, tion of these

cells

yielding

he thinks, are the source of conversion of protrypsin or trypsinogen into trypsin, which thus becomes a function of the blood.

Thus, the spleen would have nothing to do with the

process, the

hyperamia and dilation of

during the

this organ,

formation of trypsin being regarded merely

as

concomitant

phenomena. feature of interest to us in Popelski’s last paper

The only is

the fact that his experiments were performed in accordance

That he should be driven thereby to ascribe all the phenomena witnessed to the action of ‘^oxidizing bodies” adds materially to the data contributed by Schmiedeberg, Jaquet, Abelous and Biarnes, and Salkowski, proving experimentally the existence of an oxidizing substance, and is suggestive. Indeed, when, in addition to this, we realize the strength of Heidenhain’s position, the manner in which with the directions of Schilf.

it

shook to

its

very foundation the equally strong position of

by Herzen, by pointing to the inoxygen another as agency through which trypsin of could be developed from trypsinogen, “trypsin being oxidized Schitf’s views as developed

fluence

trypsinogen,” the following (piery suggests itself:

Are we not

dealing with two processes working in sequence, a part of the

trypsinogen secreted in the splenic vein being converted by

and the rest are reached, by the oxidiz-

the splenic secretion for use in the portal vein,

being converted,

when

the arteries

ing substance?

To determine whether

such a deduction

is

at all warranted

t

or whether

it

is

subject to modifications through which

various views submitted and our find

it

the

own can be conciliated, we manner in which the

necessary to closely analyze the

pancreas and the spleen are functionally governed.

The Functional Mechanism pancreas will

first receive

gan, Howell says:

of the Pancreas.

our attention.

Pef erring

—The

to this or-

“Until reeently little direct evidence had been obtained of the existence of secretory nerves. Stimulation of the medulla was known to increase the flow of pancreatic juice and to alter its composition as regards the organic constituents, but direct stimulation of the vagus and the sympathetic

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

382

nerves gave only negative results.

Lately,

however, Pawlow

and some of his students have been able to overcome the and have given what seems

technical difficulties in the way,

to be perfectly satisfactory proof of the existence of distinct

secretory fibers comparable in their nature to those described

The

for the salivary glands.

may

have obtained

results that they

be briefly stated as follows: Stimulation of either the vagus

nerve or the sympathetic causes, after a considerable latent

marked flow

period, a

The

of j^ancreatic secretion.

failure of

other experimenters to get this result was due apparently to the sensitiveness of the gland to variations in

its

hlood-supphj}-

Either direct or reflex vasoconstriction of the pancreas pre-

upon

vents the action of the secretory nerves

ulation of the sympathetic gives usually no

Thus, stim-

it.

effect

upon the

secretion, because vasoconstrictor libers are stimulated

same time; but

if

the sympathetic nerve

is

at the

cut five or six days

previously, so as to give the vasoconstrictor fibers time to degenerate, stimulation will cause, after a

long latent period, a dis-

tinct secretion of the pancreatic juice.”

The

quotation almost suffices to show that the SAunpathetic

are

fibers

and

views,

vasoconstrictors

as

elseivliere,

that the secretory nerve

is

in

the

light

the vagus.

of

our

This view

conclusively supported, however, by evidence from other direcAs to the vagus, Franqois-Franck and Hallion^^ in additions.

is

tion to the dilator effects produced on the liver state that “this

vasodilator action

is

also

found in the pancreas.”

Stimulation

of the peripheral ends of both vagi, after section, between the

cardiac plexus and the diaphragm caused a wide dilation of the pancreatic vessels, which persisted soiue time, entailing a Ioav-

ering of the aortic pressure.

They

also

obtained dilation of

by stimulating the central end of the e nerve after it had been cut on a leA’cl Avith the msophagus. have also in the experiments of Alette*'* and IxudrcAA’etzkv*® evidence of the direct action of vagal stimuli upon muscular these

vessels

fiber.

reflexly,

Having observed

that the secretion caused by stimulating

Italics are our own. Frangols-Franck and Halllon: T,oc. rit. Mette: Archlv f. Physiol., Suppl. Bd., 1894.

All

“ Kudrewetzky

:

Ibid.

383

FUNCTIONAL MECHANISM OF THE PANCREAS.

one vagus could often be arrested by exciting the other vagus, he concluded that this nerve contained antagonistic fibers. This dual

becomes unnecessary, however,

set

accepted

mechanism

the

as

the

of

Frangois-Franck and Hallion.

stricto-dilation

if

vasodilation

is

observed by

Indeed, vagal stimuli capable

of causing contraction of the vascular muscles to which strictodilation is due, can as well induce contraction of the muscular

coats of Wirsung’s duct,

and thus

arrest the flow of secretion

of pancreatic juice precisely as it does that of bile.

sjmipathetic supply Frangois-Franck

As the

and Hallion^®

obtained plethj'^smographically vasoconstrictor effects on stimulating the splanchnic, and traced the constrictor fibers to the

The

cord.

were su]iplied through the

fibers

fifth thoracic

com-

mamunicating branches to the second lumbar jority of them reaching the solar plexus by w^ay of the greater splanchnic. The fibers then formed, they contend, “a secondary inclusive, the

They

plexus enveloping the pancreatic artery.”

also state that

“this arterial path seems to be tbe only one, since the destruc-

accompany the artery suppress the pancreatic vasoconstrictor effects of any sympathetic branch stimulated.” Again, Popelski^^ refers to various ways in which

tion of the fibers that

inhibition of the flow of secretion

may

be caused.

Stimulation of the vasoconstrictor

are:

of “secretion-inhibiting” fibers supposed

The mode

special set.

fibers,

Among

these

and stimulation

by him to represent a

of termination of the sympathetic fibers

on tbe pancreatic artery as given by Frangois-Franck and Hallion readily accounts for the inhibition caused by excessive excitation of the nerves.

evolved nerves

from the

—a

These (sympathetic)

suppositious

special

fibers are thus

“secretion-inhibiting”

rather incongruous combination, since by arresting

the flow of blood to the organ, they prevent

and

may

arrest the

secretory process. It is evident that these vasoconstrictor fibers are distinct

from the true secretory fibers, for Paw’ow'® saj's, alluding to Popelski’s work ^Tly a careful preparation of the nerves. :

Frangois-Franck and Hallion:

Archives de physiol, norm, et pathol., T.

Ix, p. 6G1, 1897.

"Popelski;

Centralbl.

“Pawlow:

"The Work

f.

Physiol., Bd. x, S. 405, 189G.

of the Digestive Glands,”

Eng. Trans., London,

1902.

INTERNAL SECRETIONS OP PANCREAS AND SPLEEN.

3R4

some brandies were discovered whose excitation caused a secretion witlioiit any latent period almost as promptly as the chorda expels saliva. From the latter fact we must conclude that in the branches mentioned,

secretory

the

libers

the

of

pancreas have been anatomically separated from the inhibitory.” Finally, a proof that

we

are dealing with exaggerated constric-

tion ending in experimental

nerve

secretory

Kudrewetzki’s'”

is

and not with a true

inhibition

hy the following observation

all’orded

of

“If tbe sympathetic nerve be excited hy means

:

of an induced current, a gentle intermittent advance of the secretion

observed, hut only during the first few seconds;

is

during the

later stages of the excitation,

the secretion

is

and

We

completely arrested.”

after its stoppage,

have here, obviously,

the identical result observed in the submaxillary gland the cervical sympathetic

stimulated

is

—a

when

exacerbation of

lirief

due to the propulsion of a small quantity of blood into

activity

the secretory elements

—and

simultaneously additional evidence

sympathetic in the pancreas

that the

vasoconstrictor

fulfills

functions.

This involves the conclusion that as elsewhere the bloodplasma laden with oxidizing substance is able to reach the

—

—

is shown by a brief review of the relationnervous and vascular structures of the organ. ship between the

glandular

This

cells.

lleferring to the blood-vessels, Piersol says

sending

off

the glandular parenchyma with twigs. lobules

and form net-works which

within the capillary reticulum.

basement membrane '

thelium.

:

“The

larger

nm

within the interlobular connective tissue, vessels which pass between the lobules and supply

arterial branches

The

veins

These

latter enter the

inclose the individual acini

The

capillaries lie beneath the

in close relation Avith the glandular epi-

accompany the

A

arterial trunks witliin the

arrangement prevails in the According to Eamon y distribution of the nerve-terminals.

connective

and C.

Cajal

and

tissue.”

Sala,

fibers of llemak.

similar

the

pancreas

Some

contains

nerve-cells

others are in contact with the intrinsic vascular their finer prolonyations surround the glandular

spaces;

and

many

cells are found in the interacinous

Kudrewetzkl:

Quoted by Pawlow;

Loc.

cit.

Avails, cells.

—

FUNCTIONAL MECHANISM OP THE SPLEEN.

385

Those connected witli the vessels form a plexus around them, and send extremely tine filaments to tlie muscular elements. Alluding to the nerve-cells, Eamon y Cajal says: “We may consider this cell as a special

almost

all

cell,

all

the prolongations, of which possess the

nervous prolongations contrary to the chain, that have two fiber of

Remak,

parable

to

the

destined

celhs,

the prolongations, or

neighboring

protoplasmic

cells

establish

of

a

meaning of sympathetic

along one, or

kinds of prolongations:

and short jirolongations com-

for the viscera,

to

cells of the

prolongations

relations

ganglion.”

of

cerebro-spinal

by contact between the Berdal,

who

quotes

the

above, therefore recognizes two varieties of nerve-fiber in the

pancreas:

“1.

The

formed by the cellular proand perivascular derived from the sympathetic

nerve-fibers

longations and which supply the periaeinous plexuses.

2.

The

nerve-fibers

nerves which penetrate into the pancreas with the vessels.

On

the whole the functions of the pancreas appear to be

governed as follows:

The nervous supply of the pancreas vagus and the sympathetic systems. 1.

is

derived from the

2. When the secretory functions of 'the organ are to he enhanced, the vagal terminals cause vasodilation of its arterioles, thus increasing the arterial hlood circulating through it. S.

When

diminished

the functional activity of the pancreas is to he

its

pathetic nerves,

arterioles are

and

caused to contract hy the sym-

the hlood circulating through the organ is

reduced.

Functional Mechanism of the Spleen. tion

of the spleen includes,

—The

innerva-

as a

predominating feature, the distribution of a fair proportion of the terminal fibers to the muscular elements, which, in man, are mainly supplied to the

“Wq have evidence,” says Professor Poster, “that the muscular activity of the spleen, whether of the muscular capsule and trabeculae and arteries combined, or of the latter alone, is under the dominion of the nervous system. A rapid

trabeeulae.

contraction of the spleen

may he brought about in a direct manner by stimulation of the splanchnic or vagus nerves,” “it may also be caused by stimulation of the medulla ohlongata with a galvanic current or by means of asphyxia. Though the

— ;

INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

386

matter has not yet been fully worked out, we have already indications that the flow of blood through through the agency of the nervous system, varied to meet changing needs. At one time a small quantity of sufficiently

the spleen

blood

clear

is,

passing through or

is

is

the metabolic changes which

being held by the organ and

undergoes in the transit are

it

At another time a larger quantity of blood enters the organ and is let loose, so to speak, into the splenic pulp, there to undergo more profound changes, and comparatively slight.

afterward to be ejected by rhythmic contractions of the muscular trabecula}.”

That rapid contraction

of the spleen should occur under

stimulation of the splanchnic nerve the role of sympathetic nerves is

—

is easily

^those

it

accounted for when

supplies the organ

considered to be that I have attributed to them in the fore-

going chapters:

that of vasoconstrictor.

Indeed,

it

plain

is

that under stimulation these nerves, should reduce the caliber of the arterioles, and, therefore, the volume of blood admitted into

the organ, and that

tinued depletion of

is

should contract rapidly owing to con-

its veins.

lation of the medulla as this is

it

on the

The

constrictive effect of stimu-

we have

arteries

due to contraction of their muscular

evidently influenced in a

manner

repeatedly seen coats, the spleen

similar to that following

stimulation of the splanchnic, the smallest arteries being the flrst

obstructed under violent vasoconstriction.

But why should stimulation splenic

contraction?

distribution

of

This requires

of the nerve-terminals.

the

an

vagus

also

examination

The innervation

induce cff

the

of the

spleen was studied by Kolliker in various animals,^® and his

when viewed in the light of my conception of the functional mechanism of glandular organs, are suggestive. “The vasomotor nerves enter the organ with the large arteries. In the walls of the large arteries the main trunks form a wellmarked superficial plexus with oblong meshes in the adventitia, and a deep, more quadrate net-worlc in the tunica media; some The end in the little branched arborizations in this coat. observations,

smaller arteries and the trabecula} receive their nerves from

2®

Kolliker:

Sitzungsberlcbt

d.

WUrsb. Phys. med. Gesellschaft, No,

2,

1893.

FUNCTIONAL MECHANISM OF THE SPLEEN. the rich

maze of

387

fibers in the pulp, consisting of axis-cylinders,

Other

which, however, do not anastomose.

on the surface of the

and from

trabecula3,

fibers

form a plexus

this fibrils

into the interior of the trabeculie (which contain

muscle) and end by

free arborizations.”

Kblliker regards as sensory

fibers,

penetrate

much smooth

Free terminals, which

When we

were also found.

consider that the trabeculie penetrate deeply into the interior of the organ

from the inner surface of the capsule in every

thus forming a spongy frame-work, and that the

direction,

muscular capsule overlying the organ and this spongy frameis also supplied with vagal nerves, its contraction under

work,

the influence of the latter under stimulation also becomes self-

evident in the light of our views dilator allows

an excess of blood

elements, causing

them

acting as a vaso-

to penetrate into the

to contract

Indeed

size of the organ.

The vagus

:

Boy^’-

and thus

who

first

to

muscular

diminish the

called attention to

the rhythmic contractions of the spleen, ascribed

them

im-

to

pulses received by way. of the vagus.

A

feature of the experimental

work upon

this

organ which

tends greatly to produce confusion in the interpretation of function,

is

the belief that

it is

its

supplied with inhibitory fibers.

Thus, according to Schafer^- these fibers are contained in the splanchnic nerves and their stimulation ‘^produces a dilatation of the spleen.” It is plain, in the light of our interpretation of “inhibition,” that

phenomenon due

we

are merely dealing with an experimental

to the excessive vasoconstriction

which

elec-

produces when applied to sympathetic vasoconstrictors, and that the organ does not receive “inhibitory fibers” as text-

tricity

books call them.

The interpretation of the splenic functional mechanism in accordance with our views is greatly facilitated when the microscopical anatomy of the organ is considered in the light of P. P. Mali’s^® researches. The organ is divided, as is the liver, into lobules,

trabeculaj:

each of which

those to

is bounded by “interlobular” which we have already referred. Each

Physiol., vol.

ill,

p. 203, 1880-2.

“ Schafer; “Proceedings of Royal Society,” London, 1890, vol. lix. No. 305; and^ Journal of Physiology, 1890, vol. xx. F. P. Mall: Johns Hopkins Hospital nulletin. Sept., Oct., 1S98»

— INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

388 lobule

is

about 1 millimeter in diameter,

is

partitioned into

about ten compartments by intralobular trabeculai, and receives

an artery which sends minute branches to each compartment. There is also considerable analogy between each one of these

compartments and the hepatic lobule, the hepatic cells being represented by masses of pulp separated by venules, which back to the veins leading to the greater splenic The pulp vein the various elements transferred to the liver. vessels carry

itself is

made up

of

an extremely

delicate reticulum, in

which

are found red corpuscles, lymphocytes, remains of corpuscles

with or without pigment,

etc.

—

the organ oxidizing substance

The

arteries

—which

bring to

soon after entering the organ

assume an unusual shape: their outer coat becomes l}miphoid, forming nodules similar to the solitary follicles of the intesin which lymphocytes tine, i.e., the Malpighian corpuscles, When, after numerous subdivisions, their diamare formed. eter becomes greatly reduced, the arteries resume their normal adventitia and on reaching the pulp in the compartments break up into minute capillaries. The arrangement is, after all, an

—

uncomplicated one, and similar, in general plan, to that of other organs reviewed.

The connection between

the nervous supply of the spleen

and that of the other digestive organs liecomes evident when the distribution of the coeliac-plexus branches is recalled. splenic plexus,” say Pick and Howden,"^ “is formed by branches from the coeliac plexus, the left semilunar ganglia,

“The

and from the right pneumogastric nerve. It accompanies the splenic artery and its branches to the substance of the spleen, giving

off,

in its course, filaments to the pancreas (pancreatic

plexus) and the left gastro-epiploic ple.xus, which accompanies the gastro-epiploica sinistra artery along the convex border of If we append to this Kolliker’s description of the stomach.” the intrinsic nervous supply and the

manner

in which

it

is

connected with the blood-vessels, it will become apparent that we have a counterpart of the vasculo-nervous mechanism of have studied, all the other organs of the digestive system we viz.,

to a system of vagal fibers capable of inciting the spleen

Pick and Howden:

‘‘Gray's

Anatomy,”

p. 80G.

—

FUNCTIONAL MECHANISM OP THE SPLEEN.

389

increased functional activity by causing an excess of blood to

and sympatlietic

enter the organ,

fibers to

reduce

its

functional

by causing the vessels to resume their normal caliber. The functions of the Malpighian corjjuscles around the

activity

would thus be insured by

vessels

The pulp

fibers

from the vagus.

traced nervous filaments

Fusari-°

deed,

is also

of axis-cylinders”

possessed of a “rich

—doubtless

In-

within these bodies.

maze

of fibers consisting

sensory structures.

But here an

independent motor supply must also be present, since we also

form “a plexus on the surface of the trabecfrom which penetrate into the trabecuhn. These, we have seen, contain much smooth muscle, and the nervefilaments are connected with them by “swellings” (Fusari), have

fibers that

ula3,” filaments

evidently end-plates. is

recalled

by

a

Kupffer’s bile-alveolus, with

similar receptable:

i.e.,

its canaliculi,

Mali’s “intralobular

venous spaces,” whicli form the starting-point of the venules that ultimately end in the large trunks leading to the splenic vein.

On

The nerves

1.

omous

the whole,

we may conclude

as follows;

of the spleen are derived

sources, the vagus, or pneumogastric,

from tivo autonand the sympathetic

system. 2.

The functional

activity of the spleen is incited

vagal nerves distribtited to

its

arterioles:

hy the hy causing dilation

of these vessels, they admit an excess of blood into all the structures of the organ, causing the latter to dilate.

The

vasoconstrictor functions of the sympathetic are as evident here as in other organs studied. “The spleen,” says

Howell, “is supplied richly with nerve-fibers which, when stimulated either directly or reflexly cause the organ to diminish in size.

According to Schiifer these fibers are contained in the which carry also inhibitory fibers whose

splanchnic nerves,

stimulation produces a dilatation of the spleen.” pathetic supply of the spleen has been clearly shown.

The

s}Tn-

Bulgak"‘'“

obtained vasoconstrictor effects, the organ becoming pale and shrunken, by stimulating fibers which ]ie traced to the semilunar ganglion and thence to the left splanchnic. Tarchanoff Fusari: “

Bulgak;

Archives Ttallennes de Blologie, Turin, vol. xlx, Virchow’s Archiv, Dd. Ixlx, p. 181, 1877.

p. 288, 1894.

— INTERNAL SECRETIONS OF PANCREAS AND SPLEEN.

390

reached similar results but by stimulating cither splanchnic. Schafer and l\loore studied the same subject by means of a plethysmograph specially constructed to avoid any obstruction to the circulation in the organ’s extrinsic vessels.

They found

the spleen extremely responsive to blood-pressure fluctuations,

and obtained constriction by stimulating either splanchnic, the left, however, giving more marked results than the right. The constrictor flbers were found to raise from the third thoracic to the first lumbar inclusive, the most active arising from the sixth, seventh, and eighth thoracic. This evidence clearly shows that the role of the spleen’s sympathetic supply constrictor. S.

Hence

When

diminished,

the functional activity of the organ

the

arterioles, thus

purely vaso-

is

:

sympathetic

fibers

came

to

is

constriction

of

he the

reducing the volume of blood admitted into the

organ and passive contraction of its capsule. The role of the spleen has not been so far clearly estabHowell, in the second edition of his text-book (1907) writes in this connection: “As to the theories of the splenic

lished.

functions, the following

may

be mentioned

:

1.

The

spleen has

been supposed to give rise to new red corpuscles. doubtedly does during foetal

life

some animals throughout

life,

in

dence that the function

most of the mammals.

retained in adult life in

is

2.

This it unand shortly after birth, and but there is no reliable evior in

It has been supposed to be an organ

for the destruction of red corpuscles. chiefly

man

This view

is

founded

on microscopical evidence according to which certain

large amoeboid cells in the spleen ingest and destroy the old

red corpuscles, and partly upon the fact that the spleen tissue

seems to be rich in an iron-containing compound.

This theory

cannot be considered at present as satisfactorily demonstrated. 3. It has been suggested that the spleen is concerned in the production of uric acid. as stated above,

and

it

This substance is found in the spleen, was shown by Horbaezewskv' that the

spleen contains substances from which uric acid or xanthin readily be formed by the action of the spleen-tissue

itself.

may More

recent investigations-® have shown that the spleen, like the liver “Consult Jones and Austrian: 1906.

Zelt.

f.

physiol.

Chem,” Bd.

xlviil,

S. 110,

;

FUNCTIONAL MECHANISM OF THE SPLEEN.

391

and some other organs, contains special enzymes (adenase, giianase, and xanthin oxydase), by whose action the split products of the nucleins may be converted to uric acid, and it is

probable, therefore, that this latter substance is constantly

formed in the spleen. 4. Lastly, a theory has been supported by SchifE and Herzen, according to which the spleen produces something (an enzyme) which, when carried in the blood to the

upon the trypsinogen contained in

pancreas, acts

converting

it

into trypsin.”

The

this

gland,

treated at length

latter is

under the next heading.

The statement

that the spleen contains, as do other organs,

such ferments as adenase, guanase, and xanthin oxydase gestive, in

This fact is

view of the fact that they are is all

all

sug-

is

oxidizing ferments.

the more interesting in that, as shown below,

the plasma alone,

i.e.,

plasma deprived of

its

it

red corpuscles

which circulates in the intercellular spaces of the pulp-cords.

An

incidental

remark of Professor

bution previously referred that

I

to,

Mall’s, in the contri-

goes far toward demonstrating

have not erred so far in ascribing to the blood-plasma

per se the active part in the blood’s function.

This constitutes

such a far-reaching feature of this entire work that the follow-

“The microscopical anatomy

ing lines appear to us as timely:

shows that the ampullae and venous plexus have very porous walls which permit fluids to pass through with great ease

granules only with difficulty.

In

and

the plasma constantly

life

flows through the intercellular spaces of the pulp-cords, while

the

hlood-corpuscles

Iceep

within

-fixed

physiological experiments which I have

view.”

If this can occur in the spleen

elsewhere in the organism, especially red

corpuscles average

channels.

made it

is

Numerous

corroborate this

doubtless possible

when we

consider that

diameter about Vaooo of an inch, while the lumen of the majority of functional capillaries is less than one-half that size. Of course, corpuscles adjust themselves

but

to

it is

laries

the

in

dimensions of the

apparent that in

many

of pericellular net-works,

structures

for

surround them

—the tortuous instance— such a system

instances

capil-

could but compromise the free circulation of the fluids, and, simultaneously, the functional efficiency of the organ itself.

392

INTERNAL SECRETIONS OP PANCREAS AND SPLEEN.

THE SPLEXU-PANCREAT[C INTERNAL SECRETION. From the data already submitted as to the functions and the tunctional

relationsliip

between

tlie

of,

spleen and pancreas,

evident that each possesses its own complete mechanism, and that in both organs, as elsewhere in the economy, the oxidizit is

ing substance (adrcnoxidase) or the blood containing source of functional activity.

it

is

the

have we any reason to believe, with Popelski, that through oxidation that the intrapancreatic trypsinogen becomes converted into trypsin ? Can we say, for instance the Still,

it

is

:

intrapancreatic conversion of trypsinogen into trypsin

not

is

by the splenic ferment, but by the oxidizing substance, when the efferent vagus nerves transmit appropriate impulses? We think not, much as such a process would coincide with the effected

multiple functions that we have already ascribed to the oxidiz-

ing substance.

We ally

have seen that when the pancreas becomes fimction-

active

its

arterioles

are caused to

dilate

by their vagal

nerve terminals, and that the speed of the blood-flow through the organ

increased.

is

very rich, these close relation

is

and, though in

with the glandular epithelium beneath the base-

ment membrane, they into

Yet, while the net-work of capillaries

eticircle the secreting lobules,

reticulated

tissue

in

no way, as in the

wherein their blood

spleen, break is

poured;

up

they

merely lapse, as elsewhere in the organism, into venules, which ultimately

carry

the

blood

to

the

larger

venous

channels.

Blood and trypsinogen do not come into contact, therefore, that which text-

in the ducts of the typical pancreatic lobule:

books employ to illustrate the origin, centripetal migration,

and functional elimination of the zymogen granules. These are lost in the lobular lumina and ultimately reach the greater duct on its way to the intestine, without apparently having

come

into contact with the oxidizing substance.

But, this being the case,

how can we account

for the

e.x-

perimental evidence adduced by Schiff and Herzen and other physiologists

who have confirmed

their

explain, for instance, the digestion of 17 in 7 hours with pancreas obtained

work?

ITow

grammes

c

423

THE ADRENAL SECRETION AND THE HEART.

were most consioicuous on the papillary muscles and in the neighborhood of the great vessels, being less easily seen in the region of the apex, where they were obscured by the trabecular

net-work.”

Very suggestive in connection with .my own views are also the observations of Gad® on the vessels of Thebesius in the “In the ox, and to which Pratt refers in the following words of the action the method which he describes for demonstrating valves of the left heart, wherein water under pressure is made :

to

fill

the ventricle and aorta, he noticed that water flowed

from the foramina Thebesii. On illuminatleft ventricle he was enabled to see fine, blood-stained streams issuing from the endocardial wall into Finally he the clear water with which the cavity was filled.” “working Kennedy,® who, Magrath and labors of reviews the with artificial circulations of defibrinated blood on the isolated into the right heart

ing the interior of the

heart of the cat, observed that a small portion of the coronary

blood found

way

its

from the

leakage past the aortic valves.

manometer-record

The only

into the left ventride.

source of access other than

aortic

of

possible

was shown by a

vessels of Thebesius

Tliis leakage,

pressure,

did

as

The

not occur.”

author closes his review of the literature of the subject with

statement

the

that

“notwithstanding

servations, the vessels of Thebesius still

painstaking

these

ob-

occupy a very obscure

ferred to as constant in

Foramina Thebesii are rethe right auricle, forming in part the

mouths of small

Their occurrence in the

position in anatomical literature.

veins.

occasionally mentioned. sius

open into

as auricles

—

is

all

But the

left auricle is

fact that the vessels of

the chambers of the heart

—

^\''entricles

Thebeas well

hardly recognized.”’'

In the author’s own experiments, various agents were injected at a constant pressure, through the coronaries of fresh,

often

living, hearts of the rabbit and dog. They showed that liquids in these vessels penetrate into the heart cavities still

through the endocardial foramina, thus verifying the foregoing

"Gad:

Archiv

fiir

Physlologie, p. 380, 1886.

Kennedy: ISO?” ^

All Italics are our own.

Journal of Experimental Medicine, vol.

11,

p.

13,

TUB DYNAMICS OF CARDIAC ACTION.

424

As the cannula was tied directly into the artery, the liquid could only reach the cavities through the foramina, while in all experiments care was taken to avoid high pressures. In data.

the heart of the ox the endocardial depressions were found ‘h’egularly larger in the auricles than in the ventricles,” while

in the right auricle “they

may,” he

states,

“be provided with

thin, single valves, especially about the origin of the great veins/'

In the

left

auricle the depressions are fewer in

number and

unprovided with valves.

“Iforamina Thebesii are never absent from the ventricles" says Dr. Pratt. “In the right ventricle,

which

especially well provided with them, the larger number upon the septal wall. It is often much more difficult them in the left ventricle, although a diligent search is

is

are seen to find

never

without

a

reward”

.

.

these ventricular foramina, which office

of valves I have not seen.”

“structures,

.

.

of the vessels of Thebesius with air by

applied

to

foramina,

the

ramifications,

accessory

might in any way .

.

“On

means

characteristic,

to

serve the

the injection

of the blow-pipe

fine,

which very frequently conduct the

subendocardial air into other

Thebesian systems, or even into the great coronary veins will seldom

fail to

appear.”

The

latter point is also sustained

by

experimental evidence.

The fact that the right side of the heart is endowed with a more perfect system of canalization than the left is suggested by the following remarks: “The ease with which injections of air and blood could be made to demonstrate the connection between the vessels of Thebesius and the coronary veins caused me to doubt the opinion expressed by Danger that the foramina Thebesii in the ventricles communicate tvith the veins by capvlTo settle this point, I injected the coronary veins laries alone. of the ox with starch and celloidin masses, both too thick to pass the capillaries, and found that even these emerged from So intimate a the foramina Thebesii of the right ventricle. connection, however, betv'een the coronary veins and the ves-

I have not yet been able to, demon“By means of a very successful strate.’’ 4’he author also says corrosion preparation, made bj’^ injecting the veins of an oxsels

entering the

left ventricle

:

heart with celloidin, I was able to traee the communication. In this preparation the position of some of the foramina

425

THE ADRENAL SECRETION AND THE HEART. Thebesii was

marked by small

disks

of

hardened mass

the

formed by the oozing out of the celloidin upon the endocardium. These foramina were shown to be connected with the

The

smaller coronary veins by fine branches.

still

finer

rami-

Langer has demonstrated, lead from the

which, as foramina and branch directly into capillaries were here uninjected; they would appear only when injected from the forafications

mina themselves.” The only connection between the the coronary arteries that

attempts,

peated

was by

he could

vessels of find,

capillaries.

Thebesius and

notwithstanding re-

Bochdalek having ob-

served that the foramina of one auricle communicated with those of the other, he was able by blow-pipe injection to verify the correctness of this view, the air of one auricle having passed

out through a similar exit into the other.

To

sustain his view that the nutrition of the heart

be carried through the vessels

the coronary arteries are absolutely obliterated, a

experiments are related. tricle of

may

of Thebesius some time after

number

of

Thus, fiuid introduced into the ven-

an isolated heart, by means of a cannula passed down

and tightly held in

by a ligature passed around the auriculo-ventricular groove, only found its way through the vessels of Thebesius. Defibrinated blood, inserted into the organ through this cannula, brought on, often within one minute, “strongly marked, co-ordinated contraction of the ventricle.” As the blood thus introduced would become venous, the action would become gradually reduced, but renewal of the blood would at once cause the heart to resume its normal action. “With a periodic supply of blood,” says the author, “and with favorable temperature and moisture this may conto this cavity,

tinue

s-itu

That mere mechanical stimulation by phenomena witnessed is demonby the alternate use of Einger’s solution and defibrin-

several

hours.”

distension did not cause the strated

ated blood.

While the solution failed to sustain contractions, blood always succeeded. Another experiment served to demonstrate that a true circulation could take place between the vessels of Thebesius

and the coronary veins. The organ being disposed as stated above, two of the coronary veins were incised; “a small, but

THE DYNAMICS OF CARDIAC ACTION.

42G

steady, stream of venous blood issued

from them.” Under the same conditions the descending branch of the left coronary artery was opened. “No flow of blood occurred from the artery, although there was a free escape from an incision in an accompanying vein.” In still another experiment the trunks of both coronary arteries were ligated and the ligature around “The supply-cannula was tied into the ventricle through the oarta. On the introduction of blood

the ventricles omitted.

the left ventricle alone began to beat strongly and regularly the blood found its way in part into the right ven.

.

.

coming of necessity through the walls. . .” The blood from the left ventricle had thus found its W'ay into the tricle,

.

right one.

Finally, he refers to the striking analogy which

this nutritional system presents to that of the frog

and cat. In the frog the heart is almost entirely nourished “through the branching passages that carry tlie blood from the interior of the heart nearly to the pericardial surface.”

On

the strength of

all

this evidence. Dr.

Pratt concludes

(giving only the features that bear directly upon the question

we

are analyzing)

“1.

that:

The

vessels

of Thebesius open

from the ventricles and auricles into a system of fine branches commimicate with the coronary arteries and veins by means of capillaries, and with the veins but not with the arteries by passages of somewhat larger size. 2. These vessels are capable of bringing from the ventricular cavities to the that

—

—

heart-muscle sufficient nutriment to maintain long-continued,

rhythmic contractions.

3.

The heart may

also

nourished by means of a flow of blood from into

the

coronary sinus and

trition

auricle back

The author

veins.”

with the very appropriate remark:

tlie

be effeetively

“It

is

concludes

evident that the nu-

through the vessels of Thebesius and the coronary veins

must modify

no slight degree the existing views of the nutrition of the mammalian heart, and of the manner in which in

infarction of the heart takes place.”

The

clinical features of

this question will be considered elsewhere.

Viewed from my standpoint, the more concerned with the dynamics of nutrition

t>f

this organ,

though the

vessels of Thehesins are

the heart than with the

latter function is not to be

ignored, particularly in the sense emphasized by Pratt:

i.e.,

—

—

THE ADRENAL SECRETION AND THE HEART.

427

as a source of compensation.

auricle result

That nutrition

of the left heart,

and ventricle, constantly filled with arterial blood, can from a flow of the latter through the Thebesian vessels

but nutrition can hardly be associated with a similar process in the right heart, with nothing but venous That nublood to propel through the Thebesian channels. seems

clear,

the recognized prerogative of arterial blood, owing to

trition, its

oxygen, cannot be the active factor here

is

evident.

The right heart seems, judging from the anatomical arrangement of the parts concerned in the process, to play a physiological function of a special kind.

While the Thebesian

openings are larger in the auricles than in the ventricles, in the left auricle they are also fewer than in the right; but even

more suggestive

the fact that, while some openings in the

is

right auricle are supplied with valves, none have been

foramina

;

the right ventricle

them, while they are septal wall should

found

Again, both ventricles are supplied with

in those of the left.

is

particularly well provided with

difficult to find in

the left one.

That the

show them most clearly on the right side

is

Evidently a similar eondition exists between as suggested by Bochdalek and confirmed by

also suggestive.

the

auricles,

Pratt; but the fact that limited information supplied by works

on

anatomy usually covers only those of the right auricle to greater prominence of the latter. Thus, Gray'*

points states

that the venae Thebesii open “on the inner surface of

the right auricle.”

Finally, the openings supplied with valves

are in the right auricle, as stated

to

be most

great vessels; hence

we have seen; but they

conspicuous it

in

the

neighborhood

are also of

tlie

must only be the Thebesian openings

—

around the great vessels of the right auricle ^the venae cavae and the pulmonary artery that are provided with valves.

—

If

we can now

ascertain whether the current

which enters the Thebesian vessels from the right auricle is shut out in this location, or secured within the channels, according to the manner in which the valves close, i.e., inwardly or outwardly,

we

will be able to decide

Gray;

“Anatomy;”

whether venous blood from the venae

edition, 1901, p. 622.

— THE DYNAMICS OF CARDIAC ACTION.

42-

sizes

this fact.

Haller,

stances flowed out freely

who had

observed that injected sub-

from the surfaces of both states that “the passage from the arteries into the the left side is more difficult.”

ventricles,

cavities of

THE DYNAMICS OF CARDIAC ACTION.

430

All these features seem fully to supply the needs of the

function with which the secretion of

the

suprarenal glands

must be connected, if the phenomena witnessed in many disorders and after the use of most remedies have been correctly interpreted. That we are in the presence of a dual process of which the suprarenal secretion, operating in the right heart, and the arterialized blood in the left heart are active factors seems probable. Again, the marked power of arterial blood

—or

— used—

rather of plasma

through cotton was

when only poured tainly

deiibrinated

blood

to sustain functional

into the ventricles, as

filtered

even

activit}',

shoMm by

must alone be

that the blood

indicates

life, to

the

since

Pratt, cer-

able,

during

compensate, in case of need, for insufficiency of blood

furnished by the coronary arteries.

The assisted

contractions of the left heart seem to

by the

blood that enters

arterial

it,

me

to be greatly

and mainly by

The experiments

that Avhich enters the cavities themselves.

shown that contraction could be produced by

of Pratt having

contact with arterialized blood, the arrival into the auricle of a normal quantity of this fluid

must be

fully capable, there-

The

fore, of causing contraction of the walls of that cavity.

and the .mechanism involved The main structures upon which are in all probability as follows the arterial blood reacts are (1) the musculi pectinati and (2) the sinus venosus and appendix auriculie, all of which are so relations of the several structures :

disposed as to offer as

much

I’he walls of the cavities

surface as possible to the blood.

mentioned are provided with numer-

ous channels, the Thebesian “veins,” to satisfy this purpose.

The blood which

enters the auricle

when

it

is

dilated pene-

trates all the circuitous areas around the musculi pectinati

and

into the Thebesian vessels, and the ensuing contraction forces

the blood-plasma into the smaller subdivisions of these vessels,

from which they

find their

way

into the auricular veins.

When

the arterial blood reaches the ventricle, a process similar to the

preceding occurs. offer

The columnas

carneiu are disposed so as to

considerable surface to the blood, while the ventricular

walls are permeated with Thebesian channels, into which the

blood

penetrates

closes the

during

diastole.

The

contraction

induced

apertures of these channels, and forces the blood-

431

THE ADRENAL SECRETION AND THE HEART. plasma into their smaller ramifications and

The

veins.

the latter.

finally

into

the

larger channels carry the corpuscular elements to The role of the coronary arteries will be referred

to later on.

The activity cavities

right heart, as I view the process, owes its frmctional mainly to the suprarenal secretion brought to the I have sufficiently emphasized by the vena cava.

the power of this agent to restore cardiac action it

when

even

manner

in which it exercises its powers

On

the arterial blood on the left side.

The

similar to that of

is

penetrating the auricle

the contractile structures are submitted to fects;

and sustain

the entire spinal cord has been obliterated.

but the

orifices of the

more numerous and

its

immediate

ef-

Thebesian vessels or channels are

larger than in the left auricle.

The mem-

branous edges previously referred to as valves by the investigators quoted do not appear to

me

to merit being considered

such after careful examination of these structures in the

as

The

'ox-heart.

aperture being closed by the least squeezing of

the tissues containing them, it seems evident that' they should as readily close

larger

under the powerful contraction of the auric-

The

ular tissues.

number

of

right ventricle also presents a very

Thebesian

orifices

than the

left,

much

while

its

though thinner, plainly show the ramifications of these channels. That the venous blood charged with suprarenal se-

walls,

when the

cretion should at once penetrate the latter

begins to contract

is

self-evident.

circulation is effected in the left

heart

but,

:

i.e.,

The whole as we shall

Eetum

same way

ventricle

of the blood to the

as in the case of the

through the coronary veins. process

is

an exceedingly uncomplicated one,

see later on, it simplifies

many

obscure prob-

lems, while affording, in connection with the coronary arterial blood, a supply in keeping' with the vital importance of the

organ

itself.

Again, Dr. Pratt’s experiment, in which blood

injected into the left auricle flowed freely tricle,

need.

from the right ven-

emphasized the possibility of compensation in case of Thus, while under normal conditions, the pressure in

both

—

ventricles must be equal, reduced contraction of the right ventricle, for example through insufficiency of the adrenals would automatically cause the arrival into it, through

—

THE DYNAMICS OF CARDIAC ACTION.

432

the Thebesian foramina of the seiitum, of at least some arterial

That

blood.

does not alwaj's suffiee to maintain inter-

this

ventricular equilibrium, however,

is illustrated by the dicrotic and kindred phenomena. connection are the remarks of Professor

pulse, the pulsus paradoxus,

Suggestive in this

Porter in his review of the subject of cardiac innervation in the “American Text-book of Physiology”®:

“A

positive

dem-

onstration that the nerve-cells in the heart are not essential to its contractions,” says this observer, “is secured

by removing the tip of the ventricle of the dog’s heart and supplying it with warm defibrinated blood through a cannula tied into nutrient artery.

its

Long-continued, rhythmical, spontaneous

contractions are thus obtained (Porter'®).

contains

no

arise in the

nerve-cells,

muscular

assumption

safe

pulses

the

the

the part removed

can

contractions

only

provided we make the (at present)

tissue,

that

observed

As

do

nerve-fibers

not

originate

im-

capable of inducing rhythmic muscular contractions.”

apply —and may be elements including those the muscular and — cardiac muscle endowed

In other words,

said to

this

muscular

coats of the stomach

of

intestines,

to all

the

is

with the in-

herent power to contract, even small detached pieces, when placed in appropriate media being capable of doing body, indeed, this contractile power active,

and Porter remarks

of our views:

—almost

“The demonstration

is

In the

so.

merely, so to say, kept

prophetically in the light

that the nerve-cells are not

essential to contraction places us one step nearer the true cause

of contraction. stance.^^

It

Evidence

is

some agency acting on the

is

contractile sub-

accumulating that this agent

ical substance, or substances,

is

a chem-

brought to the contractile matter

by the the blood.”

That the “chemical substance brought

to the

contractile

matter b)^ the blood” is represented by the adrenal secretion and the oxidizing substance seems clear. Brown-Sequard over fifty so7tie

years ago urged that the inferior vena cava contained undetermined substance which contributed to the heart’s

d'V'namism.

“

of Physiology.” second edition, 1900. Journal of Experimental Medicine, vol. 11, p. 391, 1897. All Italics are our own.

Porter: Porter:

“American Text-book

THE ADRENAL SECRETION AND THE HEART.

433

THE ACTION OF THE ADEENAL SECRETION AND THE OXIDIZING SUBSTANCE UPON THE CARDIAC MUSCLE. The

histology of the

conjecture,

for

which

it

of

Its

these:

briefly

tissue is

projections.

lateral

broad

field

to

investigations

The known composed, in man, of observers.

of striated fibers, possessed

fasciculi, or bundles,

round

thick

many

the

notwithstanding

offers a

still

has been submitted by modern

facts .are short,

niyocardmm

The

directly

latter

connecting

with a similar projection of the adjoining bundles and being cemented to it, a thick close-meshed net-work is formed: a

But

characteristic of the heart-muscle.

muscles in several other particulars; smaller and their

sarcolemma and of

any

the

fluid that

contractile

peculiar:

strise

are

much more

are, therefore,

each bundle

is

are

differs

fibers

faint;

from other

are one-third

they possess no

exposed to the immediate action

may surround

structures

it

its

them.

The manner

combined in bundles

made up

which

in

is

also

of central prismatic fasciculi

round fibers, in which nuclei (one or two) with their surrounding protoplasmic area are imbedded, the whole being surrounded with flat or ribbon-like columns of muscle-fibers. The perinuclear protoplasm referred to generally contains fatdroplets and minute pigment-granules which resemble hremoglobin, and sends projections between the surrounding musof

cular fibers so that each of the latter

is

connected with and

only separated from

its neighbor by a layer of protoplasm. This arrangement does not in any way modify the manner in which the sarcous elements are disposed, while the disks, clear is

spaces, etc., are precisely as they are elsewhere in the organ-

These muscular “primary” bundles form, by their union with one or two of their neighbors, columns, or chains or “secondary” bundles, which are covered, as shown by Eanvier, ism.

—

with a sheath of loose connective-tissue cells, which cells, in turn, connect with one another by numerous projections, or extensions.

The primary

tissue sheaths

fasciculi

also

contain

connective-

which invest the muscle-fibers and are likewise supplied with connective-tissue cells. All this forms a close, though permeable, net-work, which makes it possible for a liquid to penetrate the muscular columns or chains and come into direct contact with the bare, or exposed, muscle-fiber.

— THE DYNAMICS OP CARDIAC ACTION.

434 Indeed,

the

intimate

structure

of

the

cisely supplies the required structure for the

myocardium preequable and free

distribution of such an agency as the suprarenal secretion rep-

Fluids can penetrate through the maze of cellular

resents.

muscular

tissue to the bare

the sheaths that include

fibers;

the columns or chains of muscular bundles afford a peculiar

system of canalization through which the liquids can easily gain access to them.

