THE PROBLEM OF REACTIVITY IN PATHOLOGY

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• Collection: General CIA Records
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• Document Page Count: 137
• Document Creation Date: January 4, 2017
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• Sequence Number: 14
• Publication Date: June 2, 1958
• Content Type: REPORT

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2 June 1958
THE PROBLEM OP REACTIVITY IN PATHOLOGY
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STAT
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THE PROBLEM OF REACTIVITY IN PATHOLOGY
Prdblema Reactivnosti v Pato1oi Edited by D. F. Pletsitiy
Moscow, 1954, pp 3-6, 9..33, p
95...99, 120-122, 1317132, 150-161,165-173,
213-225, 248-268, 322-330, 338-341
INTRODUCTION
This collection is dedicated to Academician A. D. Speranskiy on
his 65th birthday. The eminent Soviet scientists A. D. Speranskiy
student of I. P. Pavlov, is widely known to the scientific and med-
ical world as a very great pathophysiologist -- experimenter and
theoretician. His many years of fruitful investigation have, to a
great extent, made possible the success of the reconstruction of. Soy-
let medical science on the basis of the principles of Pavlovian nerv-
sim LEervizg.
A. boundless belief in the strength of progressive science, the
depth and definitiveness of his theoretical constructions, irrecon-
cilability to set-patterns and routines in scientific investigations,
daring and skill in the construction of his experiments, a keen power
of observation -- these are the things which primarily draw atten-
tion to the creative make-up of A. D. Speranskiy. As a real innova-
tor, he has always sought and continues to seek out unknown pathways
in science, opportunities for new generalizations, origins.), approaches
to the analysis of the very complex phenomena in the realm of patho-
logy and medicine.
After beginning his independent scientific activity more than a
quarter of a century ago, A. D. Speranskiy created his own defini-
tive trend in pathology. The sma.U. laboratory originally under his
leadership was, after several years,. converted into a large department
of the All-Union Institute of Experimental Medicine imeni A. M. Gor'-
kly. On the base of this department, the Institute of General and.
Experimental Pathology of the Academy of Medical Sciences USSR (haw,
the Institute of Pathological and Experimental Therapy) was Created
In 1944; A. D. Speranskiy continues to be its director to this day.
Hundreds of systematically performed investigations devoted to the
stuay of neural mechanisms of disease, recover and therapy, a series
of monographs by A. D. Speranskiyhtsself, which have exerted an im-
portance influence on the development of Soviet medical science, a
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series of new effective therapeutic methods, tens of masters' and doc-
torate theses -- this is a brief summary of the investigative work of
the scientific body headed by A. D. Speranskiy. It should be added
that the criticism of methodologically erroneous theories in medical
sciencq, developed under the guidance of A. D. Speranskiy, is to his
credit.
The authors of the articles published in the present collection,
the numerous students and co-workers of A. D. Sperandkiy along with
the entire scientific medical body heartily wish dear Aleksey Dmitri-
yevich health and new, great successes in his highly useful work
for the benefit of Soviet medical science on the occasion of his 65th
birthday.
This collection, which includes chiefly the work of co-workers of
the Institute of General and N rimental Pathology of the Academy of
Medical Sciences USSR, gives a fairly complete conception of the char.
eater and volume of the investigations being conducted in the Insti-
tute at the present time, and of the changes which have been made
here following the joint Session of the Academy of Sciences USSR and
the Academy of Medical Sciences USSR Dedicated to the Problems of the
Physiological Teaching of I. P. Pavlov.
As is well known) certain errors committed in the past by A. D.
Speranskiy and his students were sUbjected to criticism at this ses-
sion. They consisted, specifically, of a certain underestimation of
the role of the higher centers of the brain in the development and
elimination of pathological processes and in the inadequate anplysis
of the concrete physiological mechanisms through which the picture
of disease is mediated and. by which recovery is achieved. It may be
asserted that both the group headed by A. D. Speranskiy and he him-
self accepted this criticism properly and, have done much to surmount
the shortcomings in his work. The Ninth Session of the Science Coun-
cil on the Problems of the Physiological Teaching of I. P. Pavlov
noted in its resolution the successful course of reconstruction of
the work of the Institute of General and. Ekperimental Pathology.
The material presented in the present collection confirms, it seems
to us, the correctness of this evaluation of the activity of the In-
stitute. In contrast to the other publications of similar type,
which coMbins articles that are entirely different in their topics
and are in no way connected with one another, the present collection
is topical. Al]. the articles are dedicated to a single topic -- the
problem of reactivity in pathology. The scientific session of the
Institute of General and N .-rimental Pathology which was held at
the beginning of 1953, and which evoked the lively interest of the
scientific was also dedicated to this problem. A large portion of
the material presented at that session has been included in the pre-
sent collection.
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It is well known that the term "reactivity" introduced about 30
years ago has Obtained an unusually extensive distribution in patho-
logy and medicine.
It is revealing, in connection with this, that while in physiology
the development of the teaching about reactivity was indisruptibly
connected vith the intense study of the reactivity of the nervous
system (of neural tracts, centers and the nervous system as a whole),
in pathology reactivity was fora long time coneidered to be some-
thing independent, by means of which it was possible to explain
readily everything which had previously not been understood. It
became clear only comparatively recently that the analysis of the
phenomena belonging in the field ofp.tholwig, by means of the concept
"reactivity" does not transcend the bounds of phenomenology and is
purely formal in essence. The question arose as to the mechanisms
of reactivity of the complex organism, which is varied and changes
during the course of the disease.
At the present time, hardly anyone will dispute the neural nature
of these mechanisms. Nevertheless, such concepts, even very recent-
ly, were frequently considered to be unfounded in pathology and open-
ly hostile reactions were not uncommonly encountered. His consis-
tent and decisive defense of the idea of the neural origin of re-
actions determining the reactivity of the complex organism are to
the great credit of A. D. Speranskiy. Everything on which the group
led by him has worked in the past 25 years has in one way or another
been connected. with this cardinal question of pathology and. medicine.
Speaking of the neural mechanisms of reactivity, it should pri-
marily be kept in mind that the fruitful study of this problem is
possible only on the basis of the Pavlovian reflex principle. The
occurence of disease, the severity and characteristics of the disease
Process in the final Annlysis are determined by the character and
fate of the intermediate reactions developed. in the body under the
influences of a specific stimulus (the cause of the disease) and the
accompanying, preceding or subsequent, additional non..specific attn..
uli. Here, it should be kept lamina. that any direct influence on
a tissue is never limited to al:rarely localeffeet. It shccld be add-
ed. to this that the level of reactivity of the body, which is de-
termined, by the interaction of a very large number of reflex,reac-
tions, can be markedly altered. through a disturbance of the develop-
mental conditions of any one of them.
The difficulties of physiological analysis of the neural mechan-
isms of reactivity, therefore, are very great. The decisive role here
should naturally belong to experimental pathology. By consciously
simplifying the relationships, changing the condition of the body in
a desired direction, utilizing the rich arsenal of physiological and
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other special methods, it Caperimental patho3.og7 its even today in
a position to do much for the understanding of the mechanisms of re-
activity and, of the means of regulating it. Tae itvestigations of
I. P. Pavlov are exanples of this kind of work.
This collection, which is being brought to the attention of read-
ers, is of interest specifically from this point of view. Despite
the differences in the objects under observation and. the methods used.,
the investigations, the results of _which have been presented. in this
collection, supplement one another in a. manner of speaking. In some
of them the chief attention is given to a study of the role of the
lifferent portion of the nervous system in the development of the
pathological processes and. in the creation of immunity. Other work
has been devoted to an analysis of the significance of the central
nervous structures in disease arid resistance. Finally, the changes
are analyuldutich occur during the course of the disease and recovery
in the effector organs. Thus, all the links of the reflex arcs, along
which the reactions proceed. which create immunity, disease and re-
covery, and. which determine the level and, characteristics of reacti-
vity of the body, are brought into the sphere of the investigations.
In these investigations, questions of the interaction of the basic
pathological (specific) and the supplementary (nonspecific) stimuli
and of the significance of the time factor in the effect of each of
them occupy important places.
As the reader can see, the material which is included, in this col-
lection has been obtained, as a result of investigations performed with
the use of the most varied methods -- physiological, histological, bio-
chemical, serological, and. others. However, it is not their variety
which is most important here. It is significant that the majority of
the works wereeccomplished on the basis of a complex of different
methods, and that the method of physiological analysis is the nein
one in all the investigations. It should be. noted particularly that
in comparison with previous investigations of the Institute, signi-
ficantly greater attention has been given to the study of the part
of the higher centers of the nervous system, and particularly of the
cerebral cortex, in the occurrence, development aad outcome of patho-
logical processes, and in the reaction of the body to the effect of
extraordinary sttivii-f. This question has. been decided by different
means and by differint methodological approaches. The most important
of them is the classic method. of conditioned reflexes. Methods of
extirpation, oscillography, drug effects, histological and. biochem-
ical investigations of brain tissue were also used.
As a result, the physiological analysis of the processes under
study has undoubtedly become much more profound and precise. An
important index of this is the fact that tummy works the investiga-
tions have been brought to the stage where the results of them even
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at the present time can be directly useful for the practice of pub-
lic health.
It goes without saying there are still shortcomings in the acti-
vity of the Institute. The work presented in the present collection
is not devoid of them either, naturally. The authors of the works
here and the entire scientific body, of the Institute are very much
interested in the development of a principled working criticism of
the investigations carried out in the Institute. All comments on
this subject will be studied and considered attentively.
In recent years, the Institute has considerably .extended and
strengthened its connections with scientific-research and teaching
medical institutions of the periphery. Therefore, we felt it was
'ipossible to palish in this collection a series of works which
'have been carried out outside of the walls of the Institute but
which are similar in their character to those which are being car-
ried on in the laboratories directed by A. D. Speranskiy.
B. F. Pletsityy,
Doctor of Biological Sciences
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BRANCHES OF STUDY OF THE PHYSIOLOGICAL MECHANISMS OF ACTIVE
TIVES OF INCREASING ITS EMCMINEsS
DtlitszAsTort AND ME
" 'X*: ? Dr
A. Ya. Alymov and D. F. Pletsityy
Laboratory of the Physiology of Immunity Weed -- Professor A.
Ya. Alymov, Corresponding Venter of the Academy of Medical Sciences
USSR)
The problem of immmnity to infectious diseases occupies one of
the central places in pathophysiology. The question of the mechan-
isms by means of which the state of immunity is attained is, in its
turn, most important here, because a profound penetration into its
inner essence is the most reliable approach to the regulation of
immunity.
Undoubtedly, among the reactions which assure the creation of im-
munity., the chief significance belongs to those which alter the sen-
sitivity of the body itself. These reactions are frequently not con-
nected with any changes in the indices of the so-called anti-infecti-
ous immunity (phagocytosis, antibodies) and consist of the rapid
functional reconstruction of the body which returns it to the state
of equilibrium with the disruptive conditions of the environment.
These protective reactions of the body to the antigen are essenti-
Oly no different from reactions to other stimuli and rather repre-
sent a category of processes Characterizing the normal activity of
the body, because reasons for their occurence and development are
constantly encountered. As far as the nature of these reactions is
concerned, no doubt exists; there is hardly anyone at this time who
would dispute their neural origin.
The study of the neural mechanisms of immunity, begun by Academic-
ian A D. Speraraskiy about 2, years ago, is proceeding successfully,
especially in recent years, by virtue of the complete victory of Pay-
lovian teaching in Soviet physiology and medicine. However, the.num-
ber of works devoted to this subject are still not so great as night
be expected. The attempt of investigators to understand the evaluate
the part of cortical merhanisms in the development of ton-specific
immunity (which cannot be connected. with the activity of special anti-
infectious adaptations) is particularly valuable.
Ixtdisputably, real progress in immunology is possible specific-
ally along this line -- the branch of knowledge concerned with the
mechanisms of the adaptative reactions of the complex organism to
existence under conditions of prolonged or brief contact with the
causal organisms of infectious diseases.
Up to the present time, a larger part of the investigations has
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been devoted, to a mare specific problem -- specific prophylaxis of
infections by means of so-called active immunization.
An is well known, the stuay of vaccination was begun at the time
of the excellent discoveries of (leaner and. Pasteur. Later, work
was conducted basically in the direction of the widest application
of this method of prophylaxis and of increasing its effectiveness by
means of obtaining purified antigens and simplifying the method. of
immunization. Progress hare has been considerable. We need mention
only the fact that, thanks to the use of active immunization, the in-
cidence an1 mortality rate of smallpox, diphtheria, tetanus and a
number of other infections have dropped sharply.
At the same time, it should be noted that the development of the
theory of active immunization for a long time proceeded almost ex-
clusively according to the plan of the simplified conceptions of
Virebow and. Ehrlich.
The mechanism of active immunization has been summarized as being
simply an accumulation of specific antibodies and. an increase of the
phagocytic activity of elements of the reticulo-endothelial system.
The effect of the antibodies, particularly of the antitoxins, was, in
its" turn, considered to be most elementary: their role was reduced
to the neutralization of the microbial toxins, in the same way that
base neutralized acid in the test-tube.
I. I. 14echnikov was the first who came out decisively against
this vicious systeaof views. He justifiably asserted that immunity
which is created as a result of active immunization is a very comp-
lex phenomenon, and be pointed to the importance of a change in the
sensitivity of the body in this process.
In accordance with the state of the theory, a set pattern and rou-
tine prelfailed in gi7ing the inoculations. This was note4, for exam-
ple, in,a completely identical approach to the development of methods
of immunization against different infectious diseases;
Nevertheless, this empirical work of many years' duration made
possible the demonstration of a number of specific rules and. regula-
tions and the accumulation of a large number of facts which were of
essential significance for the elucidation of the mechanisms of ac-
tive immunity. Only relatively recently has a departure come about,
among the majority of immunologists, from the traditional but extreme-
ly erroneous schemata of Virchow and Ehrlich by virtue of the develop-
ment of citticism of Virchovian ideas in pathology and the gradual
assertion of the basic principles of the teaching of I. P. Pavlov.
An attempt eras evidenced among Soviet investigators, as P. F. Zarod-
ovskiy said, to see a reflection of the general rules and regula-
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tions of nervous system activity established. by I. P. Pavlov, N. Ye.
VVedenskiy and. A. A. Ukhtomskiy in the special rules and regulations
of immunogenesis.
It would be incorrect, however, not to mention that there were in-
vestigators among the Soviet Pathophysiologists and immunologiets
who, in their creative research in the field of immunology, had been
guided. by the basic postulates of the teach of I. Pt Pavlov long be-
fore the combined session of the two academies gcademy of Sciences
and Academy of Medical Scienceg. Aside from A. D. Speranskiy and
his studento, G. V. Eygoichikov, A. D. Ado, N. V. Puchkov, A. N.
Gordiyenko and others should be named here.
It must be granted that although the great majority of investiga-
tors who are devoting themselves to the study of the problem of active
immunization now have the proper methodological attitudes, neverthe-
less, in the evaluation of a. number of questions of principle there
is still no unanimity of opinions, and a certain theroretical dis-
persion is occurring. Numerous cases still exist where the authors
have limited themselves to a purely declarative acceptance of the
teaching of I. P. Pavlov.
Tae present communication is devoted to certain theoretical gener-
alizations and factual data on the problem of active immunization
which have been obtained in the Laboratory of Physiology of Immunity
of the Institute of Genetal and Experimental Pathology of the Acad-
emy of Medical Sciences USSR.
The\txperimental material was obtained. by D. F. Pletsityy, L. L.
Averiyanova, R. Ya. Zellmanovidh, V. D. Kucherenko.
As is well known, the prototype of immunity created under the in-
fluence of artificial active immunikltion is post-infectious immun-
ity, which is different in intensity and duration for various dis-
eases. This circumstance is often forgotten, although it serves as
the starting point for very important conclusions. As a matter of
fact, the specific mechanisms of development of individual infecti-
ous diseases are different, and, accordingly, the immunity occurring
in these diseases is alio different.
AL physiological study of the mmehanism of the immunizing effect o
indiVidual antigens is Unthinkable except on the basis of a thorough
knowledge of the mechanisms of the development of the corresponding
infectious diseases. The particular rules and. regulations of immun-
?genesis after the injection of various antigens differ from one
another to the same degree as do the pathogeneses of thi correspond-
ing diseases. It seems indUbitable, for example, that inadequate
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progress in the matter of the specific pregylaxis of typhoid and dy-
sentery are explained primarily by the lag in the study of pathogen-
esis of these diseases.
True, a small-scale reproductiod of the specific disease picture
(for example, in anti-smallpox vaccination) occurs in a number of
cases in the course of ummunogenesis after immunizations with live
vaccines. However, even here, a knowledge of the fine mechanisms of
development of the pathological progress wouLi undoubtedly make pos-
sible an improvement in the methods of immunization.
The investigation of the pathogenesis of individual diseases, like
the study of the mechanisms of immunogenesis, can be effective only
under the conditions of physiological analysis of these processes.
The theoretical basis for such an analysis should be the principle pf
nervism, the Pavlovian reflex theory. A study of the time factor and.
of the role of the site of application of the antigen are, in their
turns, of quite considerable interest in the system ;of investigations
of the mechanisms of development of disease and immunogenesis on the
basis of the physiological teaching of I. P. Pavlov.
It is well known that one and the same stimulus produces reactions
which are different in intensity and in foruidepending on the place
where it is *acting in the body. This difference is maintained even
when the stimulus acts a long time and even where, in time, it en-
ters the general circulation. Therefore, the process which arises
at the very beginning of action of the stimulus is particularly im-
portant and exerts a long and strong effect on the subsequent state
of the body.
A. M. Bezredka was the first investigator who gave special atten-
tion to the role of the site of application of the antigenic stimulus
in the development of active immunity. His ingenious experiments in
this direction are widely known. However, the error of the theoret-
ical starting potato of A. M. Hezredka, which are based on concepts
of tissue, cellular reception of antigens, finally brought his inves-
tigations into a blind alley.
A. D. Speranskiy propounded a new idea with regard to this question,
espousing the belief of the neural reception of antigens in the com-
plex organism. The accuracy and fruitfulness of this approach can
hardly be disputed.
Our investigations, which are devoted to the study of the role of
the site of application of the antigenic stimulus, are connected with
the study of tetanus.
In experiments on rabbits it has been established that a necessary
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condition for tetanus is the action of threshold doses of tetanus tox-
in on the neuroreceptor structures of skeletal muscles. In those
cases where there are no such conditions, for example, after the in-
jection of a lethal dose of tetanus toxin subcutaneously in the upper
part of the ear or into A-.-skin flap, tetanus does not occur.
The neuroreceptor apparatus of skeletal muscles is, thus, a speci-
fic system/ in its own way, with respect to tetanus toxin.
On the basis of these data it might be expected that the stimula-
tion produced by tetanus toxoid. would also be most effective after
intramuscular injection.
Experiments were done on rabbits. The animals of the control group
were immumized by means of the subcutaneous injection of tetanus tox-
oid; the toxoid was injected into the experimental rabbits intramusc-
ularly. For the rest, the experimental conditions were similar ;or
both groups of animals.
Immunization was accomplished according to the following outline.
First, the rabbits were injected with two cubic centimeters of toxoid
each; then, after three weeks, a second injection of the toxoid in a
volume of one ethic centimeter was given. After 45 days, the animals
were revaccinated by means of the injection of one ethic centimeter
of toxoid.
The dynamics of the immunity were evaluated according to the anti-
toxin level in the blood of the animals. Blood for determining the
antitoxin titer was taken at the following times: before the onset
of the experiment, 21 days after the first injection of the toxoid
(directly before the second inoculation), l4 days atter the second
toxoid injection, before revaccination and 14 days after it. The an-
titoxin content in the blood serum was calculated according to the
usually accepted method.
The results of the experiment showed significantly higher con-
tents of antitoxin in the blood of the experimental animals (which
hadLbeed injected intramuscularly with toxoid) than in the control*
(which had been immunized subcutaneously). The titer of tazoid in
the blood of the experimental animals after the first immunization
was five to ten tines higher than in the control animals; after re-
vaccination, on the average, twice as high.
Similar experiments were recently performed by us on monkeys.
These experiments confirmed the results described above. The question
of the intramuscular immunization of people ip tetanus comes,up, be-
cause the methods of immunization accepted at the present time cannot
be considered theoretically well grounded or maximally effective.
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Similar work on the review of immunizaticonehods which are firm-
ly included in anti-epidemic practice (with an account of the charac-
teristics of the pathogenesis of the infections) is also beins con-
ducted bycther authors. Thus, the data of N. A. Nhaelichenok de-
serve attention, namely, that in experimeats on rabbits the injection
of diphtheritic toxoid into the area of the lymphoid pharyngeal ring
of Pirogov gal4myer's ring shows a distinct advantage over the sub-
eutaneous route. These data have found confirmation in the therapy
of ?people (Ni. A. Khmeltchenok).
Indirect proof of the accuracy of this point of view concerning
the correlation of specific rules and regulations of immunogenesis With
the mechanisms of development of corresponding diseases has been fur.
nished by our experiments on the study of the characteristics of the
reactions of immunity et different ages.
, Here also the principle of the investigations is connected with
the experimental material attained in the snAlysis of the pathogenes-
is of tetanus. Mice and rabbits which are born with inadequately de-
veloped nervous systems do not show the clinical picture of tetanus
in the early stages of postnatal ontogenesis. The typical reaction
to the effect of tetanus toxin is established in tlumlyith the deve-
lopment of the nervous system -- the inclusion of afferent systems,
the establishment of reciprocal relationships in the central nervous
system and the development of complex forma of reflex activity. In
animals born with relatively well developed nervous systems, those
capable of independent life beginning with the first few days (guinea
pigs), the typical monifestations of tetanus can be found inmediately
after birth.
It turned out that the immune reactions of the animals undergo
exactly the same evolutio4 in the course of ontogenesis. Newborn
rabbits, for exempla, are completely inert in, the immunological sense.
No significant accumulation of antitoxin occurs in the blood of these
aninale following the effect of parenteral injections of tetanus tax-
old, and no tomeicslogAcal reconstruction of the body ewes about.
With age, as the nervous system is developed, parallel with the deve-
lopment of the capacity for reproduction of the specific reaction to
the administration or tetanus toxin., the immunological reactivity of
these animals is increased end. at the end of the first month of life
attains adult levels. Guinimpigs, right from the first few days of
life, are no different from adults in the inmuncaogieal sense.
As has been seen, even in ontogenesis the development of the mech.
animus of disease and immunity proceed in parallel, which once again
emphasizes the capacity of mutual conditioning of these processes.
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Investigators working in the field of practical immunology have
long noted the tremendous importance of the time factor in the de-
velopment of active immunity.
The essence of the matter here consists in 'the fact that even a
single antigenic stimulation leaves a stable trace in the body, which
is cometimes maintained for life. The duration of this residual re-
action undisputably points to the fact that the keeper of it is the
nervous system. Frequently, a second immunizing stimulus not only
completely restores the reaction which had been extinguiehed with time
but also notably increases it,gometimes by many times. Therefore, we
are dealing here with a purely physiological phenomenon, which has re-
ceived the name summatio#. The result of the interaction of the two
immunizing stimulations is dependent primarily on the duration of the
interval between them. Careful study of this subject by P. F. Zdrod-
ovskiy has given appreciably practical results. The so-called law of
intervals was formulated which to a certain degree has made possible
the elimination of empiricism in immunization.
It is impossible to avoil seeing reflections of general laws of
dynamics of neural excitation, which-were established, by H. Ye. VVed-
enskiy, in these rules and regulations of immunology; in both_plaees,
the reactions to simulations are determined primarily by the-prpper-
ties of the preceding stimulation and by the period whichkas elapsed
since the time of its application. With such an approach, the reacti-
vity of the body ceases to appear as a mecbnpism which has been set
once and for all, but appears rather to be in a shifting category
which is continuously changed throughout life.
However, for a long time one circumstance made it possible for
opponents of the physiologieal trend in immunology to object to the
ideas of I. F. Pavlov, N. Ie. VVedenskly and A. A. Ukhtomekiy in
the analysis of the rules and regulations of active immunity. The
objection consisted in the fact that the usual physiological'reac-
tions progress vary rapidly, while immunological reactions require
long intervals of time for their accomplishment.
The lack of a sound basis for these objections is obvious. It is
well known that many physiological processes, for example, the forma.
tion and reinforcement of the conditioned reflexes, are also develop-
ed over long periods of time. However, it seems most improbable that
the development of immunological reactions could not be recorded in
short periods of time (with which physiology ustin)ty deals).
We also occupied ourselves with the elucidation of the dynamics
of Immunity several years ago. At the sane time we set before our-
selves the task of progressing toward the understanding of those in-
terrelationshipe'which are constructed in the processe elaboration
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of active immunity between immunity proper and antibody-formation.
Our first investigations were devoted, to the analysis of the
physiological essence of the so-called negative phase of immunity)
the presence of which has long been noted by a number of authors in
the early stages of development of active immunity. We performed
two series of experiments here.
In the first of them, mice served as the experimental animals.
The dyiaamics of anti-tetanus immunity was investigated in them fol-
lowing a single and a repeated (at interval of 10 days) immunization
with tetanus toxoid.
The degree of inmmitrwas evaluated on the basis of the surviva-
bility of the enirala following the injection of a single lethal dose
of tetanus toxin after a single iimuniiirtio6 or of two single lethal
doses following a double immunization. In addition, account was tak-
en of the times of onset of tie disease, its duration, and also the
intensity of the smnifestations of tetanus. The dbeervations were
oonducted for a period of 10 days after the first and. second injec-
tions of toxoid. Every day, one group of mice was investigated) so
that the possibility existed of observing the development of immunity
day after day for ID days after the first and second inoculations.