These canals

—the

lacunae of Henle

are the intervals between the columns of secondary bundles, or their sheaths, rather, which are placed in longitudinal apposiSell weigger- Seidel

tion.

injections

interstitial

lymphatic

and Eanvier having observed that colored

of

vessels, the lacunas

substances

penetrated

the

have been considered as adjuncts,

or extensions, of the latter.

Eenaut,^' however, concluded that the penetration of the colored

weak

fluids

the lymphatics merely

into

demonstrated the

resistance of the endothelial coat of the latter,

and the

Henle being unprovided with endothelial ground for the prevailing belief that they walls, there was no He found that all the lymrepresented lymphatic vessels. phatic capillaries of the myocardium are located on the surface They are large and of the heart underneath the pericardium. bosselated and form a mesh-work which covers the whole cardiac surface, and send smaller blind pouches into the muscular spaces, or lacunae, of

The

interstices.

spaces

of

Henle should be considered, he

thinks, “not as true lymphatic cavities analogous to those ob-

served aroimd the pulmonaiy lobules of certain animals, but as mere connective-tissue spaces, which represent, in fact,

pathways for lymph.” In a foot-note Berdal spaces of Henle are crossed by “vessels,” and

states that the

in the text the

following remark as to the identity of this lymph appears: “The muscular fibers of the heart are thus bathed in conspaces

nective-tissue this luit

plasma.

to

lymph

easily

circulates;

but

is

state

Still,

"Renaut: 825.

which

not that of the l^unphatic vessels or capillaries, It is that of loose connective-tissue spaces (Eenaut).”

lymph

needless

p.

in

we

that

this

suggests

the

presence

of

blood-

can only consider this deduction as tentative.

Traitfi d'HistoIogie pratique, p. T19;

quoted by Dcrdal,

lor.

cU.,

THE ADRENAL SECRETION AND THE HEART.

The manner or arterial,

is

in which the blood-plasnxa, whether venous

distributed by the Thebesian channels

The

Meigs.^*

is

well

by Arthur Y.

in a study of the vessels of the heart

shown

435

extreme paucity of literature on the Thebesian

channels has caused them to be overlooked by practically

all

histologists; that they should be treated as capillaries in the

author^s paper to

do

so.

is,

“The

therefore, as capillaries

normal

of the

as it is for text-books

human

heart,” says

Dr.

Meigs, “differ in two ways from those of other parts of the

and some of them are larger than those found elsewhere, and of different arrangement. The accompanying illustrations are drawings which were made with the camera lucida. They are from sections of two human hearts. The first is from the heart of body:

they penetrate the muscular

.

a negro

.

fibers,

.

woman, 40 years

old,

who

died of burns.

Some

pieces

were preserved in Fleming’s solution, and others in 70-per-cent, alcohol, and they were stained in bulk with of the organ

borax-carmine and imbedded in paraffin. that of a man, 30 years old,

When still

who

The second heart

is

died of lead encephalopathy.

the post-mortem examination was made, the heart being

was injected through each of the two much as the blood-vessels would easily

quite fresh, there

coronary arteries as

receive of a solution of 3

grammes

in 600 cubic centimeters of water.

of Berlin blue (Grubler’s)

Pieces of the organ of

suitable size were at once placed in preservative fluid,

70-per-cent, alcohol,

and others in formaldehyde

some in

solution.

The

was afterward stained in bulk with borax-carmine and imbedded in paraffin.

tissue

“The penetration of the muscular fibers by the capillaries made perfectly clear by the illustrations; it is shown as well by the injected -as by the uninjected heart. The two methods

is

of demonstration

supplement one another, because, in injected which has been stained, the blood-vessels and their situation are made very obvious by the contrast of color, but the

tissue

details of the structure of the walls are obscured by the injection material, while, on the other hand, in the uninjeeted tissue,

the structure of the blood-vessels can be seen with the utmost distinctness.

” Arthur

In Figs.

V. Meigs:

1 to 4 the capillaries are easily recog-

Journal of Anatomy and Physiology, Jan., 28

1899.

—

THE DYNAMICS OF CARDIAC ACTION.

436

Their situations in relation to the muscular

nized.

very

varied.

Some

are

in

the

intermuscular

slightly indent the sides of the fibers;

still

fibers are

fibers,

others

others are within

the fibers close to their periplieries, and sometimes the capillaries are in the very centers of the fibers. This penetration of the muscular fibers of the

human

DESCRIPTION OF

DR.

heart in the adult

is

a

most

MEICS’S PLATE.

The amplification has been reduced about one-third

in the reproduc-

tion herein presented. “Fig. 1.—X 420. From a man, 30 years old, who died of lead encephalopA section of papiilary muscle of the heart cut across the fibers, bb are Injected capillaries, the one partially and the other entirely within the muscular fibers, c, A capillary which remains unlnjected; its nucleus is included. “Fig. 2.— X 420. From the same tissue as Fig. 1. v, A vein stained by the injection material, bb. Capillaries whose precise situation cannot be defined. They cannot be said to be intermuscular spaces, nor to be entirely within fibers. The effect is as if the fibers were coalescing. “Fig. 3. X 420. From the same tissue as Fig. 1. in a f. A capillary fiber, This is perhaps the g, A capillary in the center of a very small fiber. most convincing instance of the penetration of a muscular fiber by a capillary. “Fig. 4. X 420. A section of heart cut transversely to the muscular fibers, from a negro woman, 40 years old, who died of burns. The muscular fibers are of irregular shape, d, A capillary within a muscular fiber, its nucleus upon one side producing a resemblance to a seal ring, e, A capillary within a muscular fiber, its nucleus being Included, It f, A capillary in an intermuscular space; resembles a seal ring, g, A capillary in an intermuscular space; its endothelial wall appears as a simple circle. “Fig. 5. X 115. From the same tissue as Fig. 4. A large capillary, receiving many branches and surrounded by muscular tissue. The capillary and its branches are almost filled with blood-corpuscles. The capillary walls are distinctly visible, containing many flattened endothelial nuclei. Not printed in two “Fig. 6. X 42. From the same tissue as Fig. 1. colors, because the essentials show equally well in black, m, Muscular tissue. a. An arteriole; the solid black within its caliber is injection material, v, The accompanying vein to the arteriole, a; it also contained a little of the Injection material; these two vessels are in a connective-tissue interspace, c, A large capillary; it contains a good deal of the blue injection material, which Is repathy.

resented by the heavily-shaded portions. These three vessels— arteriole, vein, and capillary— give a good idea of the character of such vessels in the heart The great size of the capillary is the most striking feature.”

striking

and curious phenomenon, and

it

docs not exist at an

early embryological stage.

Tlie condition

later development,

not yet Icnown at

it

but

it is

is.

therefore, one of

how

early an age

does exist

“Very

large capillaries are found in the

such vessels are shown by find

minute veins

in

Figs. 5

and

company with the

G.

human

It is not

heart, and

common

to

arterioles in the deepest

Fig. 1 Fig: S.

Fig.

Fig.

3

Fig.

CIRCULATIDN

DP'

THE HUMAN HEART,

[Journal of Analomi/ and Physiology.']

g.

6.

[Arthur U, MBigs.]

f

>

V < i

1

437

THE ADRENAL SECRETION AND THE HEART.

is portions of the muscular substance of the heart, although it connective-tissue the and in well known that, upon the surface

found with their vena; comites, just as they are in other organs and tissues. The arrangement of the in marked vessels upon the surface and in the interstices is contrast with that found in the muscular substance proper. Here, when an arteriole is accompanied by an efferent vessel, interstices, arteries are

and composed of endothelium, being exactly like the smallest capillaries, except in size. These peculiar large capillaries are found not only in company with arterioles, and, therefore, when carrying on the function usually

this vessel is single coated

performed by veins, but also alone. When they are alone, it is impossible rto be certain whether their function was afferent oi-

It

efferent.

may

well be that arterioles are less

numerous

and that their place is taken numerous and they perform the fimction of

in the heart than in other tissues,

by the large

These

capillaries.

capillaries are so

of such size that it seems likely

The presence

reservoirs. •

of the large capillaries and the pene-

tration of the .muscular fibers

by the

capillaries indicate a pro-

vision for the blood-supply of the heart even

more bountiful

than that of the other organs.”

That

these vessels are the Thebesian channels is evident;

mode

and the peculiar endings of their subdivisions is particularly well shown in Fig. G, while the outpouring of plasma for absorption by the muscle-elements is

their

of distribution

suggested by Fig.

The is

5.

fact that the distribution of the Thebesian channels

analogous to that observed in the heart of the frog has,

have seen, been noted by Pratt.

by Lannelongue, but

This had

also

been noticed

this author considered the channels of the

human myocardium as dal, who alludes to the

vestiges of the batrachian system. latter, states that

penetrates

intercejit

and

Ber-

in the frog and in the

batrachian nrodda there are no ordinary blood-vessels.

muscular fasciculi

we

“The

cavernous spaces into which the blood

fmm

which they are only separated frog’s heart is thus a true sponge the structures of xohich, formed of muscular fibers, nourish themselves hy inihihiUort,. In mammals, on the contrary, the myocardium contains distinct vessels. The capillaries form a net-work the directly

by endothelium.

The

THE DYNAMICS OF CARDIAC ACTION.

438

meshes of which, elongated and parallel to the muscular fasciculi, are connected by short branches, which give each mesh the appearance of a parallelogram. When these vessels cross the spaces of Henle, they are covered, on the external surface, with flat connective-tissue plates.” Pratt’s observation not only includes the analogy between the

human lung and that of the mammal. Under these

frog, but also with that of the cat, a

becomes clear that in man, also, the heart-muscle he regarded as a sponge-like structure, the contractile ele-

conditions,

may

it

ments

of which are nourished and supplied with working energy by substances in the blood-plasma.

What

is

the role of the blood of the coronary arteries in

the functions of the heart?

This

may

perhaps be traced by

analyzing the effects of ligation of those arteries upon these functions.

Porter^^ refers as follows to the experimental

in this connection

“The frequency

:

work

of arrest after ligation

is

in proportion to the size of the artery ligated, and hence to the size of the area

made amemic, and

is

not in proportion to the

injury done in the preparation of the artery.

The

and descendens may be prepared without injuring cle-fiber,

circumflex

q single

mus-

yet their ligation frequently arrests the heart, while

the ligation of the arteria septi, which cannot be prepared with-

out injuring the muscle-substance, does not arrest the heart. It

is,

moreover, possible to close a coronary artery without me-

chanical

Lycopodium-spores mixed with defibrinated

injury.

blood are injected into the arch of the aorta during the mo-

mentary closure of that arteries

:

the only

spores plug

way

up the

and are carried into the coronary open for the blood. The lycopodium-

vessel

left

finer branches of the coronary vessels.

The

coronary arteries are thus closed without the operator having Prompt arrest, with tumultuous fibrillary touched the heart. contraction, follows.”

If the plasma that reaches the heart by sian channels can sustain both

its

way

of the Thebe-

nutrition and its contractions,

accounted for? The sudden the coronary arteries plugging arrest of the heart’s action by certainly points to a predominating function, and, more than

how can such

tliis,

results as these

to a function of Porter:

Loc.

cit.

lie

which they are alone the sources of blood-

THE ADRENAL SECRETION AND THE HEART. Tliat the role of the coronary blood

supply.

is

439

precisely that

which obtains elsewhere in the organism is forcibly suggested by the experiments of Langendorff, who was able, according to Porter, “by circulating warmed oxygenated dcfibrinated blood through the coronary

and dogs in

cats,

vessels, to

maintain the hearts of rabbits,

activity after their total extirpation

from the

It is clear that the blood-plasma can incite functional

body.”

when introduced through the coronaries as well as when introduced into the ventricles. “Even pieces removed from the activity

ventricle will contract for hours,” continues the author, “if fed

with blood through a cannula in the branch of the coronary artery which supplies

them (PorteP®).

It is evident, therefore,

that the cause of the rhythmic beat of the heart lies within the

and not within the central nervous system.” words represent precisely the factor of the problem which must be eliminated .to enable us to differentiate the role of the coronary plasma from that of the Thebesian heart

itself,

The

italicized

plasma, for blood will not alone induce contraction of the cardiac walls; almost any irritant will under appropriate conditions.

Indeed, in the latter case

it will sometimes undergo conwithout any external irritation; thus, “a strip of muscle cut from the apex of the tortoise ventricle and suspended in a moist chamber begins in a few hours to beat apparently

tractions

own accord with a regular, but slow, rhythm, which has been seen to continue as long as thirty hours. If the strip is of its

cut into pieces and placed on moistened glass slides, each piece will contract rhythmically. Yet in the apex of the heart no '

nerve-cells have been

contract

is

inherent

found” (Porter). in.

the contractile

Hence the power tissues, and subject,

to

as

elsewhere in the organism, to exacerbations of activity under appropriate stimulus. This fact being now established, our in-

quiry

is

simplified, since

of the processes through

we need only which

to inquire into the

nature

it is utilized.

Analysis of the requirements of the right heart soon reveals the fact that the muscle-fibers require the same bloodsupply that any muscle of the body does. Indeed, we then realize that the coronary arteries are their only source of oxy-

Porter:

Journal of Experimental Medicine, vol.

il,

p. 391,

1897.

— THE DYNAMICS OF CARDIAC ACTION.

440

The venous blood

gen.

roaches

tliat

through the Thebesian

it

cliannols has been dejileted of this gas

by the rest of the organism, and the suprarenal secretion, owing to its marked avidity for it, must, while in transit through the inferior vena cava, have deprived it of the little that might have remained

We

in loose combination.

have reviewed the ultimate distribu-

tion of the coronary arteries as given by Berdal.

from that of other text-books.

differ

It does not

These generally concur

in stating that the larger branches are distributed to the con-

nective tissue between the

large

fasciculi,

and once

tlierein

divide into arterioles, which, in turn, subdivide into capillaries

“The capillaries myocardium are very numerous,” say Bblim and von Uavidotf, “and so closely placed around the muscle-bundles that that entwine the primary muscle-fasciculi. of the

each muscular fiber comes in contact with one or .more capil-

Do

laries.”

with

fiber

its

they serve here, as elsewhere, to supply the musclesource of energy

—

i.e.,

the carbohydrates that enter

into the formation of the myosinogen

cisely

furnishing the

^besides

which sustains the combustion processes

substance

oxidizing

when brought

—

into contact with this- myosinogen

This

?

is

pre-

where a difference between the muscular functions of the

heart and those of other muscular structures appears to us to exist.

There

when we

is jiractically

consider that

fourths of a sound

;

no passive period in the

its

heart’s action

stage of octMtij recurs every three-

and the formation of mj'osinogen

contractile elements, were

it to

proceed as slowlj' as

it

in its

does else-

Still, if the coronary where, would seem totally inadequate. blood is not endowed with the mission of supplying the heart-

muscle with

its

source of energy,

are relegated to the venous

we

blood of the Thebesian vessels and

its

the myosinogen-forming products.

ergy

suggests

known

to react

present in the

itself

when we

under the hepatic

A

suprarenal secretion for source

possible

consider

that

a

of

en-

carbohydrate

effects of the oxidizing substance is

veins,

i.e.,

dextrose,

—and

that

this

sugar must pass through the right heart. As is well known, That these veins carry their sugar to the inferior vena cava. it is not used by the heart, however, was shown by a careful analysis of the whole question.

This

is

submitted in the twelfth

— 441

THE SOURCES OF THE HEART'S ENERGY.

For reasons submitted in the second volume I was on page 433 led to conclude that the minute granules referred to intermediary the through were actually supplied to the heart the liver of leucocytes. These cells were found to migrate from where cava, vena inferior the veins) to (also through the hepatic cliapter.

they meet the adrenal secretion and proceed with it to the The evidence seems incontrovertible. The right ventricle. subject is so far-reaching, however, that it had to be considered separately.

I

for the present only, refer to these

shall,

granulations as “granules (3” (Ehrlich). to

We now

have,

it

seems

me, the elements necessary to account for the functional phewitnessed, namely

nomena

:

The adrenal secretion, to contract the right auricle and ventricle and thus insure the penetration of the Thehesian Mood 1.

into the cardiac walls

(which contraction venous blood or

its

would not cause).

contained granules

account for the unusual and continuous production of energy which the heart converts into worh. 3. A continuous supply of oxidizirig substance via the coro2.

The granules

nary arteries

to

to insure the

combustion processes through which

this energy is liberated.

The annexed

colored plate shows the

adrenal secretion and the granules

f3

manner

in

which the

simultaneously reach the

right auricle.

We

can

now understand why plugging

of

the coronary

by Porter, arrest cardiac action. Referring to the effects of embolism and thrombosis of these “That part of the heartarteries, this investigator also says: wall supplied by the stopped artery speedily decays. The bloodless area is of a dull-white color, often faintly tinged with

arteries should, as stated

yellow; rarely

it is

red, being stained l)y hcemoglobin

neighboring capillaries.

The The

The

from the

cross-section is coarsely granular.

power of staining. and connective tissue soon replaces of funetion and rapid decay of cardiac tissue

nuclei of the muscle-cells have lost their muscle-cells are dead,

tliem.

This

loss

would not take place did anastomosis permit the estaldishment of collateral circulation between the artery going to the part and neighboring arteries. The objection that one of .

.

.

the coronary arteries can be injected

from another, and

that.

— THE DYNAMICS OF CARDIAC

442 tlicrefore,

they are

not

terminal,

is

ACTION.

based on the incorrect

in-emise that terminal arteries cannot be thus injected, and has no weight against the positive evidence of the complete failure of nutrition following closure.” As 1 interpret the process, the absence of anastomosis further suggests the exist-

ence of an additional source of energy; but the cardiac arrest after ligation of the coronary also indicates that compensation

from the opposite heart can only be gradually

On

established.

the whole, the coronaries of the right side are as important as if they alone supplied the needs of the functions of that

The granules ji and the adrenal secretion are furnished to compensate for the absence of arterial blood in the right auriculo-ventricular cavities and in their Thebesian channels; but, side.

the right coronaries being the only source of one of the three necessary factors

much

of the process,

We

why

can also understand

the primary fasciculi are bare. in

their obliteration

means

as

as that &f the left coronaries does to the left heart.

the contractile elements of

They

are

constantly bathed

from which they obtain the granules /? that the formation of their myosinogen. The absence

the plasma

enter into

of oxygen in this fluid renders delicate structures

perfectly harmless to the

it

that surround the primary and secondary

bundles of muscle-flber, and to the net-works of arterial capillaries that

hug the bare

—which

tion,

fibers.

The

latter,

by a rapid absorp-

the presence of sarcolemma would counteract, i.e., forming their products of metabolism The arterial capillaries, “coated, on their exter-

constantly

are

myosinogen.

:

nal surface, with

flat

connective-tissue cells”

(Berdal),

when

they cross the spaces of Henle, being the only carriers of oxygen, normally become the active factors of nutrition and function.

Their blood

is

—

the normal excitant

venous blood brings the granules

P

contracting the cardiac walls, forces nels; the bare muscle-fibers

them

into their

own

absorb

;

it

into the Thebesian chan-

the granules and convert

particular kind of fuel, myosinogen; the

capillary blood supplies the energy for this metabolism

gen

—and

The

as elsewhere.

the adrenal secretions, by

simultaneously sustains, again with

its

—

o.xy-

oxygon, the

combustion processes ujion whicb the continuous work of the Here, as elsewhere, the potential energy of organ depends.

443

THE SOURCES OP THE HEART’S ENERGY.

chemical agencies present becomes converted into mechanical energy, which manifests itself as visible motion. tlie

The

—the coronaries —presents anatomical

of which are larger than

heart

left

features which modify,

those of the right

manner in which its physiological functions Both its auricle and ventricle containing arte-

in a measure, the

are performed.

blood fresh from the heart, the Thebesian circulation does

rial

not appear to

fulfill

the primary role

does in the right heart.

it

Indeed, the various experiments of Pratt and his predecessors

and my own careful examination of the ox-heart distinctly show that the Thebesian circulation of the left heart, as regards intraventricular orifices, is much less important than that of the right heart.

Still,

the evident permeability of the inter-

myocardium material aid from the

ventricular sei)tum and the histology of the left

must

suggest that the left heart

adrenal secretion and

its

receive

granules p.

This feature will again

be referred to in the twelfth chapter.

A

may

feature that

common

be considered as demonstrated, and

to both sides, is the return of the blood,

source be the Thebesian or coronary systems, by

coronary veins.

We

whether

way

its

of the

have seen that Langer expressed the opin-

ion “that the foramina Thebesii in the ventricles communicate

with the veins by capillaries alone.”

My

conception of the

process involved would necessitate such an arrangement as re-

gards the right heart.

Indeed, so direct is this connection that even such viscid substances as starch and celloidin were found by Pratt, when introduced into the coronary veins of the ox,

emerge from the foramina Thebesii. Still, we could hardly expect such a free transit on the left side of the organ, inasmuch as the presence here of arterial blood only would suggest the presence of a structural organization similar to that of ordito

nary muscles.

Indeed, referring to the vascular connections

of the left heart, Pratt says;

“So intimate

a connection,

how-

between the coronary veins and the vessels entering the ventricle I have not yet been able to demonstrate.” Again,

ever, left

on the right

side the connection with coronarj'’ veins must evidently be a physiological one, since “a small, but steady, stream

of venous blood issued

from them” when the veins were incised had been filled with defibrinated blood.

after the right ventriele

:

THE DYNAMICS OF CARDIAC ACTION.

444

But “no flow of blood occurred from the artery, although there was a free escape from an incision in an accompanying vein” in an experiment similar to that previously referred to, also performed by Dr, Pratt. In fact, it appears to me very doubtful whether even the capillary communication between coronary arteries and the Thebesian vessels, referred to by the latter observer in his conclusions, at of

tlie

all exists

—

at least in tlie walls

my

Even disregarding

right heart.

views,

seems

it

evi-

dent that the admixture of venous blood with tlie arterial blood would greatly reduce and perhaps annul the functional efficacy of the latter as an oxidizing agent.

We

can now understand how the

An

greatly influences cardiac activity.

adrenal

secretion

increase of

it

so

augments

the force of the contraction, but the heart does not dilate as

promptly nor perhaps as completely; hence its action is slower, but more forcible ; we have seen that this represents the primary effect of all

A

drugs sufficiently active to stimulate the adrenals.

greater quantity of adrenal secretion increases the vio-

still

lence of cardiac action;

luematuria, epistaxis,

the vessels are tense, and ecchymoses,

etc.,

however, in the sense that tinuous

cardiac

may

ensue.

The

its diastole is

stimulation

through

heart acts normallj',

Con-

almost complete.

excessive

production

of

adrenal secretion, due in turn to excessive production of iodothyrin, as in exophthalmic goiter, causes the heart to contract

before

it

has

exhausted

within a narrower

field.

its

complete

diastole

involves increase of oxidizing substance;

correspondingly stimulated.

ciency occurs, the

to

work

Increase of adrenal activity

the type of the “cramped heart.”

is

and

Its contractions are sharp, but rapid

hence the

left heart

When, however, adrenal

phenomena follow an

opposite course;

insuffi-

when

total inhibition of the adrenal system ensues, the vascular walls, the adrenal secretion, the losing all their functional stimuli,

—

and contractions and lapse into

granules

the oxidizing substance,

—gradually

cease their

diastole.

THE INNERVATION OF THE HEART.

We

are again brought, by analysis, to the realization that

the efferent nerves distributed to the heart incite and govern functional activity but contribute nothing to the continuation

MECHANISM

CF CAREIAC ACTICN,

[SaJous.J

1, Inferior Yena Cava, th.e blood of which, contains Hdrenal Secretion. 2, Hepatic Veins, the blood of which contains granules /3 derived from the Liver. 3, Right ilurlole. 4, Cne of the Coronary Arteries. B, Cne S, Cne of the Coronary Veins. of the Foramina ThebesU.

i

— THE INNERVATION OF THE HEART. of vital processes per

445

Indeed, in the heart they do naught

se.

One set of nerves than in other parts of the organism. distributed to the cardiac arteries provokes dilation to increase else

another set causes constriction of these vessels

cardiac activity;

when

cardiac activity

of the heart

is

is

“The

to be reduced.

rich nervous supply

derived from the coronary plexuses"’ says Piersol,

“and includes numerous medullated

fibers

coming from the

pneuniogastric as well as the non-medullated sympathetic fibers

Numerous microscopical

proceeding from the cervical ganglia.

ganglia are found along the course of the large nerve-trunks

accompanying the branches of the coronary arteries, especially in the longitudinal interventricular and in the auriculo-ventricular furrows. cells

Many

additional small groups of ganglion-

occur within the muscular tissue associated with the fibers

supplying the intimate structure.” vailing teachings

the vagus

Briefly, according to pre-

and sympathetic are the nerves

which govern the functions of the heart. Is this true? In the light of my own views, to doubt;

and, precisely as I have shown

the kidneys,

all

it

it is

subject

to be the case

with

the nerves supplied to the heart belong to the

sympathetic system.

Acceleration.

—

Legallois, early last century (1812)

urged

that the nerves which increased the beats of the heart in a given time belonged to the sympathetic system. Although

vigorously attacked by Bezold

and others, this doctrine has and most investigators, including Heidenhain, Langley and Gaskell have accepted Legallois’s view. It becomes a question, however, in the light of my views, whether acceleration represents the motor phase of cardiac steadily gained ground,

—

action,

and therefore, whether or not

sympathetic

That

it

does

fulfills is

the role of motor,

as

i.e.,

in the kidney, the of vasodilator nerve.

shown by the experiments of E. and M. Cyon^®

who found

that occlusion of cardiac vessels did not cause acceleration in other words that it was not by reducing the blood supplied to the heart walls that the accelerators acted

—

upon the

heart. On the other hand, as will be shown under the next heading, constriction of the cardiac arteries, f.e., dimi-

^“E. and M. Cyon:

Archiv

f.

Physiol., 1867.

:

THE DYNAMICS OF CARDIAC ACTION.

44G nution

ol‘

the blood supplied to the cardiac muscle, slows the

Indeed, Eaxt^^ observed a distinct antagonism

heart’s action.

between the vagi in the neck

—owing

shown below

as

to the

—and the

presence of cardiac vasoconstrictor fibers in this nerve accelerators,

when stimulated simultaneously.

The

vagi sup-

pressed the accelerators invariably, in fact, and irrespective of the strength of the current. celeration

is

It is evident, therefore, that ac-

not due to constriction of the cardiac arteries, and

that the S3'mpathetic accelerators

producing dilation of these

The

must

act

upon the heart by

vessels.

vasodilator properties of the accelerators have, in fact,

so legitimate a claim to recognition that in his recently pub-

lished review of our knowledge

“The

marks: to

first

on the subject Carvallo*®

contain vasodilator fibers which almost always cause aug-

mentation of speed.”

He

forcibly illustrates this fact by a

table demonstrating that the vessels so influenced

creased hlood-flow in a given time, are stimulated,

“We may

and

when

closes his review

in-

the accelerator nerves

conclude therefore that the heart possesses a eomplete

essentially

by the

show an

with the following words

vasomotor apparatus the vasoconstrictor it

re-

thoracic ganglion, or stellate ganglion seems

stellate

fibers of

which reach

by way of the vagus, and the vasodilator nerves ganglia [first thoracic] and the annuli of Vieus-

sens.” Briefly,

“acceleration” represents

an exacerbation of ac-

and just as we found such increased activity produced by vasodilation and the admission of an excess of tivity of the heart,

blood, in other organs, so do

Inhibition.

—In

phenomenon should

we

the light of foregoing statements, this

assert itself as a result of excessive con-

striction of the cardiac arteries

plied to the cardiac muscle. itself

from various

The

find it here.

and diminution of the blood supThat such is the case suggests

directions.

inhibitory etfect of excessive constriction of the coro-

beyond question. Chirac'® found that the beats of a dog’s heart were soon arrested when one of the coronaries was

naries

is

”

Baxt: Arb. a. d. phys. Anst., Leipzig. 1875. •“Carvallo: Rlchet’a Dlctlonnalre de Physiol., “Chirac: “De Motu Cordis,” p. 121, 1698.

p.

347,

THE INNERVATION OF THE HEART.

447

Erichsen-® observed a similar result after tying these Leonard Hill-^ referring to the investigations of Cohnvessels. tied.

heim and Schulthess-Eechberg,-- McWilliams,-® Bettelheim,®'* and others, also states that “ligaturing one of the large branches only

frequently

is

to

sufficient

cause

Again,

arrest.'”

See,

Bochefontaine and Eoussy®® observed that substances capable of

plugging the coronaries caused cardiac arrest.

—lycopodium

—

spores, for instance

also

Porter®® plugged the left coronary artery

and says that “the closure of the artery was always promptly followed by arrest.” As the result of closure by ligation in sixty-seven dogs, he reached the deduction that in nineteen dogs

“the frequency of arrest artery

ligated.”

As

is

proportion to the size of the

in

impulses

cardio-inhibitory

transmitted

through the vasoconstrictors of both vagal trunks probably influence all the cardiac arterioles simultaneously,

the

ease

with

which the heart’s action can be arrested by exciting the bulbar center is easily accounted for. Finally Kolster,®^ Porter,®® and others have

shown experimentally that the part of the heart

supplied by an infarcted coronary artery degenerates. Yet,

if

the vasomotor impulses inhibit the heart by causing

excessive constriction of the coronaries effects

and

their offshoots, the

on the heart wall must coincide with those resulting

from deprivation of blood.

Such is undoubtedly the case: E. Weber®® observed that during partial inhibition the cardiac contractions were weakened, while

Schiff®®

found that the mus-

cular elements of the entire organ responded less or not at all to

Prangois-Eranck,

stimuli.

Pischel,®’

and others observed

that the cardiac walls were softer than usual.

Foster®® states

“Erlchsen:

London Hospital Gazette, vol. ii, p. 561. 1842. ^Leonard Hill: Schafer’s “T. B. of Physiol.,” vol. il, p. 1, 1900. “ Cohnheim and Schulthess-Rechberg; Virchow’s Archlv, Bd.

3,

Ixxxv,

H.

S. 503. 1881.

“McWilliam:

“ “

Jour, of Physiol., vol.

vlll, p.

296, 1887.

Bettelhelm; Zeit. f. kiln. Med., Bd. xx. S. 436, 1892. Sde, Bochefontaine and Roussy: C. R. de I’Acad. des

scl.,

T. xcli, p. 86.

1881.

“ Porter; Jour, of Exper. Med., vol. I, p. 46, 1896. ” Kolster: Skandlnav. Archlv f. Physiol., Bd. iv, p. 1, 1883. ® Porter: PnUger’s Archlv, Bd. Iv, Hft. 7 u. 8, S. 366, 1894. “ E. Weber: "Handworterbuch d. Physiol., Bd. 11, S. 42, 1846. “ Schlff: Archlv f. Physiol. Hellk., 9ter Jahrgang, S. 1850-51. 22,

Pharm., Bd. xxxvill, Hft.

3 u.

“T. B. of Physiol.,*’ sixth American edition, Phila.,

1895.

P1897.

“ Foster:

4,

S.

228,

THE DYNAMICS OF CARDIAC ACTION.

448

when the interrupted current

that

vagal trunk,

tlie

is used to stimulate the heart remains in diastole, motionless and flac-

When, however, the current is weak, the beats are only slowed and weakened. Coats®^ ascertained manometrically that cid.

the contractions were markedly reduced in force.

GaskelP^

and Stefani^® found that the ventricular tonicity was reduced. IVfuskens®® also found that stimulation of the vagus lessened the force of the contraction in the frog. GaskelP'^

characterizes

“most striking” the attending

as

depression of activity. Still, there is no loss of inherent muscular irritability, since, according to Foster,®* a pin prick in the heart during inhibition heats;

the morbid

may

phenomena

cause the organ to resume

deficient supply of the nutrient

components of the blood.

a

Por-

knovTi as to the constituents of

ter®® states that ‘Tint little is

the blood which are essential to the

life

of the

heart,” and that .“an abundant supply of oxygen

highly important.”

its

are, therefore, the result of

The manner

these blood constituents causes the inhibitory effects :

certainly

is

which the deficiency of

in

in the following lines of Langley’s*®

mammalian

“The

is

suggested

decrease of rigidity

in the inhibited muscular tissue shows that inhibition

is

not

caused by the development of a contractile force acting in a direction opposed to the normal one and overpowering

it.

We

are then brought to the conclusion that certain nerve impulses

—the

inhibitory nerve impulses

—are

able to lessen or to stop

the chemical change in the tissue which leads to contraction.”

The ered

(now generally considform part of the nerve bundles

role of the “inhibitory” fibers

as vagal, because they

which have been known as the vagi, or pneumogastric nerves) thus corresponds with that of the sympathetic vasoconstrictors we have found, elsewhere, to restore the arterioles to their nor-

mal

caliber after these vessels

secreto-motor

“

Coats:

nerve

Berlcht

d. k.

to

incite

had been dilated by a motor or an exacerbation of functional

Sachs. Gesellsch.

d.

Wisscnsch.,

MGaskell: Phllosoph. Trans., p. 1019, 1882. “Stefanl: Archives Itallennes de biologie, T. ** Muskens: PflUger's Archlv, Bd. Ixvl, Hft. 5

S. 360, 1869.

xxlll, p. 172,

189,'i.

u. 6, S. 328, 1897. Schafer’s “T. B. of Physiol.,” vol. II, p. 169, 1900. "T. B. of Physiol.,” sixth American edition, 1895.

!"Gaskell: “ Poster: ™ Porter: “Amer. T. B. of Physiol.,” vol. 1, second edition', p. Langley: Schafer’s ”T. B. of Physiol.,” vol. II, p. 616, 1900.

1I8,

1900.

—

44 !)

THE INNERVATION OF THE HEART.

Langley’s observation gives precision to .my view in connection; interpreted from my standpoint, it is the

activity. tliis

diminution of blood in the cellular elements which serves “to lessen or to stop the chemical change in the tissue which leads

Can we

to contraction.”

ascribed by admit that in the heart role

view of the secreto-motor

logicalljf, in

physiologists its

the vagus in other organs,

to

action

the opposite?

is

That the

composed of sympathetic fibers which carry on the same functions they do in other organs, so-called “inhibitory” nerve is

is

therefore evident.

Should we under these conditions consider the sympathetic as

“inhibitory”?

of

excessive

I

have shown that inhibition is the result “Excessive” here of the arterioles.

constriction

obviously portrays a morbid or pathological condition, one of

Indeed, as I will show in the

grave importance clinically. second volume,

many

toxins and toxics are fatal owing to their

vasoconstrictor infiuence on the cardiac vessels,

phenomena awakened

and the morbid

—

are precisely those described above

those

which the physiologist deems normal because they are expressions of a so-called physiological function he has termed “inhibition.” In my opinion the older term “moderator nerve” should replace the pernicious term

now

used,

and “inhibition” be

re-

served for the expression of the morbid process which excessive constriction of the arterioles represents.

AucaiENTATiON. contractile power,

its

of acclerator nerves.

number

i.e.,

increase of

must bo due to an action other than that Thus, von Bezold and Bevei"*^ and later

found that stimulation

Cyon^the

This action of the heart,

of

the

accelerator

increased

of beats of the heart, but not its power.

This was Again the mode of action of the augmentor nerve differs strikingly from that of other cardiac nerves; Foster,'*^ for instance, writes: “In contrast with the case of the vagus fibers, a somewhat strong stimulation is confirmed by other investigators.

required to produce an effect; the time required for the maxi-

mum *'

effect to

be produced

Bezold and Bever:

“Cyon:

Untersuch.

hoc. r(f. “Foster: Loc. clt., p. 203.

is

a.

also

d.

remarkably long.”

physiol. Lab.

These

zu Wurzburg, Bd.

11,

450

.THE DYNAMICS OF CARDIAC ACTION.

and augmentation are separate functions. Indeed, the delay in the augmentation of power, as compared witli the acceleration, is explained when, as I urged a few years ago,'*'* the adrenal secretion is regarded as the source of the increased cardiac power. This is sustained by many facts. Thus, while Noel Paton'*'* refers to the “augmentors and accelerators” as small medullated, i.e., sympathetic, fibers “which leave the spinal cord by the anterior roots of the second, third, and fourth dorsal nerves passing to the stellate ganglion,” I facts suggest that acceleration

have shounr that the three above-mentioned roots are

through which the nerves which pass to

cisely those

pathetic chain

and thence down

resell the adrenals.

On

also pretlie

sym-

to the splanchnic, to finally

stimulating these nerves, therefore, an

experimenter not only excites the accelerators which pass to the heart via the annulus of Vieussens, but also the nerve-paths to the adrenals.

This -accounts for the fact that while a large group of investigators including Cyon, Bezold, Schmiedeberg, Boehm and Bowditch observed acceleration without increase of power, others, equally competent, including Heidenhain, drills, Eoy and Adami, and Bayliss and Starling observed both phenomena. Indeed

Schmiedeberg and Bowditch both urged the presence of two different sets of nerves to account for these specific effects, the

influencing the cardiac beats, the other “acting upon Now, the the blood-pressure without influencing frequency.” blood-presupon the secretion marked influence of the adrenal

one

set

well-known, and the delay in the appearance of “augmentation” is explained when it is borne in mind that the activity of secretory organs had to be awakened before the “aug-

sure

is

mentation” and the Biedl,-*®

fest.

rise of blood-pressure could

in fact, found

become mani-

that stimulation of the divided

splanchnic only caused an increased production of adrenal secretion after 7 to 9 seconds.

submitted in the two preceding sections, the reasons which had led me to conclude that the adrenal secretion conwhich tributed to the contractile power of the right ventricle I

“

Sajous:

Jour. Amer. Med. Assoc., Feb. 4, 1905. ‘‘Essential of Human Physiol.,” p.

“Noel Paton:

«

Biedl:

Lor.

rll.

243,

1905.

451

THE INNERVATION OF THE HEART. it

reaches with the venous blood of the

Now, Brown-Sequard'*'^ had many years

vena cava. (1853) urged

inferior

earlier

the predominating influence of the blood of this vein

upon

cardiac dynamism, a view sustained by Eadcliffe (1855)

;

Castell having

but

found that a frog’s heart when detached failed

with increased vigor in carbonic acid gas, and overlooking the fact that some other substance in the venous blood to beat

might have acted on the heart, physiologists disregarded BrownAdditional evidence to this elfect

Sequard’s observation.

is

submitted in the second volume.

The

presence of “augmentor” and ‘^pressor” fibers in the

sympathetic splanchnic accounts for the fact long ago recorded

by von Bezold and Bensen,*® that section of both splanchnics lowered the blood-jiressure as

much

as

section of the

spinal

cord in the cervical region, while Strehl and Weiss found that,

removing one adrenal, the blood-pressure could be lowered by clamping the suprarenal vein of the remaining organ, thus after

depriving the blood

of

any adrenal

releasing this vein the blood-pressure

As

previous level.

secretion,

and that by

was soon restored

to its

I view the process, however, excitation of

the lower segment of the upper sympathetic cord after dividing it

should raise the blood-pressure.

Bezold found that this pro-

cedure raised the blood-pressure as level;

initial

same

much

as

seven limes

its

Ludwig and Thiry showed, moreover, that the

result could be obtained after severing all the nerves to

the heart.

Augmentor

may

also

effects

attended by a rise of the blood-pressure

be produced through the intermediary of another

Cyon and Aladoff'*” found that stimulation of the annulus of Vieussens (which also contains pure accelerator fibers) organ.

Cyon had already found in 1867 that when the cervical sympathetic was divided on a level with the inferior cervical ganglion, and its upper segment was exraised

the blood-pressure.

cited the strength of the heart-beats

was markedly increased.

" Brown-Sgquard: Exper. Researches applied to Phys. and Path., N. Y.. London, and Paris, 1853. ‘®Von Bezold and Bensen: Neue Wiirzberger Zeitung, 1866: Verb. d. Phys. med. Gesells., Wurzburg, January, 1867. and Aladoft: Bull, de I’Acad. des Scl. de St. Petersburg, vol. vii, 29

—

— THE DYNAMICS OF CARDIAC ACTION.

452

A

—

(1898)"® by the same physi-

recent study of the question

ologist

showed that these “reenforced pulsations” which he had

at first ascribed to reflex action, were in reality due

that the nerves which evolve these to the vessels of the thyroid gland

the fact

tri

phenomena were distributed it was the secretion

and that

which had produced the cardiac “augmentation.” The manner in which the thyroid secretion could produce this of this organ

effect is readily explained

by the fact that, as I have shown,

this secretion serves to sustain the functional efficiency of the

adrenal

center.

Briefly,

—that

it

is

through the adrenals

also

Cyon produced “reenforced pulsations”

though indirectly of the heart.

The following

conclusions seem to me, in the light of the

foregoing facts, to summarize the functional mechanism of the

heart

;

The nervous supply of the heart is derived from the sympathetic system and is composed of two sets of nerves' the accelerator and the moderator ( or inhibitory) nerves. 2. The accelerator nerves increase the rapidity of the con1.

tractions of the heart, by causing dilation of its arterioles

thus increasing the volume of blood admitted to

its

and

muscidar

ele-

ments. 3.

The moderator

(or inhibitory) nerves diminish the ra-

pidity of the heart’s contractions, by causing constriction, of arterioles and thus reducing the volume of blood admitted to

its its

muscular elements. “Augmentation,” Jf.

i.e., increased poiver of the heart’s conactivity of the adrenals, whose increased tractions is due to secretion traverses the heart on its way. to the lungs. As to the physico-chemical process involved hearing in

—

mind that the muscular elements are inherently contractile they are, pending additional data, as follows; 5.

The mechanical energy

depends

is

of

Uvo hinds:

adrenal secretion brought to

(1) it

up07i

the

which

the

contractile

heart

right

action

of

the

by the inferior vena cava; (2)

coionaty the continuous action of the oxidizing substance of the the arterial blood upon myosinogen foi'med from granules 3) latter baing granulations derived “>.Cyon:

from

Arch, de physiol, norm, et path.,

leucocytes. vol. x,

No.

5,

p.

618,

1898.

ADRENAL SECRETION

453

IN RESPIRATION.

The. adrenal secretion and the granulations

6.

right auricle

^

enter the

the right ventricle with the blood of the vena

and

cava.

The adrenal

7.

secretion,

owing

direct

its

to

action

on

muscular tissue, causes the walls of these cavities to contract

upon

alternately

their venous

contents

and

to

force a small

quantity of the latter into the Thebesian foramen and channels. S. This blood then penetrates the interfibrillary spaces of

—

—

around the bare muscle-cells, and its granules fS are used by the lattei' to build up their myosinogen. 9. /Is the plasma of the coronary arteries and their ter-

Ilenle ,

i.e.,

minals, the pericellular capillaries of the muscle-elements, contains

oxidizing

muscle-cells 10.

is

substance

induced as

The adrenal

(adrenoxidase)

secretion

contraction

of

the

elsewhere in the organism.

it is

and the granules

f} ,

which do not

enter the Thebesian channeds, are carried to the lungs with the

venous blood of the right ventricle. 11. The mechanical energy of the

left heart is supplied (1) by the oxidizing substance of the arterial blood, which penetrates

muscular structures and its cavities by the coronaries and the pulmonary veins, and (2) by an additional supply of granulations and perhaps of adrenal secretion, which find their way f3 , to its myocardium through the Thebesian channels that connect its

it

with the right heart. 12.

The manner

on in the walls of the

in

which the contractile process

left

heart

is

is

carried

similar to that which prevails

in the right heart.

THE ADRENAL SECRETION IN ITS RELATIONS TO RESPIRATORY FUNCTIONS. The

role

of

the

adrenal

particularly the jirocess through

the blood,

was reviewed

secretion

in

and taken up by

respiration,

which oxygen

is

in the second chapter.

I believe that the succeeding chapters, by affirming the importance of the oxidizing substance in every part of the organism, have but confirmed the conclusions reached concerning the process in ciuostion. he fact that the interchange of oxygen and carbonic acid between the alveolar air and the blood fi.

difTusion

by mere was inadequate to account for the experimental results

:

THE RESPIRATORY MECHANISM.