These experiments showed that the response of the body to the im-
munizing stimulus is of a complex phasic character. The level of im-
munity created fluctuates periodically: the phases of definite im-
munity are replaced by periods immunological depression ("negative
phase"). It turned out that the curves depicting the dynamics of im-
munity following single and double immunizationolof the ertIma's were
basically unitypical, even though they proceedecton different levels.
In evaluating these data from the point of view of physiological
concepts, the phasic character of the development of immunity should
apparently be regarded. as a manifestation4 the dynamics of the spec-
ific neural process. In doing this, the negative phase, ceases to
appear as an accidently and paradoxical phenomenon but is seen as a
regularly repeated stage of development of the state of immunity.
Analogous experiments have bean done on rats with the difference,
however, that investigations were also conducted of th4 antitoxic pro-
pertios of their blood in parallel with direct determinations of the
immunity of the animals at various times after single and double in-
jections of the toxoid.
In the first of these experiments, which was performed on 600 rats,
account was taken of the dynamics of immunity to a lethal dose of
tetanus toxin and. of antibod,y-formation in the Animal, on the first,
tenth, twelfth and fifteenith days after the administration of one
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cubic centimeter oitetanus toxoid, In the second experiment, in
which 600 rats were also utilized the dynamics of immunity to the
two lethal doses of tetanus toxin were studied at the same intervals
after the second injection (10 days) of toxibid (twice, using 0.5
cubic centimeters each time).
It was shown that the survival rate of animaln following injec-
tions of one and of two lethal doses of tetanus toxin in singly and
doubly immunized animals is affected in the same way as in the ex-
periments on mice. Here also, the periods of increase in immunity
were regularly replaced by periods of decrease of it, although after
a second injection of the toxoid the general level of resistance is
increased.
The second experiment showed a definite lack of correlation be-
tween the degree of immunity of the PntmAls aad the content of tetan-
us antitoxin in the blood. The titer of antitoxin in the blood of
the animals is, for a certain period of time, directly dependent on
the time which has elapsed since the day of immunization. No such
correlation could be found. with respect to resistance (immunity ;To-
per). For example, on the fifth dayarter the seconi injection of
toxoid, the content of antitoxin in the blood, was equal to 1/300 anti-
toxin units, while the survival rNte of the rats after the injection
of two lethal doses of toxin was 76 percent. On the seventh day, with
the same antitoxin titer only 11.2 percent of the rats survived. Oa
the 10th day the amount of antitoxin in the serum reached 1/100 anti-
toxin units, whereas the survival rate dropped to 62 percent compered
with the fifth day.
On the basis of these data -which establishe the wave -form course
of the process of development of active immunity, it might be possible
to anticipate the presence of phasic changes of immunity at small in-
tervals of time, measurable in hours, minutes and. seconds. The ex-
periment was performed on 600 rats. The animals were immunized twice
with tetanus toxoid. according to the same plan as was used in the
preceding experiment. later, the animals of each group were inject-
ed with.two lethal doses of tetanus toxin directly after the second
injection oftemoid at one, five, 12, 16 hours and. finally,' after one
day. Before each injection of toxin the antitoxin content in the
blood was determined in addition to keeping a record of the survival
rate of the RniAm3s.
As the results of this experiment showed, the immunity Of the ani-
mals increases sharply immediately after the application of the sec-
ond immunizing stimulus, becoming much greater than in the control
rats, which had been immunized once.
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After an hour, however, a notable decrease Of the intensity of
the immunity occurs, and after five hours it becomes almost two times
weaker than in the first minute after the second injection of toxoid.
At 12 hours, the resistance reaches the initial levell becoming equal
to the immunity ofonce-immunized animals. Sixteen hours after the
second immunization, a small decrease is again noted in the degree
of immunity, which at the end of the day is replaced by an increase
in it.
As might have been expected, the fluctuations in the strength of
the immunity of the animals in these short periods was not accompanied
by changes of the figures of antitoxic activity of the blood. The
antitoxin titers of the blood sera of the animals remained unchanged
for the entire experiment and were equal to 1/300 antitoxin unit.
The most important conclusion which should be drawn from the re-
sults of this experiment is that the immunity of tintre)R can be
changed instantaneously through the influence of an immunizing sti-
mulus.
On the basis of the experbments.presented above, the following
conclusion may dustifiably be drawn. The condition of immunity which
is developed through the effect of immunizing stimuli (active immuni-
ty) is the result of a specific reconstruction of the entire body,
the final expression of which is the creation of anew, as a whole
higher, leveLor resistance and of immunological reactivity. The ac-
cumulation of specific antibodies is only one of the manifestations
of this reconstruction thereby, even in the event we are dealing
with the special form of immunity which has received, the name anti-
toxic immunity. Therefore, the non-specific (not associated with
phagocytosia and antibodies) component of immunity is, as has long
ago been stated, by A. D. Speranskiy, predominant in the mechanism
of the so-called active artificial immunity.
In connection with the results of these experiments which show
that the reactivity and the immunity of the body can be altered in
very short time' intervals, we set about developing methods of active
immunization, new in principle.
If immunity and the reactions of immunity can be altered in very
short pettods of time through the influence of a specific immunizing
stimulus, it means that it can also be changed in the desired direc-
tion by artificial means in the same periods of time.
The data of our experiments give evidence to the effect that with
the proper intervals between inoculations and a definite nuiber of
inoculations the entire immunization cycle melba limited to several
hours.
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ggiemine??????=1/4
The immunity of rats and rabbits immunized lby,this accelerated
method did not lag behind the resistance of control animals which had
been vaccinated according to plans adopted in immunization of groups
of people using many-day intervals between antigen injections.
Recently, we made the same Observations on monkeys. just as in
the experiments an rats, so in the case of monkeys we studied the im-
munity to tetanus which was attained by immunization of the animals
with tetanus toxoid. Sim4ar results were Obtained recently also
during the utilization of the method of accelerated immunisation for
the creation of active immunity against dysentery (experiments on rab-
bits).
On the basis of the orientation experiments, it req be thought
that the use of the plan of accelerated immunization developed by us
might be effective also in those cases where they arm carried out on
a background of an infectious process which has already begun. We
have used these methods successfully some time atter injecting ani-
mals with one or two lethal doses of tetanus toxin*
A single injection of tetanus toxoid does not exert any effect an
the development of tetanus intoxication, whereas the fractional ad.-
ministration of this dose according to a definite plan often gives pos-
itive effects. This permits us to hope for the possibility of utiliz-
ing tetanus toxoid as an agent for the specific therapy of tetanus*
It seems to us that the most important task confronting immunology
today is a concentration of efforts for the future development of ra-
pid. and reliable methods of immunization which do not require many-
day intervals between inoculations. The data presented. thowiwomibe
forinvestigativerdsearch in this:direction.
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THE ROLE OF NERVE-
'404 50.
MECHANISMS IN THE FORMATION OF
METHOD'S'S
Professor G. V. Peshkovskiy
The Molotov Scientific-Besearch Institute of Vaccines and Sera
I. I. Mechnikov emphasized the importance of humoral factors in the
formation of acquired immunity. (I. I. Mechnikov, Immunity in Infec-
tious Diseases, Medgiz, 1947, p 309).
HUmoral phenomena in acquired immunity are expressed as the appear?
ance of specific antibodies in the blood serum. The antibodies are
not the chief nor the only cause of acquired imunity, and the mech-
anism of their action cannot be reduced to the antigen-antibody re-
action. However, the prophylactic and therapeutic significance of
immune sera cannot be disputed, and, therefore, the stuay of the phys-
iological mechanisms of their formation aad the search for methods of
increasing their effectiveness remain important problems of immuno-
logy.
The study of the physiology of acquired immunity in the portion of
it which is associated. with the formation of antibodies has, in our
opinion, three basic aspects; first, the investigation of the inti-
mate biochemical essence of the processes of interaction of the anti-
gen and the fermentative systems of the cellular elements of the mac-
eophage system as a result of which the protein complexes are formed
which play the part of the antibodies: secondly, the investigation
of the physiological trigger mechanisms of the formation of antibodies
and, fir/Oly, the physiological mechanism of their preventive and
therapeutic effects.
Until recently, the investigation of these problems was made from
the standpoint of the cellular pathology of Virchow',. while the forma-
tion of antibodies was regarded only as the result of the purely di-
rect contact of the antigens with the cellular elements. Ehrlieh's
ingenious hypothesis of "side-chains" reigned in immunology, and the
mechanism of action of prepared antibodies injected into the body
was regarded from the point of view of the antigen-antibody reaction.
Nevertheless, the penetration of the infective nidus into the body,
or the administration of antigen, with the aim of creating artificial
immunity leads to the development of a series of complex reflex re-
actions in the body.
BOwever, until very recently the reflex mechabism of the reactions
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to the antigenic stimulus was stubbornly ignored, although it is hard
to understand how the stimulus can miss the nervous system, which re-
acts most quickly and precisely to any stimulation and produces the
corresponding effect. In 1937, A. D. Speranskly wrote, "It is dread-
ful to contemplate what would have become of physiology if nerve in-
fluences had, been excluded from the processes which it studies so
persistently as they have been excluded from pathology until recent
years." (A. D. Speranskiy, Elementy postroyeniya teorii meditsiny
(gLemmxts of Construction of a Theory of Medicine) published. by VIEM
ell-Union Institute of EXperimental Medicine, 1937$ P 328). The
role of nerve reflex mechanisms in the pathogenesis of infection and
in Lassunogenesis have been extensively shown by facts obtained in
the laboratory of A. D. Speranskiy.
Despite this, the conception of the leading role of the nervous
system in immunogenesis has still not found universal acceptanee.
In the present work dataare being presented. of complex investiga-
tions which were devoted to three subjects: 1) the influence of cor-
tical regulation on the formation of serum antibodies, 2) the role
of the nerve reflex component and the receptor zone of the primary
application of the antigen in the formation of antibodies, and 3)
the elaboration of antibodies under the influence of chemical fac-
tors of nerve excitation.
The works of co-workers of A. B. Spernaskiy's laboratory (I. P.
Bobkov and. A. L. Fenelonov A. L. Fenelonov, A. V. Ponamarev, S. I.
Lebedinskayal 0. Ye. Ostryy, A. Ya. Alymov, D. P. Pletsityy) showed
the influence of the primary site of application of the antigenic
stimulus on the character of development of the infectious disease
and the formation of immunity. Based on the work of the authors
named, we investigated this subject through the examples of the
eregtion of immunity following vaccinations against rabies, tetanus,
and dysentery.
In the experiments of 70. I. Kurbatova with anti-rabies vaccina-
tion the previous data of Akker were confirmed, to the effect that
the intracutaneous administration of antirabies vaccine in the Fermy
method produces the strongest immunity, which sets in after shorter
periods than with subcutaneous vaccination. Experiments were per-
formed on a large nuMber of rabbits. It turned out, therein, that
as early as 10 days after the conclusion of the intracutaneous vacci-
nation the rabbits survived subdural infections with 10 lethal doses
of fixed virus, The rabbits which had. been given the vaccine sub-
cutaneously withstood. no more than two to five minimal lethal doses,
even 30 days after the conclusion of the immunization. It is very
interesting that inoculations of Philips' vaccine by the intracut-
aneous Method did not give better results than were obtained. by sub-
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cutaneous injections. The strength of the immunity and the periods
of its development were in this case no different from the results
of the subcutaneous inoculations given according to the Fermy method.
It was not possible to raise the degree of immunity by an additional
intracutaneous injection of phenol in the capacity of an additional
otinulus. The experiments of A. K. Volchikhina with anti-tetanus vac-
cination gave analogous results,
In the experiments of A. K. Volchikhina, another law was shown
clearly. It appeared that with very large doseo of toxoid (up to 13
cubic centimeters) and short intervals between the injections the
differences between receptive zones levelled off, and the creation
of antitoxin decreased. significantly.
Taos* data coincide with the data of the investigations of P. F.
Zdrodovekiy's laboratory; P. P. Zdrodovskiy showed the significance
of summation of the inmunogenie stimuli and the phenomena of the so..
callei worst suppression of ismunogenesis after subcutaneous immuni-
zation. It must be supposed that an aptimam frequency and strength
of the inmunogenic stimulus exists for each receptor zone, which is
determined. by the physiological lability of the given sense organ
and its relationship to the effector organs of innunogenesis.
With immunizations by corpuscular vaccines, the optimal receptor
zones maintain their significance, but here they are different.
Taus, in the experiments of E. V. Konovalov and T. A. Solov'yeva, who
used single inmunizations of rabbits with heat-killed dysentery vac-
cine prepared. from the Flexner dysentery strain NO 942 00, it was
established that the highest titers of agglutinins are seen atter the
injection of the vaccine intravenously, somewhat smaller ones after
injections int the eapsule of the knee joint, considerably lower ti-
ters atter subcutaneous injections, and the lowest, atter intraperit-
oneal injections.
At the save time, in the still uniinished experiments of T. A.
'EUkharava the best effect in:Immunizing against gas gangrene was
with vaccination into the joint, and the poorest, with intra-
venous administration. Naturally? the question arose: to what extent
does this difference depend on the properties of the receptor zone
specifically and the characteristics of the reflex mechanism in each
individual case? With the aim of deciding this question, E. V. Kono-
valov and. T. A. Soloviyeva performed experiments on the study of the
dynamics of immunity after vaccinations in a denervated joint and in
a joint, with an intact innervation.