454 of

various

Smith,

must

investigators,

has

therefore

particularly

been

Bohr and Haldane and

correspondingly

emphasized.

also refer to the fact, however, that the belief of

I

Ludwig,

Bohr, and others, that the alveolar tissues might be the seat of functions capable of fulfilling the missing requirements of

the process, has not been sustained by

my

inquiry.

On

the

other hand, the role of the adrenal secretion in the lungs as I have defined

it

has adequately met these requirements, not-

withstanding the severe

which

tests to

it

has been submitted in

previous chapters.

We

have seen that the adrenal secretion, conveyed to the

lungs with the venous blood,

is

not only able to take up oxy-

gen, but to form an oxidizing substance,

i.e.,

adrenoxidase, with

which ha3inoglobin can, in the lungs, become replenished with oxygen. The entire set of analyses submitted in this work so far, however, i.e.,

has served further to emphasize another fact

that the plasma, and not the corpuscle,

is

the dispenser of

oxygen, the corpuscle being a mere carrier from which the

becomes replenished as needed. As already stated, this precisely coincides with the conclusion to which Jaquet was led by chemical methods after Salkowski ( 1881 ) had obtained oxidations from blood alone, which he attributed, how-

plasma

itself

ever, to the blood-corpuscles.

Abelous and Biarnes having ob-

tained oxidation of salicylic aldehyde by means of blood-serum, Salkowski modified his former view and experimentally con-

firmed the results of the other investigators; Finally, we have seen how closely connected the adrenal secretion

is

with the integrity of the blood, and how readily the

haemoglobin molecule becomes dissociated in proportion as the efficienc}^ of the adrenals becomes weakened. The next important question to analyze is one fraught with considerable confusion, process

is

viz.,

the

manner in which the

respiratory

governed, and the identity of the respiratory center.

THE NERVO-VASCULAR MECHANISM OF THE LUNGS.

is is

According to prevailing teachings the respiratory center But there located in the medulla oblongata, i.e., the b,ulb. bulbar the considerable evidence on record indicating that

—

THE NERVO-VASCULAR MECHANISM OF THE LUNGS. center

is

not supreme in the control of respiration, although the

fact that it forms part of the controlling

mechanism cannot be

Thus, division of the cord below the seventh cervical

denied.

nerve

455

arrests

respiration;

costal

causes all thoracic

movements

section

below the medulla

removal of the brain

to cease;

above the medulla, the seat of the supposed center, does not stop respiration, while cessation, of this function occurs

when

the medulla is removed or extensively injured, save in exceptional cases.

After reviewing this evidence Professor Poster

“Nay, more;

adds:

if

only a small portion of the medulla

a traet whose limits have not been clearly defined,

but which

may be described as lying below the vasomotor center in the immediate neighborhood of the nuclei of the vagus nerves ^be removed or injured, respiration ceases, and death at once ensues.

—

Hence

this portion of the nervous system

the vital knot, or ganglion of life of

it as

:

was called by Flourens

nccud vital.

We

shall speak

the respiratory center.''

Yet,

how account

for the facts recited in the following

quotation from Noel Paton’s text®^:

“Both parts of the

re-

spiratory center are under the control of higher nerve centers,

and through these they may be throum into action at any time, or even prevented from acting for the space of a minute or so. But, after the lapse of this period, the respiratory mechanism proceeds to act in spite of the most powerful attempts to prevent

it.

“To determine

its

nerves upon the center

“Vagus. tract

— Since

mode

of action the influence of afferent

must be considered.

the vagus

we should expect

it

is

to have

the nerve of the respiratory

an important influence on the

center.

“Section of one vagus causes the respiration to become slower and deeper ; but, after a time, the effect wears off, and the previous rate

and depth of respiration

is

regained.

'Section of both vagi causes a very

marked slowing and deepening of the respiration, which persists for some time, and passes off slowly and incompletely. Now, if after the vagi have been cut, the connection of the center with the upper brain The italics are mine. “Noel Paton: hoc. cit.,

p. ?,9l.

THE RESPIRATORY MECHANISM.

456

tracts is severed, the

mode

of action of the center totally changes.

Instead of discharging rhythmically

it

remains for a long period

at rest, then the inspiratory center discharges violently, causing

a strong and prolonged contraction of the muscles of inspiraThis passes off, and again a period of rest of variable tion. duration sets less

to be again interrupted by another

in,

more or

long and strong discharge.

“Separation of the respiratory center from

upper brain tracts brings about a hut does not stop

nature of

its

pulses reach

its

activity.

loss of its

The

tlie

vagi and

rhythmic action,

center owes the rhythmic

These afferent im-

action to afferent impulses.

normally through the vagi, but when these are

it

cut the upper brain takes upon itself the function of maintain-

ing the rhythm.”

HowelP®

also says, referring to the “midbrain, at the level

of the posterior colliculi” (the corpora quadrigemina) a region

above the medulla oblongata;

“Martin and

that stimulations in this region caused a rate of inspiratory

ration

—that

movements and

found

increase in the

finally a standstill in inspi-

a complete tetanic contraction of the inspiratory

is,

Lewandowsky®® has

muscles lasting during the stimulation.

shown that

Booker'''*

marked

section of the brain stem at or below the inferior

colliculi causes an alteration in the respiratory rhythm similar

After cutting through

to that following section of both vagi.

the inferior colliculi further sections

add to the

He

effect.

more

considers that there

hibitory center in the midbrain which

posteriorly do not is

an automatic in-

infiuences continually

Again, OtP®

the automatic activity of the medullary center.” writes:

“I have

made numerous

e.xperiments to determine the

exact seat of the polypnceic center.

things are necessary:

nomena

to

disappear;

—

(1)

(2) causes the

that

its

To

establish a center three

abolition causes the phe-

that irritation

—mechanical,

chem-

phenomena to be present, and (3)

or electrical that the part of the nervous system exhibiting these peculiarities After numerous observations and be circumscribed in extent.

ical

"T. B. of Physiol.,” second edition, p. 640, 1907. Martin and Booker: Jour, of Physiol,, 1, 370, 1878. Lewandowsky Archiv f. Physiol., 489, 1896. Ott: “T. B. of Physiol.,” second edition, p. 451, 1907.'

“Howell;

^

*

:

“

THE NERVO-VASCULAR MECHANISM OF THE LUNGS. experiments

457

was found that pressure upon the tuber cinereum

it

with a pledget of cotton, or even slight puncture, increased the normal respirations to the point of polypnoea. Complete puncture in a normal animal was followed by a rise to

106° F.

within two hours, even though the animal was found

down

and had been subjected to considerable shock. '^f now the animal whose tuber is punctured be heated, there will result no polypnoea, even though a temperature of 107° P. be reached. I am convinced that the tuher cinereum is

a center of 'polypnoea

A

and

tliermotaxis.”

suggestive feature asserts itself in this connection:

As

and as will be further shown in the second volume the tuber cinereum is precisely the region through which the nerve path from the pituitary body to the adrenals passes to the medulla oblongata, and thence, via the spinal cord and the sympathetic nerves and ganglia, to the adrenals, whose secretion, we have seen, serves to take up the oxygen of the air and I have pointed out,

to

distribute

to

it

the

tissues,

i.e.,

to

sustain

oxygenation.

emphasized by considerable evidence submitted in the second volume, the walls and floor (of which the tuber cinereum forms part) of the third ventricle, are the pathways of a vast array of sympathetic fibers which likewise pass from Moreover,

as

the posterior or neural lobe of the pituitary

magnus

(via the nucleus

medulla and cord and thence to be distributed through the sjnnpathetic chain and its offshoots to all parts of the body including the lungs. We have here the grisei)

to the

explanation of the presence of so-called heat and respiratory centers in this region, i.e., irritation phenomena following the

—

experimental lesions in the course of these nerve-paths, a fact further sustained by the observation of many experimenters that removal of the pituitary body the seat of the heat and

—

—

main respiratory centers in the light of my views is followed by marked lowering of the temperature and dyspnoea.

How

does the respiratory center

the bulbar center

—or

centers, for as stated,

—

endowed with important functions influence the respiratory mechanism? Before this feature of the subject can be analyzed, a brief review of the circulation and is

innervation of the lungs

The pulmonary

may

prove advantageous.

circulation

as

regards vascular distribu-

THE RESPIRATORY MECHANISM.

458 tion

is

portrayed in the following description by

succinctly

Miller,” as given by

monary artery

An

length. its

Bohm

and von Davidolf^*:

“The pulmo-

follows closely the bronchi through their entire

arterial

branch enters each lobule of the lung at

apex, in close proximity to the bronchus.

After entering the

lobule the artery divides quite abruptly, a branch going to each

from these branches the small arterioles arise which supply the alveoli of the lung. ‘On reaching the air-sac the artery breaks up into small radicles, which pass to the central side of the sac in the sulci between the air-cells, and infundibulum;

are finally lost in the rich system of capillaries to which they

This net-work surrounds the whole air-sac and com-

give rise.

municates freely with that of the surrounding capillary net-work

is

exceedingly

fine,

and

is

This

sacs.’

shrunken into the

epithelium of the air-sacs; so that between the epithelium and the capillary there

mem-

only the extremely delicate basement

is

brane.

The

and the

alveoli of the respiratory bronchioles are supplied

similar

capillary

infundibula, the alveolar ducts and their alveoli,

from the lobules

The

net-ivorl's. lie

veins

collecting

with

the blood

at the periphery of the lobules in the inter-

lobular connective tissue, and are as far distant from the in-

form the and small, The bronchi, both large larger pulmonary veins. as well as the bronchioles, derive their blood-supply from the bronchial arteries, which also partly supply the lung itself. Capillaries derived from these arteries surround the bronchial These veins unite

tralobular arteries as possible.

to

system, their caliber varying according to the structure they

supply

:

finer

and more

closely arranged in the

brane, and coarser in the connective-tissue walls.

borhood of the terminal

bronchial

tubes

the

mucous memIn the neighcapillary

anastomose freely with those of the respiratory capillary tem.'’

To

avoid confusion I

may

recall the

nets sys-

fact that, while

the pvlmonnry artery and its branches contain venous blood,

and the bronchial arteries and their branches carry hlood, the pulmonary veins, on the contrary, contain Iilood.

When,

Miller:

arterial arterial

therefore, bronchial capillaries are said to

Journal of Morphology, vol.

“ Bohm and von

Davidoff:

Loe.

clt.

vlil, p. 165, 1893.

empty

— THE NERVO-VASCULAR MECHANISM OF THE LUNGS. into the is

459

veins, it is not used, or venous, blood that

pulmonary

transferred to the latter, but arterial blood originally derived

from the thoracic aorta or

The

lungs, as

is

its

primary branches.

well known, are innervated by the vagus

and the sympathetic system. These unite to form plexuses, the anterior and posterior, which enter the organs with the bronchial tubes and accompany them along their ramifications. The anterior pulmonary plexus, made up of vagal and sympathetic filaments, overlies the pulmonary artery, while the richer posterior pulmonary plexus, composed also of vagal filaments, intermixed with sympathetic fibers from the second, third, and fourth thoracic ganglia, follows the bronchi to their ultimate subdivisions.

—

According to prevailing views, the vagus both its sensory and motor fibers is alone regarded as the intermediary between

—

the respiratory center and the organs of respiration, but as

shown also

in the second volume, the neural lobe of the pituitary

contains the sjunpathetic center.

This proximity to the

respiratory center and the important role the sympathetic plays in

respiration pointedly

suggest that both centers are func-

tionally united.

Indeed, there

good ground for the belief that the experimental phenomena now ascribed to the vagus are partly of sympathetic origin sympathetic in the sense that they are is

—

essentially

vasoconstrictor as in other organs previously reSappey, for instance, writes®® “Section of both pneumogastrics in the median portion of the neck not only abolishes

viewed.

:

the sensibility of the respiratoiy lyzes the internal respiratory

mucous membrane and para-

muscles;

it also involves as consequence a mucous effnsion into the bronchi, engorgement of -

emphysema of diminution in the number the

lungs,

these organs,

and a very sensible

of inspirations.”

We

have in the

pulmonar}'^ engorgement an evident result of variation of vascular caliber, and inasmuch as we are dealing with a division of the nerve, the effect on the vessel must have been one of relaxation. On the other hand, we have in the paralysis of the internal respiratory muscles evidence that a motor nerve

“

Sappey:

“Traltfi cl'Anatomle Descriptive,” vol.

Ill,

p. 397.

THE RESPIRATORY MECHANISM.

460

—was

a vasodilator, or stricto-dilator, in onr sense

also severed.

we have

Tliese dual plienoinena indicate that the vagus, as in the case of the heart, i.e.,

sympathetic

The

must have contained

fibers.

presence of vasoconstrictor fibers

recognized.

seen

vasoconstrictor,

is,

in fact, generally

Trangois-Franck, in 1881 , showed that the sym-

pathetic nerves distributed to the lungs, caused vasoconstriction, these fibers being stimulated at the entrance into the lungs.

Bradford and Dean““ also demonstrated the presence of vasomotor nerves in these organs after a series of exhaustive experiments.

In a subsequent study of the subject Frangois-Franck®'

noted the paradoxical fact that vasoconstriction of the pulmo-

nary vessels caused the lungs to in volume.

This

is

swell, instead of

readily accounted for

being reduced

when

is

it

to the arterioles.

recalled

my

that the vasoconstriction applies only, in the light of

views,

These small pre-capillary vessels being con-

stricted, the arterial

blood was

dammed up behind

the seat of

obstruction in Frangois-Franck’s experiment, thus causing the larger portions of the vessel, which are not governed by the

sympathetic, to dilate.

A ever,

source of confusion asserts itself in this connection, how-

which we have

The experiments

also encountered while stud}dng the heart.

of Bose Bradford and Dean®^ are thus referred

“They carefully sought the points of by Frangois-Franck emergence, from the cord, of the filaments which cause elevation of pulmonary pressure and lowering of aortic pressure: that is to say, pulmonary vasoconstriction. These were located to

:

from the second

to sixth dorsal, and, in respect to

maximum

with the third, fourth, and fifth nerves. The pulmonary vasoconstrictors ascend the chain up to the first effects,

on a

level

thoracic ganglion, where they become detached, to reach the pulmonary plexuses.” The salient feature of the topography of

that the lower limit of the ganglionic chain through which they pass happens to he the upper limit of the ganglia from which the splanchnic nerves that ultimately carry these nerves

is

impulses to the adrenals are given “»

off.

While the pulmonary

Bradford and Dean: Jour, of Physiol., vol. xvl, Frangois-Franck: Arch, de Physiol., T. vlii, p. Rose, Bradford and Dean: Journal of Physiol.,

p. 31, 1894. 184, 189&. p. 57.

1894.

THE NBRVO-VASCULAR MECHANISM OP THE LUNGS. vasoconstrictors which pass directly to the lungs

thoracic

to

the pulmonary plexuses are,

from

as generally

true vasoeonstrictors, the presence in the

second,

461 tlie

first

taught,

third,

and

fourth ganglia of the sympathetic chain, of the nerves to the adrenals suggests that

many

vasoconstrictor phenomena^attrib-

uted to the direct action of nerves, should be ascribed to an increase of adrenal

seeretion

in

the blood.

Indeed Jacobi““

found that intense vasoconstriction of the intestinal vessels produced by

(inhibition)

by

replaced

ordinary

exeitation

the

of

vasoconstriction

after

splanchnic the

was

suprarenal

nerves had been cut.

The

fact,

moreover, that the introduction of adrenal extract

into the circulation produces general vasoconstriction is well

knoivn.

Mankowsky,®'* for example, noted “a great increase in

blood-pressure and stimulation of the cardiac and respiratory

This occurred “even when the animals (dogs) were under the influence of chloroform, morphine, or chloral hycenters.”

drate.”

“In

able feature

cats, says Swale Vincent,®” ‘Ty far the most noticewas an enormous rapidity of the respiratory move-

—

—

ments in the early stage.” The two now familiar stages that occur under the influence of toxic doses of suprarenal extract, as well as under that of other poisons, are well illustrated in the following observation

by the same investigator: “In the early stage of poisoning respiration is quick and shallow and the heart is excited. Subsequently the breathing and heartbeats become feeble, and Anally the respiration is deep and infrequent.”

Finally, the fact that all these

phenomena

are

independent of the cord has been shown by Biedl,®® who, as we have seen, obtained marked increase of blood-pressure after injections of suprarenal e.xtract, notwithstanding the fact that all the spinal structures had been removed.

This does not mean that the adrenal secretion fulfllls any particular function in the lungs other than that of taking up o.xygen therein; it is only intended to show that excitation of the splanchnic nerve may suggest the presence of pulmonary “Jacobi;

Archiv f. exper. Path. u. Pharm., vol. xxix, p. 171, 1892. Russian Archives of Pathology, etc.. Mar, 1898

“*Mankowsky:

“ Swale Vincent: “ Biedl: Wiener

Jour, of Physiol., Feb. kiln.

Wochen.,

lx, 1896.

17,

1898.

THE RESPIRATORY MECHANISM.

462

vasoconstrictor nerves in this great nerve-iiath,

when

the vaso-

constrictor effects witnessed in the lungs are in reality due to

the jiresence in the blood, as a result of siilanchnic stimulation, of an excess of adrenal secretion.

As

to the role of the vagus in the respiratory organs, our

views differ from those at present taught only in that they explain, as was the case with other organs, ical

phenomena

how

the physiolog-

are ^iroduced.

I have briefly referred to the fibers are distributed in the lungs.

manner

in

which the vagal

Sappey®^ also studied the

mammals, including man, the ox, and horse, and reached the “1. They follow the subdivisions of the following conclusions distribution of vagal nerves in the lungs of

particularly those of

:

air-tree to their terminal extremities;

they do not leave these

them to the lobules. 2. All those that leave tli3 anterior pulmonary plexus and the much greater number given off by the posterior pulmonary plexus preserve subdivisions and follow

their plexiform

arrangement throughout their entire distribu-

meshes are elongated only in the line of their axis, each thus constituting an elongated ellipse. 3. Their ramifications, essentially destined for the muscular coat of the bronchi and respiratory mucous membrane, have no connection with tion;

their

Berdal, on the other hand, confirms this,

the blood-vessels.”

and indicates the lowing lines

:

role of the sympathetic terminals in the fol-

“The branches

for the bronchi;

of the penumogastric are destined

the branches of the great sympathetic are

lost in the walls of the arteries.”

The statement

of Sappey that the vagal ramifications of

the vagus have no connection with the blood-vessels, introduces a feature of importance which applies to all other organs reviewed, viz.:

that besides the

vasodilator and

vasoconstrictor

nerves

which govern the function of any organ, there are sensory terminals which, as such, transmit afferent impulses to the centers (primary or subsidiary) which govern the Indeed, we have seen that section

of

the

caused loss of sensation in the respiratory

local blood supply.

vagi

in

the neck

mucous membrane,

paralyzed the bronchial muscles, and gave rise to effusion of

Sappoy:

Loc.

eit., p. 391.

THE NERVO-VASCULAR MECHANISM OF THE LUNGS.

4G3

and engorgement of the lungs.

How

mucus

into the bronchi

can

these iihenomena be accounted for without granting sen-

all

sory as well as motor and vasomotor functions to the vagal

Loss of sensation points to inhibited function, and not

supply?

engorgement of the bronchial mucous membrane. And yet we may have engorgement without functional erethism, if it is due, not to the presence of blood fully charged with oxygen, to

'

dammed

but to blood which, through the very fact of being

up in the vascular channels,

reduced therein to practically

is

The

the condition of venous blood.

effusion of

mucus

into the

bronchi and pulmonary engorgement would occur as normal consequences of such a state of things.

But how account for

this vascular dilation without granting such attributes to the

vagal plexuses?

Again, the fact that cutting of both nerves in the neck gave rise to paralysis of these muscles points to another suggestive feature,

namely

that the vagus

must

these muscles,

besides

:

the motor impulses to

the functional variations

now add

to

of

caliber

of

these manifestations of

those of afferent

incite

their

and govern

presiding over vessels.

If

we

efferent nervous activity

suggested by the loss of sensation

activity

mucous membrane, it seems clear that we vagal nerves referred to an autonomous supply espe-

over the bronchial

have in the cially

devoted to the function of the bronchial tubes and their

ramifications lobule.

doivn

— but

to

The importance

of

not including this

realize that it accounts for the

affections

from those

of the

fact

—

asserts

pulmonary

the itself

when we

complete isolation of bronchial

parenchyma, and gives ns a clue

to their original cause.

My

opinion that the vagus

lungs as elsewhere,

experimental stimulation of

i.e.,

—

as

motor nerve

—

acts in the

as stricto-dilator neiwe, is sustained

tlie

origin of the superior laryngeal)

causes the respiration to be-

come more and more rapid, the inspiratory phase being accentuated.

Noel Paton:

by

As Noel Baton writes”®: “Strong pulmonary branches of one vagus (below the

evidence.

If

the stimulus

Loc.

cil.,

p. 292.

is

chiefly

very strong respirations are

—

—

THE RESPIRATORY MECHANISM.

464

Weak

stopped in the phase of inspiration.

may

other hand,

stimuli,

on the

cause inhibition of inspiration.

‘‘Such experiments prove that impulses are constantly traveling from the lungs to the center whereby the rhythmic activity of the center

“How from

rently

is

maintained.

do these impulses originate in the lungs? their alternate expansion and contraction.

“If the lungs be forcibly inflated

Appa-

with a bellows

e.g.,

the inspiration becomes feebler and feebler and finally stops.

The nature tion

of the gas,

carried out

is

is

of

if

non-irritant, with

no consequence.

If,

which

this infla-

on the other hand,

the lungs be collapsed by sucking air out of them, the inspiration becomes

more and more powerful, and may end

in a spasm

of the inspiratory muscles.

“This shows that with each expiration a stimulus passes up

make it excito-motor nerve, mak-

the vagus which acts upon the inspiratory center to

The vagus

discharge.

is

thus a true

ing the center act in a reflex manner. the lung the vagus it

is

With each

collapse of

thrown into action, as the lungs expand

ceases to act, and, as a result, the inspiratory center stops

acting, the muscles of inspiration cease to contraet,

and expira-

tion occurs.

“While ordinary respiration may thus be considered as a rhythmic

reflex act, it

must not be forgotten

that the respira-

tory center can and does act rhythmically under the influence of the higher center, or a-rhythmically and spasmodically

these as well as the vagi are severed

from

when

it.”

The mode of action of the vagus as a “true excito-motor nerve” is thus subject in a great measure to the respiratory centers

—the

main one

of which, in the light of

my

views

is

The located in the neural lobe of the pituitary body. to impulses sensory transmit bronchi of the terminals sensory

vagal

this center

and e.xcito-motor impulses are transmitted by

it

to

the entire respiratory apparatus, including the thoracic respiraThe manner in which all these muscles are tory muscles. excited to increased activity by the efferent or excito-motor vagal an excess fibers does not differ from that of all organs reviewed :

of blood tion of

is

its

admitted into the contractile elements, through dilaAn excess of blood-plasma laden with arterioles.

THE NERVO-VASCULAR MECHANISM OF THE LUNGS. oxidizing substance

is

465

admitted, as previously shown, to the

myosinogen of the muscular elements, where inspiration is in order; hence the fact that strong excitation of the vagus “causes the respiration to become,” as Paton says, “more and

more

When

rapid, the inspiratory phase being chiefly accentnated.”

—physiologically—excessive

inspiration

is

to

cease,

the

sympathetic vasoconstrictors come into play: they restore the muscular arterioles to their normal caliber; less blood is admitted to the muscular elements and the inspirations resume their

normal rhythm.

must now be taken into account: that And from the standpoint of the clinician, this factor is by far the most important of all the physiological phenomena of the function of respiration. Indeed as will be shown in the second volume, But

a third factor

represented by the functions of the adrenals.

dyspnoea

is

often the result of adrenal insufficiency, the adrenal

secretion produced being inadequate to sustain the oxygenation

of the

body at

large.

Again, Miller, we have seen, refers to

the subdivision of the pulmonary artery “which divides quite abruptly, a branch going to each infundibulum”; ter “small arterioles arise

which supply the

from the

lat-

alveoli,” while these

on reaching the air-sac are said to culminate in “the rich system of capillaries to which they give rise.” If the “small arterioles which supply the alveoli” are abnormally dilated through

some general dyscrasia and the stream of venous blood of genation of the adrenal secretion

exposed to the

known

air,

we have

it

contains

is

oxjf-

thus imperfectly

a logical explanation of the well

—a sympathetic stimulant

beneficial action of belladonna

which, as

we

will see, causes constriction of the arterioles,

and

of potassium iodide, a powerful adrenal stimulant.

That fluctuations in the secretory

activity of the adrenals provoke dyspnoea is well illustrated by the effects of all drugs that are sufficiently active to markedly affect adrenal

may

functions. The action of venoms even more strikingly shows the morbid connection that exists between variations of suprarenal activity and pulmonary functions, even the stage of blooddisintegration being sometimes reached. Noe,®® for instance.

““No6:

Loc.

cit.

— THE RESPIRATORY MECHANISM.

466 refers to the

many

phenomena

tory

observers wlio have reported intense respira-

Viper-venom was

after cobra-bites.

also found produce at first “accelerated respiration,” then “somnolence, with slowing of respiration.” Bee-venom in suf-

by

I’hisalix to

ficient quantity gives rise to dyspnoea,

according to Paul Bert,

black blood being found in the vessels.

Toad-, salamander-,

and eel- venoms were foimd to affect respiration in a similar manner. Mosso noted that the process of death varied scorpion-,

with the dose heart

;

medium

:

stronger

doses

doses arrest

first

arrest resiiiration, then the

both simultaneously.

Paralysis

motor end-plates had evidently nothing to do with this process, since l\Iosso found the thoracic nerves responsive to

of the

the induced current.

Eemoval give rise to

the adrenals under

of

phenomena

these

conditions should

similar to a violent dose of venom.

Cybulski not only observed,'^® under such conditions, marked dyspnoea, a fall of the vascular pressure to zero, and haemoglobinuria, but also

found that the injection into the veins

of an aqueous 10-per-cent, solution of suprarenal extract “im-

mediately states that

caused

these

phenomena

after removal of both

of rats the respiration

to

disappear.”

BoineP'

organs in a large number

became “slow, painful, and

difficult.”

important features any of those generally recognized. understand why the nerve paths of the

Briefly, the functions of the adrenals are as

of the respiratory function as It is

now

possible to

heat and respiratory centers are so intimately related in the third ventricle.

Originating from a

common

center, the pitui-

tary body, the vagal, sj^mpathetic and adrenal nerves, jointly project from their

common

source, the pituitary body, to reach,

by way of the tuber cinereum, the walls of the third ventricle and the midbrain, the medulla oblongata, where they form subsidiary (and probably coordinating) centers whence the impulses to the respiratory organs are transmitted.

The newer

features of the nervo-vascular

mechanism of

respiration which I submit iu the foreadditional evidence and detail, may be pending going pages, summarized as follows:

(ordinary tranquil)

™

Cybulski: Gazeta Lekarska, March Bolnet: Loc. clt.

23.

1895.

—

4G7

THE ADRENAL SYSTEM AND THE THYMUS. 1.

The hulbar

respiratory center

the sole, or even the

is

not,

now

as

believed,

this class; it is

most important, center of

a subsidiary and, probably, a co-ordinating center.

The primary and chief respiratory center is located in the pituitary body and consists of three functionally related centers, the adrenal, vagal, and sympathetic centers, which, in 2.

turn, are connected by nerve-chains with the corresponding sub-

sidiary centers in the bulb,

and govern, through the interme-

diary of the latter, the respiratory mechanism. The chief respiratory center carries on its functions as fol-

lows :

by governing the production of the adrenal secretion, which takes up the oxygen of the air and forms the albuminous constituent (96 per cent.) of hcemoglobin, Its

adrenal center,

regulates the proportion of this oxidizing substance (the adrenoxi-

dase) supplied to the blood. Its vagal center, acting through the vagus (the intercostals

and phrenic)

as excito-motor (stricto-dilator) nerves of inspira-

provokes contraction of the muscles which dilate the larynx, the bronchi, and the thoi'ax and depress the diaphragm, and thus tion,

increase the intake of air by the lungs,

i.e.,

the supply of oxygen

from which the adrenal secretion and the hcemoglobin absorb oxygen to distribute it to the tissues. Its sympathetic center, acting, through

the

sympathetic

nervous system, as antagonist of the vagal center to provoke expiration, causes all the above-mentioned respiratory muscles to relax passively

(by constricting their arterioles) , thus en-

and bronchi to resume contract, and the diaphragm

abling the larynx the thorax to

their

normal

to rise, in

caliber,

order to in-

sure the expulsion of the expiratory air laden with carbonic acid.

THE ADRENAL SYSTEM AND THE FUNCTIONS OF THE THYMUS GLAND. In the first edition of this work (1903) I urged that there was “considerable analogy between the effects of thymus on the organism and those of the thyroid.” Parhon and Golstein"have since been

-led also to

Parhon and Golsteln;

conclude that “the relations of the

Secretions Internes, p.

690, 1909.

THE ADRENAL SYSTEM AND THE THYMUS.

468

thymus with the thyroid gland seemed very

close,” a view also

sustained by the recent experiments of Hoskins.’^® has, in fact, reported eighteen cases of infantile

which the thymus alone showed lesions-^a

fact

Euhrah'^*

marasmus

in

which suggests

that, as is the case with the thyroparathyroid apparatus, the

thymus influences in some way general metabolism. In keeping with this view is the conclusion of Basch” that a relation exists between the th3'mus and the growth of bones and also the healing of fractures-r-also a therapeutic property shown by thyroid preparations. Converselj", FischeF“ and others have observed no clearly deflned evidence that removal of the thymus influenced development, general or osseous, of young animals. the preponderating evidence sustains the positive view,

Still,

negative evidence being often due to faulty technique, or ascribable to the assumption of functions by the related organ

—the

thyroid in the present instance. Svelila’^ believes that the thyroid

gland only assumes

its

functions at birth, extract of foetal thyroid having proven inert,

while extract obtained from the thyroids of infants during the

month

same manner did thj'mus extract behave: foetal-thymus extract produced no effect, while that obtained from the thymus glands of infants in first

the

first

of life

was

effective.

month caused

Precisely in the

increase in the frequency of the pulse

and lessened blood-pressure. He found, moreover, that “among children of the same age the thymus extract is the strongest; In adults, howless so the thyroid, and still less the adrenal. ever, the adrenal outstrips both other glands.”

Svehla refers to “increased frequency of the pulse and lessened

blood-pressure”

extract:

evidence,

if its

as

the

prominent

effects

of

thj'mus

action corresponds to that of thyroid,

that a toxic dose had been administered to the experimental animal. This is sustained by the fact that other typical symptoms were present: i.e., muscular weakness, dyspnoea, and general collapse, a condition from which the animals could be saved by the timely administration of thymus extract, which

—

promptly restored the normal vascular pressure. ”

Hoskins:

’‘Ruhrkh:

"Basch:

™

Fischel:

Svehla:

American Journal of the Medlcai Sciences, Mar., 1911. British Medical Journal, Aug. 29, 190?. t. Kinderhellk., p. 1063. Zeitsch. f. exper. Pathol, u. Therap. B. 1, p. 388, 1905. Archlv fUr exper. Pathologle, Bd. xllll.

Jahrb.

TIIK

469

ADRENAL SYSTEM AND THE THYMUS.

extract seems to prove efficacious in precisely the same class of cases of exophthalmic goiter hut only when the asthenic or second stage is reached as thyroid extract.

Thymus

— —

for example, recalled his successful result in a marked case of twenty years’ standing, but he indirectly points to his patient’s advanced condition by the statement “the next three

Owen/®

months he spent mostly in bed.” His second case complained of feeling “low and weak,” sweated profusely, became bald, and had tremors and pigmentation. A third case benefited was one in which breathlessness, general weakness, and emotional outbreaks prevailed. He also refers to an extremely aggravated case treated successfully by Maude,''® in which drugs, including belladonna, had proven ineffectual. Hnder thymus tabloids, 45 grains daily, the patient rapidly improved, and invariably relapsed

when they were

discontinued.

Maude hav-

ing observed that the tremors were particularly relieved by

Owen

this foi-m of treatment,

thymus in paralysis

tried fresh

agitans, “with the result that the tremors

and the mental

benefited

were unmistakably and the muscular condition

state

greatly improved.”

An all

Maude’s cases shows that they are In the first “the heart and paralytic confine her to bed for over a year.”

analytical study of

of the advanced type.

conditions were such as to

The second “belonged

to a highly neurotic family; goiter

had and the “tremor, excessive muscular weakness, and cardiac disturbance were all well marked.” The third had recovered from a previous attack without thymus; existed since childhood,”

hence, serve

use after recurrence as the result of grief cannot

its

as

fair

The fourth was

example.

standing, and the patient

had

nervous

paralysis

symptoms,

viz.

suffered

of

thirty-two years’

from “various severe

of

various basal nerves ophthalmoplegia, paralysis of facial, ambulatory epilepsy, etc.” “She had had, in 1894, twenty-four motions in one :

.

day of almost pure arterial blood. In November, 1895, she had a sudden profuse hsematemesis, followed by collapse so extreme that she seemed moribund. After she rallied she was given 45 grains of thymus tabloids per day, for a month, and Owen: Maude:

British Medical Journal, Oct.

Lancet, July

18,

1896

10.

THE ADRENAL SYSTEM AND THE THYMUS.

470

her improvement was very remarkable; she remained in a fair state of health for many months/’ Degeneration of the arterial walls probably existed in this case, and

the loss

of'

it

seems likely that

blood can be credited with the relief afforded.

Todd’s case®® had an epileptic mother, her sister had suffered from myxcede'ma and had been cured with thyroid extract, and she was hei*self a “vei*y delicate”

girl. IST. J. McKie’s case®^ and those of 11. T. Edes®- and Philip James®® also represent instances in which there was thyroadrenal insufficieney. In a case

successfully treated by Boisvert®^ the jiresence of melancholia

shows that weakened adrenals were present and that the

also

increased insufficiency of these organs brought on by the thymus, as was the case with two of the patients referred to by Dr. Winter in which thyroid extract was used, led to recovery.

These examples, which could be multiplied, not only indicate that

thymus

extractives are active

when

there

is

impaired func-

tional activity of the thyroid

and adrenals, but they

prove that the thymus gland

is

also tend to

very similar to the thyroid in

its

upon these organs. The harmful effects of thymus in the first stage are illustrated by a case described by Watson Williams,®® who found that it aggravated the tachycardia and p}Texia: evidence that In it had been given while thyroid overactivity was present. action

the large proportion of cases reported, however, there

marked untoward

effect

produced.

It

seems to be much

active in this connection than the thyroid extractives.

some

in

cases

—

—probably

those

is

In

no less

fact,

on the border-line of thyroid

insufficiency it appears to act as a nutident tonic, as noted by Hector Mackenzie®® after a study of twenty cases in which he

had

tried

thymus gland, and

to

which further reference

is

made

below.

The connection between the thymus and

the adrenals

may

also be illustrated by the experiments of Abelous and Billard,®’ in which removal of the former gave rise to symptoms similar British Medical Journal, July 25, 1890. British Medical Journal. March 14, 1896. R. T. Edes: Boston Med. and Surg. Journal. Jan 23 1896. Philip James: Australasian Med. Gazette, July 20, lw7. Boisvert: Revue M^dicale de Montreal, June 21, 1899. Watson Williams: Clinical Journal. Dec. 11. 1895April, 1897. Hector Mackenzie: American Journal of the Medical Sciences, Abelous and Blllard: Archives de Physiologic, Oct., 1896.

“Todd; 8> 8=

N.

J.

McKle:

,

SB

“ 61

471

THE ADRENAL SYSTEM AND THE THYMUS.

skin,

the

gi-eat

muscular

blood-changes, oedema, tions of

even to discoloration of

that follow adrenalectomy:

to those

etc.

weakness—lapsing They also found

into

paralysis,

that the

secre-

the experimental animals were markedly toxic:

evi-

On the whole, this evidence, dence of inadequate oxidation. that the thymus gland indicate considered collectively, seems to supplies some substance which directly or indirectly stimulates and thereby en-

the secretory functions of the adrenal system, hances the activity of the oxidation, processes.

What

the nature of the agency tlirough which the thy-

is

and what is the specific relationThese questions are suggested by ship between these organs? the fact that, Avhile undue activity of the thymus increases that of the adrenals, there seems to be no evidence that tlie thymus

mus

stimulates the adrenals,

can

alone— i.e., independently

either exophthalmic goiter or

of

—give

thyroid

the

In

myxeedema.

all

rise

cases of the

former disease ascribed to the thymus found in available ture there

normal

We

invariably thyroidal involvement.

is

mus seems

sufficiently

active

to

bring

tlie

to

litera-

Yet the thy-

adrenals to

their

activity vdien the general vital processes are depressed.

have seen, on the other hand, that

its

removal gives rise to

symptoms recalling those of adrenalectomy. Baumann®® found minute quantities of iodine in the thy-

mus

also;

this trace,

tion

but other experimenters have failed to find even

and have ascribed Baumann’s findings

from neighboring thyroidal

such a trace of iodine

exists,

we

tissues.

to

contamina-

Even granting that

are well aware that the thyroid

power to stimulate the adrenals to ‘"a trace”; the labors of many investigators have conclusively shovoi that it must supply the organism with a considerable amount of does not owe

its

this substance.

Evidently we must look elsewhere for the solu-

tion of this problem, and, data bearing directly

upon the subbeing wanting, we shall have to seek for the required substance through its comparative behavior in the organism, and

ject

the

manner

in which its effects vary in the latter

from those

of thyroid e.xtractives.

Valuable in tliis connection are the autopsies of 61 children at the Ilopital des Enfants-Malades, of Paris, performed ***

Baumann:

Miinchener mcd. Wochenschrift,

p.

311,

1893.

THE ADRENAL SYSTEM AND THE THYMUS.

472

by Albert Katz at the request of Boumeville.*® All these children had died of various diseases, their ages varying from one month to thirteen years, though 41 were under two years of age. In all of the G1 bodies the thymus gland was present, while in 28 mentally weak and epileptic children examined by Bourneville the thymus was absent in 25. In another series, of 292 cases, it was absent in 74 per cent. But these comprise not only

all varieties of mentally abnormal children, but also various degrees of imbecility; so that the remaining 26 per cent, may have included a number of instances in which mental

development was high as compared to that of the cases in which the organ was absent. Yet, to avoid favoring our own line, .of argument, we will consider that in three-fourths of imbecile some of which were epileptics, the tliymus gland was

children, absent.

These observations become elucidative when analyzed through the effects of thyroid extract. Especially suggestive is the following casual remark of Cabot’s, in the course of a valuable paper published some years ago"®: “The fact that in myxoedematous children and cretins the thyroid treatment is associated Avith notable growth in height has led some observers to try its effects in if

dwarfed children not myxoedematous,

their development could not be helped.

I have collected 10

such cases, 3 in idiotic children and 6 in

development was mainly physical. height Avas observed in

were not

improved."'’’'-

all

It

A

to see

whom

the lack of

considerable increase in

the cases, hut the mental symptoms

seems evident that

if,

on the one

hand, the vast majority of cases of mentally Aveak children do

not possess thymus glands, and that, on the other, thyroid extract

will

enhance growth of

cedematous ones,

i.e.,

idiotic

children

(not

cretins), the oxidation processes,

my.x-

stimu-

by the thyroid simultaneously Avith the adrenals, are inadequate to alone bring on improA'ement of the mental symptoms. Again, it becomes evident that it is upon the th}Tuus that the mental development depends, and, finally, that it is to some agent which the thyroid gland does not contain that this development is due. lated

*•

Katz:

Le

Profrrfis

M6dlcal, June

“ Cabot: Medical News, Sept. “ The italics are my own.

12,

23, 1900. 1896.

—

473

THE ADRENAL SYSTEM AND THE THYMUS. This enables us to eliminate iodine,

main being

thjToiodase, as the

i.e.,

thymus gland, and, our inquiry from the oxidation process through the

active principle of the

disconnected

evident inefficiency of the thyroid to restore mental functions,

we

are led to seek for a chemical

Can we

nutrition.

body that will enliance cerebral

expect such an hypothetical agency, however,

upon the brain alone? This is hardly from analogy, and the nervous system at large must also utilize it physiologically. Our field is therefore broadened, since an agency connected with the nutrition of the brain alone, or one playing the same role in respect to the entire to concentrate its etfects

probable, judging

nervous system,

may

This

serve our needs.

fortunate, for the chemistiy of brain-

is,

to say the least,

and nerve- matter

is

far

from well known, and even a good analysis i.e., one based upon the more salient data available would be impossible

—

were the limits of the inquiry at

Of the

constituents

solid

three stand out prominently

:

all

of

narrowed.

and brain- matter, cerebrin, and lecithin.

nerve-

cholesterin,

Cholesterin, considered by Austin Flint, Jr., as a waste-product

and nervous

of cerebral

origin,

though

it

represents one-half -

shows no molecular constituent capable of (CjgH^^O), the fact that the thyroid secretes a specific agency being taken as standard; nor does cerebrin (C17H33NO3), though both this and the preceding body are of

all

the solids,

assisting us

abundance in the cerebro-spinal axis and nerves. With lecithin, sometimes termed “phosphorized fat,” which found in

represents about one-tenth of the solids, the case since its

different,

is

fonnula (C44H00NPOS,) suggests that j)hosphoi"us

represent the

constituent

we

are

seeking.

It

is

may

not only a

prominent component of the whole cerebro-spinal and neiwous systems, however, but it is also a constituent of the red and white corpuscles, milk, bile, serum, semen, and pus. Another body, protagon (Ci3oH33g]Sr5P035), has also been isolated from

brain-substance by Liebreich, cerebral

constituent

Blankenhorn.®^

considered

it

as

the

main

an opinion sustained by Gamgee and Hoppe-Seyler and other investigators are,

however, inclined to consider cerebrin.

-vvdio

:

Whether

it

as a mixture of lecithin

this be the case or not,

“ Gamgee and Blankenhorn:

and

phosphorus again

Journal of Physiology, vol.

11,

1879.

THE ADRENAL SYSTEM AND THE THYMUS.

474

appears as the only element capable of being at with the question in point.

To adopt

organic

associated

all

phosphorus as the characteristic con-

thymus gland, however, and declare minus or plus production that the mental

stituent of the

tliat

through

attributes

its

it is

of children are developed, would merely constitute a theory. As a stronger position is desired for all the deductions vouchsafed in this work, collateral evidence must be sought.

The

observations

stimulates growth,

it

of fails

Cabot,

that,

while

thyroid

extract

enhance mental development in

to

than myxcedematous ones, raises the question as whether such results can be due to the absence of phosphorus in the thyroid. If such is the case, the absence of this idiots other

to

element should also show

itself

the brain and nervous system, of

phos2)horus also exists,

is

the results obtained from

in

the extract in some other disease, in

any structure other than which a morbid deficiency

if

a feature

of

that disease.

We

know, for example, that phosphorus is introduced into the organism with food, and that calcium phosphate, by becoming deposited in the bones, gives them their hardness.

any evidence that the bones of subjects tract

is

stituent?

Is

there

which thyroid e.xsuccessfully administered lack of this hardening conin

Eefcrring to the use of thyroid extract in cretinism,

T. Telford-Smith”® makes the following statement:

“I have

found that during thyroid treatment the rapid growth of the skeleton leads to a softened condition of the bones, resulting

in a yielding and bending of those which have to bear weight, and, as cretins under treatment become more active and inclined to run about, this tendency to bending has to be guarded against.”

After referring to the experiments of Hofmeister in

rabbits and those of Eisenburg in sheep and goats in which bending of the legs Avas caused by removal of the thyroid, he adds: “While in rickets, however produced, there is perverted and delayed ossification resulting in softening and bending of

the bones, under thyroid treatment in cretinism there

is

rapid

resumption of groAvth in the skeleton, leading to softening, which is most marked in the long bones and at the epiphyses.” That we are dealing here with an absence of phosphonis and w

T, Tel ford -Smith;

Lancet, Oct.

2,

1897,

475

THE ADRENAL SYSTEM AND THE THYMUS. that the calcium phosphate

serves

harden the bones con-

to

currently with their growth seem obvious.

But why does

Marie,

ascertained by

the fact,

Simply through that the thymus is almost

this not occur in all cases

?

always persistent in cases of cretinism. When thyroid gland is administered, therefore, the increased oxidation procured with

and the

the aid of the adrenals also enhances thymic activity, assimilation of phosphorus

proven

by the

is

experiments

in

by

animals

Eisenburg, referred to by Telford-Smith.

If

thyroid caused bone-softening in these,

is

my

light of

This

increased in proportion.

it

process—

conception of the

^the

Hofmeister

is

and

removal of the

—

because

in the

adrenals were ren-

dered inadequate, and, oxidation being impaired in proportion, the

thymus

also failed functionally.

This process, however, involves the need, in the structures of the thymus gland, of a metabolic process culminating in the production of an internal secretion laden with phosphoruscontaining bodies.

Quotations from a study of the nucleins

and nucleoproteids

in

their relation to

Chittenden®® will serve to enlighten us: the

cells

which

substances

specific

internal

secretions

is

contained in the gland or

inherent quality of

all

secretion

“The manufacture

character

give

obviously

internal

a function either of

may

it

of

various

the

to

by

special

be in some cases an

the cellular elements of a given gland.

In the pancreas the formation of the active agent

is

limited to an interstitial,

occurring in

terized

epithelium-like tissue

patches throughout the gland

isolated

by

distinct

its

from the secreting

and

alveoli,

of being the source of the internal

adrenals, principle,

and especially charac-

This epithelioid tissue

vascularity.

apparently

is

is

certainly

suspected, at least,

Again, in the

secretion.

Schafer and Oliver have shown, the active which has such a marked influence upon the heart as

and arteries, is contained only in the medulla of the gland, and not in the cortex, the medulla forming about one-fourth of the gland by weight.”

“If we take the content of phosphorus as a measure of the proportion of nucleic acid contained

in

the

various et

p. Job, layo.

^ChlUenden:

.

.

forms

.

of

nucleoproteids

thus

far

Mfimolres de la Socidtd Mddlcale des HOpitaux de Paris,

Boston Med. and Surg. Journal, August

20,

1890,

THE ADRENAL SYSTEM AND THE THYMUS.

476

we

studied,

exceedingly great variations

find

of this aeid present in the moleeule;

number

evidence of the large

as

the

amount

may

be taken

in

a fact which

molecular combinations

of

present in the protoplasm of different

cells.

Thus, from the

kidneys we obtain a nueleoproteid with only 0.37 per cent, of phospliorus, while, as representing the other extreme we have in the pancreas a nueleoproteid eontaining 4.71 per .eent.

of

phosphorus and in the lymphoid cells of the thymus a corresponding body with 3.5 per cent, of phosphorus. The very .

nature of the the

nucleic

many

bases whieh

outside

acids

.

.

come from the cleavage

of these bases into other allied bodies by oxidation

own

tion; their

marked;

the

physiological

possibility

acids,

may

and, further, that

may

undiscovered reasons

exist

believing

for

action,

—na}%

other catabolic products

still

the

and reduc-

which, though mild, probability

—

is

many

that

be obtained from these nucleic other nucleic acids

in the cell-protoplasm,

that

of

body; the ready convertibility

the

the

nucleins

all

at

present

offer

good

and nucleoproteids,

which are the most prominent constituents of the protoplasm of all cells, are the most probable antecedents of the internal secretions.”

There phosphorus

evidently a sound foundation for the belief that

is

is

the active constituent of the thymus gland.

If

thyroid extract failed to improve the mental condition of the ten

cases

collected

growth witnessed,

by

it

is

was structurally unable

Cabot

notwithstanding

either because the to

the

increased

thymic gland in

all

respond to the increased oxidation

which the stimulated adrenals induced or because no thymus gland was present. That this gland is absent in the vast majority of weak-minded, but not myxeedematous, children is shown by the researches of Bourneville and Katz. That phosphorus is the main specific constituent of brain- and nervesubstance

is

a recognized fact fxilly sustained by physiochem-

That thyroid gland does not improve non-myxcedematous idiocy or weak-mindedness in children owing to the absence of phosphorus in the organism is shown by the corresponding effects it has on the skeleton of some cretins, as ical

data.

observed by Telford-Smith, the bones, by their, softness, showo*

All the Italics are

my

own.

—

—

477

THE ADRENAL SYSTEM AND THE THYMUS.

hardening that calcium phosphate Finally, that the adrenals, through the normal oxiprocures. dation processes insured by them when adequately stimulated ing

by the thyroid

the

of

absence

the

secretion, sustain the activity of the

thymus up

Hofto its proper standard is shown by the experiments of meister and Eisenburg, in which removal of the thyroid of various

—herbivorous—animals

bending

caused

of

the

legs.

The thyroid is thus able to stimulate the adrenals, and the But does the adrenals in turn can stimulate the thymus. thymus physiologically stimulate the adrenals?

The

fact,

that the tlijunus gland

ture, one calculated to

atrophy when

is

its

but a temporary strucfunctions as a building

organ are accomplished, would seem to suggest that stimulation If the deducof the adrenals is not one of these functions. appear to stand tions herein submitted are sound, it would prominently as a bone-forming organ and general pliosphorusor rather nuclein- purveying organ from the time of the completion of

its

lymphadenoid elements during intra-uterine life and growth of all tissues, including

until the final elaboration

its

frame-work,

skeletal

tlie

i.e.,

around the period of puberty,

powers gradually receding as permanent organs are developed.

This conception of itself

to

anyone

purpose does not appear to have suggested

its

so

observations

collateral

but

far,

of

a

it

is

quite in keeping with the

number

of

the

best

of

modern

embryologists.

One the

lof

the

sources

bone-marrow.

foetal

life,

of leucocytes,

In the process

the first points of

second month, but

it is

of

as

is

well

knoum,

bone-formation

ossification

is

during

appear during the

only during the fourth that the devel-

opment becomes markedly active on all sides. That the most active work of the thymus is performed during intra-uterine life

is

generally recognized; this, therefore, coincides with its

most active bone-forming period.

It

seems reasonable to con-

clude that so important a function as leucocytogenesis should

not devolve upon structures undergoing formation, and also that the bone-forming organ should be intrusted with the function

which ultimately would constitute the main active attribute of their product. Bone-marrow being the main leucocyteforming structure, we should therefore expect the thymus to

THE ADRENAL SYSTEM AND THE THYMUS.

478

assume

hone-marrow had reached

this role until the

nonnal

its

physiological development.

Kolliker

has

always

maintained that the formation

leucocytes was a function of the thymus:

he

been sustained by Prenant and

has

Oscar

Beard“^ took up the question and studied

it

care in the Baia hatis, the smooth skate.

He

the absence of leucocjdcs in

J.

ascertained that

embryonic

of

ones arc formed

first

within the thymus epithelium and from

embryos from twenty-eight

Schultze.

with considerable

earliest period

tlie

blood in vertebrates persists until the

of

a position in which

In

its epithelial cells.

forty-two millimeters long the

to

formation and emigration of leucocytes from

tlic

comes very

no part of the

and

active,

emblem, including

blood, that

tlie

is

is

not infiltrated with leuco-

elsewhere within the body of the smooth skate.

with Kolliker, that the formation of leucocytes the thymus gland, and “the

from

its

tliymus be-

happens before lymj)hoid structures are developed

'This

cytes.

time there

this

at

epithelial

by what appears

to

it

me

to be a

a function of

thymus

the parent-source

is

a conclusion which

:

is

believes,

leucocytes arise in the

first

thus

cells;

leucocytes of the body”

Beard

of

all

further sustained

is

warranted deduction

:

that

i.e.,

thymus is the main organ upon which the osseous, cerebrospinal, and nervous systems depend, and perhaps all other the

tissues, for their

We

organic phosphorus during their development.

have also seen that leucocytes are included among the

bodies that contain phosphorus.

bone-forming organ

as a

observation

that

but when we

foetal

fix

little

of the

identity of the thyroid

thymus proves

recall the fact that

the fourth month, that

but

is

The

apparently contradicted by Svehla’s

its

it

inert

inordinate activity

element

itself,

there

is

doubt as to the value of the experiments. not

prevail,

all

the

data

e.xperi mentally;

only assumes

the

submitted,

may

its

function

cause

it

ample room

to

for

If these facts do

recognized

intra-

uterine supremacy of the thymus over other glands, Chittenden’s

analysis,

and

several

physiologically

established

facts

would also have to be considered wrong. All this entails the conclusion that

exceedingly

^

3

.

Beard:

valuable Lancet, Jan.

therapeutic 21,

1899.

thymus might prove an

agent

in

selected

479

THE ADRENAL SYSTEM AND THE THYMUS. In

cases.

seems possible that, in the very cases treated

fact, it

by Cabot, the addition of thymus might have caused the improvement in the mental The absence condition which thyroid alone failed to procure. of the thymus in Bourneville’s cases supplies a firm foundation thyroid

with

referred

extract

to

Though some

for this thought.

sodium phosphate,

benefit has been obtained

from

seems reasonable to believe that in physthymus, phosphorus will

it

iological combination, as it occurs in

prove

far

more

Whether

efficacious.

through this element

activity

or,

specific

physiological body intended

matters

little.

for

th e

this

we do axis

.nervous system utilize phosphorus as an all-important

specific source of energy,

oxidation which

and associate with its

intelligent use

by Owen in a case of

may

The

unattainable through any other agency.

we

insure residts

benefit obtained

shows that these are not

j^aralysis agitans

Indeed, we must not overlook the fact that im-

vain words.

adrenal

all

structures

the

reduced

activity

reduces

the

standard

nutritional

of

and that all cells fail to appropriate through metaholism involved their ph3^siological con-

stituents.

While,

classed

a nervous

as

this the enlianced

stimulation of the adrenals procures,

its

cannot but realize, that

paired

if

cerebrospinal

entire

a

special purpose,

stimulates the adrenals, and

It also

not lose sight of the fact that the

and

suprarenal

enhances

it

does thyroid, through

as

therefore, disease,

paralysis it

is

agitans

should

not

be

nevertheless true that the

nervous system, suffers

if the adrenals underlie the whole trouble, also from impaired nutrition, and that phosphorus, its source

of intrinsic energy,

is

as necessary to it as

oxygen

itself.

The

obtained from the therapeutic use of thymus gland mainly due to the phosphorus-laden micleins it contains.

benefit

to

is

A number of authors have suggested that thymus was able compensate for the adrenals. In Boinet’s e.xperiments in

rats, for

example, eleven out of fifty which had survived some time adrenalectomy showed hypertrophy of the thymus. Anld observed the same phenomenon in four cats, though he had

removed but one

adre.nal in these animals.

nati, Wiesfe, -Hedingeii,”® Hart,"'’

Pansini and Bone-

and others have

also observed

68 06

Wart.

Wien.

klin.

Wochenschr., D.

Gesellsch., B. xi, S. 29. 1907. xxi,

S.

1119,

1908.

4S0

THE ADRENAL SYSTEM AND. THE THYMUS. thymus

liypertro]jhy of the son’s

disease,

—a

who had

in subjects

condition

in

which,

as

died of Addi-

known, the But

well

is

functions of the adrenals are arrested by organic disease.

hypertrophy does not always indicate a compensative function, especially when any of the ductless glands are in question.

Those so far reviewed, the thyroid and adrenals, are intimately concerned,

we have

seen, with the destruction of toxic wastes.

It follows, therefore, that

removal of

eitlier set of

such wastes to accumulate in the blood, and, as raise the blood-pressure.

This in

is

organs allows

well

known,

itself is sufficient to

to

produce

and congestion of the thymus with enlargement witnessed in the adrenals under the influence of many poisons. The enlargement of the thymus should not,

hypertemia similar to

tliat

therefore, be regarded as compensative.

What is

the evidence available does seeVn to warrant, however,

that the thymus sustains the functional activity of the adrenals

by contributing what

it

contributes to

all

other organs,

the

i.e.,

excess of phosphorus-laden nucleins required by the organism

during

its

development,

i.e.,

overlook the fact that wliat

nervous system to

organ

the

:

I

until puberty.

mean by “organ”

the center and

and

its

intrinsic

glandular, to which phosphorus

culating

shown

iq

the

But we must not

axis-cylinders,

in the next chapter, a sine

here includes

its

and afferent paths supph', vascular and

its efferent

nerve is,

with the adrenoxidase

nerve-fibers,

etc.,

as

qua non of functional

cir-

will

be

activity,

under these conditions that insufficiency of the adrenals or of the thymus must produce morbid phenomena similar, though less marked in degree, to those of the thyroparathyroid apparatus and the adrenals, all concerned as I have shown.

also directly,

The

It follows

we have with nuclein mehibolism and

oxidation.

participation of the secreting organs of the adrenal

system in the functional relationship with the thymus shown in a case of marasmus carefully studied by

is

well

E.

L.

Thompson,’ ““ in which “in addition to changes in the thymus extreme atrophy was found in the thyroid, parathyroids, and medullary suprarenals.” Having had the opportunity to examine the thymus in 20 cases of marasmus at St. Ann’s Asylum, in infants from birth to 1 year of age, he found in, every case “a loo

Thompson:

Amer. Jour. Med.

Scl.,

Oct., 1907.

— 481

THE ADRENAL SYSTEM AND THE THYMUS.

So marked was the and other cases referred to, sustained by con-

notable atrophy of the thymus gland.”

evidence in this tributory

data, that Thompson concludes that “all marasmus exhibit marked atrophic changes in

collateral

infants dying of the

thymus gland.”

The important

role I ascribe to the

phosphorus in organic combination to

thymus,

all tissue,

i.e.,

to supply

accounts for the

morbid influence of atrophic changes in the thymus upon the organism which the “marasmus” portrays, in the light of the above facts, since, by causing atrophy of the thyroid, parathyroids,

and adrenals,

inhibits the functions of the identical organs

it

which, as I have sho^vn, combine to sustain oxidation, meiaholisni,

and nutrition. Though unable to account for the manner in which it exercised so potent an influence on the body at large, Friedlieben, as long ago as 1858, stated that “the size and condition of the thymus was an index to the state of nutrition of the body,” an observation confirmed, as stated by Thompson, by a

number

of

investigators,

among whom he mentions

heimer,^®^ Stokes, Euhrah, Eohrer,^®-

l\retten-

and Dudgeon,^®® who

all

noted that “atrophy of the thymus gland in children and wasting

hand in hand, “Dudgeon stating, moreover, that atrophy of the thymus gland was “the most characteristic lesion found in cases of marasmus.” of the tissues go

On 1.

the whole, the above evidence seems to

That the function

of phosphorus in

and growth

of

osseous systems,

thymus is organic compound as long

the

of the

hody,

demand

particularly

its

to

me

to suggest

:

supply an excess

as the development

cerebrospinal

and

it.

That impairment of the functions of the thymus underlies some of the disorders of nutrition which inhibit the development of the cerebrospinal, nervous, and osseous system during 2.

and early adolescence. That certain diseases of mdrition in children and adolescents, especially marasmus, rachitis, and trophic disorders of the brain and nervous system, are due, in part, to impairment

infancy, childhood, 3.

of

the functions of the thymus.

”2 loa

Dudgeon.

Bd. Ixvl, S. 55. 1897. 1 Klnderhellk., cxslv, p. 847, 1902. Jour. Path, and Bact., vol. x, p. 173 1905. ,

482

THE ADRENOXIDASE AND THE NERVOUS SYSTEM.

THE CIRCUJjATION OF ADRENOXIDASE IN THE NERVOUS SYSTEM. e

—

have now seen that aclrenoxidase

the oxidizing body of the Idood derived originalljf from the adrenals takes part in the functions of tlie many organs reviewed, in so far as their supply of oxygen

That

concerned.

is

Of

can be no doubt.

—

this applies to all organs there

the whole series, however, one, the nervous

system, including the cerebro-spinal system and all ganglia and nerves, is the most complicated by far. It must, therefore, re-

due attention to ascertain whether it also depends for its oxygen upon the adrenals. We shall see under the next heading

ceive

that such

is

the case, and, moreover, that the large proportion

many

of phosphorus which

of

tially

components:

its

stance of Schwann, the lecithin,

etc.,

the white sub-

contain, brings

it

within the reach of the thyroparathyroid secretion,

The adrenoxidase and

thyroiodase.

essen-

i.e.,

the

the thyroiodase constituting

the two active agents of the adrenal system, we shall be able,

moreover, to realize

why

the neiwous system ft so manifestly

involved in the diseases of the ductless glands.

Again, I would

while Harvey

call attention to the fact that,

revealed to us the circulation of the blood in practically

all

organs, the one exception in his epoch-making discovery was the

nervous system, and for obvious reasons: identity

of

bringing

it

the nen'e-cell, to view Avere

Its

histology,

and staining methods capable

unknown

in his time.

The

the of

explanation

of the circulation in the nervous system (apart, of course, from its

known nutrient

nerve

cells

vessels, AA'hich are, in reality, external to the

per se) sul)mitted in the next chapter, an amplifica-

tion of that published in 1903 in the present work,

the

first effort

is,

I believe,

of the kind in Avhich histo-chemical data

—and not

mere assumptions

—

are the basis of analysis.

or oxidizing sul)stance,

is

axis-cylinders of nerves.

shown

The

adrenoxidase,

to circulate in the neuraxons, or

If the reader will ask himself:

How

does the neurotoxin of tetanus, shown by IMarie and Morax,

IMeyer and Hansom, and others to ascend in the axis-cylinders of nerves, in

these

perfonu this feat? he elements,

phenomenon.

as

I

Avill

inteqjret

conclude that circulation it,

alone

accounts for the

CHAPTER

X.

THE POSTERIOR PITUITARY AS A GEXERAL XERVECEXTER AXD AS CO-CENTER TO THE ANTERIOR PITUITARY IN SUSTAINING LIFE. THE IDENTITY OF THE LOWER BRAIN. In

the foregoing chapters, I

nrgecl

that certain centers

in the medulla oblongata were probably but subsidiary centers

which received nervous impulses from the pituitary body by I way of the tuber cinereum and other basal structures. obtained by physiologists phenomenon in that it was caused

held, moreover, that “inhibition” as

represented a pathological

by excessive constriction of the cardiac

arterioles,

provoked by

vasoconstrictors contained in the nerve stimulated, the vagus.

As is well known, it was the work of the brothers Weber (1845) which first suggested that the heart could be “inhibited” by stimulation of a definite region in the medulla. Their experiments differed from those we have reviewed in that the tissues of the base of the brain were traversed by the current, thus

exciting structures

in

which we

have seen sympathetic and other nerves pass from the pituitary to the bulb. One pole having been placed in the nasal cavity of a frog fifth

and the

vertebra,

the

gradually resumed poles

upon the

on the spinal cord over the fourth or action momentarily ceased, then normal activity. Approximation of the

otlier

heaiUs its

and stimulation of the cord “Not until the medulla oblongata between the corpora quadrigemina and the lower end of the calamus scriptorius was stimulated,” says William T. Porcerebral hemispheres

])roduced no effect

upon the

heart.

did the arrest take place. Cutting away the spinal cord and the remainder of the brain did not alter the result.” The level

ter,

from structures below the brain is also suggested by the effects of experimental injury of the bulbar area which I lourens termed le na’iid vital. of fibers

31

(483)

— THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

484

Galen had already noticed that death ensued when a spot in the floor

tain

which

But

is

now known

the fourth

of

ventricle

as the center of the vagus

much

Legallois and Flourens have added

edge of

its

physiological relations,

we have seen, “The results of

as

is

close

cer-

that

to

was injured.

to our knowl-

and the spot in question,

considered as the respiratory center.

still

various

show,

investigations

liowever,”

says

Beichert,^ “tliat Flourens’s area, as well as certain other parts

of the medulla oblongata that have been looked

upon by others

as being respiratory centers, are not such, but are largely or

wholly collections of nerve-fibers which arise chiefly in the the

of

roots

vagal,

spinal

and

glosso-pharyngeal,

accessory,

trigeminal nerves, and which, therefore, are probably nerve-

paths to and from the respiratory center.

Moreover, excita-

tion of the ‘nceud vital’ does not excite respiratory movements,

but simply increases the tonicity of the diaphragm; nor

is

the

destruction of the area always followed by a cessation of res-

While the precise location of the center is still in ‘is abundant evidence to justify the belief in its That we existence in the lower portion of the spinal bulb.” are again dealing with the aggregate of centers to which the

piration.

doubt, there

Flourens body projects its fibers suggests itself. located his “vital Imot” in an area flve millimeters wide heiween the nuclei of the vagus and spinal accessory nerves again in the lower end of the calamus scripto-rius : i.e., a region comprised in the area to which the Weber brothers applied pituitary

one electrode,

tlie

or inhibition was

An

when

other being in the nose, first

cardiac arrest

observed by them.

interesting relationship seems to

these two sets of experimental

which the pituitary body sends

results.

me

Indeed, the area to

fibers

its

to exist between

thus becomes the

source of antagonistic effects involving the same structures

Weber

file

constriction of its in the

manner previously

by Flourens

in the

same

the floiy of impulses to

^

:

i.e.,

undue myocardium, coronaries and ischamiia of the

brothers caused arrest of the heart by causing

Reichert:

Loc.

cit., p.

45C.

described, while the lesion produced area,

when

sufficiently severe, blocked

and from the

heart.

Flourens’s 7ioeud

485

THE LOWER BRAIN.

no more the respiratory center than the area traversed by the current can be called an “inhibitory” area. We are simply dealing with the results of two morbid factors: vital, therefore, is

—and

physiological

and

(Weber)

overstimulation

therefore

(Flourens)

interruption

functional

—impulses

of

transmitted

through the medulla and the cord.

In the

fifth

chapter reference was

made

to the fact that

shown by Howell, con-

the posterior pituitary lobe alone, as

tained an active principle. This lobe, the “infundibular,” has long been termed the “neural” portion of the whole organ, and appears to me to present anatomical features that further

suggest a direct connection between

Hence the use

centers.

it

and the cerebro-spinal

words “physiological impulses

of the

transmitted through the medulla and the cord.”

becomes

all

the

more worthy

The

of a searching inquiry,

question

inasmuch

a casual examination of the mutual relations, anatomical and physiological, of the cerebral structures traversed by the as

current in the experiment of the

Weber brothers

suffices

to

show that the elements thus submitted to excessive stimulation coincide with those which would normally fall under the influence of the posterior pituitary body.

The

physiological

characteristics

of

the parts influenced

by the current must first be ascertained. In the frog, the distance between the nose and the medulla being very short, a current would implicate all elements in its direct path, considering the

character

animal, the lizard,

about the

appear to

floor

me

of

etc.,

the

of

the

structures

traversed.

In this

the nasal nervous terminals, the tissues

median ventricle and the habenula, would be involved. In man the

as the paths that

distance between the olfactory area or the nasal of the fifth pair

and the medulla

is

subdivisions

also relatively limited, and.

the intervening structures are of such a nature as to also allow the current to pass uninterruptedly in a straight path. But the of the median or third ventricle, which in its anterior portion overlies the base of the skull and is very thin, becomes what appears to be the inevitable path of free conduction, owing floor

proximity of the olfactory bulb and the trigeminal nasal terminals to the medullary centers. Of special interest here, however, is the fact that in man (and to a great extent in the to this

:

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

4

PHYSIOLOGY OF THE POSTERIOR PITUITARY.

501

come from every part of the underlying structures and only reach the basal structures through paths that are continuous '

and irrespective of the nerves which arise directly from the two lobes and pass upward by way of That a profuse padding the interior of the infundibulum. of cellular tissue is Nature’s resource under such conditions “The is well illustrated by the following remark of Dejerine’s: vessels of the central nervous system are surrounded by two with the capsule’s

tissues,

sheaths of a different kind

and belongs in nature,

the internal

is

connective in nature

mesodermic layer; the external, neurogliar

to the

is

:

developed at the expense of the external, or ecto-

The

dermic, layer.”

capsule has been compared to the cerebral

cortex, perhaps with justice, as

we

shall show.

Berkley, referring to the various cellular structures in the

deeper portion of the lobe supplied with long extensions, say^:

“The

axis-cylinder extensions of all the cells in the inferior

portion of the to the larger

lobe

turn upward.

.

proportion of the smaller

.

.

Those belonging

of the superior border turn upward and intermingle with the marginal fiber net-work. All the axis-cylinder processes and the .

.

cells

.

long dendrites have a general tendency upward and forward, both dendrites and neuraxons branching as they proceed on-

ward

:

cells of

but

the dendrites of the inferior and

all traces of

median

the lobe are lost some little distance below the superior

and then the neurons only are intermingled with the extensions of the smaller superficial cells, jDassing them, however, before the border is finally reached, where they spread out into a most extensive fret-work of fine varicose fibers, still edge,

retaining

something of their previous

ment from the threads

longitudinal

arrange-

of the uptending fibers being coarser

than the lateral and intermingling branches. It is doubtfnl whether any of these fibers pass beyond the limit of the lobe into the infundibulum our sections give no evidence of such an arrangement.” This upward tendency of all cells, and the ;

evident concentration of their functional activity at the upper extremity, seem to us to further emphasize the identity of the posterior lobe as a powerful source of energy. Its junction with tlie end of the infundihulum becomes, under these circumstances, the normal pathway for all the energy that the

—

—

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

502

can accumulate.

01 gall

or processes

organ

is its

We

Capsule and j^rotojilasiuic extensions serve a similar purpose, but the neck of tlie

all

own

functional limit.

must not

lose

sight of the fact, however, that other

nerves penetrate the organ.

This

Berkley says, in this connection

:

is

shown by the

fact that

“the nerve-fibers accompanying

the larger arteries are sometimes distinctly seen coming from the infundibular tract into the body of the posterior lobe of the

glaud and ramifying through it.” That tliere is no connection between these and the nervous structures previously described, however,

shown by the additional statement: “Connections between the fibers of the vascular supply and the nerve-cells of the organ, we have never been able to observe. That these are the nerves through which the organ receives its own functional energy i.e., the impulses to its vessels and alveoli, is

as in the case of other organs, is probable.”

The

prevailing view that the embryonal supporting sub-

stance of the brain and spinal cord, the ependymal neuroglia,

mammal

almost entirely atrophies and disappears in the adult

would tend

my

counteract

to

belief that the capsule

and

its

underlying structures are important factors of the posterior Berkley, alluding to the writings of various

lobe’s functions.

observers in this connection, and referring to the infundibulum

and other

which he had just “After reading these statements, it was some-

tissues

described, says

:

of

third

the

ventricle

thing of a surprise to find the above-described beautiful speci-

mens

of several types of ependymal neuroglia extending from

portions of the middle and inferior regions of the cavity of the third ventricle and reaching to the periphery, all portions,

all

and subpial endings being readily distinguishable. The region examined is, therefore, very interesting not only from the great variety of neuroglia-cells that may be seen within a very limited area, but from the bodies, branches, tentacles,

fact that varieties of the

supposed

to

ependymal

neuroglia-cells, previously

have entirely disappeared from the central nervous

.system in the adult

mammal,

are found present in perfect con-

dition in the brain of a very high order of animal, and are not confined, as has reptiles,

previously been supposed, to those

amphibia, and fishes/’

of adult

;

503

THK PITUITARY AND THE BASE OF THE BRAIN.

submitted are considered collectively, it seems to me that the following conclusion is warranted Removal of the hemispheres in an animal does not arrest its If all the data I have

normal 'bodily movements under external stimulation^ because these movements are dependent upon func-

power

execute

to

tional structures situated in the base of the brain

and in the

and which the posterior pituitary probably governs. Of course, this appears to contradict at once a great mass of experimental and clinical testimony, but the contradiction Eemoval of the motor areas in the rabbit is only apparent. gives rise to no detectable differences in the movements; the In the dog, the injured animal is similar to an intact one. spinal cord

same procedure, according tion of voluntary

body”; hut this

to

movement is

Foster, causes “loss or diminu-

in the corresponding part of the

only temporary, and the animal

may

re-

cover to such a degree that the temporarily paralyzed limb

cannot be told from the normal one.

Careful examination of

the brain after death shows that no regeneration of the lost part

had occurred. Even removal of the whole motor area causes no appreciable difference between the movements of the two sides of the body to a casual observer. In the monkey the results have been unequal: “^^hile in some instances recovery of the movement has, in the monkey, as in the dog, after awhile taken place, in other instances the

be

permanent.”

.

.

.

“The

‘'paralysis’

facts,

has appeared to

however,

knowledge relating to the permanence of the

within

our

effect are neither

numerous nor exact enough to justify at present a definite as stated by Foster. “On the other hand, the positive cases, where recovery has taken place, are of more

conclusion,”

value than the negative ones, since in the latter the recovery

may have been hindered by concomitant events of a nature which we may call accidental.” I might add that a single case of recovery in the monkey, when the motor area has been completely

removed, demonstrates that, generally speaking, the structures are functionally similar in all higher animals, including man, judging from such instances as the crow-bar case, or

one reported by Brown-Sequard,^^ in which an entire

Brown-S6quard

:

Socidte de Biologie, 1876.

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

504

was destroyed and in which the only syinptonig were amaurosis and slight headache. This emphasizes the identity lobe

of the cerebral hemispheres as

an aggregate of centers which

record impressions and are the seat of reason, intelligence, and

but

volition,

applicable in

also

it

word “motor”

suggests that the

its literal

sense to

tlie

is

only

areas in the lower cerebral

mechanism i.e., the intermediary through which the mandates from the hemispheres are executed. :

I

have previously referred

afforded by

misleading information

to the

Nowhere

the use of electrical stimulation.

organism does this seem to be more applicable than

in the to

the

brainl This feature and the complexity of the processes involved are fully emphasized in the following lines of the late Dr. Foster: “Some writers appear to entertain the conception that

movement, such

in a voluntary

that

as

the forelimb,

of

all

is that the Vill’ stimulates certain cells in the cortical area, causing the discharge of motor impulses along the pyramidal fibers connected with those cells, and that these

that takes place

motor impulses travel straight down the pyramidal tract to the motor fibers of the appropriate nerves, undergoing possibly some change at the place in the cord where the pyramidal fiber makes Junction Avith the fiber of the anterior root, but deriving their chief, if not their AA'hole, co-ordination from the cortex

itself:

starting-point.

tJiat

is

to

That such

say,

co-ordinated at their untenable and that the

being

a view

is

misleading are shown On the by tlie following two considerations, among others: co-ordination one hand, as was shown in a previous section, the simplicity of the electrical

movements may be namelv in the absence of

phenomena

carried

out

is

apart

from the cortex, and we can hardly

of the hemispheres ; be tAVO quite distinct systems of coshould there suppose that :

employed ordination to carry out the same movement: one some AA’hen Avhen A'olition Avas the moving cause, and the other thing else

led

to

the

movement.

On

the

otlier

hand, the

cortical analogy of speech justifies us in concluding that the by the processes do take adA'antage of co-ordination effected action of other parts of the nervous system.”

processes Deferring directly to the general character of the “Hence, while admitting, as involved. Professor Foster says:

505

THE PITUITARY AND THE BASE OF THE BRAIN.

we must

do, that in the intact

pyramidal tract play

animal the cortical area and

part

their

carrying

in

voluntary

out

movements, their action is not of that simple character supOn the contrary, we are posed by the view referred to above. driven to regard them rather as links true, but

still

links

—

in a

complex chain.

we may probably speak

urged,

—^important

links, it is

As we have

already

of the changes taking place in

the pyramidal fibers as being, on the whole, of the nature of

but we would go heyond the evidence if we concluded that they were identiccU with the ordinary efferent

efferent impulses;

impulses of motor nerves:”^-

All the features emphasized in

these quotations, especially in the last lines, appear to isolate the se,

me

to

hemispheres from the source of motor impulses per

and to confirm what experimental evidence obtained

removal of the hemispheres had suggested:

i.e.,

after

that the lower

cerebro-spinal structures constitute the executive intermediary

which the cortical mandates are actively realized. well Imown, these lower structures, in turn, manifest their activity through the centers imbedded in them; what is there to replace the energy in the form of motor impulses tlirough

Yet, as

which

is

is

erroneously supposed to be awakened by the “will” in

“certain cells of the cortical area”?

Professor Foster partially answers this question

“The

says:

much

when he

discussion in a previous section has shoivn that

body is carried out by the middle portions of the hrain, and on these the motor area must have its hold as on the spinal mechanisms. The details of the co-ordination of the

of the nature of that hold are at present

unlcaown to us.” It would appear from the facts reviewed that what might be termed the central brain and the spinal cord constitute an entity a mechanical entity, perhaps made up of working centers, beginning with the olfactory bulb and the other nerv-

—

ous

structures

anteriorly, i.e.,

—

distributed

to

the

nasal

mucous

membrane

and terminating with the end of the spinal cord:

the neural tract of lower forms.

—but

ordination, and sensation

Motility, unconscious co-

only, in the case of the latter,

to the extent of transmitting sensory impressions to their re-

The

italics

are

my

own.

— TUK rOSTKUIOR PITUITARY AND THE NERVOUS SYSTEM.

oUG

spective

perception-centers

—

^ivould

enter

witliin

scope

tlie

of

this central brain.

As

to the source of the transmitted energy or impulses,

apart from the sensory connections with underlying structures

—

which the cortex to

possesses,

^the

ascribe to the cortical areas

strates the

phenomena

predilection of most writers motor functions but demon-

need of such an agency to logically account for the

To

witnessed.

ascribe to the central brain or its

centers per se attributes of a similar kind to shifting to fictitious

it

would simply amount

a convenient, but unknouai, quantity, and a

one besides, in the sense that

account for something.

have so far traced to

In

tlie

its origin,

it supplies

nothing to

only nervous system that I that of the suprarenal .glands,

the conversion of chemical energy into neiwous impulses was

found to be a functional attribute of the anterior pituitary body. That so extensive a system as that represented by the central brain and cord should likewise need a center such as that represented by the posterior pituitary body for the conversion of some form of energy of external source to satisfy

the needs not only of

its

efferent,

but also

its

afferent,

im-

pulses seems clear.

That the middle brain is the source of the motor phenomena witnessed is not only suggested by the fact that normal muscular contractility promptly recurs after removal of the liemispheres, but also by the following experiment by Professor M. Duval: “If a part of the gray substance of the cortex designated as the center of certain movements is cauterized, the same movements are obtained when the electrodes are

applied

upon the eschar thus produced.

•

experiment shows,” says the author, “that the

.

gmy

.

This

cortical

the not a necessary experimental condition Indeed, he states that production of localized movements.”

substance

for

is

the underlying white substance of certain parts will also cause

circumscribed motions in certain groups of muscles, of the cortex of one side

etc.

followed by

Can the removal the assumption of compensative functions by the opposite side? After the usual period of paralysis, due to shock, the normal l)e

motions promptly recurred, precisely as they had on the other To ascertain whether the cortex at all possessed motor side.

THK PITUITARY AND THE BASE OF THE BRAIN. attributes

Vulpian passed an electrode through

the

was far more

easily

that part

The underlying

in contact with the cortex being insulated. white substance was thus alone stimulated. latter

it,

607

He

excited than the

found that cortex.

It

seems clear that in these experiments the increased excitability

was due

proximity of the central brain. “All the brain can persist,” saj^s Brown-Sequard, “after

to the closer

functions of

tlie

the complete destruction of an entire lobe.’”®

and

clinical evidence,

Experimental

however, only eliminate motility and co-

The

ordination from the hemispheres.

cortex, as regards cere-

bral localization, merely loses the “motor” attribute suggested

by the tenn “motor area,” and is shown, by its functional relations with the underlying structures, to be a vast sensitive surface, to the “areas” of which the term “sensory” might be

more fittingly applied. The practical bearing

of this

may

be illustrated by an

experiment that will recall some of the familiar features of the earlier portions of this

work and

to the central brain as the source of

same time point motor phenomena. This at the

experiment, referred to by Professor Foster, is as follows:

“It

has been observed that in certain stages of the influence of

morphine the cortex and the

rest of the neiwous system

are

in such a condition that the application of even a

stimulus to an area leads not to

momentary a simple movement, but to a

long-continued tonic contraction of the appropriate muscles.”

As previously shown, many drugs raise the hlood-pressure and thus congest the adrenals and indirectly the hrain. Cerebral hyperiemia, Ave have seen,

is

tlie

source of the majority of

phenomena that follow the ingestion

of drugs that are

ciently active to stimulate the adrenals.

The

suffi-

intense headache

and other agents is obviously due to this congestion of the cerebral vessels; muscular contractions, tetany, etc., are of quinine

also familiar results of suprarenal overactivity; indeed, digitalis,

one of tbe most active suprarenal stimulants, is particularly active in predisposing muscles to contraction and in experimental animals suitably dosed a minimal current without the drug will produce maximum effects prolonged tetany with it.

—

“M.

Duval:

Loc. cit, p. U5.

—

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

508

In the course of the statements to which

I

have referred,

Foster, after ascribing the temjiorary paralysis obsen^ed after

operative interference to a condition “of the nature of shock,”

remarks:

“But, even giving

full

weight to this consideration,

there remains the fact that the cortical area

is

associated with

various co-ordinating and other nervous mechanisms belonging

limbs by such close

to the

ties

that these are thrown into dis-

when it is injured. And, side by side with this, we may put the remarkable fact, previously stated, that during an abnormal condition of the cortical area simulation of the area instead of producing the appropriate movements confined to the limb may give rise to movements of other parts culorder

—

—

minatmg

in epileptiform convulsions/’^*

If the word “associated” is given its full meaning, limbs and co-ordinating mechanism constituting one class, and the cortical

surface the other,

the

hemispherical mantle of gray

matter being considered solely as a great sensory surface, the de-

mands of experimental evidence seem to me to be satisfied. What are epileptic convulsions after all but manifestations of Can the latter ‘be credited e.xcessive motor activity? to the cerebral cortex, as is now taught in text-books? Ob.

.

.

viously not, since experimental evidence proves that the cortex

has no motor properties per

se.

But

irritation of this sensory

surface or an accumulation of physiological toxics, which peri' odically becomes sufficiently great to so stimulate the vasomotor

center as to

cause

sory cortex, but also of brain, are the

not only of the sen-

violent hypersemia,

clearl}'^

its

executive mechanism, the middle

defined causes to which physiological and

chemical evidence points.

Could the cortex without the middle

brain give rise to the same phenomena? case

shown by the preservation of

is

all

That such is not motor functions,

cluding co-ordination, after removal of the hemispheres. deed,

it

is

only

when

the middle brain

experimental animal thus deprived of of its

dynamic center lienee

it

All italics are

my

thing,

its

the in-

In-

removed that the sentient cortex and

is

practically loses its identity as a living

seems clear that the motor phenomena caused

own.

—

509

THE PITUITARY AND THE BASE OF THE DRAIN.

ly stimulation of the motor areas of the cortex are manifestations of activity of the central gray matter at the base of the brain, incited therein

by sensory impulses from these cortical

areas.

What so

evidently

preserved

The

lower brain?

this

constitutes

animals

in

co-ordination, their

hemi-

member

of the

of

deprived,

spheres, points to the cerebellum as a possible

Includ-

group of organs to be considered in this connection. ing this

the

therefore,

organ,

structures,

and beginning with

we would now

anterior

the

the posterior pituitary body;

have':

infundibulum; the central gray matter, fomiing “a bed

for the development of the nuclei of the cranial nerves”; the

tegmental system,

i.e.,

the reticular formation in the medulla

continued to the subthalamic region, and to which belong the red nucleus and

otlier

All

bulbar nuclei.

this

forms what

Poster so aptly characterizes as ^^a more or less continuous column of gray matter” connected with the spinal cord by various ties, besides being, as it were, “a continuation of the spinal gray matter.” It is as evident that the optic thalami and corpora quadrigemina are also members of the group, since these related organs appear to be necessary for the success of

the experiment in which both

moved. animal spheres,

cerebral

hemispheres are

Thus, referring to the frog. Poster says: it

is

“In

re-

this

comparatively easy to remove the cerebral hemi-

including

the

parts

corresponding

the

to

corpora

behind, intact and uninjured, the optic thalami

striata, leaving

with the optic lobes, the representatives of the corpora quadrigemina, the small cerebellum, and the bulb. be carefully fed and attended to, very long time If,

:

for

with this

illustration,

more than a

list

it

may

If the animal

be kept alive for a

year, for instance.”

we now examine the annexed from His’s work, and, therefore, not

before us,

originally

recently drawn, a rather suggestive coincidence appears, indicating, perhaps, a total independence, in the

region

containing

the

embryo, of the

enumerated

from the which subsequently develops into the hemisphere of the same side. In mammals the latter is at first insignificant, all

structures

vesicle

l)ut

it

develops

structures.

The name

The

very

rapidly,

soon

outline of the latter

of each part

is

overlapping is

given on the cut

the

middle

colored bluish gray. :

a feature that wdll

— THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

510

convey the mutual relations of the various structures included in this system than a verbal description. better

Again, the location of the posterior pituitary at the

head of the entire spinal system,

verj^

as shovTi in the illustration,

adds further testimony to that already submitted to demonstrate the functional relationship between the nervous struct-

ures lying in the posterior pituitary, including the floor of the

fourth ventricle, and the bulb.

A summary pituitary

of all these facts,

body has a

(1) that the posterior history Avhich distinctly

i.e.,

phylogenetic

identifies it as a part of the entire neural tract;

that

(2)

it

presents clearly defined histological characteristics of an active

neural organ; (3) that these characteristics extend to the infundibulum, the tuber cinereum, the floor and sides of the that these structures are continuous with

third ventricle; (4)

the reticular substance of the tegmental region, the medulla,

and tlie cord; (5) that the posterior pituitary body has been found to be in direct relation with the olfatory center and the bulbo-spinal axis in

all

classes of vertebrates;

that a

(6)

current passed between the olfactory and medullar centers

may

cause heart-inhibition and death; (7) that various nerve-centers are included in the structures with which the pituitary is functionally connected in is

all

vertebrates;

(8)

that sudden death

caused by a puncture in the region of the vagal bulbar center

through

interruption

of

the

efferent

and

through Avhich the cardio-pulmonary system

afferent is

impulses

incited to ac-

tivity and governed; (9) that electrical excitation of the exposed pituitary body causes an instantaneous rise of the blood-pressure

of over 100

mm. Hg.

the opposite,

i.e.,

(10) that removal of the pituitary causes an immediate and great fall of the blood-pres;

sure; (11) that division of the base of the brain across the path of nerves known to originate in the pituitaiy body prevents the action of drugs, such as antipyrin, which lower the temperature, and also the action of jnis and other septic materials which cause

functions carried on normally to cease by removal of caused after removal of the brain are the pituitary, seems to me to warrant the conclusion that fever; and finally (12)

that

all

:

The

posterior pituitary body is the chief center of the spi-

MEHIAN ANE ITERTICAL SECTION CF A TWC AND NE-HALF MONTHS’ EMBRYO,

[His.]

[CaiisidEra'hly Enlarged.] 1,

iiq.TiBduct of Sylvius,

Pons

2, Ivledulla Dblongata,

3, CsTB'bBlluiii.

Tubercula Quadrlgemina, B, PostBrlor TubBrcula QuadrlgBmlna. 7, Infundibulum and Pituitary Bodies. B, TubEr ClnerEum, B, Dptlc Thalamus, !, Fourth VBntriclB. 11, Hypoglossal IMetvb [Twelfth Pair], 12, Third VentrlclB, 13, 4,

yaTolil,

HemlsphETB

I

5, ilnterior

ITbsIdIb.

*

THE POSTERIOR PITUITARY

511

IN DISEASE.

system, and, as such the primary source of certain excitomotor impulses noiu hetieved to arise in the hull).

ml

Evidence.