Denervation of the joint was accomplished by means of transaction
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of the aciatic anl femoral nerves and smearing the blood vessels with
ammonia.
For the purpose of exCluding the effect of the operation itself on
immunogenesis, the denervations of the joints were performed in all
the experimental and control rabbits. The vaccination was performed
in the experimental rabbits in the denervated joint, and in the joint
of the opposite extremity in the controls (this joint had also been
denervated in thecontrol rabbits). -
sNor.
Th. agglutinin titers after a single vaccination into the denerva-
ted joint were considerably less than after the injection of the
antigen into the joint with the innervation intact. Revaccinations
of the control rabbits in the denervated joints did not increase the
antibody titers. Revaccinations of the rabbits in the joints with
innervations intact, those which had been vaccinated in the denerv-
ated joint capsules, sharply increased the agglutinin titers. It
does not appear possible to explain these results by an alteration of
the rate of resorption from the denervated joint, because special ex-
perimenta in which the resorption rates of Bacilli prodigiosum from
denervated a d normaljoints were determined showed that they were the
same.
The same rules and. regulations apply in principle to the enteric
immunizatione of animals with impaired innervations of the gastro-
intestinal tracts. Thus, in the experiments of Ye. Ye. Kostromina
with the enteric administration of dysentery vaccine to rabbits in
which the vague nerves had been trwasected under the diaphragms, the
maximal agglutinin titers barely reached the minimal titers for the
control animals, which had not been subjected to vagotomies.
Thus, on the basis of the experiments presented and also the data
in the literature (A. Ya. Alymov and D. F..Pletsityy) we should con-
clude that the intensity of immunogenesis depends on the frequency
and strength of the immunogenic stimulus, on, the primary site (re*.
ceptor zone) of application of the antigen and on the physiological
condition of the peripheral end of the sense organ,
In any method of immunization, however, not only the condition of
the peripheral end of the sensory organ and the primary site (re.
captor zone) of Application of the antigenic stimulus but also the
state of excitability of the other sensory organs is of primary sig-
nificance to the intensity of immunogenesis. Thus, it has been es-
tablished by the experiments of L. A. Pervushina-that when the ex-
citability of the nervous system is increased:by strychnine, and dy-
sentery vaccine is administered intraperitoneally, inmunogenesis is
increased markedly.
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M.-Ya. Sergeyeva, after increqping the excitability of the nervous
system, also obtained an increased formation of agglutinins (by
three to four times, compared. with controls) as a result of enteric
vaccination with dysentery vaccine.
In the state of chloral-hydrate anesthesia, however, the formation
of agglutinins was markedly decreased. It should be noted that narco-
tic inhibition of immunogenesis is most intense when the narcosis is
used in the first stages of vaccination and. very slight when the nar-
cosis is used only during the period. of revaccination, which also de-
finitely speaks for the reflex:mechanism of the first phase of im-
munogenesis. These rules and, regulations were established by numer-
ous experiments of our colleagues N. P. Yefimova and L. V. Kalygina
during the study of the effect of narcosis on the intensity of for-
mation of antitoxin after immunization of rabbits with diphtheria
toxoid. These data completely coincide with analogous data of oth-
er authors, particularly with the data of P. F. Zdrodovatiyis lab-
oratory.
The decrease in immunogenesis in the state of anesthesia is also
connected with a decease in the absorptive function of the macro-
phage (reticulo-endothelial) oystem of I. I. MMchnikov. In our ex-
periments, performed in conjunction with L. I. Baykher and A. P.
Kayllskiy, and in the experiments of A. P. Kayltakiy it was es-
tablished that in the state of anesthesia a delay in the removal of
Bacilli prodigiosus microbes from the blood stream occurs, and para-
llel with this, the intensity of formation of agglutinins also de-
creases. For purposes of excluding any individual peculiarities of
the rabbits, the control and the basic experiments were always per-
formed an one and the same animals at intervals of seven to 14 days.
It turned out, by so doing, that the injection of an emulsion of a
culture of Bacillus prodigiosus during anesthesia was always accom-
pan.ied by a delay in its disappearance from the blood stream compared
with the initial injection, which was given without anesthesia, and
it did. not, produce any increase in the titer of agglutinins. At the
same time, the injectione Bacillus prodigiosus without anesthesia
always led to a marked increase of the agglutinin titer and, to a .
more rapid removal of these microbes from the blood stream compared
with the initial injection during anesthesia. The microbes were re-
moved most vigorously at the time of the second injection nude with-
out anesthesia. This is expl.ained by the fact that the original in-
jection of tbe microbes, when the animals are in a state of anesthes-
ia, does not leave any residual state of increased. antigenicity fol-
lowing it.
In the regulation of the formation of antibodies a significant
role must be played also by the chemical factors of nerve excitation,
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1
which represent, according to A.A. Ukhtomskiy, "the chemical tail" of
the process of excitation, prolsniging the action of the nerve stimul-
us and preparing the substrate for the reception of subsequent nerve
impulses at its new level of physiological lability. A study of the
influence of the chemical factors of nerve excitation on immunogen-
soils is paticularly important in view of the fact that the immune
reactions occur at lengthy intervals which far exceed the periods of
time during which the nerve stimuli begin and end.
Our co-workers have studied the effect of the chemical factors of
nerve excitation on the formation of antibodies during immunization.
N. P. Yefimova and L. V. Kalugina showed in experiments on rabbits
that against the background effect of physostigmine, acetylcholine
injectedaxily in the intervals between imounizations leads to a very
marked increase of the antitoxic titer of diphtheritic antiserum.
Using the sane method of administration adrenalin reduces the forma-
tion of antitoxins by several times. Ibis effect of the mediators
is intimately related to the condition of cortical activity. Al-
though acetylcholine stimulates immunogenesis, even on the background
of anesthetic exclusion of cortical regulation, even though to a les-
ser degree than without anesthesia, adrenalin, on a. background of
anesthesia, completely suppresses the formation of antitoxins.
M. D. Poptsova showed that even with the enteric route of vacina-
tion of rabbits by liquid dysentery vaccine, perenteral injection of
acetylcholine chloride increases the formation of agglutinins by two
to four times. It is important to note that under the influence of
acetylcholine chloride high titers of agglutinine are maintained even
two and. a half months after the conclusion of the vaccination, where-
as in control rabbits a sharp drop in the titer occurs by this time
-- almost to the initial level. This stimulating effect of acetyl-
choline chloride occurs only in the presence of a definite dose of the
mediator. An increase of the dose of the acetylcholine chloride proves
to be ineffective end produces a faster drop in the agglutinin titers
after the conclusion of the vaccination.
In principle, the same results were obtained by D. V. Berezhnykh
with the parenteral method of administering dysentery vaccine. Pars-
hal
with an increase in the agglutinin titer under the influence of
acetylcholine chloride, using parenteral vaccination against dysent-
ery, the intensity of the phagocytic reaction was also increased. in-
tensification of the phagocytic reaction in rabbits which have re-
ceived acetylcholine chloride was less than the increase in the agg-
lutinin titers. The phagocytic number of the index of intensity of
phagocytosis in the experimental animals only slightly exceeded those
in the control animals, which had, been injected with physiological
saline solution instead of acetylcholine chloride.
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In the experiments of D. V. Berezhnykh the vaccinations were per-
formed three times at intervals of seven days, and the determination
of the agglutinin titer was made, as in the experiments of other
workers, before the second and third injections of the vaccine and at
10, 20, 30 and 70 days after the third. vaccination. In the intervals
between the vaccine injections the rabbits of the control group were
injected every other day with physiological Wine solution, while
the rabbits of the experimental group were injected. with acetylcholine
chloride. Tae experiments were performed on 24 rabbits. Seventy
days after the conclusion of the vaccination and 91 days after the
beginning of the experiment, at which time the agglutinin titers of
six rabbits (two controls and. four experimental) had dropped. marked-
ly and equalled from 1:20 to 1:80, the control rabbits were injected
with physiological saline solution only, while the experimental rab-
bits were injected. with acetylcholine chloride in the usual dosage.
After 8 days, the agglutinin titers had. not increased in the control
animals, while in three out of four experimental rabbits receiving
acetylcholine chloride it reached 1:160, 1:240 and 1:320. (Analo-
gous results were obtained in P. F. Zdrodovskiy's laboratory by A. A.
Klimentova (1948) and I. Ya. Uchitelt (1949). It should be noted that
these authors did not inject the mediators in the process of vaccina-
tion proper). In this experiment of D. V. Berezhnykh apparently a
conditioned reflex restoration of immunogenesis was seen. It should
be emphasized especially that the conditioned reflex restoration of
agglutinin formation was produced. by acetylcholine chloride but not
by physiological saline solution. It is probable that not just any
stimulus coinciding in time with the action of the unconditioned-re-
flex immunogenic stimulation is suitable for the conditioned-reflex
restoration of agglutinin formation but rather only an adequate sti-
mulus T.tich constantly accompanies neural regulation of tbe complex
biochemical processes of antibody formation. Apparently, only sOoh
a conditioned-reflex stimulus can renew the entire complex reaction
chain underlying antibody formation. This is, perhaps, just the key
to the resolution of those contrdictions which occur in the investi-
gation of the question of the part of the conditioned-reflex mechan-
ism in the formation of antibodies.
The entire complex of our investigations of the neural regulation
of antibody.formation ami of data existing in the literature make
it possible for us to exprees the supposition that antibody forma-
tion occurs in a biphasic form. In the first phase, it is accomp-
lished according to a reflex mecbripism with a definite receptor
zone determining the original intensity of immunogenesis, and in
the second phase it is continued through the direct contact of the
antigen with the effectors. Neuro-humoral regulation, which assures
the prolongation of action of nerve stimuli, plays an essential part
here. Tae regulatory role of the central nervous system in the sec-
ond phase of antibody formation completely corresponds to I. 1). Fax-
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lov's conception of the function "...of trophic nerves, which deter-
mines, inthe interest of the body as a whole, the precise measure of
the definitive utilization of this material by each organ." (I. P.
Pavlov Polnoye sObraniye sodhineniy Complete Collection of His
Works : 1951$ Vol I, p 5820
It should be emphasize& that the mechanism of inimmity can in no
way be reduced nerely to the formation of antibodies. Antibodies are
only one of the links in the complex chain of activity of the body's
protective devices. It must be supposed further, that the therapeut-
ic and prophylactic effect of immune sere cannot be reduced simply
to the neutralization reaction of the antigen by the antibody. In
all probability, antibodies which are injected from without or which
are formed in the body are themselves the stili ofdefinite sense
organs: and they reflexly inhibit pathological reactions which occur
under the noxious influence of infectious agents. Thus: for examge:
tetanus antiserum probably inhibits the generalization of excitation
produced in the motor center by the effect of the tetanus toxin. The
experiments of N. D. Speranskiy$ completely confirmed. by the experi-
ments of our co-worker, H. A. Ehrustaleval showed that tetanus anti-
serum when injected into the body with. some delay atter the injection
of tetanus toxin, privents the development of tetanus only on a back-
ground of increased excitability in the nervous system of the ani-
mals from the effect of strychnine. These experiments permit us to
make the assertion above. This fact, which would appear tobe para-
doxical at first glance, can be understood correctly in the light of
the teething of I. P. Pavlov and A. A. Ukbtomskiy on the interkela-
tionship of excitation and inhibition.
Here is what AA. Ukhtccskly wrote on this subject in his time.
"Our school sees in them (in inhibition and. excitation -- G.P.) the
result of a conflict of excitations in the neural elements, and it
Ehe schoog is inclined to connect the decline in impressibility by
a stimulus: which is noted. in the Weber-Flexner Law, with inhibition.
Since the phenomena of immunityland resistance are also connected
With the latter, the bridge between the concepts of nerual and. humor-
al inhibition is outlined." A. A. Ukhtomskiy writes further: "For
our part, we have become convinced. that physiological science is,
indeed, progressing in its entirety as a common front. The research
of the immoralists and that of the neurologists are intertwined to a
much greater extent that appears at first glance: and they will mutu-
ally contribute ideas to another until a really general theory is con-
structed which regards the various forms of stimulation and excita-
tion as particular instances." (A. A. Ukhtomskiy, A. Collection of His
Works, published by the Leningrad State University: 1950, Vol I, p 324).
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ON THE ROLE OF THE NERVOUS sysmoi AND ITS HIGHER CENTERS IN THE
MECHANISMS OF REACTIVITY CHANGES IN TOXIC-INFECTIOUS PROCESSES
AND IN IMMUNITY
O. YIL. stryy
Laboratory of Infectious-Disease Pathology (Head -- O. Ya. Ostryy,
Doctor of Medical Sciences).
A. D. Speranskiy and his co-workers have accumulated facts for the
past 25 years from the various fields of pathology, including also
that of infectious diseases. These facts have shown that the react-
ivity of the body may be altered to a significant degree by various
types of operations on the nervous system. A series of facts was
established, demonstrating the role of nerve-reflex mechanisms in
the processes of reactivity Changes of Rnimla to various toxic-in-
factious stimuli.
The study of the action of extraordinary stimuli on the peripheral
ends of the sensory organs in the mechanisms of compensation and pro-
tection occupied an important place in our work.
I. P. Pavlov pointed out that "once the normal, or specific, sti-
muli are established for the appropriate organ, the physiological pro-
blem comes Alp of analyzing the mechanisms of action of these stinmal
or of determining on what specifically they act and 'where the point
of their application is located." (I. P. Pavlov, Complete Collection
of His Works, 2946, Vol II, p 465).
As is well known, it has also been shown in our combined investi-
gations with A. Ya. Alymov that a certain dose of streptoccocci when
injected intravenously into the ears of rabbits led to their deaths
from septicemia in 80 percent of the cases. The same dose of mic-
robes injected into the femoral vein brought on the deaths of only
an insignificant number of animals (34 percent).
Thus, not only the character of the pathological process but also
simultaneously, the character and. degree of the compensatory capaci-
ties of the body were deternined by the site of injection of the mi-
crobee. If the reactivity of the neural apparatus in the area of
the femoral vein is altered (by means of novocaine injection), then,
disturbances of the cOmpensatory functions of the body, and deaths
of the animals occur to the same degree as after injection through
the auricular vein.
G. N. Kryzhanovskiy and IL S. Delitsina established the fact that
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one and the same dose of tetanus toxin, which is incapable of causing
disease whom injected intracutaneously, eubcutaneously, into a tendon,
spinal cord, brain or even into the subarechnoid space, muses di-
sease even with a fatal outcome when it is injected intramuscularly.
A particularly striking effect is obtained, as N. S. Delitsina
has shown, when this dose of toxin is injected into the masticatory
muscles of rabbits. These muscles, as is known, in rodents are in a
state of increased excitability of a dominant type. Under these ex-
perimental conditions, all the animals died in the next few days with
signs of marked trismus and opisthotonus.
Analogous facts were obtained in the experiments of Z. I. Sobiyeva
in the study of the disease mechanisms of anaerobic infections.
A dose of microbial cutlture which did not produce the disease
when injected intracutaneously proved to be entirely adequate to
cause a fatal disease when injected intramuscularly.
The same kind of rules and regulations were noted also in our ex-
periments with M. D. Speranskiy in the study of the pathogenesis of
diphtheria.
In order to demonstrate the importance of pathological stimulation
of appropriate nerve apparatus in disease mechanisms, special experi-
ments were performed.
G. N. Eryzhanovskiy established the fact that if the nerve branches
leading to the isolated muscle of a skin-muscle preparation are adequa-
tely transacted the injection of tetanus toxin, under these conditions,
did not cause the disease.
The significance of pathological forms of stimulation of nerve
apparatus in muscles in the disease mechanisms of anaerobic infec-
tions was revealed by the investigations of Z. I. Slbiyava. It was
shown that under the conditions of transection of the posterior roots
of the spinal cord, that is, with a disruption of the afferent por-
tion of the reflex arc, the development of anaerobic infection is
markedly inhibited if the microbe is injected into a muscle of the
deafferentated extremity. An especially marked decrease in the mor-
tality rates of animals is shown when they are infected 30 days af-
ter the operation indicated, whereas almost all the control animals
infected by the same dose die in the first few days after the infec-
tion.
The same effect was seen with the simultaneous disruption of affer-
ent and efferent links of the "reflex arc" by means of transactions
of the three basic mixed nerves of the posterior extremity (sciatic,
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femoral) obdurator).
Thus) by sparing the body to some degree from excessive pathogenic
otilulation, we can make possible its equilibrium with the environ-
ment, even when there are virulent disease organisms or active toxins
in its internal milieu.
Basing ourselves on the law established, we can approach the
search for planned methods of acting on the body for purpose of pro-
phylaxis and therapy. In other words, based on the mechanism of neur-
al activity determining the reactivity of the body to environmental
factors) it is possible to help the body surmount extraordinary sti-
mulations even under conditions which under pther circumstances would
inevitably cause disease or even the death of the animal.
In the experiments of G. N. Kryzhanovskiy and Z. I. Sobiyeva data
were obtained which showed the possibility of preventing the develop-
ment of tetanus and gas gangrene by ihjecting the animals withletanus
toxin or anaerobic microbes in novocaine solution (one to 10 percent).
The experiments of G. N. Kryzhanovskiy with the injection of tet-
anus toxin mixed with novocaine led to results which extended the
earlier data obtained by S. I. Lebedinskaya in this connection. At
the sane time, G. N. Eryzhanovskiy showed that for inhibiting the
development of tetanus the injection of novocaine does not have to
be made exactly at the same place where the toxin is injected, Under
conditions where tetanus develops from the injection of toxin into
one of the posterior extremities) an elimination of the muscular ri-
gidity can be attained temporarily by injecting novocaine into the
opposite extremity or into a muscle of one of the anterior extremi-
ties. In doing this, as has been shown by electrophysiological ana-
lysis, the increased electrical activity in the nerves of the ex-
tremity involved. by tetanus disappears.
The same law was revealed in our experiments performed in conjunc-
tion with M. D. Speranskeya. The injections into guinea pigs of ab-
solutely lethal doses of diphtheria toxin following the preliminary
injections of two percent novocaine solution into the same sites do
not produce the disease in many animals.
Thus, the facts presented again confirmed the vary important role
of reflex mechanisms in the processes of disease and resistance of
animals to toxic-inEectious stimuli. The important role here belongs
to functional alteration of the threshold of reactivity of the nerve
apparatus.
It has been shown in our previous experiments that one and the
sane dose of tetanus antiserum can exert different prophylactic and
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therapeutic effects depending on the site of injection of the strum
and of the toxin.
It has been established in the experiments of G. N. Eryzhanovskiy
that the best effect from the use of tetanus antiserum for prophyl-
actic purposes has been obtained from the intramuscular injection of
it.
Precisely the same law was established in the work of Z. I. Sobi-
yeva: gas gangrene antiserum exerted the greatest prophylactic and
therapeutic effects when injected intramuscularly.
Thus, the data obtained in the study of the role of non-specific
stimuli in the mechanisms of reactivity changes with respect to toxic-
infectious agents have been develdped in a new way in experiments us-
ing specific stimuli.
If so-called "passive" immunity is connected with the site of in-
jection of the serum, as the development of the disease is connected
with the site of injection of the toxin, then it is important to elu-
cidate the significance of the same correlation in the development of
active immunity.
It was established in the experiments of L. N. Fontalin that one
and the same dose of tetanus toxoid when injected intravenously, in,
tramuscularly or into the spleen stimulated the elaboration of anti.
bodies in different ways. Whereas no signs Of antibodies were seen
on the 30th day of immunization when the toxoid was injected in cer-
tain doses intravenously and intrasplenically, a distinct increase of
the antibody titer was observed when the same dosage of toxoid was in-
jected intramuscularly.
In order to elucidate the role of the nerve apparatus of muscles
in the processes of active immunization, L. N. Fontalin performed
the following experiment.
A group of animals (21 rabbits) was immunized with precipitated
tetanus toxoid into muscles which had their innervations disrupted:.
Simultaneously4 22 control rabbits were imOunized by the same meth-
od but using normal muscles. As a result, on the 30th day of immu-
nization the antibody titers were three times lower in-animals of the
experimental group than in the control animals in which the to:cad
had been injected into normally innervated muscles.
Evan more striking data were obtained by L. N. Fontalin by immun-
izing rabbits under the same conditions but with unchanged tetanus
toxoid. Here, the differences in antibody titers on the 30th day
after immunization were even greater: the antibody titers of animals
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,
of the experimental group were 18 times lower than the antibody ti-
ters of the control animals.
Thus, it follows from the material presented that the mechanisms of
disease and of protection cannot be dissociated from one another,
and that the reflex functioning of the nervous sytem underlies these
mechanisms.
The material presented, as is seen, showed that the most react-
ive innervation zones with respect to a certain pathogenic agent are
the zones through which it is easiest to cause the protective reac-.
tion of the body with respect to this pathogenic stimulus.
Our work, therefore, completely confirmed the statement by I. P.
Pavlov that "extraordinary stimuli acting in the Capacity of patho-
genic agents represen the specific stimuli of those protective de-
vices of the body which are intended to fight against the correspond-
ing pathogenic agents." (I. P. Pavlov, Complete Collection of His
Works, 1946, Vol II, p 350).
We ascribe tremendous importance to the study of the effect of the
functional condition of the higher central nervous system centers --
the cerebral cortex -- in increasing the resistance of the body to
the toxic-infectious stimuli and in the stimulation of the immunolo-
gical processes of defense.
We established in investigations of previous years that non-spec-
ific stimulation of the nerve-receptor apparatus of the lung reflex-
ly increases the resistance of the body to tuberculosis. Further t
study of the processes which belong in this category, conducted by
N. A. Kryshova and her co-workers in the Institute of Physiology of
the Academy of Sciences USSR, showed that protective inhibition oc-
curring in the cerebral cortex is of great importance in the thera-
peutic effect of the method proposed. by our Institute of treating
extrapulmonary forms of tuberculosis and certain other diseases of,
non-tuberculous etiologies by intravenous injections of bismuth car-
bonate suspensions.
Z. I. Sobiyeva studied the effect of inhibition of the higher
centers of the brain on the compensatory processes of the body. By
injecting animals repeatedly with certain doses of bromides and lat-
er infecting them with anaerobic microbes, she noted that under
these conditions the duration of life of the infected animals was in-
creased. by more than three times compared with the controls. The
same picture vas seen when animals were infected on a background of
anesthesia proiuced by amytal.
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If an intensification of the processes of cortical inhibition
(from the effect of bromide or mertal) leads to an increase in the
resistance to microbes, then it is important to clarify how the
reactivity of the body is altered when the animals are infected on
a background. of increased ocrtical excitability brought about by the
action of phenamin. The experiments of Z. I. Sobiyava showed that
after repeated injections of phenamin into rats their resistance' is
decreased, and such rats die in larger numbers from gas gangrene
than do the controls.
The role of the central nervous system in the compensatory mech-
anisms in tetanus was noted in the experiments of N. G. Eryzhankovskiy.
The removal of one hemisphere of the brain and the injection of min-
imally pathogenic doses oftstanus toxin into the muscles of the cor-
responding anterior extremi,,. produce and considerably aggravate the
the disease compared witk.;%perated animals. This is expressed in
a shortening of the incubation period and in a lengthening of the
duration of the disease.
The data of L. N. Pontalin are in complete accord with these ex-
periments; they showed that after the removal of one hemisphere and
the injection of tetanus toxoid into the muscles of a posterior ex-
tremity (0n the side corresponding to the removed hemisphere) a de-
crease in immunogenesis occurs. On the 21st day after immunization,
the antitoxin titer in the blood of such animals was, on the average,
2.5 times less' than in the control animals. Thus, the result of re.
moval of one hemisphere was, on the one hand, an aggravation of tet-
anus, and, on the other, a disturbance of the process of creating
immunity to tetanus.- This means that the disease processes and the
processes of immunological defense are most intaimately connected
with the functiondistate of the higher centers of the central ner-
vous system.
At present, we are utilizing the method of functional change of
the reactivity of the body by means of cooling the head for purposes
of intensification of the processes of inhibition. Our experiments
performed in conjunction with N. D. Speranskaya showed that in white
rats in whcih the head-cooling was performed for one and half hours
there was an increase noted in the resistance to anaerobic infection.
When the cooling is performed before the infection of the animals,
the morbidity rate and the mortality rate of the latter are signi-
ficantly decreased. If the cooling is performed after the infection*
it does not exert any prophylactic or therapeutic effect, and the ani-
mals die in the same numbers as the controls.
The analysis of the physiological mechanisms underlying this fact
is being continued at this time,
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We also established WI the preliudnary experiments) the fact
that -following repeatedhead-coolings a condition is created wherein
the application of a bag with sand at roam temperature to the head
of the animal instead of ice gives the same effect as was obtained
with the preliminary coeltng, namely, the resistance oP the body to
anaerobic infection is increased.
? Out of 18 such animals infected with lethal doses of anaerobic
microbes none of them died from gas gangrene, whereas in the control
group of 18 rats 14 died from this disease.
The question of altering the reactivity of the body to anaerobic
infections by the conditioned-reflex method is a subject for our fu-
ture investigations.
Therefore, it has been possible to observe rules and regulations
in the processes of infectious-disease pathology and immunity, which
were established by the study of the physiology of nervous activity,
particularly of the physiology of the cerebrum.
Under conditions of altered reactivity of the higher centers of the
central nervous system an inactive stimulus may become: an active one,
and, contrariwise, extraordinary stimuli may lose this property.
I. P. Pavlov mentioned that the pathologic process "... can also be
well analyzed, that is, reduced to known physiological processes and
their various fluctuations..." (I. P. Pavlov, Twenty Years of Ex-
perience in the Objective Study of Higher Nervous Activity (Behavior)
of Animals, 1938, pp 738-739).