Clinical

—^The

various

that

facts

have

I

enumerated in the summary in support of the conclusion just submitted being of a physiological kind, it seems evident that I

should, in view of the important functions ascribed to the

organ, also be able to adduce clinical evidence.

Indeed,

if

it

holds the important relation to the nervous system I believe it does, its influence in the pathogenesis of general neuroses

be very great. posterior lobe,

must

No disease having so far been associated with the it may prove profitable to seek among the symp-

toms of typical disease of the anterior lobe what signs might be assigned to implication of the posterior, with which it is intimately blended.

Acromegaly, which

may

be attended by irregularity of the

reflexes, paresthesias, localized pains,

plegia, etc.,

and known

to be

vasomotor neuroses, para-

due solely to lesions of the pituitary,

suggests itself as a profitable field of study in this connection. It is interesting to note, in this connection, that quite a

number

of

exceptionally able clinicians

for

instance —

sis,

the organic disease of

them

^liave

—von

Eecklinghausen,

considered acromegaly as a trophic neurotlie

pituitary being considered by

Again, the neural canal of lower' fonns

as secondary.

(as a whole) also produced a fluid capable of nourishing nervous elements and

led Collina^^ to suggest that the pituitary

that deficiency of this fluid, by reducing the

nutritional processes, gave rise to acromegaly:

activity

of tlie

further evidenec

and these organs is marked clinically to have attracted considerable That the various theories adduced also bear upon

that the tie between the nervous system sufficiently

attention.

nutrition of the nervous elements

favor of

my

view.

impaired nervous

is

practically all cases of aeromegaly

become

significant as testimony in

Indeed, the clinical signs that point to action are numerous, and are present in

sufficiently

when the

anterior lobe has

enlarged or functionally disordered to in-

volve the posterior lobe, either directly of tissue, etc., or indirectly

in the later stages, '“Colllna:

by pressure, continuity by overstimulating the adrenals, or,

by causing insufficiency of these organs.

Gazzetta degli Osped.,

.Ian.

8,

1899.

THK POSTERIOR PITUITARY AND TdE NERVOUS SYSTEM.

512

a previous chapter I have,

Ill

on good grounds,

I believe,

ascribed to overactivity of the adrenals the stage of “erethism,”

and

to insufficiency of these glands that of “cachexia.”

But,

if we ask how these states are produced by the adrenals, the answer which Avould not have been available before now seems to be within our reach.

have previously referred to the vicious

I

Though primarily

tains in acromegaly.

its

until well advanced:

own

i.e.,

Even

untoward sj’mpupon

until pressure occurs either

structure by the pathological

posterior pituitary.

that ob-

located in the anterior

pituitary, the lesion probably gives rise to no

tom

circle

elements or upon the

upon the whole organ, marked general symptoms.

slight pressure

shown by de Cyon,^® gives rise to But if the posterior pituitary is also considered as a factor the production of the symptomatic phenomena, as a source nervous energy, we not only have the vascular erethism as

in of

of

suprarenal overactivity, but distinct evidence of nervous ere-

thism besides. lines,

This

is

well illustrated by the following quoted

Gauthier’s definition of the erethic stage of acro-

i.e.,

megaly as given by Hinsdale^": “The phenomena of erethism which characterizes the first stage embraces, first, a painful hypcrcesthesia, which manifests itself in headaches and rheumatic pains; second, an hypertrophy of the muscular fibers which

may

give

to

patients

a

muscular power greater than

usual; third, palpitation of the heart accompanying the hyper-

trophy of that organ

;

and, finally, the polyphagia and polyuria

which may be considered of the activity.

respective

But

to be connected with

organs.”

an erethic state

Everything here points

to

these are only the milder manifestations.

over-

Tam-

burini, for instance, describes a case in which “the mental symptoms, on account of which the patient was sent to the

asylum, began to show themselves only a year before her admission.

They

consisted chiefly in delusions of suspicion ac-

companied by threats and acts of violence. The patient presented, in a marked degree, the bodily changes characteristic of acromegaly. While in the asylum she was confused, resistive,

De Oyon: HInsdulc:

Archives de Physlologie, July, Loc. ct7., p.

1^0.

189K.

— 513

IN DISEASE.

THE POSTERIOR PITUITARY

Only tlie anterior lobe was involved, the posterior presenting no change either in volume or sti’ucture.” This typifies the irritability or stimu-

and refused

{Uid suicidal,

lier food.

.

.

.

by pressure without organic change. The phenomena jiroduced are of another kind when both organs are involved in the morbid process, as appears to be

lation induced

and

the case in the following instance reported by Jolinston

patient, a woman, “was taciturn and and her memory was bad. Her utterance was thick and indistinct, as if her tongue were too big for her mouth. Her gait was slow and shuffling; her expression partly

Monro^“

intellect-

The

:

ually obtuse,

The skin of the the mucous surfaces are

melancholic, partly demented.

.

.

a

of

is

dull-yellowish

Hearing

.

The

ished.

.

tint;

.

pale.

Eeflexes are dimin-

somewhat impaired.

is

face

.

for

subject of these notes remained in hospital

She

about four weeks.

no

scarcely ever spoke, took

interest

She in anything, and slept about sixteen hours daily. was readmitted in September ^blind, more deaf, more drowsj'^, very feeble in muscular power. She could no longer rise without assistance. Control over the sphincters was lost. Paralyzed. For a couple of months before death there was a .

—

.

.

.

discharge of clear fluid from the nose.

body

is

much

.

represented by a large, red mass,

softer than

brain-substance.”

destroyed, the posterior lobe

The

.

.

The

.

.

pituitary

almost diffluent entire

organ being

had obviously followed the

fate

of its mate.

In a symptoms

case described

Pirie^® the history of the nervous

by

very clearly defined, though the author was un-

is

“The disease first when menstruation finally ceased.

fortunately unable to obtain an autopsy.

manifested

itself

in

1886,

Pains and pariestliesia of the arms and legs were

felt,

and

and feet were getting larger Along with the development of

the patient noticed tliat her hands

and more awkward. physical

.

.

.

symptoms a peculiar

took place.

alteration of mental

sluggish and irritable, and she suffered of

life.

.

.

.

much from

the ennui

Breathlessness on the slightest exertion ap-

Johnston and Monro: Pirle:

condition

Attacks of narcolepsy overcame her, she became

London Lancet,

Glasgow Medical Journal, August, Oct.

5,

1901.

1898.

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM

514

and ultimately the muscle weariness so gained upon her that she had to take entirely to hed. Sensory disturbances are marked. Shooting jiains in combination with jicaretl,

,

.

paresthesia, tingling,

arms and

and numbness are complained

Xeuralgic pains are

legs.

of the body, viz.

:

tlie

of in the

felt also in various parts

A remarkfound in the lower front of the abdomen and chest up to about

the face, chest, back and loins.

able perversion of thermic

limbs and over

,

sensibility

is

the level of the fourth rib, the patient having no sensation of heat in these regions. Sternberg remarks particu.

.

.

on the occurrence of pain and parsesthesia

larly

valuable

as

signs for diagnosis in the early stages of the disease; they are

probably due, he considers, to changes in the cutaneous nerves.”

In a previous chapter

symptoms are impairment of both,

that

it

remarked

:

‘^Vhether the mental

certain functions of the pituitary itself, or to

now seems

evident

organs are involved in the pathogenic process.

If the

is

hotli

I

ascribable to the cereliral hvperaemia or to the

as yet

impossible to say.”

far-reaching meaning of this

fact

is

It

apprehended,

it

seems

—

hidden under the whole fabric of which we only now see the outline a truth of ovemdielming imporclear that there lies

—

tance to us physicians:

i.e.,

the fact that

it

is

not alone in

acromegaly that the typical signs of impaired function of the posterior pituitary appear, hut in other syndromes directly the adrenal system:

ascrihdble to

i.e.,

myxeedema, cretinism,

exophthalmic goiter, and Addison’s disease, which include in their aggregate the majority of organic changes of a morbid Irmd to which the system is liable, besides nervous phenomena. be briefly illustrated by further quotations from Dr. Pirie’s excellent paper, entirely devoted to the one case. As regards the muscular system, the author states that “mus-

This

cular

may

atrophy

is

a

prominent feature, affecting the thenar,

hypothenar, and interossei muscles of the hands, the forearmand arm-muscles, the calf- and thigh-muscles, and also the glutei,”

refers to Duchesnau,'®

and

“who has made

study of the atropliy of muscles in acromegaly. it

in

some

a

special

So marked

is

cases that it has been mistaken for syringomyelia.

Ducliosiiau

:

Thi'se de Lyon, iS9I.

515

THE POSTERIOR PITUITARY IN DISEASE.

progressive muscular atrophy, or amyotrophic lateral sclerosis;

has also been mistaken for Charcot’s cervical pachymeninEeferring to the gitis hypertrophica and for erythromelalgia.” it

“Its chromatogenous functions are disturbed,

sA;m, Pirie says:

much

rheumatoid

as in

Small freckles are frequent;

arthritis.

patches of a yellowish bronzing occur also

and the insides of the thighs.

chest,

on the

face,

Numerous small

ing such as occurs in Addison’s disease.)

many

(Mollusca fibrosa are described in

warts are present.

the

(Motais describes a bronz-

and xanthoma-like tumors by Dallemagne.) The patient from a brownish seborrhoea, especially troublesome in the scalp. The hair is thick and coarse and stands straight Profuse upward. There is a scanty beard and moustache. cases

sufi'ers

The heart

perspirations are constantl}'^ complained of.

There

lated.

the minute.

is

A

tachycardia, the heart beating about

soft, systolic, basic

Palpitations and fainting

fits

murmur

is

di-

is

98 to

heard at times.

Dyspnoea

occur very often.

is

marked, and asthmatic-like attacks occur, during which the patient has to

“The soft The scalp .

.

.

lumbar

sit

up

in bed

and

fight for her breath.”

.

.

.

parts are remarkably changed as well as the hones. is

much

thickened, as

is

also the skin of the face.

In addition to the kyphosis there is a compensatory and also a certain degree of scoliosis. The are enormously hypertrophied. The ribs are thick-

lordosis

clavicles

ened and expanded, the costal cartilages feel bony, and there are

nodular projections resembling the

Tachitic

the junctions of the ribs and their cartilages.”

chaplet’

.

at

“With

.

.

regard to the organs of special senses, the skin of the eyelids is thickened and puffy. The lacrymal glands are hypertroIncreased

phied.

laerymation

occurs

at

times,

noticed a colloid-like secretion between the

“There

and I have

ej^elids.”

.

.

.

amblyopia, nearly complete in the left eye, and colorvision for blues and yellows is defective. Bitemporal hemiis

anopsia

is

The pupils contract in accommodation and though very sluggishly in the case of the left the ophthalmoscope optic atrophy is found.”

present.

react to light,

With

eye.

“She suffered much

at this time from polydipsia and and for over twelve months there was an almost constant dribbling of saliva from the mouth. The .

glycosuria,

.

3.3

.

.

— THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

616

thyroid

-vvas

greatly enlarged, but under treatment with thy-

much

roid substance it diminished

how dependent

the

suprarenal system

“It

organism

when

in

upon

is

size.”

We

tlie

integrity

have seen the

of

infectious diseases develop.

I

can fully agree with Harlow Brooks-' wlien he says:

is

quite natural to expect pronounced abnormalities in the

various portions of the nervous system in a disease which exhibits so

many

neurological symptoms”; and his statement that

“examinations of the nerve-tissues have shown quite extensive

and general changes” further sustains dence of this kind, garnered from all

my

feature it serves to support

of,

the strongest kind.

is

thought

Evi-

deductions.

sides

long before the

me

appears to

words, therefore, rather than

my

own, when he reviews the

pathology of the disease, and which seems to

me

portray

to

parvo the main landmarks of neurological pathology.

in

of

again prefer to use the author’s own

I

I

have only omitted those of the author’s own estimates that do not bear directly upon my subject and what text was not purely descriptive: ‘‘Peripheral Nerves are,

for

tlie

.

—The

trunks of the peripheral nerves

most part, enlarged; this

is

due to an

directly

increase in the connective tissue of the endoneuriuui and peri-

neurium.

Often the sheaths of the nerve-trunks also show

This general connective-tissue

considerable thickening.

hj'per-

plasia frequently so encroaches on the nerve-fibers as to destroy

them, and degenerated nerve-fibers are quite commonly found

some of which may show complete (Arnold, Comini).

These conditions

the entire nerve-tnmk,

destruction

axis-cylinder

may

persist throughout

extending even into the nerve-roots.

(Arnold, Duchesneau.)

“Ganglia

.

— In

connective-tissue

macroscopically

the posterior-root ganglia, also,

elements

greatly

the ganglia

are

increased,

often

we

so

considerably

find the

even

that

enlarged.

Idicroscopically the ganglionic cells are sometimes pressed upon

Arnold reports that he and atrophied (Marie, ]\Iarinesco). found vacuoles in the nerve-cells. In Cases I and II of the author’s, the alterations in

« Harlow Brooks: Archives 1898, p. 692.

tlie

of

ganglion-cells were slight.

Neurology and Psychopathology,

vol.

1,

No.

4,

THE POSTERIOR PITUITARY

517

IN DISEASE.

detemiine whether the nerve-cell lesions are secondaiy, perhaps directly dependent on the connectivetissue hyperplasia about the cells and fibers, or are primarily “It

is

difficult to

Perdue to defective nutrition of the ganglion-cell bodies. haps these ganglionic changes are wholly, or in greater part, responsible for the degenerations and atrophies which take place in the muscles of the voluntary system.

—The

changes in the sympathetic ganglia and trunks have been made the subject of special study by several very prominent investigators, among whom are Marie, Marinesco, and Arnold, and have been looked upon by ‘‘Sympathetic

many

Qancjlia

.

Finding, as we do,

as factors of an etiological nature.

such pronounced change

in the blood-vessels,

at all strange that lesions in

it

does not seem

the sympathetic ganglia should

be present; but a view intimating a dependence or relation of the vascular changes to the lesions in the sjmipathetic sys-

tem

is

not in accordance with our oivn ideas expressed at the

close of this

In general, the changes in the sym-

paragraph.

pathetic ganglia are very similar to those already described in

the ganglia

and trunks

of the cerebro-spinal system.

cases the size of the ganglia

In some

considerably increased (Arnold,

is

Marie, Marinesco), and, microscopically, the connective-tissue

web

.

.

thickened

is

often

reported .

“Arnold

The

and proliferating. as

has

exhibiting

found

ganglion-cells

evidences

of

vacuolization;

are

degeneration.”

not

infrequentl}'^

considerable deposits of pigment are seen within the cytoplasm.

may

But, as in Case II, the ganglion-cells

be normal; the Nissl

bodies are present in normal arrangement, volume, and shape,

and show no deviations in their staining reactions; and the pigmentary deposit is not abnomially abundant. The sympathetic ganglia in the case reported by

normal.

It

is

Gauthier were also

advisable, at this point, to call attention to the

fact tliat the interstitial hyperplasia is

characteristic of the sympathetic system,

by no means a lesion but is simply an ex-

tension of the general process so often alluded to.

The growth

may depend in part on lesions in the walls of the vessels or both may be referable to tlie common factor of deranged nutrition. Cord and Medulla The pathological findings in both of

eonnective tissue in the sympathetic ;

.

—

— THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

518

the cord and medulla differ greatly.

Virchow, and also Fritsche

and Klebs, have rejjoi-ted hyiiertrophy of the medulla. The was enlarged in the case reported by Linsraayer.

spinal cord

observers have reported various degenerations in the Baruch’s case was associated with symptoms of S 'ringo3 myelia; Debierre gives a case with diseased posterior columns, j\Iany

cord.

while Arnold, Dalleraagne, and Tamburini have found at autopsy irregular degenerated areas in the cord, affecting, however,

no

any degree of constanc)^”

special place with

That the trophic

changes

in

the

nerve-tissues

explain

and myological symptoms in acromegaly is obvious, but these occur in advanced cases, •i.e., when such morbid changes have had time to occur. The signs which several of the neurological

point to the posterior lobe as the seat of an important center in keeping with physiological data enumerated

occur during the early or erethic stage,

viz.,

on page 510

the painful hyper-

numbness, the vasomotor neuroses and the palpitation. Their presence is explained by the marked rise of blood-pressure produced by irritation of the pituitary body proper, observed by Cyon, and confirmed by Masay, and by the long-recognized identity of the posterior pituitary as the neural lobe, its h istology and nervous connections. sesthesias in the extremities, the tingling,

Pending additional evidence in this direction the nature of the process through which the pituitary influences the nervous system requires study.

THE HISTOLOGY AND PHYSIOLOGICAL CHEMISTRY OF THE NEURON.

We

are first brought to inquire into the relationship between the modern conception of the structural composition of the cerebro-spinal axis and the views 1 have submitted.

Granted, therefore, that

tlie

seat of a process through

posterior

pituitary

which chemical energy

body is

is

the

converted

into nervous ciiergj', and that this constitutes the nervous impulses which the cerebro-spinal axis transmits to the various

organs,

how do

the nerve-elements utilize this

energy when

functionally active? I

logical

WaldeyeFs neuron as the morphounit of the cerebro-spinal axis, and the processes of

refer,

of course, to

— 519

THE PHYSIOLOGY OF THE NEURON. /

which are not in contact, but other, as to

make

it

possible,

sufficiently

when

close,

one to the

required, for a nerve-impulse

These facts have been to cross the interval between them. satisfactorily established by modern methods, especially through

and Eamon y Cajal.

the labors of Golgi

But the manner in he., how the closed

— —

which the gap between the processes is impulse passes from the terminal brash of the axon of one nervous element to the dendrites of the next is still to be

been suggested, however, that the processes behave, in a limited manner, as do the pseudopodia of the amoeba, and that by a slight extension the interval between It has

determined.

the processes

When

closed.

is

the processes are not in con-

be in a state of “retraction.” Much as such a function would facilitate and shorten our anal^dical work could incontrovertible e.xperimental facts be adduced to tact they are said to

by a review of tlie literature of the Indeed, subject, to recognize that such facts are not available. the majority of physiologists and neuro-histologists now consider the question of “amoeboid movements of the neuron” in the light of a working hypothesis. There is one feature of the investigations in this direction which may serve to throw more light upon the whole quessustain

we

it,

tion if one

me

are brought,

of the

in the present

more prominent deductions submitted by i.e., the work is taken into consideration :

fact that certain drags cause overactivity or insufficiency of the

adrenals.

Much of the physiological work done in connection with neuron includes the administration of various toxics,

the

—

strychnine, chloroform, morphine, etc., and amoeboid movements or other active manifestations of the protoplasmic processes

are thus ascribed to the action of the

neurons of

drugs upon the

views, the changes

form witnessed should be ascribed to increased or reduced

when

blood-supply

meaning sents

I

one

Demoor.

will

of

toxic doses

give in

the

the

complete

are

given.

To

illustrate

outline an experiment

key-stones

Before doing

to state that I will

to

my

whereas, in the light of

'per se,

of

the

entire

my

which repre-

tlieoiy,

that

of

may, perhaps, be ivell consider the terms "neuron" as applying this,

neiwe-cell,

however,

it

including processes;

"neiiraxon"

— THE POSTERIOK PITUITARY AND THE NERVOUS SYSTEM.

520_

to the (usually) single aiul long jirocess

the center of the nerve-fiber, and

is

which extends along then called “axis-cylinder;

—

many processes some of which end in many branches or tufts other than the neuraxon. With F oster and Sherrington Ave will consider that neuraxons carry “dendrites'’ to the cell's

—

impulses away from the into the cell.

Two

—

cell, while dendrites transmit impulses other prominent morphological features are

the “gemmules” minute projections all along the dendrites and their terminal twigs, Avhich recall those on the stems of

the moss-rose, and the varicose, or irregular, swellings that may be observed in the course of the dendrites or their terminal tivigs.

The experiment

of

Demoor was

He

briefly as follows:

dog by injections of morphine; a second dog was given morphine for some time, then killed by cutting the medulla; a third was trephined. The next day a piece of the left hemisphere of the latter dog was removed; the animal being then morphinized, another piece ^but of the right hemisphere this time was removed. Portions of the hemispheres of the two killed dogs having also been removed, all specimens were The cellular changes treated in precisely the same manner. were found to be similar in all specimens taken from the morphinized animals: their gemmules had disappeared. Alone of the series the piece removed before morphine had been given Now the Avas covered Avith regularly distributed gemmules. h-illed

a

—

—

fact I

wish to emphasize

is

this:

Avhile

this

experiment

is

thought by its author to show that the retraction of the gemmules constitutes the inactiA'e state, as induced by morphine through the local action this drug is noAV thought to have upon nerve-cells, the retraction of the gemmules is due to general Amsoconstriction

of

all

arterioles,

including

those

of

the

ad-

by a direct action of the morphine upon the sympathetic We thus have, instead of a purely center. (See page 1272.)

renals,

an example of the general physiological process through Avhich the neuron passes from the active to the passive state, the circulation of oxidizing substance in the neuron being local effect,

thus inhibited.

Again, the same structures treated by different methods have been found to yield different results. Thus; H. H. BaAV-

:

521

THE PHYSIOLOGY OF THE NEURON.

dcii" found that “all material treated according to the slow method of Golgi shows, as a rule, an almost absolute freedom

The varicose cells occasionally occur.” from varicosities practically yield found to rapid were the mixed method and the same results when the dendrites had taken the stain: the In gemmules were almost invariably present and regular. in others some sections almost every dendrite was varicose; hardly any. All these results were similar whether nonnal or ;

“toxic” material was used, and the author concludes that “it is

impossible for an unprejudiced observer to differentiate or

between the two kinds

distinguish

who has upheld clusion

that

of

retraction theory,

tlie

“imperfect fixation

is

Lugaro,^®

material.” also

reached the con-

very largely, though not

entirely, responsible for the

formation of varicosities and the

disappearance of ge.mmules.”

Weil and Trank summarize what

a review of the literature of the subject shows,

“The

are

there

.

—

Demoor and .

.

records

occasionally

contradictions,

of

when they

say:

findings have been in almost every case positive, although

as,

of

for

of

example,

negative

results

between the

Soukhanoff on the

effects

and even

investigations of

chlorofonn.

Eetraction of the gemmulse and coincident swelling of

the dendrites form the essential features of every description.”

Judging from the foregoing estimates as to the effects upon dendrites, these phenomena are to be considered as artifacts: he., as artificially produced changes. Under stains

of

these conditions,

it is

clear that the latter should appear, irre-

spective of the condition of the animal at the time of its death

whether under the influence of toxics as stated, fatigue,

he., etc.

That prevailing views

my

in this connection are erroneous

is

fimi belief after a critical analysis of available experimental

evidence.

and valuable in this conH. H. Goddard,^^ which con-

Particularly instructive

nection are the experiments of

sisted “in cutting through the entire head of the animal at a single blow with a very thin sharp knife, the parts of the head falling instantly into large dishes of Cox’s solution warmed

“

H. H. Bawden: Journal of Comparative Neurology, May, “Lugaro: R1 vista dl patol. nerv. e ment, vol. iii, 1^98.

*

H. H. Goddard: Jour, of Corapar. Neurol., Nov.,

1898.

1900.

THE POSTEUIOU PITUITARY AND THE NERVOUS SYSTEM.

522

to 39° C. old, sisters

what

tired,

Ill

liis

first

experiment, puppies about seven veeks

from the same

litter,

were used, the one while somc-

the other after having slept.

pyramidal

A

careful count of

somewhat fatigued cells showing varicosity, while cells from the same region of the puppy killed after sleeping was 8.5 per cent. In the former animal 15.9 per cent, of the cells showed much varicosity; in the latter only tlie

cells

of the

cortex of the

J3uppy gave a proportion of 31.1 per cent, of

In the second experiment

0.8 per cent, shoived a similar state.

on waking in the morning; the second at night when tired and very sleepy. While it “was

the

lii*st

of

two

difficult to find

sisters

was

killed

a single varicosity on the dendrites of the morn-

ing puppy, for long distances in the cortex of the. evening

puppy” it was difficult to find a cell “whose processes” were It is evident that in these in“not more or less varicose.” stances at least the stain was not alone the source of varicosities, since it was only in the tired puppies that the varicosities

were very marked, while in the thoroughly rested animal

none could be found. Judging from these experiments,

practically

drites

varicosity

coincides with a fatigued condition.

of

the

den-

This corresponds

exactly with the experiment of Demoor, previously described, since retraction of the gemmules is accompanied by varicosity; •

so that fatigue

duced similar

and a large dose

of

morphine must have pro-

results.

If the staining process alone caused the formation of varithe same method having cosities in Demoor’s experiments,

been used for

all

specimens,

—how

—

is

it

that one of the latter

showed gemmules (which means absence of varicosities), and that tliis solitary specimen is precisely from the only animal which had not received morphine? Berkley-® found that poisoning with alcohol “in considerable doses, continued over a moderate time, ivill produce decided and ascertainable lesions of the nutrient structures and nervous elements of the cerecharacter to the pathological lesions produced by otber more virulent soluble poisons. The terminal

brum”

very' similar in

twigs of the dendrites were also found to have become varicose “Berkley: Brain, vl,

1897.

W'inter,

1895;

and Johns Hopkins Hospital Reports,

vol.

523

THE PHYSIOLOGY OF THE NEURON. gemmides being very scarce or

or beaded, the again,

may

is

a condition which,

add, chloroform, chloral hydrate,

wc

and other toxics used

and others with similar results, all tend in the one

by Demoor direction:

Here,

absent.

as 'does fatigue, moi’phine, and,

i.e.,

This

to morbidly reduce functional activity.

a wcll-lmown characteristic of the bromides.

is

a study of the

In

under the influence of poisonous doses of potas‘‘If the primal ascending sium bromide, H. K. Wright^® says several ampullous teraiination, dendron is followed to its visible cortical cells

:

or varicose swellings of varying size are

“on the basal processes

also

varicosities

met with,” are to be

.

.

seen

;

.

but

they are small and, like those of the ascending protoplasmic process, are sharp in outline, and shorn of the lateral projections which

obtain on the unaltered part of the extensions.

One may be seen on each secondary branch, and ranges in size from a small and scarcely recognizable to a readily obvious swelling. None of them, however, reach the dimensions of the apical projection and its branches.” If the method of staining is the cause of all this, we are brought to tlie conclusion that it must be selective as to the parts of the dendrite it affects, and that only functionallyimpaired cells are so affected by the stain as to show varicosities. Even tlien staining methods would furnish precious indications. But it seems clear to me that, while the newer chrome-silver methods

still

furnish imperfect pictures of the

morbid alterations of the neuron, they cannot with justice be said to either cause or prevent the formation or disappearance

of

gemmules and

varicosities;

in

other words, that they are

The marked tendency

not artifacts of the Golgi method.

of

the swellings to locate at the apices, and the gradual reduction of the varices as the cell-body

is

approached

other hand, a well-known pathological principle

morbid

effects

:

impaired general nutrition are

of

recall, i.e.,

on the

that the

first felt

by

terminal structures.

And

the painstaking experiments of Weil and

not appear to

me

Frank do

in the least to prove their conclusions that

“the varicosities must be regarded as artifacts” and that “they

“

H. K. Wright:

Brain,

Summer,

1898.

THE POSTERIOU PITUITARY AND THE NERVOUS SYSTEM.

524

depend for their presence and their amount on the form and of.” Demoor employed the same method in

method made use

each of his comparative experiments and his results were not similar, tlie non-morphinized specimen alone differing

from all comparative experiments, and likewise obtained results which distinctly showed a marked difference between the rested and fatigued animals. In these and other experiments referred to,

Hubbard used

others.

the

patiliogenic

the identical

method

in both his

including fatigue, was

agencj'',

allowed

cient time to produce alterations in the cortical cells,

if

suffi-

nutri-

tion has anything to do with the process.

In Weil and Frank’s experiments the animals were overwhelmed by the quantity of toxic administered, and death occurred, viewed from my standpoint, by arrest of the adrenocardiac functions, long before any marlced action upon the cells The doses of morphine admincould possibly have occurred. gramme istered were 0.38 and 0.41 (6 and 7 grains), respectwith death in 15 minutes; of strychnine nitrate, 0.018 gramme (Vs grain), death in 20 minutes; of hypertoxic urine, ively,

125 to 150 cubic centimeters (4 to 5 ounees), death in 15 to 25 minutes. evident.

—

meters

That these

are overwhelming doses in rabbits

is

killed with serum (30 cubic centiminutes; others with clhoroform inhala-

One animal was 1 ounce) in 5

by tracheal clamping in 8 minutes. The rest, six animals, were destroyed instantly by instrumental procedures. In none of these animals was there any distinction tions in 10 minutes; one

had been sleeping, eating, or romping, etc. That some were old and others young in the series of nineteen is probable as is well known, erethism, espeestablished as to whether they

;

cially in

such delicate structures,

is

greatly influenced by age,

and a few months in the rabbit represent as many decades in man. The weight of each animal was not recorded in order to establish

the relative action of a given

dose of the

to.xic

used per pound of animal, though, of course, in the experiments, the large doses used precluded any usefulness on this score.

Finally, the authors themselves will surely admit that “no and “very varicose,” “slightly “varicosities,” varicosities,” slightly

varicose,”

the

method of notation

utilized

by them,

—

;

526

THE PHYSIOLOGY OF THE NEURON. conveys but

Ami

exact information.

little

even this sus-

still,

Indeed, the short period

tains a deduction oiiposite to theirs.

toxics in the of time that elapsed between the injection of the animals killed in this manner represented by 108 blocks of

—

slides

—^must

have

sufficed

mules and the formation of cent, of these blocks show no

of

retraction

initiate

to

varicosities,

since only

the gem10.3 per

When, on the other

varicosities.

hand, the proportion of animals killed instantly by instrumental procedures 93 blocks of slides is analyzed, over two

—

—

and a half times as many, no

f.e.,

28 per

cent., are

found

to

show

varicosities.

But a

Why

fair

question suggests

itself

do the remaining 72 per cent,

in

this

connection

show any varicosities?

Only 14 per cent, of the blocks from the instantly killed animals are recorded as “varicose,” the remaining 58 per cent, being entered as “slightly” or “very slightly” varicose. In their explanation of the scope given these terms, the least

some

Now,

cosities.”

and the second

varicosities”

first

as “only very

means “at few

vari-

the authors state that “in the first nine cases

here recorded the brains were placed in fixing fluids within three to five minutes.”

we may

Nothing

is

said of the rest; so that

immersed

infer that the ten other brains ivere

longer intervals.

We

sion of myosinogen

after

have previously seen, when the conver-

myosin was studied, that oxidation i.e., until all the oxygen That this must be the case with the brain, into

processes continued even after death:

had been utilized. which contains one-fifth of the blood the entire encephalon is evident.

whole body, and

of the

that products of metabolism, especially

CO 2

,

should form in

It normally follows that

we

have in this factor a potent cause for the retraction of gemmules and the formation of varicosities. Indeed, the contrast between the for itself to

when compared

to

results

reached speaks

those of Goddard,

who

resorted

procedures in which the exact condition at the instant of

death were preseiwed, “the parts of the head falling instantly into large culture dishes warmed to 39° C.” Even continua-

normal brain temperature was insured. And what “It was difficult to find a single varion the dendrites of the morning puppy,” i.e., the thor-

tion of the

were Goddard’s results? cosity

526

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

oughly rested animal; while in the thoroughly tired one “for long distances in the cortex it is difficult to find a .

.

.

whose processes are not more or less varicose.” That fatigue is the result of an accumulation of products of metabolism and especially CO, is generally recognized. cell

Goddard’s procedure appears to

me

to represent as nearly

perfect a one as available staining methods (Cox’s and the rapid

method show considerable parallelism in Weil and Frank’s report, while the mixed and slow methods appear unreliable and contradictory) will allow; his results, in my opinion, portray the actual changes that are produced in the neuron under the influence of certain poisons and during sleep: i.e., when the hlood-supply of the hrain is reduced.^’’ (See plate p. 1264).

Weil and Frank state that they

‘^are

able fully to cor-

roborate the statement of Cajal that normal and toxic material

of

cannot be differentiated by the number of varicosities or

The

gemmules.”

care with which such experiments

must

be conducted, apart from the method of staining adopted; the

need of immediate immersion, and other details to which we have referred, invalidate any opinion that the distinguished Spanish histologist he can show

may have

that his

e.xpressed

experimental

on

this

score,

physiological

procedures

were as perfect as his staining work must have been. 1

must

unless

Indeed,

express the belief that the greater part of the physio-

work done so far in this connection is valueless owing to the absence of the precautions to which I refer. histological

Again,

Eamon

y Cajal’s conclusions that “the nen^e-cells

do not move, but on the other hand, that the neuroglia-cells do move” (which underlies his view as to the gemmules and varicosities showing no difference Avhen normal or “toxic”), has been

sliown

liy

Dercum

to

embody

its

own

refutation.

“Cajal,” says the latter author, “points out the fact that the processes of the neuroglia-cells have numerous short arbores-

” We wish to particularly emphasize the fact that we are in no way criticlsing adversely the work of Drs. Weil and Frank. We have nothing but praise to express for these investigators. Much of the searching inquiry to which we are submitting their paper Includes the use of features introduced for the first time in the present w'ork, and obviously unknown to them. Indeed, if our views eventually prove to bo sound, we will owe much to the counter-evidence Drs. Weil and Frank and, we may add. Dr. H. Heath Bawden have published. S.

—

—

627

THE PHYSIOLOGY OF THE NEURON. cent and

plumed

and

collaterals,

states that in these cells

lie

two different phases can be obseiwed: tion,

—that

is,

first,

a stage of contrac-

which the cell-processes become shortthat stage in which the cell is relaxed,

a stage in

ened; and, secondly, a

—

is, a stage in which the processes of the neuroglia-cells are elongated. He maintains that the processes of the neuroglia-cells

represent an insulating and non-conducting material, and that

during the stage of relaxation these processes penetrate between the arborizations of the nerve-cells and their protoplasmic processes,

and

make

so

difi&cult

or impossible the passage of

the nerve-currents; on the other hand, in the stage of contraction the processes of the neuroglia-cells are retracted,

no longer separate the processes of the latter

are thus permitted to

come into

nerve-cells,

contact.^^

and they and the Evidently

Eamon y Cajal admits the very thing against which he contends, for if the nerve-cell processes are at one time not in and at another are in contact, they must certainly move, and the question before us is self-admitted. It matters contact

not whether the processes

of

much, but that they move at

the all is

nerve-cells

move

little

or

the question at issue, and

Eamon

y Cajal admits, though he malces the movement a purely passive one.”““ To me it appears clear that, since

this

Eamon y

Cajal held the neiwe-cell to be a passive structure,

requiring an independent connecting-link to close the circuit

with the adjoinng cell, he must have denied both the gemmules and the varicosities any physiological importance. His opinion, therefore, that normal material cannot be differen-

from toxic .material, when applied to the retraction of gemmules and the formation of varicosities, cannot be said to rest upon solid premises, and, for the time being at least, to in no wise affect the question. tiated

In a comprehensive review of the anatomy and physiology of the neiTOus system,. L. F. Barker^®

marks:

“The

makes the following

re-

physiologist of the present day sees in the func-

^ We win see farther on that Cajal’s observation as to the relaxation and contraction of neuroglia-cell processes is valuable In that it proves that the tips of the gemmules do not transmit nervous energy. S. -"Dercura: University Medical Magazine, April, 1897.

—

L. F. Barker:

New York

Medical Journal,

May

15 cl acq., 1897-98.

— THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

528 tions

the nervous system, even ia those which are most complicatxTl, only certain manifestations of energy. Moreover, he believes tliat in neurons, as in all other cells of the body of

and

as in the world generally, the law of the conservation of energy during transfonnation holds, and consequently regards

phenomena of irritabilit}', as CA’hibited by a neuron or by groups of neurons, as the kinetic representative of the potential forces of the cells and their foodstuffs. The metabolic the

and the

activities

vital manifestations of the cell are

—another

tant processes

which

concomi-

example of the inseparable connection

between what we terra matter and energj". There has been in man}' quarters a certain amount of hesitancy in exists

accepting the view that the capacities of the nervous system, particularly those of the brain,

chemical and

the

going on within it

has in

happily

tlie

now

physical

constituents

its

past proved

are

a

which are continuall}'

a hesitancy which, though

:

serious obstacle

to

For the plant,

disappearing.

fast

dependent directly upon

alterations

progress, all

is

the evi-

dence goes to prove that under the influence of sunlight and heat marked chemical and physical changes take place witliin it

be

which we recognize in

its vital processes.

In the animal

granivorous, camiyorous, or, like man, o.mnivorous

it

—

it

is

the cliemical energj' introduced as food which represents, in

the main, the source of the energy of the organism.

The

.

physiologists have been struggling for fifty years or

.

.

more

gain an insight into the nature of tuhat they call nerveimpulses, by which is to be understood the occurrences inside to

axons: to

for example, at the time

believe

Their

that they

efforts

are

when we have good reason

functionally

have supplied us

witli

extraordinarily

active.

a multitude of data, phys-

and chemical, interesting enough, no doubt, but which can serve as only the barest prolegomena to an explanation of the ical

essence of the" occurrences.

If

we

are so badly informed con-

cerning these elementary and fundamental phenomena we

may

very well be content to be modest for some time to come in our

claims as regards a physiological psychology. impossible that in

concerned which

which

yet

the nervous

system

do not exist outside

remain

to

be

recognized

It

is.

by no means

forms of energy are body and

the animal

and

studied.

.

.

.

529

THE PHYSIOLOGY OF THE NEURON.

Truly, to find out the properties of a single neuron would be a task appalling enough; but, when we remember that of the

no two are just But instead of burying

millions of neurons in one individual perhaps alike,

the quest would seem hopeless. pessimistic

in

ourselves

or

reflections,

being discouraged by

by what may perhaps forever remain to us unknowable, we may profitably turn to the consideration of some of the points which, lie more within our ken. One point, self-evident enough when one’s attention is

what

is

at present unattainable,

directed to

it,

hut which often appears to have been overlooked is the unremitting character

in connection with the neurons,

With a metabolism

of their activity.

occurring within the nerve-units

is

it

as complicated

as that

inconceivable that there

can be any period in which alterations in chemical structure,

and consequently energy transformation, are not going on. From moment to moment, throughout all the hours of the day and night, analytical and synthetic processes are taking place, associated with the alterations in physical forces

necessarily

accompany these changes.

thing that

lives,

the neurons

which

In common with every-

know no

absolute repose.

As

I

have said, in speaking of their metabolism, periods of extrava-

gant activity

may

alternate with

change, but total rest istence.

We

is

periods

more economic

of

inconsonant with continuance of ex-

are forced to

believe

that what

we

ordinarily

speak of as the passage of a nerve-impulse represents, as

it

were, a stormy process in the nerve-fiher, and that just as absence of a storm does not

probability

minor

mean

absence of weather, there are in

—

all

—

currents, if you will passing and fro in a given nerve-fiher in the intervals between the more violent excitations.” The words that I have italicized will doubtless recall some of the more prominent features previously emphasized alterations

to or fro or passing to

in respect .to

functions

of

the relative nervous the

various

organs

processes

reviewed.

involved I

have

in

the

termed

“passive” that form of energy continuously transmitted to tissues and vessel-walls. A quiet and steady flow of blood into the cellular stnictures, sustained by the tonic contraction of the arteries, and a stream of nervous impulses to the tissues coinciding in rhythm, perhaps, with that sent to the vessels.

THE POSTERIOR PITUITARY AND THE NERVQUS SYSTEM.

580

suffice to insure mitritiou

and

plied read}^ for active work.

to hold the structures thus sup-

What

is

the source of this energy?

If the posterior pituitary reinforces tlie flu.x of impulses

when seem

functional

activity

is

demanded,

and

to require another source,

brain and the cord are included in

energy would

jiassive

as the lower, or middle, tJie

‘^sphere of influence”

of this organ, the hemispheres are the only parts of the en-

cephalon that can supply of

tlie

But they do

need.

Bemoval

not.

hemispheres, we have seen, does not impair muscular

tlie

jump, a pigeon can fly, etc., and, after a period of shock-paralysis immediately after the opera-

activity; a frog can sJiort

movements

tions,

return

—evidence

that

nutritional

their

metabolism, incited and regulated by nen-ous impulses, conEvidcntljq

tinues. to

hemispheres have nothing

the

therefore,

do with the process; they are solely the seat of the “mind,”

and constitute an organ among the vasomotor

nerves

(

nutritional nerve-system.

et al.),

We

are,

supplied with

itself

Gulland,

Obersteiner,

Cavazzani, Frangois-Franck,

rest,

Huber,

Hurthle,

and probably with its own therefore, brought back to

the posterior pituitary as the only organ capable of satisfying

the needs of the situation

:

i.e.,

as the only source of passive

energy.

This suggests that metabolism

may

through the

suffice,

agency of the blood’s o.xidizing substance, to sustain physioduring the intervals between “stormy processes

logical activity

of the nerve-fibeF’; but this

is

promptly shoAvn

to be a

wrong

interpretation Avhen the effects of section below the medulla are recalled. diately

As

relaxed,

all

the arteries of the organism are imme-

a continuous stream of impulses

served to hold the vessels in tonic contraction jiassive

must have

evidence that

a factor to be reckoned with. Thus, co-ordinated muscular movements continue

nervous energy

the fact that all

:

is

after removal of the hemispheres relegates to the lower brain

the

function

of

supplying

active

energy

—and,

passive energy likewise, the need of the latter being division of the medulla.

Indeed, passive energy

described as passing to and intervals

between

tbe

more

obviously,

shown by

may

well be

fro in a given nerve-flber in tbe

violent

e.xcitations,

while

active

energy can as fittingly be likened to “a stormy process in the

— 531

THE PHYSIOLOGY OF THE NEURON. both ascribable,

nerve-fiber”:

it

now seems

liirely,

to the one

organ, the posterior pituitary body. establish the functions of the posterior pituitary within

To its

proper physiological limits, however,

it

is

necessary to as-

elements in general and neurons in par-

how nervous

certain

ticular are nourished, since it

is

upon the degree

of perfection

with which the nutritive processes are carried on by the blood that the functional integrity of these stnictures depends.

The

that a general nutritional

fact

is

have shown; but

further

it

finds

the

— —

statements of Professor Barker’s phasize a generally

known

fact

process prevails,

of

primary motive agency,

which the adrenal system

I

support in the following ^which,

of

course,

but em-

that, “in the absence of sub-

from the thyroid gland, the nervous system undergoes very important and serious metabolic modifications, evidenced by the remarkable nervous and mental phenomena with which all are now familiar. On restoring these substances to the body by the administration of a thyroid extract the symptoms may sometimes be made to disappear.

stances in the body derived

It

likely,

is

in the

main

however, that the neurons find their staple foods nutritive constituents of the blood as derived

from

the food digested in the stomach and intestines and purified

by the lymph-glands and have,

I

I

believe,

liver.”

satisfactorily

shown that the thy-

roid secretion incidentally sustains the activity of the anterior

pituitary body,

pouring

its

and therefore of the entire adrenal system, by

secretion into

the blood.

we have also two upon which I

The

functions

Among

digestive organs

reviewed.

ever, are

laid considerable stress,

spleen and pancreas,

tance

of

trypsin

—and

—the

derivatives, into

i.e.,

I called attention to the great

splenopancreatie

version of albuminoid substances,

we have

of

benign products.

the

the latter, how-

ferment

—

in

the

impor-

the

con-

and especially of their toxic These albuminoid substances,

seen, then pass

through the liver, and, after traversing the cardiopulmonary circuit are distributed broadcast throughout the organism. There is a feature which I kept in abevance,

—

however,

^though a well-known one, since at the time its true weight would not have asserted itself i.e., the fact that albuminoids include nucleins derived from the animal and vegetable :

34

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

532

ingested with food, which nucleins contain at least 3 per We can now realize how great is the of phosphorus.

ceJls

cent,

of the pancreas

role

jihj'siological

and of the spleen

the

in

organism. Indeed, the functions of these two organs to constitute one of the pillars

As

rest.

upon which the

may

be said

vital functions

constituent of calcium phosphate, phosphorus

a

found in the bones, blood, milk,

and other

teeth, cartilage,

in quantities which bespeak of

etc.,

prominence, since calcium phosphate

is

is

tissues; in the its

functional

represented by nearly

pounds among the organism’s constituents. Sodium jihoswhich gives the blood, lymph, and other body-fluids their alkalinity and fluidity, and the potassium and magnesium phosphates, which fulflll much the same role, obviously find But it is when in phosphorus their main dynamic attributes. we reach the nervous system that the functional worth of this six

phate

—

element reaches

How

etc.

highest mark.

nervous

are

sheaths,

its

—

adequately

structures

supplied

—neurons, with

oxidizing substance, their phosphorus, etc.?