In his time, I. P. Pavlov proposed a different viewpoint from con-
cepts that immunity is manifested only in leucocytosis and reactions
of the "antigen-cell-antibody" type without consideration of the very
important role which the nervous system plays in the processes of im-
munity.
BC welcomed new facts which disclosed the power of the nervous
system and its capacity to regulate the defense immunological reac-
tions leading to an equilibrium of the body with the microbial med-
ium.
I. P. Pavlov pointed out that at present conditioned-reflex changes
of immunity are known which pegtain to the first signal system.
Of late, more and more facts are being accumulated 'which show the
correctness of the conclusion drawn by I. P. Pavlov in his time.
Here should be mentioned not only the work accomplished under the
leadership of A. D. Speranskiy but also the great number of investi-
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alra4.1t^a. .
gations performed in the laboratories of K. M. Bykov? A. G. Ivanov-
Smollinskiy, V. N. Chernigovskiy, A. 0. Bain, P. I% Zdrodovskiy,
A. EL Ado, V. S. Galkin, A. M. Gordiyenko, G. V. Vygodebikov, N. V.
Puchkov, G. V. Pnshkovskiy and many other Soviet scientists.
On the basis ofewerythinivtich has been presented, the conclusion
may be drawn that the reactivity of the body, that is, its relation-
ship to the environment, no as well as in pathology, is deter-
mined by the analyzer systeM:agnsisting mostly of sensory organ
unite, which play a most important role in the formation of the body's
response reactions produced by the effect of various environmental
stimuli on it. Reactivity and its changes are expressions of the
degree of quantitative and qupittative reactions which underly thel
equilibrium and maintenance of the unity of the body-with the condi-
tions of its existence.
The reactivity of the peripheral nerve apparatus and that of their
higher representatives to stimuli of the environment increasee.
pre-
oipitouel,y on ascending the evolutionary ladder, which increases the
defensive functions of the body. I. P. Pavlov wrote that in the
higher animals "The neural apparatus....was made reactive to the
highest degree, that is, it was made accessible to the most varied
phenomena of the external world." (/. P. Pavlov, Twenty years of
penance in the Objective Study of Higher Nervous Activity, 1938,
p 67).
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MATSHIAL ON THE QUESTION OF THE ROLE OF THE CEREBRAL
CORTEX IN ASSIST/EWE TO TETANUS
D. F. PletsitYY
Laboratory of the Physiology of Immunity (Head -- Professor
A. V. Alymov, Corresponding Member of the Academy of Medical Sci-
ences USSR)
In recent years, much factual material has been accumulated. which
sheds light on the importance of the condition of the nervous system
as a whole and of certain individual links of it in the process of
the disease, tetanus.
It has been shown that the injection of tetanus toxin into an
area with various peripheral nerve receptor apparatus and also a dis-
turbance of the central nerve connections can produce a radical in-
version of the process in connection with clinical manifestations of
the disease and the complete development of the disease. Claude Ber-
nard showed. that the development of tetanus can be eliminated. by
acting on the effector structures (intoxication of the myoneural end.-
plate with curare).
Therefore, intaferances with the pathological process in tetanus
at the afferent, central and effector parts of the reflex arc can be
evAlly effective in affecting the outcome of /the disease.
The elucidation of the role of the cerebral cortex in the devel-
opment of the tetanus dtsease process and in the resistance to tetan-
us is of particular interest.
The role of the cerebral cortex in the development of tetanus, as
in the majority of pathological processes generally, apparently con-
sists chiefly of the compensation of disorders produced by the dis?
turbanCe of normal activity of lower neural structures.
The method of putting animals into a drug-indilted sleep may be
used to advantage for studying the functions of the cerebral cortex
in the development of tetanus and of the resistance to tetanus, along
with other methods of investigation.
This method has been extensively utilized in recent years not
only in experimmtalpathollbysiological investigations but also cli-
nically in the treatment of a number of diseases.
Sleep therapy is based on the work of I. P. Pavlov, which was de-
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1
voted to the experimental studyvof the pathogenesis and therapy of
certain disorders of higher nervous activity, chiefly of neuroses.
Based on concepts of the protective role of inhibition in the cere-
bral cortex, I. P. Pavlov proposed utilizing prolonged sleep in the
capacity of a therapeutic measure in certain mental illnesses. This
kind of therapy has at the present time obtained vary wide-spread
distribution and recognition in a number of mental illnesses.
Later, the use of prblonged sleep was proposed also for the ther-
apy of internal diseasei (r. A. Andreyev). Considerable clinical
experience which has been aceumulated in this direction shows that
the given method is veryJeffective in certain internal diseases (hy-
pertension and. peptic ulcer).
In hypertension, peptic ulcer, and other diseases, where the
primary and leading pathogenetic link is apparently the presence of
corticiiisorders, the effectiveness of this method can be evalua-
te& within the plan of I. P. Pavlov's conceptions of protective
cortical inhibition.
The understanding of the mechanism of the therapeutie effect of
volonged sleep in other internal diseases, in the development of
which the chief roles do not belong to cortical disorders, is such
more complex.
In tetanus, the combined administration of narcotic agents and
of tetanus antiserum has boon used with relative success for a long
time now. However, experimentally, the effect of narcosis and pro-
longed sleep on the course of tetanus intoxication has been entire-
ly inadequately investigated. There is very little reference to
this subject in the literature.
Recently, appropriate investigations were conducted in the labor-
atory of V. S. Galkin (work of V. A. Koslov). It was shown on exper-
iments on mice and rats that under the influence of prolonged (last-
ing for tens of hours) cyclonal anesthesia an inhibition occurs of
the development of tetanus during the entire duration of the anes-
thesia in the animals. The same effect has also been noted in cases
where animals already sick were placed under anesthesia. It should
be noted that the experiments mentioned were conducted under condi-
tions of injecting the animals with very large doses of the tetanus
toxin (100 to 1000 =O.
Brief periods of anesthesia according to V. A. Kozlov's data, di&
not affect the length of life of animals inoculated, with tetanus.
Bilyard in experiments OA gam). :pigs and N. V. Colikov in experi-
ments on rabbits note that in doing this the course of tetanus is, on
the other hand, made more severe. /hue, N. V. Colikov, after anes-
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-
thetizing rabbits which were in states of local tetanus, observed
that iamediately after coming out of the anesthesia, signs of general
tetanus developed in the animals for a short time. Anesthesia,
therefore, made possible the demonstration of the process.
The present investigations do not help much in the elucidation of
the role of the cerebral cortex in the development of thepathologic
process and of resistance in tetanus. As a matter of fact, in all ,
the quoted works anesthesia was achieved by means of compounds which
act not only on the cortex but simultaneously also on subcortical
centers. However arbitrary the division of anesthetics into "cor-
tical" and "basal" might be, nevertheless, within certain limits
Selectivity of their actions on various parts of the central nervous
system actunlly does occur.
For solving the problem posed it was necessary, naturally, to
make use of an anesthetic agent which would act primarily on the
cerebral cortex. As is well known, ohloralhydrate is such an ag-
ent.
Our observations were made on rabbits.
The preliminary experiments showed that it is most convenient to
give the chloral hydrate tolhe animals by mouth, After being diluted
in distilled waier which had. been heated to 25-300 Co the anesthetic
was introduced directly into the stomachs of the rabbits by means of
a thin rubber stomach tube, to the end of which was attached a small
funneL
It was established that 15 cubic centimeters of 20 percent aqueous
solution of chloral hydrate introduced into the stomach represents
the highest dose that a rabbit can tolerate. Under the influence of
this quantity of the substance the animals fell into a deep sleep,
which lasted 15-27 hours.
A dose equal to 10 cubic centimeters of 10 percent aqueous solu-
tion of chloral hydrate produced only a light sleep in the animals
which lasted four to eight hours.
The experiment was performed on 30 rabbits weighing two to two and
a half kilograms -- 15 experimental rabbits and. 15 controls. Fhb-
bits of each group were given one MD of tetanus toxin (30 mouse MIA)
per kilogram of weight)under the skin of the outer surface of the
left thigh. Ten to twenty minutes after the injection of the toxin
the experimental animals were given chloral hydrate anesthesia.
The rabbits were injected with 15 cubic centimeters of 20 percent
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aqueous solution of chloral hydrate. After several minutes, :they be-
came sluggish and. did not move much, and after 10-15 minutes they be-
gan to fall asleep. After 20-30 minutes they were usually in a deep
sleep. The rabbits for the most part,lay on their sides. The depth
of the anesthesia gradually increased, and the maxim= was reached
seven to ten hours after the production of anesthesia. The respira-
tion of the animalsabecame superficial, often hardly noticeable, the
body temperature decreased. by several degrees, the corneal reflex
disappeared. Aweak reflex muscular reaction could be noted only
through the effect of strong pain stimuli (prick, pinch).
At the end of 12-14 hoursi occasionally earlier, the first period
of awakening occurs in the AnimPlii. The rabbits get up, take food:
for a certain time (30-50 minutes) .they are in a state of partial
wakefulness, and then they fall asleep again. This sleep comes upon
them unexpectedly: in a number of cases it was possible to find
sleeping rabbits with their heads burried in their troughs.
The set:ond phase of sleep lasts mix to eight hours. Sleep at this
time is considerably more superficial: the pnlmaiR respond even to
weak stimulations and can easily be aroused.
Men, the second. period, of awakening and, wakefulness follows, dur-
ing which the rabbits get -up, eat, move about (unsteady gait).
The last stage is the phase of interrupted sleep. In this, the
rabbits wake up periodically -- every 30 to 60 minutes. Gracbuoiy,
the waking period. becomes more prolonged, and the periods of sleep
become shorter and shorter. Sleep becomes superficial; in the last
few hours, the rabbits sleep aitting up. The existing state of in-
hibition of the central nervous system, specifically of the cerebral
cortex, can be judged only by the immobility of the animals and. by the
closed eyes.
From the short characterization presented of the hypnotic effect
of the dose of .chloral hydrate uped, it is seen that the inhibition
of the central nervous system developing under the influence of the
anesthetic agent is not the same during different periods of sleep.
Oa the basis of the observations presented, the following concept
may be constructed of the dynamics of this inhibition.
In the very first phasevehlorel hydrate undoubtedly acts chiefly
on the cerebral cortex. Hovevostterwards, its action diffuses to
lower structures of the brain and spinal cord. At the peak of the
first period of sleep a deep inhibition of the entire central ner-
vous system is seen which is so considerable that it is more accurate
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to speak here not of sleep but rather of anesthesia. Recovery of
the active states of various central nervous system centers occurs in
reverse order, as the animals emerge from the condition of narcosis:
first, the spinal centers are released from inhibition, later, the
brain stem and subcortical ganglia, and, finally, the cortex. In
the last period of action or chloral hydrate, sleep is achieved, there-
fore, apparently exclusively on account of the inhibition of the cor-
tex.
Later, the rabbits were injected daily with 10 cubic centimeters
of 10 percent aqueous solution of chloral hydrate. Under the influ.
ence of this dose an unusual sleep state developed in the animals,
which, was not accompanied by a diffusion of inhibition to the sub-
cortical area of the brain or to the spinal cord.
The animals became adynamic, and 20-30 minutes after the injection
of chloral hydrate, alight sleep cane upon them. The rabbits re-
mained in the sitting positions, lowered their beads and closed their
eyes. On the first day, they remained in this condition for 1042
hours, and on the second to third day, for six to eight hours. Under
the influence of strong stimuli (prick, jolt), the animals awoke for
a short time. Sound stimuli also brought the animals out of the
state of sleep: the rabbits opened their eyes, moved their heads,
sometimes moved about, but fell asleep again right away. The effect
of the chloral hydrate) continued for several hours after the con-
clusion of the period of the distinctly evidenced somnolent state,
which expressed itself in general inhibition and lack of mobility of
the animals.
The picture described, above was notably changed.with the develop-
ment of tetanus intoxication in the animals. Oa the second to third
dayefter injecting the rabbits with tetanus toxin, the hypiotic dose
of chloral hydrate mentioned produced a progressively diminishing
effect. In the period of the expressed general tetanus it was al-
most inactive and did not exert any notable hypnotic effect.
The development of tetanus in the experimental animals was charts**
terized by the following peculiarities.
The first injection of the chloral hydrate, which produced. pro-
found anesthesia, inhibited the appearance of the signs of tetanus.
While in the majority of control animals, distinct phenomena of loc-
al tetanus 'could be noted 36 hours after the injection of toxin,
there were no pathological disorders in the experimental animals at
that time. However, later (48-52 hours after the injection of the
toxin), the picture of tetanus in both groups of animals became the
sane. The temporarily inhibited pathological process thus developed
in an accelerated fashion when the animals came out of the anesthesia.