The Physiological Chemistry tions

myelin,

of

white

or

substance

axis-cylinders,

blood-plasma,

—The Schwann—a

of Nerves. of

their

funcjelly-

like homogeneous and transparent material which surrounds the axis-cylinder of nerves, and is only separated from it by It ^may be said to be unknown. a thin protoplasmic film which, and acid, is a fatty substance, blackened by osmic after death, coagulates and becomes opaque, loses its homo-

—

now

universally considered as a pro-

geneity, etc.

Myelin

tective coat:

a function which the overlying neurilemma alIs myelin fatty in the true sense of the word?

ready

fulfills.

is

in quantities, a very large iiroportion of about one-half, according to some obdried nerve-substance

Examined chemically

—

gervers

—

consists of a peculiar body:

cholesterin.

This body

but an alcohol; like gl 3Terin, however, which is “Though also an alcohol, it forms compounds with fatty acids. we do not know definitely the chemical condition in which Professor cholesterin exists during life in the medulla,” saj^s comFoster, “it is more than probable that it exists in some

is

not a

fat,

in bination with some of the really fatty bodies also present

533

THE PHYSIOLOGICAL CHEMISTRY OP NERVES. the medulla, and not in a free isolated state.” cliolesterin, Vhite’ nervous matter contains

.

a

.

less

but

less,

considerable, quantity of complex fat whose nature

According to some authorities rather

“Besides

.

is

than half this com-

which we have be present also in blood-corpuscles and in mus-

plex fat consists of a peculiar body, already seen to

lecithin,

Lecithin contains the radical of stearic acid (or of

cle.

still

disputed.

or of palmitic acid), associated, not

—

as in ordinary fats

oleic,

—with

simple glycerin, but with the more complex glycerin-phosphoric

and further combined with a nitrogenous body, neurin,

acid,

an ammonia compound of some considerable complexity; therefore of remarkable nature,

since,

though a

fat,

it

it is

con-

and phosphorus.” Cholesterin (C28H44O), (C44H50NPO0), and neurin (CsH^jlSrOa), as shown by

tains both nitrogen lecithin

the formulas, are all oxygen-containing bodies.

May

this sup-

posed coating and insolating material, myelin, not be to the nerve what myosinogen Cholesterin,

“It

tions.

is

is

we have

to

muscle

?

seen, is associated

with hepatic func-

singular,” says Professor Poster, “that, besides

being present in such large quantities in nervous tissue, and to a small extent in other tissues

a normal constituent of bile.”

and in blood, cholesterin

I have previously referred to

the fact that this alcohol, the only one

body in a free formation of

state,

and

bile,

is

which occurs in the

combines with glycocholic acid in the is thus eliminated by the liver. This

view sustains that of Austin Flint, who looked upon cholesterin as an excrementitious product derived from the nervous sys-

tem

:

i.e.,

the result of nerve-metabolism.

Cholesterin

is

pres-

ent in abundance in the white substance of the cerebro-spinal axis, as well as

in the myelin, or white substance of Schwann,

We have seen, however, that the elimination of excrementitious products by the liver is carried out by the in

nerves.

combination of various agencies cholic

acids

from

derived

process in which the

nating

role.

:

mainly glycocholic and tauroacid through an oxidation

cholic

oxidizing substance plays the predomi-

That an oxidation process

also occurs in a nerve during functional activity is suggested by the following lines of Mathias Duval “Direct experimentation has shown that the ;

functionating nerve

is

the seat of increased comhustion; this

—

—

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

534

accompanied by the liberation of heat, the presence of which Schiff has demonstrated even np to the nerve-centers, under

is

the influence of fear, of excitation of the senses, of any cause

—

in a

word

—which produces —“a conspicuous component

cerebral activity.”

I^ecithin

of the brain, nerves,

yelk of egg, semen, pus, white blood-corpuscles, and the electrical

organs of the ray”

—suggests

its

identity as at least one

we are seeking by the

of the sources of energy

fact that

merely allowed to stand at the ordinary temperature tions

acquire an acid reaction and

intestines it

are decomposed.

sometimes breaks up into

its

In the

constituents;

its

if

solu-

fatty

and cliolin (Howell). Neurin and therefore a decomposition product of

acids, glycerin, phosphoric acid, is,

in reality, cholin,

As previously

lecithin.

stated, Tappeiner®^ obtained fatty acids

These

as a result of cholic-acid oxidation.

facts, of course, are

we

only cited as mere landmarks to indicate that

with oxidizable bodies. concerned, therefore,

it

As

seems probable that we have in lecithin

an agency capable, by the character of bohydrates, phosphorus,

are dealing

far as the nerves themselves are

—

etc.,

molecule,

its

i.e.,

car-

of acting as a potent source of

working energy when brought into contact with the oxidizing substance; and in cholesterin the main waste-product of nervecatabolism.

Admitting, then, that we have in the lecithin of myelin a body capable of acting as a source of energy in a way similar

myosinogen in muscle, how does the oxidizing substance of The nodes of Ranvier and tlie the blood-plasma reach it? to

nedrilemma that covers them allow axis-cylinder,

but the myelin

itself

silver stains to reach the

does not permit of this.

This suggests that the nodes themselves ing them may allow the blood-plasma to

i.e.,

—

the rings form-

filter

through them,

thus bringing the oxidizing substance in

immediate contact

anatomy

of nerves indicates

with the axis-cylinder. that such

may

be

The

the case.

finer

Indeed, the nodes referred to occur

and separate the nerve, as is well known, into as many segments, which recall, in a measure, the muscleof fiber and the liver-cell or, at least, features characteristic at regular intervals,

both these structures. Tappelner;

If the blood-plasma can penetrate the

Zeltschrlft fUr Biologie, Bd.

xli,

S.

GO,

1876.

— —

—

535

THE PHYSIOLOGICAL CHEMISTRY OF NERVES.

nodes of Eanvier as do stains, there only lies between it and the Rxis-cylinder an extremely delicate layer of protoplasm, Mauthner’s sheath, which in no way would impede the en-

—

trance of the fluid into the axis-cylinder

The term

“cylinder”

in accordance

latter:

itself.

the tubular shape of the

suggests

with Eemak’s view that

The

liquid.

who

prevailing view, however,

an albuminous

that of

is

made up

considers the axis-cylinder as

consists of a

it

delicate, longitudinally striated tube, filled with

M.

Schultz,

of fibrils united

by an intervening unknown substance. This seems to me to vividly recall the arrangement of muscular flbers as regards their relation with the blood-plasma: i.e., minute flbers into which the plasma

may

Again, we must not lose

freely enter.

sight of the fact, in this connection, that the axis-cylinder

is

nothing hut the elongated axon of a neuron, and that the now referred to, therefore, represent the intimate

fibrillffi

structure of a neuron’s axon. flbrillse

Now,

as Schafer holds that these

and as the have good reason to

are extremely fine tubes filled with fluid,

character of this fluid

is

not known, I

believe that they are channels for the

hlood-plasma:

i.e.,

for

the oxidizing substance.

But there

is

another feature which points to the axis-

cylinder as a channel for the oxidizing substance:

that the so-called “medullary sheath”

i.e.,

Schmidt,

them

The

strias

rep-

them were at first termed “clefts” or “incisures” by Lautermann, and others, but Eanvier considered

as protoplasmic septa

segment of the nerve into bers.

the fact

the myelin itself

contains a supposed “supporting frame-work.”

resenting

i.e.,

W. H. Wynn,®^ who

which subdivide each internodular several

gives

an

conico-cylindrical excellent review

chamof this

subject and the results of personal researches, refers to those

and Golgi,®'* who “from the examination of fibers treated by a mixture of bichromate of potash and osmic acid, and afteiward by nitrate of silver, find that each cleft is

of Eezzonico'*®

occupied by what appears to be a thread of substance passing spirally around the fiber.

“ W. H. Wynn:

darkl3'--stained

They

consider,” he

Journal of Anat. and Physiol., April, 1900. Rezzonico: Archivio per le Scl. med., Torino, vol. iv, 1880; and Gazzetta med. ital. lomb., Milano, vol. 1, 1879. Golgi; Arch, per le Sol. med., Torino, vol. Iv, 1880.

“

— THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

536

adds, “that the supporting frame-work of the sheath consists of a chain of funnels surrounding the axis-cylinder, each funnel being fonned by a spiral thread.” TizzonP® “believes

that

there

cylinder,

niann.”

nerve

but

is

one net^work

and that it McCarthy

has

been

is

m

stated

is

closely

the

structures,

wliich pass

medullary

the

slits of

have shown that,

to

hardened with

chromate,

investing

connection luith the

picric

sheath

acid

contains

axis-

Lauter-

“after

a

and ammonium minute,

rod-like

rapidly between the axis-cylinder and

the primitive sheath so as to give the cross-section of a fiber tlie

appearance of a wheel.

The

rods stain with carmine and

luematoxylin, which do not stain the myelin.

It

is

not possible

to isolate the rods as separate elements, for they are

not

dis-

from one another, but united.” Finally he refers to the fact that Lautermann, von Stilling, Eoudanowski, and McCarthy all believe that there is “a system of hollow canals in the sheath of the axis-cylinder,” and himself reaches the conclusion that the cones they form are protoplasmic, and not comtinct

posed of neuro-keratin, as

is

He

usually held.

divides “each

cone into six segments placed at regular distances apart and

converging from the primitive sheath to

tlie

axis-cylinder.”

shown in the annexed illustration, reproduced from his paper. If we now consider the segments as canaliculi leading from the axis-cylinder, we can readily see how the blood-plasma can penetrate the myelin and its oxidizing substance, and these bodies carrj" on, when brought into contact, a reaction similar to that which occurs in muscle-fiber. Indeed, This

if

is

well

the various features enumerated are collectively considered,

become apparent that the myelin, or white substance of Schwann, tvhen in contact with the oxidizing substance of the

it will

blood-plasma undergoes a reaction in which chemical energy

is

liberated.

When we

consider that the axis-cylinder

continuation of a neuron’s axon, for the various

is

as stated, the

not difficult to account

phenomena, known under the general term

“nerve-degeneration,”

Archlvio per

le

of

the disorganization of myelin, the

i.e.,

dissolution of the myelin,

®°Tizzonl:

it

is,

etc.,

Scl.

— at

med., vol.

the distal end of a nerve,

Hi,

fasc.

1,

1S78.

the physiological chemistry op nerves.

when the

latter has

been

cut.

Vei7

537

suggestive, in this connec-

“Waller are the following lines by Professor Barker*®: comresulted there severed proved that if a motor nerve was tion,

plete

degeneration of the fibers in the peripheral end,

even

Diagram op Relation Between Longitudinal and Transverse Sections, Showing Cones Cut Across at Different Levels. 1,

cone;

at base of cone; 2, 4, through interval

through middle of cone; between two cones. In 1,

3,

2,

through apex of and 3 the cone

segments and protoplasmic sheaths are seen. In 4 only the thin protoplasmic sheaths beneath primitive sheath and around axis-cylinder are visible. (IF. U. Wynn.)

to the muscles

which they govern, the central end remaining As a matter of fact, the changes charac-

apparently intact. teristic

of

the Wallerian

degeneration could not, as a rule, be traced farther in the central end than to the first node of Panvier.” Stewart®^ states that “in the degenerated nerve Barker: hoc. cit., p. 740. Stewart: “Manual of Physiology,”

p.

607.

538

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

the substances soluble in ether are relatively increased owing, in part, to fatty degeneration of the axis-cylinder,” and that

“the percentage of phosphorus

is markedly diminished (Mott and Barratt).” Another process which seems to acquire a certain degree

of light

is

nerve-regeneration.

It is obvious that if we grant the axis-cylinder, as the extension of the axon, all functional and nutritive attributes, we may easily explain peripheral

nerve-degeneration,

but not regeneration, the peripheral segfor by reason of the section. We know,

ment being unprovided

on the contrary, that a piece of the nerve must be removed in order to prevent reunion, and that otherwise in two or three weeks, and often earlier, its functions will be restored. Xew cylinders and fibrils grow, acquire myelin, and, perhaps, guided

and

assisted

the

peripheral

by (nucleated) neurilemma, soon meet those of segment and become connected with them.

Physiological functions of a normal kind

must underlie

this

even in the peripheral end of the nerve; otherwise

process

union would not take place. Finally (we can only refer to a few of the more prominent processes involved in the vast subject

now claiming our

attention)

the

functional

phenomena

that follow after division of the cord distinctly indicate the

continuation of nutrition and the functional activity

impaired

“In the

—

in the distal fragment.

mammal

—though

Foster, for instance, says:

(dog) after division of the spinal cord in the

and apparently spontaneous movements lumbar cord. has thoroughly recovered from the operation

dorsal region regular

may be observed When the animal

in the parts governed by the

the hind-limbs rarely remain quiet for a long period of time;

they move restlessly in various ways; and, when the animal

suspended by the upper part of the body, the pendent hindlimbs are continually being drawn up and let down again with a monotonous rhythmic regularity suggestive of automatic is

rhythmic discharges from the central mechanisms of the cord. In the newly-born mammal, too, after removal of the brain

movements

spontaneous in nature are frequently these movements, even when most highly

apparent!}'’

obseiwed.

But

developed,

are very different from the movements,

all

irregular

and variable in their occurrence, though orderly and purposeful

539

THE CIRCULATION OP THE NEURON. in their character, which

we

recognize as distinctly voluntary.”

Indeed, the nervous energy that myelin and the oxidizing substance procure

hemispheres and

a frog deprived

that which allows

is

its

of

its

middle brain “to sink in water as though

the animal were of lead.”

The axis-cylinder composed of fibrils into which bloodplasma penetrates being continuous with the axon of a neuro'n, we are brought to realize the nature of the parallelism between phenomena of the latter and those of the supraBut we must glands to which I have already referred.

the functional renal

not lose sight of the fact that each “medullated” nerve-fiber is

divided by the nodes of Eanvier into as

many

subdivisions,

and that each intemodal segment receives its own supply of Does the neuron receive its supply through this chain of segments, or, rather, through the axis-cylinder that passes through them? That the former mechanism alone prevails is

plasma.

improbable, since so prominent a part of the entire structure

would hardly be sup-

as its cell-body, the seat of its nucleus,

plied in so indirect a manner.

The very importance

of

its

existence of direct supply.

Does such

we have not The Circulation op the Neuron. Barker,

far to seek.

functions betokens

a vascular system

tlie

exist

?

Fortunately,

—

in a review adduced for or against the neuron doctrine,®® concludes that “it may be said, with fairness, that the control instituted by hundreds of histologists in various parts of the world has practically in every instance in which of the facts that have been

the

method

of Golgi or the

method

of Ehrlich has been

em-

ployed gone to confirm the conception that the neuron is a unit in the sense of Waldeyer.” The latter investigator’s words, giving the gist of his doctrine, are also quoted: “If we review the main advance, made certain by the anatomical investigations discussed, it limitation,

now

lies,

in

my

tional elements of the nervous

system

consider the nerve-units-neurons), collaterals,

Eamon y Barker:

opinion, in the sharper

possible, of the anatomical as well as the func-

with Cajal.”

their

The

(for such

and

also

end-arborizations,

the

by

we have

to

discovery

of

Golgi

and

S.

following lines of Waldeyer’s are also

American Journal

of Insanity,

July.

1898.

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

540

quoted

:

“If we assume, with Golgi and B. Haller, the existence

of nerve net-works, the conception

we can

still

the

retain

is

somewhat modified, but

nerve-units

—

.

.

which

of

all

tends to show that, while the neuron doctrine stands on a solid foundation, there is a stumbling-block in its way which has not as yet been removed.

Especially

is this true since the investigations of Apathy, of Naples, who, after several years’ stud}',

has unquestionably demonstrated the existence of a net-work of what he terms “neuro-fibrils.”

That Apathy’s

“neuro-fibrils” as well as Golgi

nerve net-works are not

but

nerve-elements,

and Haller’s

fine

capillaries

which serve for the circulation of blood-plasma, seems to me probable. In the following extracts the italicized words will serve to call attention to the various links between these struct-

ures and others that

we have

Professor Barker sum“Apathy has been convinced for some twelve years that the nervous system is composed of two varieties of cellular elements entirely different from each The nerve-cells, the other nerve-cells and ganglion-cells. architecture of which is quite in accord with that of muscleanalyzed.

marizes Apathy’s views as follows

:

:

A

give rise, he thinks, to neuro-fibrils.

cells,

turn, passes out of a process of a nerve-cell

neuro-fibril, in

and then goes through

a number of ganglion-cells, and ultimately, after leaving the ganglion-cell with which it is connected, passes more or directly to a muscular fiber or to a sensory cell. fibrils are, as

last less

The neuro-

conducting substance for the nerve-cells, Avhat the

The

muscle-fibrillce are as contractile substance for the muscle.

pathways to be followed by the neuro-fibrils are predestined from the earliest embryonic stages, for they correspond, according to Apathy, to the intercellular protoplasmic bridges."

That we have all required elements in support of evident; we have seen that muscle-fibers are, in cate

tubes;

that

vascular

channels

blood-plasma should be protoplasmic

for is

the as

need of their penetrating into and out of the

What

appears to

me

as conclusive

my

belief is

reality,

deli-

transmission

obvious as

is

of

the

cells.

evidence

is

indirectly

afforded by the deductions of Ehrlich, suggested by his study of the

and their processes “Ehrlich found,” says Barker, “that by

methods of staining living

with methylene-blue.

nerve-cells

541

THE CIRCULATION OF THE NEURON.

in salt soluinjection of a solution of methylene-blue dissolved the axistion inti'a vitam into the blood-vessels of an animal, cylinders of

numerous

PiQ.

The

of the nerve-fibers

(particularly

1 .—

sheath

many

sensory)

(see Fig. 1), as well as

nerve-endings

(see

2),

Nerve-fibers from a Frog Injected with Methyleneblue (Method of Ehrlich). {After KiiUilccr.) axis-cylinders

Is

the fibers

are

stained

dark

blue.

In

places

somewhat stained. The nodes of Ranvler and the at some of the nodes are well shown.

the myelin divisions of

were stained after a time, when exposed to the

air,

blue color, the other tissue-elements remaining

little

all

Fig.

affected.”

It seems

clear

that,

if

a solution

an intenseor not at

introduced

through blood-vessels can stain the axis-cylinders, the liquid

;

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

o42

within the latter must be more or in the blood-vessels.

plasma, including

its

Again,

I

less

a continuation of that

have suggested that the blood-

oxidizing substance, was the liquid in the is true is shown by Ehrlich’s observa-

axis-cylinders; that this

tion that the conditions in the nerve-structures essential to the methylene-blue reaction” were, he thought (188G) “(1) ;

oxygen saturation; (2) alkalinity.”

J

liave

shown that these

are the essential attributes of blood-plasma.

Fio. 2.— Sensory Nerve-ending Stained with Methtlenb-blue (Method of Ehrlich) in the Exocardium of the Left Auricle OF A Gray Rat. (After Smirnow.)

This seems to

me

to afford an insight into the physiological

chemistiy of the axis-cylinder of the neuraxon when a short distance below the latter

it

has become a medullated nerve.

Indeed, the prevailing view that the myelin represents a protective

and insulating coat may

doubt, especially

composition

is

at least be said to be

when coupled with the

unknown, and that

tliere is

to

another external coat

the neuro-keratin neurilemma, which suggests, by tion, that it is

open

facts that its chemical

an isolating covering and that

its

composi-

it also fulfills this

•

—

:

543

THE CIKOULATION OF THE NEURON. role

in.

That the

non-medullated nerves.

the seat of

in}’elin is

and a dea combustion process during which heat is If we composition product, cholin, is formed, we have seen. liberated

now

consider

myelin, lecithin,

component carbohydrates and phosphorus, and

composition

the

i.e.,

of

as regards carbohydrates,

analogy,

the

of

active

to myosinogen,

its

prob-

the

a source of energy, as does the latter That such is the itself.

ability that it serves as

when in contact with oxygen, suggests case,

however,

is

shown by the

fact that the contents of the

neuraxon or axis-cylinder fulfills the conditions necessary for methylene-blue staining, as laid

down by

Ehrlich,

i.e.,

oxygen

saturation and alkalinity, the characteristics of blood-plasma.

Indeed,

it

seems to

me

permissible to conclude that

Myelin, or the white substance of Schtvann,

1.

structure what myosinogen is to muscle-fiber

source of energy. 2. The axis-cylinder are

:

made up 3.

A

and the

is to

i.e., its

nerve-

immanent

canaliculi .derived therefrom

of fibrils that serve as channels for blood-plasma.

part of this blood-plasma penetrates into the axis-cylin-

der through Ranvier’s nodes.

and

Lecithin, a body composed mainly of hydrocarbons

Jf.

phosphorus, the active constituent of myelin and a prominent component of the electric organ of the ray, when exposed to the action of the oxidizing substance liberates energy: i.e., nervous energy.

Continuing our quotations from Professor Barker’s cle,

I

will

appear to fihrils.

arti-

introduce the various points of comparison which

me

to sustain

my

interpretation of Apathy’s neuro-

“Inside the ganglion-cells a reticulum of fine

fibrils

derived from the neuro-fibrils in transit can be stained a beautiful

deep-violet color

That the

by Apathy’s chloride-of-gold method.”

method can be considered as similar in action method and that the stain follows the same channels and affects the same chemical constituents of the plasma is shown by the following remark of Professor Barker’s: “With a little care and a good sample of methyleneblue the nerve-endings and the axis-cylinders of medullated latter

to the methylene-blue

fibers,

with which they are continuous, can be stained in a

way far surpassing in constancy and completeness the best

re-

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

544

suits of the uncertain gold-cliloride procedure.”

As

the methy-

and a .modified chloride-of-gold stains were those mainly used by Apathy, no confusion can occur on this score. Indeed, if we convert all of Apatliy’s neuro-fibrils into lene-blue

minute

capillaries, their identity as inherent parts of the gen-

eral circulation is placed

on a

solid foundation

by

tlie

following

remark of Professor Barker’s: “The doctrine of the fibrillary nature of the axon and unstainable portion of the protoplasm of the nerve-cell has recently received support from the studies

of Lugaro^® and Levi.*®

under

nerve-cell

The

fonner, too, in his studies of the

pathological

conditions

—

poisoning with lead and arsenic

come very

distinct in the nerve-cells.”

to the one system i.e.,

—for

That

the adrenal sj'stem, and that

it

“made up

its

is

evident.

mentary

“Each number near its origin, and in the course which it

fibrillge

mentary

—

are being given

fibril.”

The

itself

tj^pifies

lated” nerve-fibers,

may

off

at

it

at

Apathy any rate

follows ele-

short intervals until

be reduced to a single

fibrillary structure of

as clearly reproduced here as

but

neuro-fibril is,”

of a large

finally the neuro-fibril

now

cell-body extensions, on the other,

of “^elementary fibrils,’

fibrils

this directly points

precisely coincides with the

becomes a normal consequence.

—

be-

similarity of the neuro-fibril, on the one hand, to the

axis-cylinder and

states,

after

may

through which the morbid changes can occur,

foregoing remarks bearing upon this system,

The

example,

finds that the fibrils

an axis-cylinder

can well be; the giving

the irregular

distribution

and particularly those

ele-

of

off

is

of

‘“non-medul-

of the ““sympathetic”

system.

All this recalls a structure which appears to

me

to be inti-

mately connected with the general circulation, the neuraxon and its cellular extensions, and Apathy’s neuro-fibrils all

—

being considered as component parts of the general vascular

system

i.e.,

:

The is

that

it

prevailing view concerning the role of this structure affords a supporting frame-work for the nervous ele-

Both

ments. lated

Virchow’s neuroglia.

in tlie white matter

nerve-fibers

separated

Rlvista di patol. nerv. e mentale, vol. i, 1896. Rlvista di patol. nerv. e ment., vol. i, 1896.

Lugaro: y the way plexus, and axon represent a continuous

therefore,

found thickened, globular, animals must be connected.

that etc.,

But

the

vascular

:

it

It

clear

enters is

with

neuroglia-fibers

by Berkley in

his

jxiisoned

this fact siigjjests that these

649

THE CTROULATION OF THE NEURON. structures

should

'

the influence of the

should show

less,

under

swellings

irregular

present

likewise

agencies, and that the axis-cylinder

same

and

the intracellular fonnation of plexuses

anastomoses interposing a barrier to the too free passage of That such is actually the case is illustrated by the plasma.

annexed plates hy Berkley, which represent the lesions found ill the neurons of the poisoned animals to which reference has been made. If the protoplasmic processes or dendrites are the first to

bear the brunt of the vascular engorgement, the plasma being carried to them through fibrils connected with their tips, these tips or extremities should first

pressure.

This

from the second

is

show evidence of the expansile

well illustrated in Fig.

a “psychical cell

1,

which shows, using

cellular layer of the cortex,”

Berkley’s words, “a few pathological tumefactions on the upperOthermost branches of the apices of the apical dendrite.

wise the cell

is

This

normal.”

cell

was

selected

from a section

derived from the brain of an animal poisoned with ricin, death

A

having occurred in thirty-six hours. however, off

is

that

the greatest

it is

feature of importance,

—that giving

the main, or apical, dendrite

number

of subdivisions

—which

shows the

evi-

dences of engorgement; the extremities of the other dendrites

show more or

are not thickened, but they of

engorgement as the main trunk

marked evidenees

less

This ob-

approached.

is

way

viously suggests that the plasma penetrates the neuron by of the laterals

main dendrite and that cellulipetally

;

in

it

finds

other words,

into

the apices of the collaterals

may not

instead

This feature

Fig. 2, especially by the larger stem of the cell,

also it

is

were

it

mean

that

subsequently show thiek-

enings; being terminals, they should naturally do so pressure exceeds a given limit.

of

preeisely as if

this does not

col-

its

of their tips,

—

them by the main trunk main .stalk of a plant. Of course,

supplied to the

that,

way

entering these collateral branches by

way

its

is

when

illustrated

main trunk.

the

by

This

a projection-cell from the second layer of the cortex, shows

the effeets of fort ’'-eight hours’ ricin poisoning: 3

i.e.,

of

some-

what more prolonged engorgement.

Worthy Berkley

of special notice, also,

(referring to Fig.

is

2), that:

the fact emphasized by ‘There

is

now

distinct

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

O')0

diminution of the gcmniulac wherever the swellings are found” which suggests that these minute ball-tipped projections from

—

all collaterals

are stnicturally similar to them, and that,

when

the engorgement exceeds in centrifugal pressure the resistance of a given area, the walls of the latter, including the gemmules,

more or

are

that

all

less flattened out.

Suggestive, likewise,

is

the fact

the gemmules stand out boldly in both preparations.

As many

as thirty-six or forty-eight hours having elapsed be-

fore death ensued, the animals were evidently submitted to a

primary period of intense stimulation, during which the gemmules were overdistended to such an extent as to cause them Indeed, the sudden cessation to lose their retractile property. of adrenal functions

and consequent death must have left the had been suddenly

cerebral stnictures much, as if the animals killed.

Of marked

interest in Fig.

3

the presence at the ex-

is

tremity of the main, or apical, dendrite of a section of what to represent a fiber or capillar}' from which the neuron with which it is connected might have derived its bloodsupply. The fact that it crosses its path suggests that the den-

me

appears to

drite itself

may

be a branch of the vessel.

Berkley describes

“Projection-cell of the long apical neuron as follows process variety, showing numbers of large swellings of the prothis

:

toplasm of the apical dendrite, thinning of the protoplasm of the stems in the interval between tlie nodules, and considerable The lateral branches loss of the gemmuhe along the margins. have mainly disappeared.

The

basal

processes

are

retained

intact.”

The nodules seem

to

me

also

to

illustrate

the

process

through which the collateral fibers become detached from the main stem, as shown by the denuded cells represented by Pigs.

4 and

5.

The thinning

of the

plasma between the stems would

deaccount for the manner in which the lateral branches are sufficiently tached, viz.; when the apical dendrite becomes of the more engorged the plasma ceases to circulate in one or nournodules, and the intervening protoplasm, failing to be the be should That the ha«al processes ished, disintegrates.

(corresponding in this with the condibut normal tion of the same' stems in Figs. 1 and 2) seems last to yield in this cell

LESIONS IN THE NEURONS OF ANIMALS AFTER RICIN POISONING-. [BerklBy.] [Johns Jlopkins Hospital Meports.\

i

i

.

I

:

'

i i

¥

*

1

i

THK OIKCULATION

when we

consicler

OXi"

551

THE NEURON.

only to the cell-body,

their proximity not

which contains a large supply of fibrils, but also to the axiscylinder {ax. in the drawings), which is the only centrifugal channel through which the engorged plasma can escape.

A

and 3 which shown by Figs. 1, the .adrenal phenomena brought on by

feature of the cells

strikingly links

them

toxics in the general

to

organism

is

the fact that, although they

from animals in which the doses of ricin injected were reduced with each animal, the morbid phenomena as exemplified by each cell in turn are correspondingly intensified. In other words, the adult rabbit represented by Fig. 1 was given subcutaneously a dose of 0.5 milligramme, and death occurred The in thirty-six hours: the cell only shows apical lesions. are derived

.

second adult rabbit was given the half of the previous dose, i.e., 0.250 milligramme, and death occurred in forty-eight hours: the entire apical dendrite tinctly involved.

The

of the last dose:

i.e.,

and two

of the collaterals are dis-

third adult rabbit was given the half

0.125 milligramme, and death occurred

markedly studded

in seventy-two hours; the apical dendrite

is

with thickenings, and

collatei’als

appeared.

It

is,

all

but two of

its

perhaps, unnecessai’y to lay

sti’ess

have

dis-

upon the

fact that this is due to the prolongation of the excessive vascular

tension:

i.e.,

of the time during which central vascular con-

caused peripheral capillary engorgement. And this need not be ascribed only to ricin. Berkley emphasizes this

traction

assertion

when he

many ways

says:

“The poison

similar to that of

ricin,

whose action

many toxalbumins

source, is capable of exerting a deep

is

in

of bacterial

and extensive degenerative

influence on the protoplasm of the nerve-cells of the bi-ain.”

And says:

this

may

further be extended to other toxics, for he also

“Poisoning with alcohol in considerable doses, continued

over a moderate time, will produce decided and ascertainable

and nervous elements of the cerebrum, very similar in character to the pathological lesions produced by other more virulent poisons.” We thus have evi-

lesions of the nutrient stnictures

dence in support of my opinion that poisons capable of causing congestion of the cerebrospinal and other nervous tissues do so by raising the blood-pressure and by thus driving the adrenoxidase-ladcn plasma into their neuroglia

and neyrons.

That the

THE POSTEUIOR PITUITARY AND THE NERVOUS SYSTEM.

5o2

alterations in the elements of the

neuron should he due to the same centrifugal pressure that prevails in the capillaries of all peripheral structures

obvious.

Finally, the fact that jihenomena witnessed occur under the influence of congestive poisons affords the complemental evidence in favor of my contention that a

neuron

is

is

directly connected

ivitli

the circulation hy one or

more

of its dendrites, which serve as channels for blood-plasma.

Even

the haemorrhages brought on by excessive pressure,

hematuria,

epistaxis, hamiatemesis,

engorged neuron shown in Figs. 6 and ley’s

series.

The

freel}^ inside

take their exit from the cation

if,

as

7,

and

from Berk-

also

observation of Apathy’s, therefore, that his

by way of the dendrite, ramify

‘T-ellulipetal neuro-fibrils enter

and anastomose

are exemplified in the

etc.,

cell

the cell-body, and, then reuniting,

by

wa}'^

of the axon,” finds its appli-

interpreted by mj^self, his neuro-fibrils are con-

sidered as blood-plasma channels. Still,

the identity of the

fibrils

in the cell-body as blood-

by the fact that they are continuous with the plasma-containing axis-cylinder and While this constitutes strong evidence, the fact that fibrils. tliey are blood-charulels can. only be determined by ascertaining the nature of the process in which the plasma takes part. This capillaries has so far only been suggested

ina}f

probably be done by inquiring into the composition of a

neuron’s ground-substance.

The Physiological Chemistry is

of the Neuron.

the nature of the ground-substance:

—What

that between the

i.e.,

After reviewing this subdivision of the general sub“A neuron is made up, like all other cells, ject Barker says In the latter a centrosome and of nucleus and protoplasm. fibrils?

:

an attraction-sphere are present; at onstrated in a ceidain

mic ‘portion of the eral

exoplasmic

number

cell

portion

least

it

has been dem-

The

of nerve-cells.

protoplas-

can be roughly divided into a periphand a central endoplasmic jiortion.

In neurons, as in musclc-cells, though less distinct in the former than in the latter, tliere is a tendency to a fihrillar}^ structure, the fibrilla; tending to occur in the peripheral ex-

oplasmic portion of both nerve- and muscle-

cells

in the endoplasmic portion of the jirotoplasm.

rather than

In both exo-

fig 6 .

fig ?

lesions in the neurons of rnimals after RICIN POISONING-1 [BerklBy ,]

[Johns J/ojtkins Hospital Rejmrts.^

:

I

i-i

f

t

653

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON.

plasm and endoplasm there can be made out in tissues which have been fixed a more or less homogeneous ground-substance granin which are deposited larger and smaller masses of a ular

nature.

corresponds,

The ground-substance

in

tissues

and stained by the methods of Nissl and Held to the ‘unstainable substance’ of Nissl, and the masses of granules to the ‘stainable substance’ of Nissl and the pigment.

fixed with alcohol

“The

'stainable substance’ of Nissl in healthy animals of

the same age and species, with the same method of fixing and staining, is tolerably constant in appearance and arrangement

group of nervecells: a fact of extreme importance for neiwe-anatoniy and The axons appear to be entirely devoid of the pathology. ‘stainable

of the sanie

and dendrites

in the cell-bodies

Whether the stainable subfrom solution through the bodies pre-existent, though invisible, first of

substance’

Nissl.

stances represent bodies precipitated

acfion of reagents or

brought into view through the action of fixing or staining reagents in the hardened tissues, in either case they appear to yield the chemical tests characteristic of the

group of nucleo-

Whether the staining reaction characteristic of the stainable substance depends upon chemical relations or upon purely physical conditions must, for the present, remain un-

albumins.

decided.

“The

fiinstainable portion’

—^though

ground-substance,

important than the stainable, nature and stnicture are in general.”

Still,

out by our analysis

—that

of the cell-body,

probably

still

is

functionally

is,

the

much more

not so well understood;

its

as obscure as those of protoplasm

the link with features previously brought

now seems within

reach.

Held has maintained that the stainable Nissl bodies represent simply substances precipitated of fixing mixtures;

from solution by the action

Fischer was led to the same conclusion.

Barker says, in this connection, that he repeatedly convinced himself of the homogeneous ajipearance of the protoplasm of the neiwe-cell Avhen it is

from the

examined immediately after the removal

That the ground-substance

living liody.

geneous, and that the unstainable portion sociation

But

of

some of

its

the stainable portion

constituents,

we have

is

is

homo-

a product of dis-

are therefore

probable.

seen has yielded the chemical

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM.

554

tests “characteristic of the

group of uucleo-albiiniins.” group of nitrogenous

not, therefore, dealing with the

which

lecithin,

the

main

We fats

dividual constituent which It

is

to

constituent of myelin, belongs, but

with what probably represents, not a mere artifact, but an ures.

are

in-

precipitated by the fixing mixtimportant to detennine, therefore, the exact nais

ture of the Nissl “bodies,” and perhaps by a process of exclusion ascertain that of the unstainable substance.

“Held,” says Professor Barker, “undertook a most careful

and exact chemical

of the granules

studj'^

in

alcohol tissues.

Thus, he found that the Nissl bodies arc insoluble in dilute and concentrated mineral acids, in acetic acid, boiling alcohol, cold or boiling ether, and in chloroform.

they

are

easily

soluble

in

dilute

With pepsin and hydrochloric-acid

On

the other hand,

and concentrated

alkalies.

digestion he found that the

ground-mass of the protoplasm vanished and that the Hissl bodies alone remained undigested the reveree of what occurred on treatment ivith an alkali. The Xissl bodies yielded no reac:

tion with Millon’s or Adamkiewicz’s reagent.

Held obtained,

however, slightly positive results with Lilienfeld and Monti’s

microchemical test for phosphorus, and a considerable quantity of the gray matter of the spinal

marrow

after digestion with

pepsin and hydrochloric acid examined by Siegfried, of the

showed the presence of Held concludes, however, from these various rephosphorus. actions, that the Nissl bodies belong to the group of the nucleophysiological

albumins

:

Halliburton,

a

laboratory

view

of

which

who found

Leipzig,

agrees

which coagulated at from 55° as

with the investigations

of

in the gray matter a micleo-albumin

much as 0.5 per cent, of The large proportion

to 60°

C.

and which contained

phosphorus.’’ of phosphorus further sustains the

preponderating role that the oxygen of the plasma must play in the neuron, owing to the activity of the reaction between these two .elements.

It also indicates a close relationship be-

tween the neuron and all other cellular structures of the orThus, referring to Held, Barker says: “He asserts ganism. that in numerous experiments with his method (fomiol freezing) he has found in the most different organs constituents of the cell-body which behave not only tinctorially, but also mor-

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON.

555

phologically, exactly as the stainable substance in nerve-cells.

He

described

them

gland-cells,

in

in

liver-cells,

the

of

cells

pancreas, in the cells of some sarcomatous tumors, in certain connective-tissue cells, but especially in

lymph-glands. of Nissl

is

not

normal and pathological

also asserts that the stainable substance

Cajal'*'*

specific

for the nerve-cells, as he has

demon-

and of the connective-tissue elements." Hissl’s bodies appear to me, therefore, as constituting an organized component of the ground-substrated its presence in certain of the leucocytes

nucleo-albumin rich in phosphorus,

stance of the neuron,

a

which, judging from

similarity to a large

its

number

of cellular

structures elsewhere in the organism, represents the cell-struct-

ure

itself, precisely as is

the hepatic cell

when

free

from glyco-

gen, bile, or the agencies from which these are derived. to the

neuron what the neurilemma, Mauthner’s sheath,

are' to

the intemodal segment

does the protoplasmic

membrane

of

etc.,

and includes

a nerve,

of

It is

—the

Schwann

—

as

nucleolated

nucleus.

The

must be the equivalent of myelin: the white substance of Schwann. We have seen that this is also unstainable. Even picrocarmine does not stain it, and unstainable portion

Rahvier states that, the axis-cylinder becomes stained at the nodes because there is no myelin in this region of the nerve.

The

similarity between myelin of the nerves

cerebro-spinal system is emphasized

and that of the by Foster when he saj's:

“Obviously the fat of the white matter of the central nervous system and of spinal nerves (of which fat by far the greater part must exist in the medulla, and for nearly the whole of the medulla) is a very complex body indeed, especially so if the cholesterin exists in combination with

(or protagon).

and, indeed, in

Being its

tlie

lecithin, or cerebrin

so complex, it is naturally very unstable,

stability resembles proteid matter.”

also suggests, however, that protagon, a nitrogenous

taining phosphorus isolated

may

This

body con-

Liebreich from brain-substance, be the unstainable substance we are seeking. Hoppe-Seyliy

and DiakonolT, having found it to be composed of lecithin and cerebrin, the direct connection with the former is not re-

ler

Cajal:

Revlsta trlmest. mlcrograflca, vol.

1,

No.

1,

March,

1896.

'

THE POSTERIOK PITUITARY AND THE NERVOUS SYSTEM.

556

moved.

Protagoii

Howell tlie

states

readily

up

breaks

into

constituents.

its

“while protagon seems to be regarded as principal form in which lecithin occurs in the brain, simple that,

lecithin is believed to be present in the nerves and other organs,” and he refers to Noll,"® who found “the quantity of

protagon in the spinal cord may amount to 25 per cent, of the dry solids; in the brain, to 22 per cent.; and in the sciatic nerve, to 7.5 per cent.” That it is difficult to analyze this question is suggested by his closing remark “Regarding the :

synthesis

of

lecithin

the

in

body,

portance of the substance, nothing the important role that

the

or

physiological

We

known.”

is

have seen

probably plays as myelin;

it

im-

its

pres-

ence in such large quantities, as a constituent of protagon, in the cerebro-spinal system plainly points to it as of the unstainable ground-substance of the neuron.

What

is

the role of cerebrin, which, with lecithin, forms

protagon, and from which

In a study of the chemistry of neiwe-degeneration Halliburton and Mott"® it

is

readily separated?

had previously shown that in general paralysis of the insane “the marked degeneration that occurs in the brain is accompanied by the passing of products of deOf these,” says the authors, generation into the spinal fluid. “nucleo-proteid and cholin are those Avhich can be most readily Cholin can also be found in the blood.” Having detected. refer to the fact that they

continued this work, they now find “that this

is

not peculiar

to the disease just mentioned, but .that in various other de-

generative nervous sclerosis,

alcoholic

diseases neuritis,

(combined beriberi)

sclerosis,

cholin

disseminated

can be also de-

The tests that they employed were the hlood.” mainly two: (1) “the obtaining of the characteristic octahedral crystals -of the platinum double salt from the alcoholic extract and a very interesting of the blood”; (2) a physiological test

tected

in

—

one,

I

.may

add,

if

the

functions

arc included in the process, namely:

of

the

adrenal

system

“the lowering of Iilood-

which the authors consider as “partly cardiac in origin and ]iartly due to dilation of peripheral vessels,” and pressure,”

“Noll: Zeltschrlft fUr physiol. Chetnie, Dd. xxvii, S. “Halliburton and Mott: Journal of Physiology, Feb.

370,

1S99.

28,

1901.

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON.

557

“which a saline solution of the residue of the alcoholic extract produces/’ This fall “is abolished,” they further state, “if the I may incidentally remark animal has been atropinized.”

embody the pathogenesis of most neuroses attended with degeneration, viewed from my standpoint, since we have here the phenomena incident upon arrest of function, But diauto-intoxication., and toxic suprarenal insufficiency. rectly bearing upon the subject in point is the evident iden-, that these few lines

product of degeneration.

tity of cholin as a

and putrefaction,” says Howell. we have seen, a waste-product of normal

decomposition

lecithin

in

But

likewise, as

it is

It “has its source

nervous-tissue metabolism, being eliminated with the bile in a

modified form.

and is

That

cerebrtn

is

of physiological metabolism is

found in pus-corpuscles and

present considerable analogy.

a product of putrefaction suggested by two facts: it fonnula and that of cholin

also

its

Even taking

as

standard that

furnished by H. Muller, which has given rise to considerable

CJ.H33NO3, while cholin is CgHj^NO,. becomes the functional ground-substance of

controversy, cerebrin

Lecithin, therefore,

is

the cell-body of the neuron, just as the neuron

and

its

it

is

in the nerve.

Both in

continuation, the nerve, therefore, the vascular

carry blood-plasma, which, by passing through their walls, maintains a continuous reaction, of which the phosphorus of the lecithin and the oxygen of the blood-plasma are main reagents and chemical energy the end-result. The relationship fibrils

between the vascular etc., is

well

But

fibrils and the ground-substance, nucleus, shown in the engraving on page 558.

though a useful product of metabolism, requires in its formation the aid of protoplasmic function, as does, in the muscle, tlie elaboration of myosinogen. In the cell-body this is probably performed, we have seen, by structures which the Nissl bodies, as nucleo-albiimins, represent. Indeed, lecithin,

in a study of the action of fixatives found'’’’’

that,

“when

a soluble colloid

upon protoplasm Plardy fixed by the action of

is

a

fixing reagent, it acquires a comparatively coarse structure in the process, which differs wholly or in part from the structure of the solulile colloid.” Again, that those jirotoplasmic

" Hardy:

Journal o£ Physiology,

May

11,

1899.

S

558

Fig.

THE POSTERIOH PITUITARY AND THE NERVOUS SYSTEM.

."i.

—

chematic Representation op the Lower Motor Neuron.

The motor ceR from the ventral horn of the spinal cord, together with all Us protoplasmic processes and their divisions, its axis-cylinder process with its divisions, slde-flbrlls or collaterals, and end-ramiflcatlons (telodendrions, or motor end-plates) In the muscle represent parts of a single cell or neuron, n'. Nucleolus, c, Cytoplasm showing the dark colored Nlssl bodies and lighter ground-substance. (7, 'Protoplasmic processes (dendrites) containing Nissl bodies. (Harker.)

659

THE PHYSIOLOGICAL CHEMISTRY OF THE NEURON.

stnicturcs are supjilicd by a vascular net-work similar to that of other

cellular

structures

shown by the observations of

is

Apathy, who took them for nerve-fibrils. to this feature of his investigations, says:

Barker,

“As

referring

to the relations

on the one hand, and Apathy makes very definite

of the neuro-fibrils to sensory surfaces,

muscular

tissue,

on

the

other.

the

chapter of his article.

A

statements,

especially

neuro-fibril

entering the cjdoplasm of an epithelial cell of a

in

last

up (very much as in a reticulum composed of the elementary

sensory surface in the leech breaks ganglion-cell) into a finer

A

fibrils.

large

number

of

the constituent

perhaps the majority, leave the the

cell

fibrils,

however,

in order to take part in

formation of a complicated interepithelial fibril-plexus.”

Neuron and

nerve,

therefore,

appear to be similar to other

organs as functional entities and to be subject to the same laws,

including

the

circulation

through

them

of

oxidizing

plasma.

This explains for the

first

time why tetanotoxin was found

by Bruschettini, Marie and others and why, in shown by Marie and Morax (see p. 1441), tetanotoxin, injected into the tissues, enters and ascends the axis-cylinders of nerves an observation confirmed by Meyer and Eansom. The role of the blood-plasma seems so clearly defined in the in the nerves

fact, as

—

foregoing analysis that I deem .all

—

parts of a neuron

cylinder

—are

it

permissible to conclude that

neuraxon or axis-

cell-body, dendntes,

channels for adrenoxidase-laden blood-plasma.

Are dendrites provided, as are the cell-body and the axismyelin? We have seen that, as stated by Barker,

cylinder, with

“the stainable substance of Nissl in healthy animals

same age and staining,

is

species,

of

the

with the same method of fixing and

and arrangement and dendrites of the same group of nerve-cells.”

tolerably constant in appearance

in the cell-bodies

He also states that “the axons appear to be entirely devoid of the stainable substance of Nissl”; but Berkley,^® referring to the nerve-fiber terminals which are extensions of the axon, writes: “The researches of Flechsig, as well as my own, have shown that these

fine

branches are furnished with a thin layer

of myelin nearly to their termination.” Berkley

:

J ohns Hopkins Hospital Reports, vol.

As

this refers to intra-

vi, p. 89, 1897.

.

,

V

f

*w

f

4

•

y

560

THE POSTERIOR PITUITARY AND THE NERVOUS SYSTEM

cerebral nerve-fibers, I

am

nervous system

upon

is built

brought

conclude that ike entire

to

same plan:

the




Tablets of from

to 2 grains (0.033 to 0.13 Gm.) of the desiccated gland can

be taken after meals.

Asthma, to arrest the paroxysms, by augmenting the pulmonary and tissue intake of oxygen and the cardio-vascular propi;lsion of arterial blood. From 5 to 10 minims (0.31 to 0.62 c.c.) of the 1 1000 solution of suprarenalin or adrenalin 6.

:

in 1

drachm

of saline solution should be injected,

drop by drop,

into a superficial vein, or hypodermically. 7.

To prevent

the recurrence of serous effusions in the

pleura, the peritoneum, the tunica vaginalis, etc., after aspiration,

by reducing the permeability of the

local capillaries

and

restoring the circulatory equilibrium.

In neuralgia or neuritis, as pointed out by Cai'leton, applied to the cutaneous surface over the diseased area to pro8.

duce ischaemia of the hyperamic nerves and thus arrest the

One

pain.

to 2

minims

(0.12 c.c.) of a 1 to 1000 adrenalin

ointment should be applied by inunction.

PITUITARY ORGANOTHERAPY. I have submitted elsewhere in this M'hich

have led

pituitary body as

work the manj^ reasons from those who consider the a secreting gland, and to attribute to tliis

me

to

differ

organ the functions of a composite nerve-center. Pituitary organotherapy, tbough of marked value, does not mean to me, therefore, as did the organic preparations reviewed so far in the

present chapter, the scientific use of a substance which carries on well-defined functions in the body, but rather the use of a

—

PITUITARY ORGANOTHERAPY.

7G()

tissue

mainly in chromafjin suhslance and nucleins, or in substances capable of producing jointly the effects of

rich

at least

adrenal preparations

generally

(a

recognized

modified,

faet)

and indeed improved, through their combination with other components of the pituitary body. I may recall in this connection that of the two lobes, as shown by Howell, Silvestrini,

Thaon,’®^ and others, the posterior

is

the only one whose e.vtracts

are active therapeutically, but that, as shown by Crowe, Cushing,

and Homans,’"'*

it

death in animals

—

not removal of this lobe which causes

is

as

it

should, were

it

like the adrenals

the thyroparathyroid body, a secreting gland important to

but removal of the anterior, which thera])eutically \\'biit

therefore, will not

offer,

inert.

is

explanation of the role of pituitary preparations take the

so-called

and

life

1

secretion into

will ac-

fact we have at our shown by Wiesel, the the active composterior lobe is rich in chromaffin substance ponent of adrenal tissue and that it is mainly the physiological though advantageously modified as a effects of this substance

count;

it

will

the

utilize

disposal for this purpose,

only certain that,

viz.,

as

—

— —

therapeutic agent through

its

condjination with other constit-

uents of the same tissue, I repeat

—that we

The phenomena awakened by

witness.

pituitary are strikingly those

and Bose’"® found, in 1896, that subcutaneous injections of pituitaiy extract produced a rise of temperature which lasted but a couple of hours. An intravenous of adrenal preparations.

IMairet

marked myosis, slowing of the cardiac beats, and hyperthermia as main

dose produced ful

respiration, powersigns, the animals

Schafer and Vincent'"" then found that pituitary substance raised the blood-pressure besides containing a depressor substance and that this substance when applied to recovering, however.

—

—

mucous inend)ranes caused blanching, as tion of adrenalin is applied.

mammals

it

They

is

the case

when

a solu-

also noted that in small

caused, in toxic doses, paralytic

symptoms which

they also consider analogous to those caused by adrenal extracts. According to Jas. Barr,'"^ pituitary extract actively produces ^o^Thaon: L’hypophyse, p. 99, 1907. tj Crowe, Cushing, and Homansi Bulletin of the Johns Hopkins Hospital, i

May,

i

1910.

Malret and Bose: Schiifer

Barr:

Arch, do physiol.,

and Sw’ale Vincent: Lancet,

Nov.

13,

1899.

p.

600,

1896. p.

Jour, of Physiol.,

8i.

vol.

xxv,

1899.

PITUITARY ORGANOTHERAPY.

767

and it is also known to produce glycosuria. In awakens all the typical phenomena, physiological and pathological, to which the adrenal product gives rise. The marked advantage of pituitary owing, doubtless, to the fact that it is bound up in organic combination with other arteriosclerosis,

other words,

it

—

components of the organ pressure to which

it

more

thus being

—

that

is

gives rise

sustains the rise of blood-

it

much

reliable in shock

longer than does adrenalin,

and other emergency cases. and the muscular tone,

It seems also to sustain the temperature

cardiac, vascular, intestinal,

and

uterine, longer than the adrenal

advantage

It possesses also a great practical

active principle.

over adrenalin and other adrenal principles in that

administered by the mouth without compromising

A fonn

product called “pituitrin”

its

b}"^

of a powder, is available on our

dose of which this dose

termed

market for

oral use, the

given as 10 to 30 grains (0.66 to 2 Gm.).

most

But

Gm.) being

cases.

also a liquid extract of the posterior lobe,

iS

can be

manufacturers, in the

too large, 5 to 10 grains (0.33 to 0.66

is

sufficient in

There

is

it

its effects.

“infundibular

extract,”

the

infundibulum

wrongly

being

the

pedicle which unites both lobes of the pituitary to the base of

This infundibular extract

the brain.

affects mucous membranes and should be applied only eight or ten times the same quantity of saline

precisely as do adrenal extractives,

when

diluted in

solution.

It

may

doses, or intramuscularly in 3- to 15-

c.c.)

doses.

Another liquid preparation in small flasks containing 15 cent,

extract,

grains (0.2 agent.

the

Gm.)

minim (0.62 minim (0.2 to

be given orally in 10- to 30-

c.e.)

quantity

is

also available,

minims (0.92

for

one

of the posterior lobe,

i.e.,

c.c.)

injection

to 2

0.92

“vaporole,”

of a 20 per

representing

3

which contains the active

The

injection should be given intramuscularly in the gluteal region, under strict antisepsis.

CAuniAc Disorders.

— As

sIiomti

by Benon and Delille,^®® and corrects

pituitary gland raises the depressed arterial tension purely functional disorders of rhythm. It is

recommended

in doses ranging

S°c. ae rnnpp^o de Mddecine de Paris, Oct., Thfrnp.. Gongres 1907.

Jan.

from 22

3 to 6 grains (0.2

and

April

23,

1907,

and

PITUITARY ORGANOTHERAPY.

768

to 0.4 Gni.)

of the whole glaiul, in inyocanlial weakness, par-

due

ticularly in that

receding, scanty. theless

OBSTETRICS.

the

jmlse

While serves

heconiing more

is

less active

valuable

a

when

infections

to

the hlood-pressure

than digitalis as a diuretic, purpose

in

it

never-

connection.

this

is

and the urine

rapid,

It

is

advantageous in mitral disorders when there

is

hyposy.stole

and

in chronic myocarditis, particularly that

to alcoholism.

It

is also

due

useful in the tachycardia of certain neuroses and during

menopause.

These results have been confirmed by

Trerotoli,^®”

Parisot,"" and others. It is contraindicated in aortic affections in any disorder in which high vascular tension prevails, and where there is a tendency to anginal pains, which it tends greatly to aggravate.

Pituitary gland

preferred to adrenal and particularly

is

adrenalin, as stated above,

when

former being useful in urgent

the action

is

to he sustained, the

Kenon and

cases.

Delille,

how-

and recommend pituitary gland only when Leonard Williams,”' on the other hand, deems

ever, prefer digitalis,

the latter it

fails.

superior

to

classic tonics

.

digitalis,

strophanthus,

what he terms the ‘Runaway heart of

in

states,” influenza,

pneumonia, bronchitis,

hut low blood-pressure, and in

]W)int,

instances

are

etc.,

all cases in

to.xic

with tachycardia,

which there

is

post-

—which, from my viewhypoadrenia—Williams regards

In these cases

cardiac debility.

to.xic

and other

strychnine,

of

pure

command. In heart- failure and shock, it has been highly recommended by l\Tummerv and Lymes and Bell and Wray, 15 minims (0.92 pituitary preparations superior to any remedy at our

c.c.)

While

of the extract being injected intramuscularly.

virtues effects

number

its

would seem to recommend it for the perpetuation of the of adrenalin, which are, at best, but temporary, the of cases in which

it

has been tried has been too limited

so far to warrant an opinion as to its actual value.

Obstetrics.

—Oale”^ found,

in the course of

comprehensive

experiments, that (in keeping with the adrenal secretions) the action of extract of pituitary was “a direct stimulation of involuntary

muscle

without

any

relation

to

innervation.”

and 33, 190 grains (0.50 Gm.) in divided The symptoms tend to return, however, on dis-

doses daily.

Cases subsequently treated were also

continuing the remedy. benefited, but

no cures were

effected.

from my viewpoint, corresponds precisely with that referred to under the preceding heading. We have seen in the fifth chapter that the main pathological condition, that to which all the prominent symptoms of ex''.I’iiis

mode

of

action,

ophthalmic goiter were due, was a general dilatation of the artePituitary extracts causing constriction of these vessels rioles. as long as it is administered, it offsets for the time the morbid

That such

phenomena enumerated.

is

actually the case was

M'ho found, experiand Carrion, their effects produced “always mentally, that pituitary extracts by raising the arterial tension,” producing at the same time

demonstrated by

II allion

“an intense vasoconstrictor action iqion the thyroid body. here precisely the physiological action necesof sary, the va.soconstrictor jiower of the adrenal component Briefly,

we bave

Renon and

Delllle:

Hallion and Carrion:

Soc.

Oesthfirap.,

I Mil.

March

13,

1907.

—

—

773

PITUITARY ORGANOTHERAPY.

the pituitary gland superseding the vasodilator action of the thyroid, the underlying cause of the disease.

Nervous and 1\Iental Diseases and Myopathies. Eenon and Delille used pituitary in 10 neurasthenics in whom tachycardia, irregular vascular tension, often beloiv normal, a sensation

of

.

were present.

myasthenia,

ojipression,

In these

insomnia,

cases, 3 to 5 grains

daily proved remarkably useful,

and

anore.xia

(0.2 to 0.3

Gm.)

though no complete recovery

was noted.

and Vincent’-® obtained a complete recovery in a

Delille

grave case of bulbo-spinal myasthenia by the simultaneous use

Parhon and Urechia and Leopold-Levi and de Eothschild’-’ had also obtained favorable and ovarian

of pituitary

e.xtracts.

results with pituitary in

good,

in

effects

similar cases.

of

cases

chorea

in

Browning’-® observed

which this disorder

oc-

curred in conjunction with stunted growth, as shown under the next heading.

In epilepsy,

it

was tried by Mairet and Bose,’-® but only

—

served to increase the

of attacks

since

number Spitzka has shown that

these were due to abnormal eleva-

tion

of

the

blood-pressure.'

a result to be expected,

In some instances

it

provoked

delirium. Sollier

and found

and Chartier’®® it

tried pituitary in

useful in depressive states.

mental disorders

It raised the blood-

pressure, reduced the pulse, suppressed profuse sweating,

improved the asthenia.

The

and

synthesis of perceptions and the

association of ideas were improved,

and mental operations were more promptly. Stunted Growth and Imbecility. In the case of a child years, which had shown the evidences of hypothyroidia with

incited

of 3

idiocy sufficiently to suggest the use of thyroid, Leopold-Levi

and de Bothschild found

this agent useless. The case being attended with marked myasthenia, they administered pituitary extract D/b grains (0.1 Gm.) twice daily, which corresjionded

with of

grains (0.5

Gm.) of the

improvement appeared within

a

fresh gland.

few days.

The

1“ Pf'iRe and Vincent: Soc. de Neurol., Feb. 7, 1907. Leopold-Levi and de Rothschild: Ihxd. Journai of Medicine, Sept, i»o Soiiicr

and Chartier:

''e Physioi.. p. 600, 1896. Congrfis de Dijou, Aug., 1308.

]\[arked signs

intelligence

1909.

—

PITUITARY ORGANOTHERAPY.

774

PARESIS.

developed to a remarkable degree, and soon reached that of a child of a corresponding age, 3 years, though before the treat-

ment

Two

did not exceed that of a 7 or 8 months’ infant.

it

similar cases, one of which showed symjitoms of Little’s disease,

were similarly benefited. Browning’''" used pituitary only in undersized or backward

He

children and youths (not real dwarfs or midgets).

following histories

A

gives the

:

had made little or no recent advance in growth. On pituitary, with some accessories for the chorea, she gained a couple of pounds in weight and over an inch in height in three and a half months, the chorea 1.

frail,

choreic girl of 14 years

A

boy of 2 years, after a period of cessation of growth, increased from 25 to over 30 disappearing.

pounds

(i.e.,

2.

slightly

rachitic

over 20 per cent.) in six months on the somewhat ^besides recovering in all

—

irregular administration of pituitary,

ways, and keeping up his good progress since, though at a slower

Browning noted when growth

rate.

way

it

is

usually keeps on satisfactorily.

once started up in this 3.

A

somewhat choreic

boy of 13 years and of scanty physique received pituitary, x\lthough his growth besides at times arsenic and accessories.

was said

to

have been at a standstill previous to

this,

he gained

and 10 pounds in weight in the next eight In another ton months, on somewhat irregular con-

2 inches in height

months.

tinuation of the pituitary, he in height

and

1

1

pounds

made

in weight,

a further gain of 3 inches

—when the

inquire anxiously for agents with the opposite record for a j'ear and a half,

of. 5

father began to

effect.

is

a

inches in height and over 20

pounds in weight, the patient having been under 70 pounds at the

This

5(!

inches and

start.

Intestinal Paresis.

—

Bell

and Hicks’®" have found

pitui-

tary extract of value in paralytic distention of the intestines. It never failed either in post-operative or other ^larcsis if given the intestine begins to distend in 15-

intramuscularly

minim

when

doses (0.02 c.c.) repeated in an hour,

if

rc(]uired.

I

he

he beneficial then sustained by daily doses if need be. few influence of the injections was, as a rule, noticeable in a I

effect is

minutes. Browning: Lnr. Ht. ‘“Bell and Hicks: British Medical Journal, March

27.

19irJ.

OVAKIAN OKGANOTHEHAPY.

775

OVARIAN ORGANOTHERAPY. As

is

well known, the ovaries correspond in

with the testes in

tlieir

many

particulars

Eemoval of the utenis and

upon development.

inlluence

the former prevents the normal development of

the appearance of menstruation, while their removal after puberty arrests menstruation

and

is

followed by atrophy of the remaining

structures of the genital apparatus.

The whole organism

is

in-

the ovaries, for their destruction or absence causes

fluenced by

grow without the general physical attributes of the This led Brown-Sequard to consider the ovaries as tlie source of an internal secretion. This view has been upheld by many observers who found that ovaries transplanted in the abdominal cavity, t.e., elsewhere than in their normal location, restored to the other genital organs the power to develop and girls

to

female

sex.

The identity of this and the manner in which it carries

carry on their physiological functions.

supposed internal secretion

on

its

function have, however, remained obscure.

My own

view, submitted at the beginning of this chapter,

does not cover this feature:

it

refers only to the

which ovarian preparations produce their it is

in

It points out

awakened by adrenal substance,

that these are similar to those

and that

effects.

manner

—not

probably to the presence of this substance

—

in the ovaries that they must shown by Schafer, a close homology between the interstitial of the ovary and the same cells in the adrenals; both sets of organs are derived from the Wolffian body; ovarian extract raises the blood-pressure and slows the heart, as sho^vn by Federoff,^^® Jacobs,^®* and otliers. Eemoval of the ovaries, moreover, reduces the oxygen intake 10 per cent., as shown by Loewy and Eichter,^^'^ while ovarian extract restores

necessarily an internal secretion

There

be attributed.

it;

it

exists, as

has been, therefore, regarded as an oxidizing ferment.

Neumann and metabolism

Vas^'"'

noted

that

Senator observed

;

ovarian

that

enhanced

e.xtract

ovarian,

preparations

in-

creased diuresis and the excretion of urea and phosphoric acid. Its phy.siological effects are those of adrenal preparations, therefore, in every respect. 133

Fedoroff:

Jacobs:

La Gyndcologle,

Oct. 15, 1891.

Dublin Jour, of the Med.

Loewy and

Richter;

Neumann and Vas:

Berlin, klin.

Monats.

f.

Scl.,

Sept.

1.

1897.

Woch., Bd. xxxvi,

Geburtsh.

u.

S.

1095,

1899. 433,

Gyn., Bd. xv, S.

1902.

OVARIAN ORGANOTHERAPY.

776 Its eU'ects

been

liavc

on oxidation are

clearly

recognized

so striking, in fact, tliat tlicy

by many

clinicians.

among

authorized to classify ovarian organotherapy agents,” write Ualcbe and Ijepinois.*'’^

be admitted,

is

“Tliis conclusion,

are

it

must

Curatcllo and

that reached by several authors.

Tarulli believe that

“W’e

the oxidizing

internal secretion of the ovaries favors

tlie

the oxidation of phosphorized organic substances, hydrocarbons,

and

According

fats.

to

Gomes,

it

enhances

oxidation

and

hydrolysis and favors the elimination of phosphates.

Albert Eobin and Slaurice Binet have shown that there

menstruation an increase of the respiratory exchange.

is

during Keller,

studying the general exchanges, found that there was increased nitrogen oxidation. in

enhances

itself,

We

have ourselves found that menstruation,

vital

functions and particularly the great Sauve'^’" states that ovarian

function of general oxidation.”

extract increases the haunoglobin content of the blood.

The prepamiion in general use is which may be given in doses of 2 to 5 Gm.) twice daily. The fresh organ may 15- grain

product should

(0.6

to

1.0

grains (0.132 to 0.33 l)e

Gm.) doses where

is not available.

first

the desiccated gland,

employed the

in 10- to

pharmaceutical

It soon loses its effect; small doses

be given, then gradually increased.

Ovarian preparations have been tried in

many

disorders, but

mainly in connection with those of the genital apparatus that they have been found of actual value. Natural axd Artificial ]\1 exopause. In disorders occurring in the course of the physiological menopause, or when it

is

—

the latter

is

produced by bilateral oophorectomy, ovarian prep-

arations have proven of considerable value in a large proportion of cases since Brown-Sequard first introduced their use. Experi-

ence has shown, however, that the improvement lasts only as long as the agent is administered, and tliat, furthermore, certain

phenomena

:

the palpitation, trembling, and “nervousness,” dis-

appear earlier than the others, bility,

and psychoses, though

the cutaneous disorders,

—

i.e.,

the asthenia, flushes, irrita-

effects in all

symptoms, including

especially acne rosacea and eczema,

are promptly realized, sometimes as early as the fourth day. nalche and Ldpinols; Bull. ggn. Sauve; Parts mOdical, April 1,

d.

thdrap., Jan.

1911.

8,

1902.

777

CORPUS LUTEUM ORGANOTHERAPY. These tlie

effects

are normally explained by the influence of

remedy on general oxidation and the improvement of

antitoxie functions of the blood,

ttie

the imperfect hydrolysis

tissue wastes being the underlying cause of the

phenomena

of

other

than the general asthenia.

The

best results are obtained in

grown obese

young women who have

after removal of the ovaries, or in

whom

obesity

is

In physiological menopause they marked, as a rule, and sometimes fail altogether to In such instances, good results may sometimes be

due to ovarian insufficiency. are less

appear.

Gm.) desiccated remedy alone. In

obtained by giving simultaneously 1 grain (0.066 thyroid, or by depending

upon the

latter

congenital ovarian insufficieney, desiccated ovary has caused the

appearance of menstruation.

W.

E. Dixon,’®® of Cambridge University, recalls that the

presence of ovarian tissue in the body, however small in amount, is

sufficient to

prevent

tire

distressing sjunptoms

which frequently

follow comjffete extirpation; even transplanted ovaries are some-

times able to prevent the menopause attending removal of the ovaries.

Hence the

beneficial effects of ovarian preparations.

Of late, however, the general attention has been centered upon the therapeutic use of the essential structure of the ovary, the corpus luteum.

CORPUS LUTEUM ORGANOTHERAPY. The consensus

of opinion at the present time is that the

internal secretion of the ovary

The function

is

produced by the corpus luteum.

of the corpora lutea in the early stages of their

life is to initiate

growth

j^i’ocesses

of this internal secretion

in the uterine cavity by

and subsequently

means

to ^rreside over the

nidation and development of the ovum, and the cyclic engorge-

ment preceding menstruation.

The

recent labors of Fraenkel’®®

confirming his previous investigations have strongly sustained the internal secretion theory and the above functions.

He

its

controlling influence over

found, moreover, that the therapeutic

value of corpus luteum was limited to cases presenting symjjtoms of vasomotor origin due to absent or deficient ovarian activity. ’“Dixon;

Practitioner, May, 1901.

laopraenkel:

Archiv

f.

Gynekologie, B.

xci,

S.

705, 1910.

CORPUS LUTEUM ORGANOTHERAPY.

778

Tliis coincides with tlie earlier conclusion of J. G. Clarke*^®

that the

ollice

of the corpus luteuni was,

among

others, that of

—

“a preserver of the ovarian circulation” a fact which explains in turn the presence of adrenal-like tissue, whose secretion, as is well known, is eminently capable of sustaining vascular Indeed,

tone.

as

generally

is

believed,

it

corpus

the

is

luteum which produces the ovarian internal secretion; it should, in accord with what I have stated concerning the mode of action of the ovaries, also produce effects similar to those of

We

adrenal preparations.

hypernephroma witnessed

is

of

need but

children

one

recall that in the adrenal

the

of

phenomena

essential

the extraordinary development of the genital organs,

those of a child of 5 years, for instance, being practically those of an

adult.

primary

Bouin, Ancel, and Yillemin*'*^ found that the

effect

was a violent

of toxic doses of lutean extract

elevation of the blood-pressure, sufficient to produce effusion into all

serous

The

cavities.

physiological

effects

therapeutic

of

doses have not been sufficiently studied to show positively, as

was the case with the ovaries, that they are all those of adrenal preparations, though Avhat there is known points in that direc-

One

tion.

fact

is

certain, however, viz., the functions of the

organ should not be ascribed to is

its

internal secretion

its

;

mission

probably limited to that of sustaining the circulation of the

ovarian circulation, as pointed out by J. G. Clarke.

The

‘preparations available include desiccated corpus luteum

{glandulce lutei desiccatce), which (0.2 to 0.3

Gm.) doses it

be given in

three times dail 3^

istered before meals, but

gastric disturbances

may

if,

may

as is

It

is

3- to 5-

sometimes the

case, it causes

be administered during, that

say, in the course of, the meal.

The term “lutein”

applied to the same product, but

it

is

grain

usually admin-

is

is

to

sometimes

misleading, and

its

use

should be discouraged.

The

indications for desiccated luteum are similar to those

for ovarian preparations.

Natural and Postoperative IMenopause.

—

It

must be

said that the evidence as to the therapeutic value of desiccated

luteum

is,

to say the least, conflicting.

^lorley,*^'

’"’Clarke: Johns Hopkins Hospital Report, vol. 11, No. >*> Bouin, Ancel, and Vlllemln: Nouveaux Rem6des, March ’“Morley: Jour. Mich. State Med. Soc., Nov., 1909.

who 8,

supplied

1907.

'

CORPUS LUTEUM ORGANOTHERAPY. desiccated luteum to ten physicians,

779

and obtained reports

use in 18 cases, 14 of which sulfered from postoperative

from natural menopause, states tliat 12 improved, and that hut 1 failed to be relieved.

pause, and 4

5

o£ its

meno-

were cured,

C. A. IIill““ also reported results obtained with extract of

corpora lutea in 12 patients, ranging in age from 25 to 38 years,

who showed

symptoms after The “nenmusness” was completely

the most severe type of nervous

removal of both ovaries.

relieved by the treatment in each case.

In only 2

cases,

however,

was there complete relief from flashes of heat. In another case, suffering from insomnia, which had continued ever since the operation over a year before, and was uninfluenced by hypnotics,

complete relief was attained after the use of 50 5-grain (0.33

Gm.)

One

an increase in sexual desire, wliile in the remainder no noticeable change was experienced. No complete cures were obtained. Several cases had interrupted capsules.

case reported

and others, who ceased treatment, were comowing to return of symptoms. The preparation each case was given in 5-grain (0.33 Gm.) capsules three

treatment

onl}',

pelled to resume in

times daily, one-half to one hour before meals.

On

the other hand, Ellice McDonakT'*'* publishes a report

of 20 personal cases in Avhich he had used a similar preparation.

“The five

though they

results of this study, small

be,

extending over

years,” writes this observer in his conclusions,

“seem to menopause need not be value is in cases in which the

indicate that the control of surgical

sought in the corpora lutea.

Its

uterus and ovaries or uterus alone are retained. it

Particularly

is

valuable in the treatment of scanty menstruation and the

premature menopause.

have treated a number of cases at the outdoor dispensary of the Kensington Hospital for Women, with I.

extract of the whole ovary,

But the

therefrom.

and never saw any

d'efinite results

lutein extract, being the essential part of

the ovary, does seem

to help in some degree and should -be accompanied, in suitable eases, by dilatation of the utenis, with the use of the stem pessary following operation, as advised by

Manson.

At

least,

administration of lutein

operations on pregnant

in

whom

is

indicated after

miscarriage

Gynecology, and Obstetrics, Dec., 1910. Jour. Amer. Med. Assoc., July 16, 1910.

S'i'-gery,

McDonald:

women

is

feared.

7S0 i

OUCUITIG OKGANOTHEUAPY.

his is particularly true in the early weeks of prej^Tiancy during

the iinhedding of the ovum, as it has been shown experimentally that the corpus lutcum has a definite effect under such cir-

cumstances.” It is obvious that the clinical experience at our disposal still

is

too limited to warrant any decision as to the actual value

of corpus luteum, though

must be said that many desultory have been published in which its rise was extolled.

cases

McDonald

it

rightly lays stress on the facts that “the manifesta-

tions of the surgical

menopause are

and extreme to

too varied

allow explanation by the mere absence of the internal secretion of the ovary.

The

internal secretion of the ovary

is

but

a factor

in the process of the menstrual life.” I

would go one step further and express

a

doubt that we

are dealing at all with an “internal secretion,'’ a designation

applied to almost any organic juice nowadays, and reiterate what I

say elsewhere,

than

is

viz.,

that true internal secretions

are

fewer

generally believed.

ORCHITIC OR TESTICULAR ORGAXOTIIKRAPY.

From

the standpoint of therapeutics, testicular prepara-

tions can hardly be regarded as of

The

more than

historical interest.

influence of the testicles on the body at large

is

well

known.

Castration influences the development of the organism in particulars. acteristics

Eunuchs preserve

to

a

certain

many

extent the char-

of infantilism, the skin remaining soft and white,

and weak, and the voice high pitched. Yet thej' are usually tall, owing to inordinate growth of the bones. They lack courage, initiative, and intelligence. It is evident, their muscles flabby

therefore, that the testicles do not carry on genital functions

onl 3^

Brown-Sequard taught that they carried on

1st, procreation

;

a dual role:

2d, the production of an internal secretion

which stimulates and sustains the energy of the nerve-centers and cord, and capable, moreover, of endowing the individual with physical, moral, and intellectual characteristics of sex. Ilis own physical and intellectual activity having been greatly improved at the age of 72 j'oars, by injections of^ an extract prepared from the testes of young dogs, he concluded that it

—

TESTICULAR ORGANOTHERAPY.

781

marked therapeutic value. No one who, as I did, saw Erown-Sequard before and after he had submitted himself to possessed

could

treatment

this

imagination

his

stretch

sufficiently

attribute the change in his appearance to auto-suggestion,

to

lie

literally looked twenty years younger.

The from

prevailing opinion

is

preparations

testicular

that the beneficial effects obtained are

not

due necessarily

though the existence of such

internal secretion,

is

to

an

not denied,

but to nucleo-albumins, substances that are rich in iffiosphorus, resembling greatly lecithins and glycerophosphates.

As previously from

my

stated, the testicular active principle, sperniin,

viewpoint,

is,

or at- least corresponds with, as to its

physiologieal action with the adrenal principle.

that

the

Shaw,^''®

latter

oxidation

sustains

unaware

of

and

any such connection, writes:

and, according to Poehl,

is

body

tissues.”

urged that the adrenal secretion carries on as

a

Batty

“Spermin carrier,

responsible for those internal oxida-

tions which take place in the

catalytically

have seen

an oxygen

possesses the very curious jiroperty of being

tion

We

metabolism.

ferment.

its

Again, I have

oxygenizing func-

Pantchenko^'*®

states

that

“Spermin acts catalytically, thus increasing the oxidizing power of the blood, and simultaneously activates the intraorganic oxidation processes where these are weakened.” Moreover, as is the ease with the active adrenal secretion, spermin gives, according to ]\Iari, the guaiac and Florence hasmin test which consists in adding a drop of iodine-potassium iodide solution to the fluid obtained by soaking a seminal stain in water.

At the point

of contact of the

two drops, dark-brown needle-

shaped or rhomboidal crystals will form which resemble the crystals of hasmin.

Dixon

states that a constituent of orchitic extract is

altered by boiling;

McCarthy holds that

and regularity of the heart much

it

un-

increases the force

as does digitalis.

It enhances

the resistance to disease, increases the production of urea, and also acts directly as

shown by Poehl

upon the cardio-vaseular system. ]\Ioreover, fact which indicates that it is not specific

—a

““Shaw: “Organotherapy,” Pantchenko:

p.

205,

Tribune mOdicale,

1905.

vol,

.\xvil,

p,

11,

1896,

—

KIDNKY OKGANOTHliUAl’Y.

782 to tlie testis

it is

in the female as

a ul>i(iuitous constituoiit of the whole organipin,

M-ell

as the male.

Testicular preparations, including sperniin, have been reeoin-

niended in a host of disorders, particularly tabes, neurastlienia, melancholia, impotence, and paralysis agitans; in several cuta-

neous disorders, eczema and psoriasis; in disorders of nutrition, gout, obesity, and glycosuria; but others again have failed to

obtain any favorable results.

mended by Poehl and

Spermin has

the foregoing disorders, but in

rheumatism, as typhoid

also

been recom-

his followers not only in the majority of

many

others besides, in acne,

marasmus, and in various infections, such diphtheria, and even cholera. It has been

syphilis,

fever,

tried in Addison’s disease, but adrenal preparations are to be

preferred.

is

In the light of the analysis submitted above, however, there belief that beneficial effects were obtained

good ground for the

in all these maladies.

That the nucleo-albumins of

orchitic

extract acting as would glycerophosphates could be beneficial in

the disorders enumerated, no one can deny.

he

said,

This can hardly

however, of the cutaneous and nutritional disorders,

unless the spermin the extract contains, hy enhancing oxidation

and the destniction of Spermin itself agent.

toxic wastes,

—

as

proves to be the aetive

adrenoxidase

—

is

unquestionably

capable of doing this actively, and in syphilis and marasmus to markedl}'^

enhance the functional activity of

all tissues.

the beneficial role of spermin in infections finds

its

Again,

explanation

I have repeatedly emphasized, viz., that the oxygenized adrenal secretion, the active agent of spermin, from my view-

in a fact

point,

is

an active participant

in all

immunizing

processes, local

and general. The main point to determine, however, is whether orchitic extract, or spermin. a (fords better or as good results in any of the disorders enumerated than other remedies at our disposal.

The

evidence available indicates that such

is

not the case.

KIDNEY ORG ANOTIIEi;.\PY. That the kidneys produce an internal secretion is still Brown-Sequard, having removed the kidneys and problematic. caused urajmia, found that the injection of a glycerin extract of

783

KIDNEY ORGANOTHERAPY. kidney prolonged the

life

of the animals as

compared

to those

in wliich the same operation was not followed by the use of

tlie

This experiment, which has been repeated by others, forms the basis of the belief that the kidney produces an That such a conclusion may not be warinternal secretion. kidney extract.

ranted

is

suggested by the fact that the kidneys, along witli so far reviewed,

some of the organs tissue

—the

so-called “adrenal rests”

times develops

—and that

as such they are capable, as

immamizing functions

factor in the

are also rich in adrenal

from hypernephroma somean active

of the body, of counteracting

temporarily the toxmmia or “urasmia” brought on by removal of Indeed, the relief afforded

the kidneys.

is

but epliemeral, death

two days in rabbits, in which

being postponed but one to

Bitzou“" repeated Brown-Sequard’s experiments.

Dromain and

de Pradel Bra’^** had also noticed that injections of kidney extract lessened the

of epilepsy, another toxaimia.

fits

Dubois^'*®

and EenauP®® have also found that kidney extracts were endowed with antitoxic power.

That we

are again dealing

the adrenal principle

mainly with a manifestation of its powerful blood-

further suggested by

is

pressure-raising property.

Tigerstedt and Bergnian found that

rennin possessed this power; Bingel and Strauss^®^ recently confirmed their observation, and found that

its action corresponded with that of adrenal and pituitary extracts, those of other organs causing depressor effects. The rise of pressure produced by kidney extract was high, t.e., from 40 to 60 mm. Hg, and

lasted from fifteen to thirty minutes. The authors concluded, moreover, that “the action of rennin, like that of adrenalin, is

exerted in the muscles of the peripheral vessels.” action, however, is

more

like that of pituitary

Its general

body

extract, the

adrenal principle being doubtless combined organically, as in the pituitary, with bodies

which prolong and perhaps control adLike adrenal prepara-

vantageously the action of the former. tions kidney extract produces

sustains

my

’”Bitzou: T,,

.

niol.,

opinion that

dilatation

action

is

of the

pupil.

This

duo to adrenal principle.

Jour, de physiol, ct de path, gdner., Nov. I.'i, 1901. Pradel Bra: C.-r. heh. dcs sel. et mdm. de la Soc. de

Paris, 1895. '“Dubois: Soc. de Biol., p. 287, 1.90.8. '“Renaut: Bull. gdn. de thOrnp., T. 117,

Strauss: 9r

its

Deut. Archly

f.

pp. kiln.

.8

and

27,

1904. S.

Med., xcvl,

470,

1909;

July

KIDNEY ORGANOTHERAPY.

784

Even the oxidizing power

1 liave cattribiitecl to the adrenal

secretion seems to be reproduced

“very

little justilication

Batty Shaw/®^ who 4ilso finds

;

for the existence, of an internal secre-

tion” in the kidney, remarks that “possibly nephrin and other renal preparations provide a

means

of stimulating oxidation in

—

general, the kidney merely sharing in this oxidation”

accurate estimate from

my

Shaw

viewpoint.

a verj'

adds, moreover,

that “similar good results have been reported as a result of

treatment by means of spemiin and testicular extract,” both of which, as I have shown, also owe, in all probability, their therapeutic effects to the adrenal principle they contain.

The

therapeutic application of kidney preparations has re-

ceived considerable attention, and favorable results have been

reported in about one-half of the cases of chronic nephritis, or Bright’s disease, in which

it

was

The mode

tried.

the light of the facts submitted above,

is

of action, in

mainly an increase of

the antitoxic power of the blood and diminution, therefore, of

Page and

the irritation of renal apparatus.

example,

report

marked amelioration

maceration prepared as follows:

A

in

for

Dardelin,'''®

18

cases,

verj^ fresh

using

a

kidney from a

is cut into minute pieces, washed with fresh water to remove the excess of urine, then hashed and pounded into pulp. This pulp is put into 300 grammes (9 ounces and 5 drachms) of fresh water to which the physiological proportion of salt, 7.50

pig

to 1000, has

been added.

It is then allowed to macerate for three

hours, stirred occasionally, and kept in a cool place to avoid

fermentation.

The

red water of the maceration

is

divided into

three parts to be drunk by the patient during the day.

It is

more conveniently given, however, in tablet form, as “nephritin” Only the active

prepared in this country by Heed and Carnrick.

used in this preparation, the dose

substance of the kidney being from 10 to 15 5-grain (0.33 Gin.) tablets daily in divided is

doses, given between meals.

Kidney advantage field is

for

prejiarations have also been used with

in

puerperal

intoxications

more

or less

and epilepsy, but their and particularly

essentially the various forms of nephritis,

the

])revention

of

uramiia.

’“Shaw: Lac. Ht., p. 21fi. ’“Page and Dardelin: Press© m^dlcale,

They

Dec.

also

21,

1904.

tend

to

increase

MAMMARY GLAND ORGANOTHERAPY. diuresis

and reduce

tiie

As

albumin.

785

stated above, however, favor-

able effects are to be expected in about one-half of the cases.

MAMMARY GLAND ORGANOTHERAPY. by some that the

It is held

internal secretion, but

weak that by

it

gland produces an

is

on the subject

and in

this country

by the

is

so

Introduced

can hardly be taken into account.

it

Bell, of Glasgow,

Shober,

mammary

what evidence there

late

John H.

has shown therapeutically marked stimulating action

upon the uterus, but the manner in which it produces this effect has remained obscure. An extract lowers somewhat, and but temporarily, the blood-pressure and the pulse. According to Shober, it diminishes the blood supplied to the uterus and thus controls liaBinorrhage, its action resembling that of ergot,

point, therefore,

would

it

though

From my

free of the unpleasant effects of the latter drug.

view-

act by causing constriction of the

arterioles.

Mammary

gland

is

prepared in the form of a tablet

made

of the desiccated gland of the sheep, each tablet representing 20 grains (1.32

Gm.)

of the fresh gland.

The

dose

is

from

3 to 6

tablets daily.

The

therapeutic applicaiion

is

restricted to the genital ap-

In cases of uterine fibroids characterized by excessive menorrhagia and metrorrhagia the bleeding was found by Shober paratus.

to be cojitrolled in a

few weeks and the periods become regular,

normal, and free from pain. patient’s health

in size

up

Ther'^ is improvement in the and weight, and the tumors themselves diminish

to a certain point.

better condition for sity for

The

patient

is’

thus placed in a

any needed operation, and often the neces-

an operation

is

postponed.

Where

there

is

evidence of

inflammatory or degenerative changes, or when serious pressure symptoms are not controlled after a reasonable trial, operation should not be delayed. In 43 cases of uterine fibroma treated by Fedoroff, cure

is

claimed to have been obtained in 33. while there

was a marked reduction of the growth in 43 ])or cent. Mammary gland is also, useful in cases of subinvolution unassociated with Jnalignancy or structural changes. Pozzi has advocated use in uterine hemorrhage of any kind attending metritis.

its

;

THYMUS ORGANOTHERAPY.

78(j

]\rammary gland 1ms also been recommended involution and to enhance lactation.

to assist uterine

on the use

JUit the reports

of this agent have been antagonistic. TI I YM U S

In the ninth chapter

ORG ANOTIl E R AP Y. 4G7), 1 submitted the experimental

(p.

me to suggest, in 1907, that the function of the thymus was to supply an excess of phosphorus in and

which led

clinical evidence

organic combination during the growth of the body, ularly while the development of the osseous

demanded such

i.e.,

partic-

and nervous systems

This was sustained by the recognized

a reserve.

and adolescents, especially and trophic disorders of the brain and

fact that certain diseases of children

marasmus,

rachitis,

nervous system, were due, in part, to the functions of the thymus.

While

it

cannot be affirmed that this theory actually represents

the function of the organ

—

the

many hypotheses— all

yard of

thymus Jiaving been the grave-

that can be said for

it is

seems to account for the clinical results obtained under

that its

it

use

better than any hypothesis so far advanced, besides correspond-,

ing with the laboratory findings of

Diseases of the Thyroid.

by

tried

its effects.

—In

who obtained

ilikulicz,^®'*

simple goiter

it

was

first

sufficiently favorable results

in 5 out of 11 cases to render operation unnecessary, at least for

the time being,

lleinbach'-"''^

considers

probably superior to

it

thyroid because the unpleasant effects of the latter are avoided for the

same reason

it is

especially suitable

has to be used continuously.

This view

is

when organotherapy

based on the employ-

thymus in a large number of cases in the Breslau clinic, ilikulicz gave from 2]/> to 4 drachms (10 to 10 Gm.) of the raw sheep thymus on bread three times a week, increasing the dose to 7 drachms (28 Gm.) if required. IVe have seen that in oxophthalmic goiter it had proven

ment

of

efficacious in the

advanced oases, and also when other remedies had been used fruit-

hands of Owen'"®

in those of Claude’'’’

in

gave 45 grains (3 Gm.) daily to a severe ease, wliieh greatly improved, relapsing whenever the treatment was

lessly.

The

latter

IM Mikulicz:

Berlin, kiln. Woch., Bd. xxxii, S. ni2, 1895.

.Mittheil. uus den Grenzgebiet. d. Brit. Med. Jour., Oct. 10, 1890.