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Later, with the generalisation of the process, a *ore rapid de-
velopeent of tetanus was found in the experimental enimals. Their
deat occurred. in the :majority of cases sooner than in the control
%a A protocol of ane of the experimente is presented
pabbit o 29014. Weight 2,700 grs Rabbit No 1701. Weight 2,2005rems
Experimental Control
9 January 11:00 o'clock
Oae MLD of tetanus toxin (30 amuse MLD per kilogrea(e weight)
Was injected subcutaneously into the external sweat:we of the lett
thighs of both rabbits. Fifteen cubic centimeters of 23 percent
chloral hydrate solution were introduced into the !stomach of the ez..
perimental rabbit (No 2934) 3.5 minutes after the injection of the to..
xin.
-9 January 12:00 o'cloztk
Rebbit sleeping with even deep
sleep, lying on side. Withdraws
extremity vhen paw is pricked with
a needle or pinched.. Corneal re-
flex maintained. Does not react
to sound stimuli.
fktbbit completel,y healthy;
no abnormalitiea in behavior.
9 atinUarY 5:00 p.m.
Superficial, hardly detect.. Eame as above.
able respiration* Temperature
35,140 c. le corneal reflex.
Does not react to painful:6th-
mull.
Same
9 Januar" 7:00 p.m,
filaav3
10 Jenuary 8:30 man*
Rabbit sleeping. Lies re ob./
down with snout buried in feed.
ing trough. Part of the food. is
eaten. Respiration is deep and
stertorous!. ra response to a
strong sound. stimulus!, the rabbit
wens eyes, raises heed, but then
-38-
An incipient predasinemee
of tows of the extensor muscles
of the left posterior extremit4
is noted. When thrown on the
floor frost a height of 20 to 50
centimeters, the rabbit, on is?
lighting, extends the hind. paw.
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- Rabbit NO 2904. Weight 2,700 grams
(contid
falls asleep again. Reacts to
painful. stimuli. Temperature 36.2P
CO
10 January
The rabbit awoke, went for his
feedingtrough. Gait unsteady.
Eats. Toms of the left bind paw
is normal.
Babbit No 1701, Weight 2,200 grams
10:20 &M.
(cont 'd
During locomotion of the ani-
mal, an extensor rigidity of
the left hind paw is noted.
10 January 1:00 p.m.
Rabbit site motionless with Ease as above.
closed eyes -- light sleep. Wakes
up in response to slight sound or
tactile stimuli*
3.0 Jeumary 4:00 p.m.
The rabbit does not sleep, is
alert, has normal gait. No signs
of tetanus. Mn cubic centimet-
ers of 10 percent chloral hydrate
introduced through gastric tube.
Distinct local tetanus
10 Jhuary 7:00 p.m.
The rabbit sits motionless with
closed eyes, with the head drawn in,
On stimulation, opens eyes, moves
head, but then immediately falls
asleep mein. No signs of tetanus.
Same as above
11 January 9:30 a.m.
The rabbit does not sleep* Nark-
ed local tetanus. At 10;15 ewe*, 10
cubic centimeters of 10 percent
chloral hydrate introduced through
gastric tube.
Evident local.letanus
11 January 11:00 a.m.
Rabbit sleeps lying on side*
-39-
Same as above
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?
?
Muscles of the left hind, paw are
weak.
11 January 11:45 a.m.
Babbit woke up. As soon as it
stood up, local tetanus appeared
again in full measure.
3.3. January
aabbit sits witia closed eyes.
On stimulation, ik opens eyes and.
moves about, and then again begins
to doze. The sieps of tetanus do
not disappear durtng asap.
f 11 January
Rabbit is not sleeping. Marked
local tetantuk. When placed on the
left side with a rapid. movement,
the rabbit goes into a condition
of general tetanus.
12 January
Rabbit is not sleeping. Mark-
ed local tetanus. Tonic contrac-
tion Of the muscles of the trunk
amd anterior extremities is seen.
On strong painful stimulation,
brief convulsive attacks develop
in the animal. Given 10 cubic cen-
timeters of 10 percent chloral hy-
drate.
Same as above
1:00 p.m.
Marked local tetanus
5:00 14111,0
Marked local tetanus. When
placed on the left side with a
rapid movement, the rabbit eaa.
ily returns to its original pos-
ition.
9:30 a.m.
Marked local tetanus. A cer-
tain tonic contraction of the
muscles of the trunk and. anter-
ior extremities.
12 January 1:00 p.m.
Rabbit sits motionless, with
closed eyes. The left hind. paw is
extended. backward, and the muscles
of the trunk are contracted. Is
aroused by sound stimulation,
but than falls back into a somt-
nolent state.
-140-
WIII.,????=???????=ge6
Marko& local tetanus. When
placed on the left side with a
rapid. motion the rabbit goes
Into a state of generalized. tet-
anus.
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u
12 January 1:40 p.m.
Under the influence of sound
stimulation (door was slammed) the
rabbit awoke, made several steps
and went into an attack of general-
ized tetanus. The attack lasted
for three minutes.
Same as above
12 January 4:30 p.m.
The rabbit shows marked con-
tractions of the muscles of the
trunk and all the extremities.
When stimulated, it goes into a
state of generalized tetanus.
12 January 9:00
Rabbit is in state of general-
ized tetanus. Immobile. Macias
of trunk and extremities Ore mark-
edly contracted. The head is
thrown slightly backward. Tan
cubic centimeters of ten percent
chloral hydrate solution given.
Same as above
a.m.
When stimulated, rabbit de-
velops brief attacks of general-
ized tetanus. Capacity for lo-
comotion is preserved.
13 January 10:15 a.m.
Rabbit is not sleeping. Con-
dition of the animal is serious.
ties extended, head thrown
back, tail raised. Trismus.
$sme as above
13 January 4:30 p.m.
Rabbit in very severe condi-
tion. Muscles contracted to their
limits. Opisthotonus, trismus.
Respiration is superficial. It was
not possible to administer chloral
hydrates
Rabbit lies immobile. Mark.
ed contraction of the trunk and
extremity muscles, twitching of
front paws.
14 January 8:30 a.m.
Rabbit in agonal state. Ma- Rabbit in state of general-
possible to administer chloral ized tetanus.
hydrate.
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?=1?111?1?11
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Rabbit died.
14 January 11:10 &at.
Sails as above.
14 January 4:30 p.m.
Same as above.
15 January 12:00 noon
Same as above.
16 January 9:00 a.m.
Rabbit in very severe con.-
ation. Does not respond to
stimulation. Respiration hard-
ly det6ctable.
16 January 3:30 p.
Rabbit died.
As seen from the protocal presented, the course of tetanus in the
experimental rabbit was more severe than in the control. This found
its reflection in the earlier generalization of the process and the
significantly smaller total duration of life in the experimental ani-
mal (/hick:died 50 hours sooner than the control).
The experimental rabbit": infected. with tetanus died sooner than
did the control animals, (see Table).
The Effect of Chloral 'dmt. Anesthesia on tbe.Length of Life
of Rabbits Xnf.ctsd with Tetanus Tnxin
Designation
of
group
Experimental
rabbits
No of
rabbits
13
Control
rabbits 23
Average length
of life of rab-
bits after In-
jection of tom-
in in dais.
6.38
947
Mortality rate
days after the
3th
a? rabbits according to
injection of the toxin
i I
110 11 12i 13114; 15tbk6th
I ?
1 1 2 7 3. 2- c
- 1 3 2 k 1 - 1
410
a
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..,=?????14
Note. Two experimental rabbits which died following the first ad-
ministration of chloral hydrate are excluded from the record; two
control rabbits which became sick but which did. not die are also ex-
cluded.
The total duration of anesthetic sleep in the experimental animals,
which was established orientatively, was 25-45 hours.
Thus, the inhibition of the higher centers of the brain which de-,
velops under the influence of chloral hydrate is not only incapable
of eliminating the pathological process in tetanus, but even notably
decreases the protective, compensatory capacities of the sick body.
This conclusion is not unexpected. The effect of chloral hydrate
on animals infected with tetanus can be explained in the following
way: under normal conditions of body activity the cerebral cortex
exerts an inhibitory influence on the functional activity of the low-
er centers of the central nervous system. Under pathological condi-
tions, as are being observed. here, particularly in tetanus, such in-
hibitory influences on the part of the cortex acquire particularly
great importance, because the strength of the bodily resistance to
the developing disease process is to a considerable degree determined
by them. Naturally, the substitution of an active condition of the
cortex by an inhibitory one leads to the cessation of action of this
protective mechanism and, therefore* to an increase of the patholo-
gical process developing in the subcortical structures of the central
nervous system.
Evidently, the generally accepted evaluation which has recently
been made of drug-induced sleep as a kind of universal therapeutic
agent and the consideration of its mechanism of action on a plan with
the idea of I. P. Pavlov of protective cortical inhibition are dis-
putable. It might even be said that these views not uncommonly con-
tradict the Pavlovian conception of the leading role of the cerebral
cortex in the activities of higher animals forms.
As a, matter of fact, does it not appear strange that, at a time
when a question of the body's life or death is at stake* the cutting
out or weakening of the functions of the cerebral cortex' the organ
which accomplishes the supreme control of the normal course of the
vital processes, should be a useful measure? Is it right to speak of
the protective role of cortical inhibition in these cases?
It must be supposed that an active, alert condition of the cere-
bral cortex, not an inhibited one, is a most important condition for
the successful resistance of the body to the development of disease.
Not only the shorter length of life of experimental animals but also
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OM.
the increase of functional activity of the cerebral cortex in rabbits
in the process of development of tetanus speak specifically for stadia
a point of view.
If the dose of chlanalwArate which produpes sleep in health
animals is inactive at the peak intensity of the menifestationo of
tetanus, then this fact should, evidently, be understood as meaning
that the body itself actively counteracts the development of an in-
hibitory state in the cerebral cortex. What considerations can be
adduced to the effect that this couhtereffect must be blocked rather
than supported?
In connection with what has been stated, it is fitting here to pre-
sent the very interesting observations of V. N. Popov, which, unfor-
tunately, have not been published.
Several cats were inoculated with lethal doses of tetanus toxin.
During the period of generalized tetanus they were divided into two
groups experimental and control. Ihf experimental animals daily
began to be subjected to adequate biological stimulation ofTusany,
hours' duration (direct proximity of mice). As 'a result of such a
prolonged excitationl three cats, which were in states of generalized
tetanus, recovered.
However, abundant clinical and experimental material nevertheless
mentions definitely the effectiveness of the method of drug-induced
sleep therapy in many diseases, particularly in certain infectious
diseases. It apparently should be considered that an irradiation of
inhibition occurs thereby to a significant depth, leading to a gener-
al diminution of reactivity of the central nervous system. Facts
showing that under conditions of drug-induced sleep inhibition of a
number of defense reactions also occurs speak for such a conception
of the therapeutic effect mechanism of drug-induced sleep.
;
?;??0?70
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RE ROLE ROLE OF TES PERIPHERAL NERVE APPARATUS IN THE
MECHANISWOF ACIFION OF TETANUS AAT/SERUM
T. V. Mitina
The department of pathological physiology (Head -- Professor
I. I. Fedorov) of the Vvov Medical Institute tue The Laboratory of
the Physiology of Immunity (Head 4.- Professor A. Ye. Alysov, Corres-
ponding Member of the Actulemy of Medical Sciences USSR) of the Inst-
tutu of General and Experimental Pathology
It has been shown through the work of Soviet scientists, mainly
that of A. D. Speranskiy and, his co-workers, that the so-called. pass-
ive immunity cannot be reduced to a simple neutralization of toxins
which are circulating in the blood.
Immune serum is a stimulus of sensory apparatus which ploy an im-
portant role in the development of "passive" immunity.
The response reaction to stimulation depends on the time of ac-
tion of the new stimulus anti the functional state of the receptors.
The administration of specific serum to the body produces differ-
ent effects depending on which nerve apparatus the serum acts on
first. Thus, the so-called passive immunity is, as a matter of fact,
active; it is dependent on the general physiological rules and reg-
ulations to the same degree as all the other processes which occur in
the complex organism.
The fact that immune sera act on the nerve endings has been estab-
listed not only in physiological experiments but also confirsed by the
histological investigations of Ye. A. Kirillov (1949), who showed
that as early as 15 minutes after the subcutaneous and intramuscular
administrations of sere there could be seen, in addition to the gen-
eral tissue reaction, a reaction on the pert of the peripheral nerv-
ous system.
By acting on the sensory nerve apparatus in a definite way, condi-
tions may be prepared for the more effective action of tetanus anti-
serum.
This thoughtalso underlay our experimental investigation.
We used the stimulation of sensory apparatus by glucose solution
for intensifying the effect of the serum. The choice of glucose as
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a stimulant was dictated. by the fact that a stimulating effect of
glucose on sensory nerve endings in blood-vessel 'mills was demon-
strated in the laboratory of I. I. Fedorov.
The experiments were done on 164 guinea pigs. The experimental
nnimelln, which had. been infected with tetanus toxin, were injected
with five cubic centimeters of 20 percent glucooe solution ami the
corresponding antitoxic serum in such a email dose that it in it-
self would not prevent the development of intoxication.
Control animals were injected, with the serum and the toxin only.
The injections were always given intramuscularly in the area of the
upper third of the right thigh.
The mixture of tetanus toxin, antitoxin and glucose was prepared
ex tempore.