’“Reinbach:

'“Owen: Maude:

London Lancet, July

18,

189C.

Med.

u. Chir., B. ,

I.

S. 202, 1896.

787

THYMUS ORGANOTHERAPY'.

S. Solis-Cohen^®*' also advocates its use in this dis-

interrupted. ease,

having found that

exerted

it

influence mainly

its beneficial

upon the nervous symptoms of the disease without affecting the exophthalmns. Huston White*®” found that the nervous symptoms were alone improved. These observations coincide with my own view of the manner thymus gland produces its beneficial effects. The

in which

excess of thyroiodase produced in exophthalmic goiter causes,

we have

seen, too rapid oxidation of the

combination in the

phosphorus in organic

tissues, particularly in those of the

nervous

Thymus, supply-

system which are extremely rich in phosphorus.

ing phosphorus in organic combination, replaces that lost by the

nervous system, thus procuring marked benefit in this one direction.

As

5 grains (0.33

to 30 grains (3

Gnu)

Gm.)

thymus are equivalent

of the dried

of the fresh gland, this dose can readily

be given three times daily.

—

Eachitis, or Eickets. The same explanation, i.e., the purveying of phosphorus in oiganic combination ^to the osseous

—

system, in the present connection benefit

thymus has procured

used thymus gland in

1%

over 100 cases, obtained especially in

—accounts for the undoubted

having Mendel, drachms (6 to 13 Gm.) daily in

in this disorder.

to 3

marked

benefit in a large proportion, but

tbe nervous symptoms, including spasm of the

had previously been

glottis.

It

marked

benefit.

by Stoppato,*®* but without In Mendel’s cases both fresh and commercial tried

tablets were tried, the cases being subdivided as follows’:

1,

those which showed prodromal

symptoms only; 3, those in which deformity of the osseous system was the chief feature; 3, those marked by spasm of the glottis, and, 4, those in Yvhich splenic enlargement was the most important sign. Marked improvement was noted in all after from three to four weeks, and dentition and the closure of the fontanelle proceeded satisfactorily. No untoward symptoms were noted a marked advantage over thyroid preparations. In a case of stunted growth, obviously

—

of osseous origin, in a

boy of 14 years, E. Webb Wilcox*®^ obAssoc., Aug.

iMWhiVi? vol.

m wiicox.

18,

786, 1899. xllx, S. 134,

1900.

p.

i,

Woch., Bd.

1902.

Boston Medical and Surgical Journal, Aug. 60

13,

1908.

BRAIN AND NERVE ORGANOTHERAPY.

788

tained 9i/4 inches growth in three years by the persistent use of 2 grains (0.13 Gin.)

The view

thymus night and morning.

that these effects are due to the addition of phos-

phorus in organic combination to the body

further sustained

is

by the results of experimental observation by Hart and Nord-

mann/®® that the tlijunus had a definite relation to assimilation, and that it took an active part in the resistance of the organism to infection. As I will show in the second volume, page 878, nucleo-proteid, in so far as is

concerned,

BRAIM’

is

its

phosphorus in organic combination

an active participant in the immunizing

process.

AXD NERVE SUBSTANCE ORGANOTHERAPY.

"While these agents have given good results, the theorj’^ that

brain and nerve substance possess or produce au internal secretion has never been sustained scientifically.

The

clinical results,

though quite discordant, particularly in

the neuroses and psychoses in Avhich these preparations have been

have shown a tendency to harmonize since the introduction by Sciallero^"^ of an oily extract. Page,^®® who has obtained unusually good results in neurasthenia by means of injections

tried,

them to its antitoxic and antispasmodic Wassermann and Takaki had previously shown that effects. tetanus toxin was neutralized by contact with brain substance, and that when a fatal dose of tetanus toxin was injected with The same brain substance the fatal effects were prevented. of this extract, ascribes

observations were

made

b}' Babes ; in and Nobecourt; in in epilepsy by Lion and also Kaplan,

in the case of hydrophobia

strychnine and morphine poisoning by tetanus by Krokiewicz

;

using Poehl’s opocerebrin several years earlier.

—

in

Sciallero,

idal

accord with Dana’s experience

who

obtained encouraging results

and epilepsy, used his oily extract “cephalopin” in doses varying from 1 to 5 c.c. (16 to 81 minims). Ko untoward effects were obtained. Although it is very improbable that brain extracts injected

in neurasthenia, hysteria, chorea,

tic,

into the tissues act as they do in the test-tube, lished that they act

much

it

seems estab-

as do the lecithins on the market,

Hart and Nordmann: Berlin, kiln. Woch., May Sciallero; Riforma Medlca, Jan. 27, 1904. ^“Page: C.-r. de I’Academie de M6d., March 30,

2,

ISIO. ,

1909.

i.e..

HORMONE THERAPY.

789

by furnishing phosphorus to the organism in an assimilable form, Be or as nucleo-proteids in enhancing the immunizing process. this as it may, these substances seem to have produced effects which suggest that they are worthy of further study.

HOKMONE THERAPY. The word “honnoue” was applied hy Starling

to the

group

—

by various organs the ductless glands in work which could enhance the functions of other organs. Precisely as I had held three years earlier of substances secreted

the group studied in this

—

(the adrenal secretion exciting the thyroid, the pituitarv'^, the

pancreas, etc.; the thyroid secretion exciting the adrenals, etc.), these hormones were secreted by the organs which produced

them

normal functions, and reached the distant structures they influenced through tlie intermediary of the blood. The functions I had previously attributed to the adrenal secretion in in the course of

the tissues, or to the thyroid secretion in respect to cellular phos-

phorus, embodied precisely the same idea.

We may

regard as

“hoi-mones,” therefore, the various internal secretions already described.

While the hormones previously described influence the various organs, others affect only one organ or a system of organs. Bayliss and Starling termed “secretin” a hormone formed in the duodenal mucous membrane under the influence of hydrochloric Carried by the circulation to the intestinal mucosa, the pancreas, and the liver, it activates the producacid from the stomach.

tion of the secretions produced by these organs.

1907 (see

vol.

ii,

p.

As I suggested in 861), this hormone presents several proper-

ties of

adrenal extractives. Be this as it may, the question has not been sufficiently developed as yet to warrant any conclusion as to the use of these substances in therapeutics.

Another hormone, however, has been obtained from the mucosa by Zuelzer, Dohni, and ]\Iarxer^““ which has been found to enhance peristalsis. It being impossible to obtain gastric

it

in

sufficient quantities

from the stomach, it was sought after elsewhere, and was found in ample quantities in the spleen that junkshop in which red corpuscles (which, as I suggested in 1903,

—

are the

common

’“"Zuelzer,

carriers of the adrenal principle) are

Dohrn, and Marxer:

Berl.

klin.

Woch., Nu.

4G.

broken up

1908.

HORMONE THERAPY.

790 along with other

cells.

This splenic hormone

lates intestinal peristalsis to a

specifically stimu-

degree so remarkable that the

movements in the experimental animal may readily be shown cinematographically ten to fifteen minutes after an intraintestinal

venous injection.

This hormone (available as hormonal in the trade) has been found of considerable value in chronic constipation, intravenous injections

(20

c.c.

—

—

5

drachms

—in

children and 40

c.c.

— 10

drachms in adults) giving 71 per cent, of recoveries, beginning from the second to the seventh day and lasting from six months to two years (Zuelzer). The injection gives but little local pain thus used, and causes a slight rise of temperature (hormone fever).

In intestinal paralyses following abdominal operations

or volvulus

it

has also given satisfactory results in some cases.

Henle*“’ also obtained favorable results, but they did not seem to be lasting. He found it advisable to enhance the action of the remedy by means of enemas and purgatives to insure elimination of the intestinal contents.

In intestinal occlusion the use of hormones has been recom-

mended, but care is necessary lest the violent peristalsis provoked aggravate any intestinal lesion that may be present. The recent observations of Saar^®’ and UngeH“® suggest, however, that the peristaltic action promoted by the hormone is not violent, even where there

is

obstruction.

50th German Congress of Surgery, April, Medizin. Klinik, Nu. 2. 1910. Unger: Berliner med. Woch., No. 11, 1911.

Henie: Saar:

1911.

INDEX TO VOLUME Abdominal

dilation of, versus

vessels,

contraction

capillaries,

of

Adrenal haemorrhage and acute hyperchild,

exophthalmic

(See

goiter.

Accelerator cardiac phenomena, Achondroplasia, 205. Acne, spermln in, 782.

Acromegaly,

445.

pituitary extract in,

posterior pituitary

symptomatology

in,

514.

512,

515,

608.

treatment of, 618. Addison’s disease, 97. adrenal extract in, pathogenesis of, 99.

99.

ad-

the

Infection,

disorders,

764.

in effusions,

762.

in neuralgia,

disorders,

in shock,

764.

764.

diseases,

in surgical heart in

761.

cardiac disorders, 765.

in surgical

surgical

421.

Adrenal, unilateral removal Adrenalin, 751.

765.

submersion,

60.

(See also Adrenals.)

in respiratory

in

respiration,

pulmonary functions,

755.

765.

754,

453.

467.

764.

in

in haemorrhage,

in sthenic

tions,

brospinal plasma-channels, 573. functional activity and, 233. functions of the thymus gland and,

765.

757.

from haemorrhage,

in neuritis,

pulmonary

65.

respiratory func-

as the foundation of immunity, 620. as source of engorgement of cere-

in collapse, 754.

in collapse

in

to

421.

capillary hsemorrhage,

in cardiac

relation

its

764. 765.

in bacterial in’

oxidizing agent, in

unexplained properties of the, 56. Adrenal system, in cardiac functions,

764.

in ascites, 762. in asphyxia,

14.

causes a rise of temperature, 66. distributed by the red corpuscles as

in,

sure, 13.

in asthma,

17.

11,

globin, 58.

of

(See also Suprarenal.) extract and vascular presdisease,

of

63.

as the oxidizing agent of the haemo-

138.

in Addison’s

constituent

a

action on muscle,

727.

Adrenal

764.

secretion

action on heart,

Adiposis dolorosa, thyroid extract Adrenal.

118.

of,

haemoglobin,

haemorrhagic,

renals,

in children, 120.

Adrenal

pituitary extract in, 770.

Adenoma,

123.

121.

tions of, 764.

spermin in, 782. symptomatology of, treatment of, 103.

the

treatment of, 124. Adrenal hajmorrhagic pseudocyst, 126. Adrenal insufficiency, 80, 115. Adrenal opotherapy, 750. Adrenal preparations, general indica-

771.

body

of,

infant,

symptomatology

516.

of,

616.

of,

in

of,

123.

increased functional activity of the adrenals as a cause of, 25. pathogenesis of, 118. prognosis of, 124.

607.

pathogenesis, 608. pathological anatomy

pathology

in the

in adults,

llyperthyroidia.)

diagnosis

adrenia,

337,

573.

Aberrant

FIEST,

ness, 764.

septicaemia,

764.

in toxaemia, 756, 764.

Adrenal functions, toxins, venoms, and drugs

poisons,

large in doses as Inhibitors of. 19. Adrenal haemorrhage and acute hyperadrenia, 116. diagnosis of. 123. in the adult, 123.

4.

Adrenals, action of drugs on, in the production of lowering of the temperature, 49. in production of muscular weak-

752.

failure,

of,

of

41.

variations of the sure,

blood-pres-

44.

as a cause of adrenal htemorrhage. Increased functional activity of the,

25.

cancer of the, diagnosis,

symptoms,

137.

140.

138.

treatment, 141. diseases of the, 56. ( 791 )

792

INDEX.

Adrenals, function of the, 56. functions suppressed by removal

of,

9.

Assimilation,

governing center of the,

hmmatomata

of,

immunity,

70.

in,

622.

Augmentor cardiac

9.

11,

13,

Axis-cylinders 453.

of

the,

morbid effects of drugs and venoms on the. 39, 54. nervous supply of, 8, 11, 12, 14, 17. splno-adrenal communicating fila415.

relations of, with the vagus.

the

vasomotor

296.

12,-

system,

11,

17.

14,

removal

animals, effects

of, in

of, 5.

man, 5, 6, 7. sarcoma of, 137. toxics which depress the blood-pressure by causing passive conin

gestion

of

the,

in,

764.

Bacterins,

8.

696.

the

nervous

of,

system,

Blood-clots, -platelets

dase,

-pressure,

in.

121.

droplets

338.

adrenoxi-

of

on ad-

drugs

44.

which depress

the, by causing passive congestion of the adrenals, 30. Bone necrosis, thyroid extract in, 711. Brain and cord, minute circulation of,

788.

lower, identity of, 483. neuroglia-fibers as the capillary sysof,

583.

substance in epilepsy, 788. Brain substance in hydrophobia, in

morphine poisoning,

in neurasthenia,

710.

in strychnine in tetanus,

Bright’s

Amblyopia in acromegaly, 515. Amyotrophic lateral sclerosis, 515. Anmsthesla as a symptom of acro-

521,

of,

of

64.

action

tions of the,

toxics

tem 85.

Alcohol, action of, on neurons, 522. Alcoholic insanity, neurons in, 590. Alopecia, thyroid extract in, 734.

ing,

disintegration

as

and nerve substance organotherapy,

64.

prophylaxis and treatment of, 94. Adynamia, general, thyroid extract in,

ApiUhy’s

(See Exophthalmic

incomplete. (See Hgperthgroidia.) Basophile leucocytes, 680. Benign hypothyroldia, chronic. (See Hypothyroidia.) Bilirubin, formation of, 337.

circulation

Adults, adrenal hmmorrhage diagnosis of, 213. functional hypoadrenia in,

megaly,

plasma-channels,

562. of,

482.

retraction of

449,

goiter.)

233.

blood-platelets as droplets in

phenomena.

renals in production of varia-

tumors of, 8. Adrenoxidase and the motor nerves in their relation to muscular contraction,

as

Basedow’s disease.

30.

which produce congestion or venous stasis in the, 23. of,

515.

Bacteria, relations of, to liver. 341. Bacterial infection, adrenal extract

toxics

tuberculosis

765.

543.

131.

with

in,

452.

433,

17,

441.

and respiratory chemism, and the circulation, 18. malignant hypernephroma

ments,

leucocytes

as a symptom of acromegaly, thyroid extract in, 710.

6.

internal secretion of, action on the heart,

neutrophile

654.

Asthma, adrenal extract

126.

hffimorrhage into, in

Ascites, adrenal extract In, 762. Asphyxia, adrenal extract in. 764.

788.

poisoning,

kidney

disease,

Bromides, action

of,

Bronchopneumonia, in.

on neurons. pituitary

plasma-

channels, 540, .544, .568. vermiformis, functions

Appendix

in.

523.

extract

770.

renal insufficiency,

as

extract

Bronzing, a symptom of advanced ad-

578.

neuro-flbrils

788.

788.

784.

514.

neuron-gemmules dur-

788.

788.

515.

Bulimia as a symptom of acromegaly, 512.

of,

in

glycosuria,

363.

325.

Appetite, excessive, as a

acromegaly, In

glycosuria,

512. 363.

symptom

of

Cachexia parathyreoprlva. (See Ilypopnrathyroid tetany.) Cancer of the adrenals, 137.

793

INDEX. Cancer of adrenals, diagnosis

symptoms

of,

140.

adrenal

ex-

138.

of,

thyroid extract

in,

739.

727.

treatment of, 141. Capillary haemorrhage, tract in, 765.

Cardiac disorders, adrenal extract

in,

pituitary extract in, 767. sthenic, adrenal extract in,

adrenal

and

in epilepsy,

788.

in hysteria,

788.

in neurasthenia,

in

insuflaciency,

supply

of, 296.

nervous dual (See also Intes-

tines,

Liver,

Pancreas,

Stomach.) Diphtheria, pituitary extract

788.

spermin

in,

•

212

.

Drugs, morbid effects renals,

120.

in,

extract

hormone

chronic,

ther-

562.

of,

neuroglia-fibers as the capiliary sys-

tem of, 583. Corpus luteum extract

In

menopause,

778.

organotherapy,

etiology,

777.

193. 196.

of

young

in,

710.

extract

in,

children,

thyroid

extract

734.

in,

testicular extract in, 782. Effusions, adrenal extract in, 762.

Endemic cretinism,

196.

Enuresis, thyroid extract in, 733. Eosinophile leucocytes, 667. Epilepsy as manifestations of excess-

motor

ive

activity, 608.

cephalopin in, 788. kidney extract in, 783, 784. opocerebrin in, 788. thyroid extract in, 710, 716. Epinephrin, 751. Erysipelas, pituitary extract in, 770. Exanthemata, thyroid extract in, 711. Excessive activity of the thyroparathyroid disorders apparatus, due to, 212.

Exophthalmic

196.

pathogenesis pathology of,

of,

222

198.

body

In,

514.

sporadic, 197.

etiology

.

of,

223.

larval.

symptomatology

of,

193.

thyroid

in,

710.

extract

goiter, 214.

asthenic or myxeedematous stage

193.

posterior pituitary

treatment of, 198. Cretinoid pachydermia,

197.

(See Hypothyroidia.) pathogenesis of, 216. pituitary extract in, 772. posterior pituitary body in, 514. sthenic or first stage of, 217.

symptomatology Deafness as a symptom of acromegaly, 613.

thyroid

brain, substance in, 788.

764.

apy in, 790. Cord, minute anatomy

Cretinism, endemic,

chronic,

734.

523.

754.

adrenal

on the ad-

515.

Eclampsia, thyroid extract

Eczema,

790.

extract

of,

64.

92.

Cholera, spermin in, 782. Chorea, cephalopin in, 788. pituitary extract in, 773. Chronic benign hypothyroidia. (See Ilypothyroidia.) constipation, hormone therapy in,

from hmmorrhage,

39,

Dyspnoea as a symptom of acromegaly, 513,

prophylaxis and treatment of, Children, adrenal hoemorrhage in, diagnosis of, 123. Chloroform, action of, on neurons,

Constipation,

770.

Disorders due to excessive activity of the thyroparathyroid apparatus,

S3.

in,

in,

782.

212.

174,

tic, -788.

adrenal

and

Diseases of the adrenals, 56. of the thyroparathyroid apparatus,

788.

Cerebral activity, mania and, 572, 590. suhoxidation, melancholia and, 513. Cerebrospinal substance, minute circulation of, 562. system, general center of, 483, 591. Childhood, functional hypoadrenia of,

Collapse,

thyroid ex-

tract in, 734. (See Glycosuria.) Diabetes.

765.

513.

Cephalopin in chorea,

Dermatitis herpetiformis,

Diabetic coma, 363. apparatus, Digestive

757.

Catalepsy

Delusions as a symptom of acromegaly, 612. Dercum’s dfsease, thyroid extract in,

of,

216.

thymus extract

in,

786.

thyroid extract

In,

728.

of,

794

INDEX.

Exophthalmic

transition

goiter,

stage

221.

of.

treatment

Growth, stunted, pituitary extract

228.

of,

Haematoma, adrenal, Febrile infections, thyroid extract

in,

rickets,

tions,

Forme

cardiac

in

func-

421.

fruste de la maladie de Base-

dow. Fractures,

Functional

(See HypothyroUUa.) thyroid extract in, 710.

mechanism

activity,

of old age, 88.

prophylaxis and treatment of, 96. prophylaxis of, 89. treatment of, 89. Functions of the adrenals, 56. of the parathyroids, prevaiiing views

to

the,

formation of, 335, 339. molecule, formation of, in the

prevailing views as

nals,

formation,

its

347,

356,

Giycosuria as a symptom of adrenai insufficiency,

symptom ity,

as

363,

365.

of adrenal overactlv366.

a symptom of excessive formain,

Headache,

pressure

and,

Heart, accelerator phenomena

of,

of,

445.

active inhibition of, due to excessive vagal stimulation, 446. adrenal system In functions of, 11, *421, 433.

augmentor phenomena

of,

449.

foramina Thebesii in the functions 421,

441.

mechanism

functional

of,

452.

512.

of,

phenomena

of,

446,

452.

innervation of. 444. leucocytes and nutrition of, 441. fibers, inhibitor of non-existence nutrition

and the func-

substance

tions of,

433,

441.

“palpitations” of, 512, 515. Heart-failure, pituitary extract in, 768. surgical, adrenal extract in, 764.

Hormone

therapy,

366.

sis,

789.

constipation,

790.

in,

782.

(See Exophthal-

mic goiter.) in,

786.

Golgi’s fibers as plasma-channels, 585. Gout, testicular extract in, 782. (See Exophthalmic Graves’s disease.

paraly-

790.

in volvulus,

Goiter, exophthalmic.

thymus extract

441.

of,

occlusion, 790. in post-operative intestinal

76.

ptyalin and, 418. testicular extract

goiter.)

a source

as

512.

in intestinal

363.

drugs as a cause of, 362. non-convcrtcd sugar and, pituitary

plasma-channels,

568.

in chronic

tion of dextrose, 367.

coma

515.

as

fibers

oxidizing

360.

as a

736.

446.

607.

Glycogen and

in,

138.

sufficiency,

Haller’s

inhibitor

568.

extract

adrenal pseudocyst, 126. Hair, coarseness of, and adrenal In-

hypertrophy

143.

Gastric Juice, formation of. 297, 302. Gerlach’s fibers as plasma-channels,

Gigantism,

thyroid

Haemorrhage, adrenal extract in, 755. Haemorrhagic adenoma of the adre-

of.

143.

liver,

339.

Haemophilia, of

general, 233, 294. the brain versus retraction of the neuron-gemmules, 577, 578. hypoadrenia, 82. in the adult, 85. prophylaxis and treatment of, 91. in childhood, 83. prophylaxis and treatment of, 92. of infancy, 83. prophylaxis and treatment of, 90.

as to the,

distributed by the red corpuscles as oxidizing agent, 65.

335,

of

of the thyroid,

63.

as the oxidizing agent of the, 58. dissociation of, in glycosuria, 365.

205.

Foramina Thebesil

126.

Haemoglobin, adrenal secretion a constituent of,

738.

Fever, genesis of, 628. leucocytes in, 620. Fcetal

In,

773.

790.

Hyaline cells, 652. Hydrophobia, brain substance

in,

788.

Hyperadrenalisra. 115. Hyperadrenia, 115. acute, 116.

Hyperaemla, thyroid.

206.

HypertEsthesia, the posterior pituitary body and, 512.

Hypernephroma,

129.

795

INDEX. Hypernephroma, diagnosis

of.

132,

134.

malignant, of the adrenals, 131. of the kidney, 132. pathology of, 136. prognosis of, 137. treatment of, 137. Hyperthyroidia, 212. (Seo Iti/ftcrlhiiHyperthyroidism. roUlia.)

Hypertrophic rosacea, thyroid extract in,

(See AOOisou's

(See Ilypothyroidia.) Infancy, adrenal haemorrhage in, diagnosis of, 123.

childhood,

of old age,

in,

thyroid

83. 92.

Influenza,

90.

110.

symptomatology,

110.

of, 96.

446,

Insufliciency

(See

513.

in,

in,

pituitary

also

790.

cytogenous

tissue

of,

316,

of,

subepithelial

membrane

321.

functional

mechanism

of,

325.

pituitary

extract

in,

773.

of,

633.

thyroparathyroid apparatus

leucocytosis

In,

Kidney pituitary body as 624.

321.

143,

623.

the seat of the,

of,

minute anatomy of, 307. nervous supply of, 305, 326. phagocytes and their rOle in

the, 312.

prophylactic functions of, 309. secreting glands of, 308, 314. villi and lymph-follicles of, 314.

691. to,

center,

Thymus.)

790.

fenestrated

Cretin-

620.

Immunizing

420.

420.

321.

197.

620,

392,

pituitary extract in, 774. post-operative, hormone therapy

734.

698.

In,

(See Adrenals.) 362,

paresis,

general

relation

711.

700.

in,

adrenals in, 622. adrenal system as the foundation

its

in,

of

of the adrenals.

177.

of,

ism.)

in

19.

(See Thyroid.) Intestinal occlusion, hormone therapy

Myxccdema.)

(See

Ichthyosis, thyroid extract Idiocy and disease of the

leucocyte

stimulation,

the adrenal, 80, 115. Internal secretions and organotherapy,

Intestine,

Immunity,

nervous

452.

of the thyroid.

treatment of. 184. Hypothyroidism. (See II ypotliyroUUa .) Hysteria, cephalopin in, 788.

Imbecility,

770.

767.

of the spleen, 362, 392, of the thymus. (See

183.

myxoedematous,

extract

extract in, 711. pituitary extract in,

of the pancreas,

175.

symptomatology

bodies,

pituitary

770.

thyroid extract

183.

progressive.

201.

diseases,

Insanity, alcoholic, neurons in, 590. the posterior pituitary body in, 512.

tetany.)

of,

204.

poisons, venoms, and drugs in

Hypoparathyroid tetany, 741. symptomatology of, 742. treatment of, 744. Hypoparathyrosis. (See Hypopara-

of,

of,

Inhibitors of adrenal functions, toxins,

112.

Hypothyroldia,

90.

205.

large doses as, of,

of,

Inhibition, active, of heart due to ex-

109.

lliyrokl

Lorain type

cessive

prophylaxis and treatment prophylaxis of, 89. treatment of, 89. pathogenesis

83.

193.

Infundibular extract,

88.

treatment,

myxcedema,

Infantilism,

of, 94.

prophylaxis and treatment of, of infancy and childhood, 83. prophylaxis and treatment of,

etiology

II ypertliyrouUa.)

myxoedema.

Infectious

85.

prophylaxis and treatment

pathology

action of the,

of

Impotence, testicular extract in, 782. (See Incompiete Basedow's disease.

myxoedematous,

82.

in-

628.

Mongolian,

(Iiseti8C.)

terminal,

mechanism, mode

Infantile

in the adult,

of

prophylaxis and treatment

115.

80,

chronic progressive.

in

functions

center,

testine, 309, 322, 325.

functional hypoadrenia in,

735.

Hypoadrenalism, Hypoadrenia, 80.

functional,

Immunizing

extract,

703,

782.

Bright's disease, in chronic nephritis, in

784. 784.

796

INDEX.

Kidney in

extract, in epilepsy. 783, 784. intoxication, 784.

puerperal

functionai mechanism oi, 289, hypernephroma of the, 132.

organotherapy,

293.

Mammary

gland

fibroids,

extract.

in uterine Involution, 786. functional mechanism of, 280,

organotherapy,

782.

ism of, 266, 269. Lacrymation, pilocarpine and, 266. Lactation, mammary giand extract

in,

exophthalmic

(See

goiter.

classiflcation

eosinopbile,

functional

mechanism

immunity, and fever,

of,

776. 710.

Mental diseases, pituitary “xtract

In,

phenomena

of

acromegaly,

512,

514.

Migraine, thyroid extract in, 710. Milk, fluid portion of, as au immunizing serum, 311. Mitral disorders, pituitary extract

In,

768.

520, in,

523.

788.

Motor areas

691.

654.

physiological chemistry of, 647. relation to nutrition, organic func-

and immunity,

of gray substance as sensory areas, 508. nerves, an autonomous system, including vasomotors, 233. and glandular secretion, 262.

and muscular contraction,

233,

247,

of,

233,

261.

633.

Lifer the pituitary bodies as co-centers in sustaining, 483.

vasoconstrictor

function

261.

Liver, blood-pigments of, 334, 360. hepatic artery, functional vessel of,

Muscles

separate

with

supplied

not

vasoconstrictors,

253,

261.

in acromegaly, 514. adrenoxidase and the motor nerves in their relation

Muscular atrophy

326.

hepatic cell a miniature sponge, hepatic cell-canaliculi, 340, 360.

339.

minute anatomy of, 326, .360. pancreas and spleen, combined functions

in, in,

poisoning, brain substance

639.

620.

neutropbile, 653. in assimilation,

tions,

ovarian extract thyroid extract

Mongolian infantilism, 205. Morphine, action on neurons,

650.

of,

667.

in

of,

brain,

functions

483.

of,

Lungs, innervation of, 454. nervo-vascular mechanism of, 454. vagal system in functions of, 421. (See also Renpiration.)

Lupus, thyroid extract Lymph-follicles,

735.

In,

intestinal,

functions

of, 314.

Lymphocytes and hyaline

cells,

652.

Malarial fever, enlargement of spleen and adrenal overactlvlty, 332. Malignant hypernephroma of the. adrenals,

contraction, to,

233.

confusion

in

prevailing views

of.

236.

359.

physico-chemical functions, 326. Lorain type of Infantilism, 204.

131.

neoplasms, thyroid extract in, 711. gland extract in lact tion, 786.

In,

773.

543.

Ldpine’s glycolytic ferment as the oxidizing substance, 4U, 412. Leprosy, thyroid extract in, 735. Leucocyte granulations as secretory products, 644. Leucocytes, basophile, 680.

Mammary

Menopause, corpus luteum extract 778.

Lecithin as the active body of myelin,

Lower

782.

insufflciency, 513.

IlyperthyroUlia.)

534,

in,

Melancholia as a symptom of adrenal testicular extract in, 782.

786.

Larval

289.

785.

Marasmus, spermln

Lacrymal glands, functional mechan-

uterine

In

786.

process

functional

motor nerves and,

of,

261.

233.

source of chemical energy In. 239. hypernutrition and adrenal overactivity,

512.

weakness, action of drugs on adrenals in production of, 41.

and adrenal Insufficiency, Myasthenia, pituitary extract

613. in,

773.

thyroid extract in, 710. hulbo-spinal, ovarian extract in. 773. pituitary extract in, 773. Myelin and the functional energy of nerves, 534, 543. pituitary disorders,

Myocardial

tract

in,

ex-

768.

Myocarditis, chronic, pituitary extract in,

768.

Myopathies, pituitary extract

in,

773.

797

INDEX. Myosinogen, functions fiber.

muscle-

in

of,

261.

and the oxidizing substance, physiological chemistry

Myxoedema, etiology

185. 191.

of,

incomplete. infantile,

(See Ilt/pothyrokUa.)

193.

pathogenesis pathology of,

of,

191.

186,

Neutrophlle leucocytes, in

614.

Myxoedematous

653.

654.

cachectic stage of acro-

in

megaly,

514.

Nutrition, leucocytes in,

idiocy,

633.

197.

Obesity,

testicular

extract in,

782.

201.

diagnosis of, pathogenesis

thyroid extract

in,

724.

710,

204.

Obstetrics, pituitary extract in, 768. 201.

of,

symptomatology, 201. treatment of, 206.

Myxoedeme

assimilation,

Numbness

710.

in,

192.

of,

infantilism,

in,

186.

of,

thyroid extract

fatigue and sleep,

in

of,

522.

191.

symptomatology treatment

581.

579,

varicosity

.

pituitary body

posterior

234.

240.

of,

functional Neuron, lecithin, the ground-substance of, 557. lymph-channels of, 586. physiological chemistry of, 518, 552. physiology of, 519. transmission of vibrations between,

Eypothy-

(See

fruste.

roldia.)

Old age, functional hypoadrenia of, 88. prophylaxis and treatment of, 96. Opocerebrin in epilepsy, 788. Opsonins enhance phagocytosis, how, 696.

Narcolepsy

in

acromegaly,

513.

Nephritin,

784.

Nephritis,

chronic, kidney extract

in,

Optic atrophy in acromegaly. 515. Orchitic organotherapy, 780. Organic functions, leucocyte in its relation

633.

to,

784.

Nerve substance

in

neurasthenia,

of the action

organotherapy, 788. Nerves, myelin as source in.

534,

636,

energy

of

643.

physiological chemistry

of,

532.

Nervous diseases, pituitary extract

in,

773.

energy, source of, system, circulation in the,

533,

adrenoxidase

482.

general center of, 483, 591. Nervous system, including neurons,

composed of plasma-fibrils surrounded by myelin, 560. Neuralgia, adrenal extract in, 765. in acromegaly, 514. Neurasthenia, brain and nerve substance in, 788. cephalopin in, 788. pituitary extract in, 773. testicular extract in, 782. thyroid extract in, 710. Neuritis, adrenal extract in, 765, Neuroglia-cells as links between circulation and neurons, 570, 687. -fibers as plasma-channels, 539, 643. -fibrils of the brain and cord, their capillary supply, 582.

Neuron, circulation

of,

539,

659.

direct continuation of circulation some of its dendrites. 652.

functions of gemmules, histology of, 618.

Organotherapy.

677.

by

of,

700.

internal

secretions and, 700. Osteomalacia, thyroid extract in, 710. Osteomyelitis, thyroid extract in, 710.

Ovarian extract,

703,

775.

in

bulbo-spinal myasthenia,

in

menopause,

643.

536,

of

fundamental principle

preparations, 788.

organotherapy,

773.

776. 775.

Oxidation, thyroparathyroid apparatus in.

143.

Oxidizing substance and the digestive organs, 296. and glandular secretion, 262.

and myosinogen,

261.

as a reagent in all functional processes,

293.

Pachydermia, cretinoid. Pachymeningitis as a acromegaly, 515. Pancreas,

internal

197.

symptom

secretion

of

of,

362,

381,

385,

420.

functional

mechanism

of,

420.

in

the formation of glycogen, 356. the posterior pituitary body and, 513, 514. Paralysis agltans, parathyroid extract Paraesthesia,

in,

747.

testicular extract in, 782. Parathyroid extract in paralysis tans,

747.

agl-

798

INDEX.

Parathyroid organotherapy, 739. tetany. (See limMparathyrokl

Pituitary extract, tet-

the,

the,

the internal

secretion

Parry's

views

Exophthalmic

(See

disease.

696.

Phloridzin and glycosuria, active

as

lecithin,

363.

principle

of

processes,

center,

168.

posterior, as an aggregate of neu596.

as central sensorium,

598.

histology of, 493, 500. as general center of nervous sys-

tem, 483, 511, physiology of, extract.

591.

493,

large

in

doses

as

in,

770.

inhibitors

of adrenal functions, 19. Polydipsia in acromegaly, 515. Polyuria and adrenal insufflciency,

Post-operative

paralysis,

intestinal

hormone therapy

in,

790.

Progressive hypoadrenia, chronic. (See Addison’s disease.) hypothyroidia. yxo’dema .) (See Prurigo, thyroid extract in, 734. Pseudo-Graves's disease. (See Hyper-

U

thyroidia.)

Psoriasis,

testicular

thyroid extract

extract in, 782.

in,

734,

735.

in,

784.

Pulmonary system. Innervation

of, 454.

Rachitis, thymus extract in, 787. Red corpuscles as carriers of oxygen

supply the plasma its oxidizing substance, 247. Removal of the parathyroids only, 146. to

Renal extract, 703. nervo-vascular ism and, 454.

Respiration,

of,

453,

mechan-

454.

pulmonary, adrenal secretion

acromegaly, 771. disease, 770. in Addison's in bronchopneumonia, 770. in bulbo-spinal myasthenia, in cardiac

disorders,

in chorea,

773.

767.

myocarditis, in diphtheria, 770. in erysipelas, 770.

768.

exophthalmic goiter,

772.

in heart-failure,

in imbecility,

773.

in,

60.

Respiratory center, identity of, 454. disorders, adrenal extract in, 761. functions, adrenal secretion and, 453. system, innervation of, 454. Rheumatic pains in acromegaly, 512, 615.

in chronic

768.

diseases,

in Influenza,

770.

in Intestinal

paresis,

mental diseases,

Rheumatism, spermln

in.

chronic, thyroid extract

773.

in infectious

in

Poisons

physiology

591.

704.

in

in

767.

Pneumonia, pituitary extract

624.

body as the seat of thyroparathyroid center,

770.

Puerperal intoxication, kidney extract

593.

483,

phylogeny of, 491. body as the seat of the immunizing

rons,

in typhoid fever, organotherapy, 765.

512.

533.

as active principle of myelin, 543. nervous energy and, 533, 536, 543. posterior pituitary body and, 693. proportion of, in nuclein, 632. Pilocarpine and lacrymation, 266. and sweating. 279. Pituitaro-adrenal nerve, governing center of the adrenals, 70. Pituitary and giycosuria, 76. bodies as co-centers in sustaining vital

770.

in tachycardia, 768.

Pitultrln,

t/oiter.)

Peyer’s patches, function of, 314, 325. Phagocytosis, how opsonins enhance,

Phosphorus

pneumonia,

in shock, 768.

in tuberculosis, 770.

146.

of,

773.

in stunted growth, 773.

149.

functions of the, prevailing as to the, 143.

removal

of

773.

in obstetrics, 768.

in

147.

of

in myopathies, nervous diseases, 773.

in neurasthenia,

uiiu.)

Parathyroids, dual function theory of effects

in

770.

774.

782. 710,

729.

Rickets and adrenal insufflciency,

515.

in,

205.

foetal,

thymus extract in, 787. thyroid extract in, 710. Iligor mortis, nature of, 240, 244. Rosacea, hypertrophic, thyroid

ex-

tract in. 735.

773.

in mitral disorders, 768. In myocardial disorders, 768.

Salivary

glands,

ism

of,

functional

270,

275.

mechan-

INDEX.

799

of the adrenals, 137. Scleroderma, thyroid extract in, 735. Seborrhoea, thyroid extract in, 735.

Surgical heart-failure, adrenal extract

Seusorium commune,

Sweat-glands,

Sarcoma

adrenal extract

surgical,

Septicaemia, in,

598.

Shock, adrenal extract extract

in,

and

768.

in,

Addison’s disease,

in cholera,

in

insufficiency,

pilocarpine,

275.

in organic

of,

functions, 294. Syphilis,

spermin

thyroid extract

in, in,

and

782.

711.

acromegaly,

514.

in syphilis,

782.

adrenal secretion, action

Terminal hypoadrenia,

782.

in typhoid

fever,

pathogenesis

782.

(See also Testicular organotherapy.) Spleen as a leucocytogenic center, 333, in

of,

malarial fevers,

332.

mechanism

functional

of,

385,

389.

internal secretion of, 362, 420. post-prandial enlargement of, and adrenal overactivity, 332. Splenic vein, path for spleno-pancreatic

secretion,

Spleno-pancreatic

367.

internal

secretions,

on

of,

369,

392,

albuminoid

poisons,

404.

Sporadic cretinism, 197. Status hypoparathyreoprlvus. (See Ilypoparathyruid tetany.) parathyreoprivus. (See Hypoparathyroid tetany.)

Sthenic cardihc disorders, adrenal extract in, 765.

Stomach,

functional

mechanism

of,

296.

nervous supply of, 297. physico-chemical functions of, 296. vascular supply of, 300. Strychnine poisoning, brain substance 788.

Stunted growth, pituitary In, 773. Submersion, adrenal extract in, 764. Suprarenal. (See Adrenal.) apoplexy,

6.

hmmorrhage,

110.

of,

702.

782.

in glycosuria, 782. in gout, 782. in impotence, 782.

in melancholia, 782. in neurasthenia, 782.

in obesity, 782. in paralysis agitans, 782. in psoriasis, 782. 782.

organotherapy, 780. (See Spermin.) Tetania parathyreopriva. (See Bypoparathyroid tetany.) Tetanic spasm due to hyperoxidation, 234.

Tetanus, brain substance in, 788. due to adrenal overactivity, 234. thermal phenomena in, 234, 236. Tetany, hypoparathyroid, 741. thyroid extract in, 710.

Thymus

extract in diseases vt the thy-

roid,

in

786.

exophthaimic

in goiter, in rachitis,

in rickets,

goifi^r,

786.

786.

787. 787-

gland, adrenal system and the, 467.

organotherapy, 786. Thyroid, diseases of, in.

thymus extract

786.

dual function theory of the, 147. effects of internal secretion of, 148.

5.

Surgical diseases,

adrenal extract

in,

752.

disorders,

in eczema,

on, 66.

112.

of,

in tabes,

420.

362,

in,

treatment

of,

109.

110.

of,

symptomatology Testicular extract,

335.

enlargement

768.

Temperature, action of drugs on adrenals in the production of lowering of the, 49.

marasmus, 782. rheumatism, 782.

action

adrenal

Tabes, testicular extract in, 782. Tachycardia, pituitary extract in,

782.

782.

in diphtheria,

in

and

702.

in acne, 782. lin

764.

280.

275,

Syringomyelia

578.

577,

in,

mechanism

functional

Sympathetic nerve, role

3.

Skin diseases, thyroid extract in, 734. Sleep and cerebral ischemia, 626. retraction of the neuron-gemmules during,

adrenal extract

515.

764.

removal of adrenals and,

Spermin,

of,

Sweating

764.

pituitary

764.

in,

septicaemia,

thyroid extract

in,

737.

extract in adiposis doiorosa, 727. in alopecia, 734. in asthma, 710.

800

INDEX.

Thyroid extract

bone necrosis,

In

in cancer,

739.

in chronic

rheumatism,

711.

Dercum’s

710,

729.

disease, 727.

in eclampsia,

710.

chronic,

eczema

734.

734.

young

of

children,

734.

in enuresis, 733. in epilepsy, 710, 716.

in exanthemata,

in fractures, in goiter,

problem,

150.

as

710.

728.

404,

in ichthyosis,

711.

735.

malignant neoplasms, In menopause, 710. in

710.

spermin

710.

tract

in seborrhoea,

in,

in syphilis, in surgical in tetany,

Vaccines,

Vaporole,

711.

disorders,

in tuberculosis,

views

209.

symptomatology

of,

207.

treatment of, 209. organotherapy, 708. (See nypcrihuroidla.) Thyroidism. Thyroiditis,

chronic,

in cardiac functions, 421.

767.

pressure,

extract

adrenal

node

of 261.

of action. 255, 274,

294.

tem, 233. Impulses, the posterior pituitary as the source of, 597, 598. Venoms as inhibitors of adrenals, 19. morbid effects of, on the adrenals, 39,

Thyroparathyroid apparatus, diseases 212.

disorders due to deficient activity

54.

functions of, 314. Vital process, the pituitary bodies and, Villi,

174,

696.

Vasodilators,

206.

209.

of the,

gland extract

Vasomotor functions and adrenal sys-

206. of,

786.

mammary

and, 13. Vasoconstrictors as suljdivlslons general motor nerves, 253,

711.

functions of the, prevailing as to the, 143. diagnosis

Vascular

737.

711.

fever,

hypermmia,

711.

786.

Vagal system

734.

710.

in typhoid

in,

735. 735.

diseases,

in skin

in,

involution,

in rickets, 710. in scieroderma,

in,

its formation, 342, 346, 360. Uterine fibroids, mammary gland ex-

735.

734,

8.

Urea and

710.

734.

in psoriasis,

420.

782.

in,

thyroid extract

in osteomalacia, 710.

in prurigo,

369,

770.

in obesity, 710. in osteomyelitis,

404,

392,

pituitary extract in, 770. thyroid extract in, 711. Typhoid fever, pituitary extract

710.

in neurasthenia,

of,

,

Tuberculosis of the adrenals,

711.

in migraine, 710.

myxoedema,

764.

420.

cretion,

735.

in myasthenia,

thyroid extract

711.

.

711.

in insanity, 711. in lupus,

163.

which produce congestion of the adrenais, 23. Toxins, conversion of, into benign products, 369 392 404, 420. in large doses as inhibitors of adrenai functions, 19. Trypsin as the spleno-pancreatic se-

735.

734.

in infectious tonsillitis, in leprosy,

infectious,

cellular

of

Toxics

rosacea,

diseases,

in infectious

activator

phosphorus, 152. as Wright’s opsonin, Tic, cephalopin in, 788.

Toxaemia, adrenal extract In, Toxic albuminoids, reduction

710.

in hypertrophic

body as the seat

168.

secretion

in,

in haemophilia, 736.

in

of,

738.

adynamia,

in general

623.

pituitary

Tonsillitis,

711.

infections,

in febrile

immunity,

center,

herpetiformis,

in

143.

in

In dermatitis in eczema,

apparatus, in genoxidation and immunity,

eral

in cretinism, 710. in

Thyroparathyroid

intestinal

483,

593.

Volvulus, hormone therapy

In.

790.

of the, 174.

disorders due to excessive activity of the, 212.

thyroparathyroid opsonin, secretion as, 163.

Wright's

J

.>

A

I