First we used a dose of serum equal to one antitoxin unit. The
experiment was performed in the following way. Al,]. the animals were
divided into three groups. The animals of the first group (four
guinea pigs) were given only tetanus toxin in am amount equal to one
MLD. All these guinea pigs became ill with tetanus and died on the
fourth day after the injection of toxin. The second group (ifix gui-
nea pigs) were injected. with tetanus toxin in an amount equal to one
MLD in a mixture with one antitoxin unit of tetanus antiserum. Mark-
ed local tetanus developed in all the animals of this group. Finally,
guinea pigs of the third group (also of six animals) were Wected
with toxin in a mixture with tetanus antiserum and five cubic centi-
meters of 23 percent glucose solution. In all the animals of this
group the manifestations of tetanus developed. later than in the gui-
nea pigs of the control groups; proceeded in an appreciably milder
fashion, and recovery occurred quicker.
As seen from the results of this experiment, glucose solution
made possible an intensification of the therapeutic effect of the ser-
um.
In another experiment we used a smaller dose of antitoxin, namely,
0.1 antitoxin unit. The animals were also divided, into three groups.
The guinea pigs of the first group were injected with toxin alone in
an amount of three MLD, as a result of which all four guinea pigs quick-
ly died with signs of generalized tetanus. The animals of the second
group (six guinea pigs) were injected, with a mixture of three MLD
of toxin and. 0.1 antitoxin unit of antitoxin. In this case, the serum
proved to be entirely ineffective, and all the guinea pigs died with
signs of generalized tetanus. The animals of the third group (10
guinea pigs) were injected with three MLD of tetanus toxin, 0.1 anti-
toxin unit of tetanus antitoxin and five cubic centimeters of 20 per-
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cent glucose solution. None of these 10 guinea pigs became sick with
tetanus.
The intensifying action of glucose was particularly well demon-
strated in this experiment: the dose of serumwhich had been com-
pletely ineffective by itself proved to be effective when injected
in conjunction with glucose.
Later, we injected a still smeller quantity of antitoxin .- 0.01
antitoxin unit; toxin was also injected in the same dose as previous-
ly -- three MLD. The animaln of the first group, which had been in-
jected. with three MLD of tetanus toxin, became sick:with tetanus,
and they all died, with signs of generalized tetanus. The animals of
the second group (12 guinea pigs) received mixtures of three MLD of
toxin and 0.01 antitoxin unit of antitoxin; here, the two guinea
pigs died with signs of generalized tetanus, while the remaining 10
marked local tetanus occurred. The animals of the third group (16
guinea pigs) received three NEMI of tetanus toxin, 0.01 antitoxin
unit of antitoxin and five cubic centimeters of 20 percent glucose
solution. No tetanus infection was produced under these conditions.
On the third day after the injection of the mixture mentioned,
slight disturcances in motion were observed in seven guinea pigs of
this group. These disappeared after two days.
As seen from the results, the intensifying effect of glucose man-
ifested itself very distinctly in this experiment also.
In the next experiment we used a still smaller dose of tetanus
antitoxin., namely, 0.004 antitoxin units. Two groups of animals
were sUbjected to the experiment. The animals of the first group
(16 guinea pigs)vwere injected with the dose of antitmdlimentioned
and one MLD of tetanus toxin. Well expressed local signs of tetanus
developed in all the guinea pigs. The animals ,of the second group
(alno 16 guinea pigs were injected with mixtures of one MLD of toxin,
0404 antitoxin units of antitoxin and five cubic centimeters of 20
percent glucose solution; of this group, four guinea pigs did not
develop tetanus; the incubation period was increased in five 'guinea
pigs) the disease in one guinea pig was limitei to asymmetry of the
extremity. In the majority of the guinea pigs, rapidly progressive
local manifestations of tetanus developed.
It follows from the data presented that in this case also glucose
intensified the effect of the autitoxia.
In the next experiments, we used the same dose of antitoxin (0.004
antitoxin units) but with a significantly smaller quantity of tin
(three MLD).
...M????11.1
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In one of these experiments, the control group of guinea pigs
(eight animals) received a mixture of antitoxin and tetanus toxin;
one guinea pig of this group died from generalized. tetanus; in five
guinea pigs, local manifestations of tetanus developed; in two, the
process was limited to an asymmetry of the posterior extremities.
Eight experimental animals were injected with amixture of anti-
toxin, tetanus toxin and five cubic centimeters of 20 percent glu-
cose solution; in five animals, no tetanus developed; in the
other three, signs of asymmetry of the extremities were seen.
She intensifying effect of glucose was demonstratel quite dis-
tinctly in the given experiment also.
Afterwards, we used entirely small doses of the antitoxin
(0.0004 antitoxin units) and quite considerable quantities of the tox-
in (three MLD).
Four control guinea pigs which were injected with antitoxin and
tetanus toxin in the doses mentioned died on the third day with signs
of generalized tetanus. Out of five experimental guinea pigs which
received, in addition to antitoxin and tetanus toxin, five cubic
centimeters of 20 percent glucose solution, two died with signs of
generalized tetanus, one did not become sick, local tetanus develops
in one and signs of asymmetry of the extremities were seen.
The result of this experiment also demonstrates the capacity of
glucose to intensify the effect of tetanus antiserum.
In the last experiment, we utilized a negligible dose of serum
(o.wook antitoxin units) and three NW of tetanus toxin. This
dose of serum when injected in a mixture with glucbse did not pre-
vent the development of tetanus, but death of the experimental ani-
mals occurred two daysiater than in the control RnimeilR which had re-
eeived the indicated mixture of antitoxin and. toxin without glucose.
With the use of an injection of 0.000004 antitoxin units and
three MD of tetanus toxin, the control and experimental animals
died at the same time.
From the data presented, it follows that the administration of
glucose in 93 percent solution simultaneously with tetanus antiserum
increases the effect of the latter.
Without excluding the role of glucose as a nutritional agent in-
Unsifying the metabolism at the site of injection and also exerting
a detoxifying effect (V. V. Vasillyeva, 1941), a special distinction
should. be given to the property of glucose of stimulating the sen-
sory neural apparatus.
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.11= ? ? ? ? ? ? I. ?
'lbs results of our preceding investigation establishing the cap-
acity of glucose to alter the course of experimental tetanus intox-
ication after subcutaneous and intracardiae adninistration of it are
also in complete accord with the data presented in the present re-
port (T. V. Mitina, The Effect of Stimulation of the Sensory Nerve
Apparatus of the Heart on the Course of Experimental Tetanus Intoxi-
cation. In the book: Oa the MerhAntams of Disease and Recovery,
Livov, 1951).
The mechanism of action of glucose on the nerve-receptor appara-
tus consists, apparently, of increasing their excitability, which
then induces the rapid development of defense reactions even with
small quantities of the specific serum.
The effect of glucose on the sensory apparatus was also confirmed
in our next experiment.
Guinea pigs were injected.with a mixture, of antitoxin, tetanus
toxin, and glucose simultaneously with a one percent novocaine solu-
tion. It turned out that the injection of this mixture did notIca-
vent the development of tetanus or the deaths of the animals. %bus,
after the injection ofta mixture of four cubic centimeters of one
percent novocaine solution, five cubic centimeters of 20 percent glu-
cose solution, 0.1 antitoxin jnits of antitoxin and three MAD of
tetanus toxin, all the seven experimental animals became ill with
tetanus and died from it. At the same time, in 20 guinea pigs which
were given the same mixture without novocaine, no signs of tetanus
developed. It may be supposed, thus, that glucose, by acting on the
sensory nerve endings, changes their initial states, increases their
excitabilities and, by the same token, prepares an appropriate back-
ground for the action of the serum.
The results of our experiments coincide completely with the data
of M. D. Speranskaya, who Observed a significant increase of the
effect of tetanus antiserum experimentally ca rabbits atter it was
injected, on a background of strychnine intoxication of the svimila.
Strychnine, in the opinion of M. D. Speranskaya, increases the ex-
citability of the peripheral nerve sensory endings.
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THE EFFECT OF A DISRUPTION OF HIGHER NERVOUS ACTIVITY ON Mit DEVEL-
OINENT OF DIPHTHERITIC INIMICATION AND OF ARTIFICIAL IMMUNITY TO
DIPHTHERIA
N. M. Shtyrova and N. V. Stankevich
Department of pathologicalivhysiology of the Irkutsk Medical Insti-
tute (Head -- Professor N. M. Shtyrova)
Recently, many investigations have been made, devoted to the study
of the role of the functional state of the higher central nervous
system centers in the development of infectious diseases and the
development of immunity. In this group afe primarily the numerous
and quite contradictory experiments on the study of the effect of
anesthesia on the processet of infection and immunity.
Investigations on the effect of disruptioa of higher nervous act-
viity on the course of bacterial intoxications are of great interest
(L. I. Kotlyarevskiy, L. S. Gorsheleva and L. Ye. Khozak).
However, the datz obtained in these experiments are still far too
inadequate to permit one to consider that the question of the effect
of the functional state Of the higher centers of the central-nervous
system on immunogenesis and the development of disease is conclusive-
ly solved.
Ubis also stimulated us to perform experiments on animals for the
study of the development of diphtheritic intoxication and immunity
to this disease in various functional conditions of the cerebral .cor-
tex.
The experiments were performed on guinea pigs, in which the change
of the functional state of the cerebral cortex, under the given ex-
perimental conditions, produced the elaboration of a conditioned-de-
fense reaction, leading to a disruption of higher nervous activity.
An electric current served as the unconditioned stimulus. A bell
was used in the capacity of a conditioning stimOlus for one group of
animals; for the other group, the light of an electric light was
used.
The elaboration of a conditioned-defense reflex was accomplished
in a special chamber of the Ye. A. Vladizirova type which had been
modified somewhat by us.
She chamber consists of two different-size boxes with glass side-
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walls connected by a corridor. The floor of the larger box can be
pulled out; it contains transversely-situated, holes, In the areas
between the holes there are exposed electric wires which connect up
with a source of electric current (the city lighting circuit).
On the roof of the larger box there is a recess for an electric
light bulb with an external switch; the button of the bell is also
located here.
The guinea pigs were placed one by one into the large box of the
chamber. After a certain time, the bell was rung (conditioning sti-
mulus) with a subsequent (after a second) switching on of the elect-
ric current (unconditioned stimulus).
Ode
In doing this, a voltage was selected, with the aid of a transform-
er, to which the animals responded with motor defense reactions.
Usually, it was 90 volts.
After two to three combinations of the bell and current, a condi-
tioned defense reflex was elaborated by the guinea pip. To the
combination of the light and the current the reflex was elaborated af-
ter five or six experimental sessions.
Afterwards, a single ring of the bell or flash of *e electric
light was adequate to put the animals into a state of marked exci-
tation and to make them run squeaking into the opened door of the
corridor, through which they entered the chanber of the other box.
The sound conditioning stimulus thereby produced a more marked exci-
tation of the guinea pigs than did the light.
The experiments were conducted daily at one and the sane time over
the course of a month. in the experimental animals there was fre-
quently noted a disorder of the intestinal function (diarrhea), ul-
cerative keratitis developed, and a loss of weight was observed (the
weight dropped by 40-100 grams). Two guinea pigs died with the signs
described above. One guinea pig Y04th the sane signs recovered three
days after the experiments were concluded. A scar and a circumscrib-
ed corneal opacity remained on its affected eye. It is very interest-
ing that following injectii3n of it with 30 MLD of diphtheria toxin,
it again developed an ulcer at the same spot on the cornea ("second
blow", according to AL 1). Speranskiy).
The experiments were performed on 40 guinea pigs.
In the first series of experiments, the conditioned-defense reaction
was elaborated in experimental guinea pigs weighing 400 grams by
means of daily experiments for a month. After this, they were all in-
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jected with 1.5 MD of diphtheria toxin. At the some time, the
same dose of diphtheria toxin was injected also into control gui-
nea pigs of the same weight which had not been sUbjected to the
effects of any additional stimuli.
In the group of animals where the bell served as the condition-
ing stimulus, all the experimental guinea pigs (fiveln number) died
eight to seventeen hours after they had been injected with diph-
theria toxin. Of the five control guinea pigs, only two died; here,-
the deaths of the animals did not occur immediately after the injec-
tion of the toxinl as was the case in the group of experimental gui-
nea pigs, but rather on the third day.
In another group of experiments, where the electric light was
used in the capacity of a conditioning stimulus, all the experiment-
al AntrAls died 18-24 hours after they had been injected with diph-
theria toxin; of five control guinea pigs one survived; the others
died on the third day.
In the second series of experiments the experimental guinea pigs,
weighing 330 grams, were immunized with a single injection of diph-
theria toxoid, after which the conditioned defense reaction was
elaborated in them.
Control animals of the same weight were immunized at the same
time as the experimental animals and were not sUbjected to any ad-
ditional procedures.
Thirty days after the immunization, all the guinea pigs (experi-
mental as well as controls) were Injected. with 30 MLD of diphtheria
toxin each.
All five experimental animAla of the first group (the conditioning
stimulus was the bell) died 16-33 hours after the injection of the
toxin. Of the five control guinea 'pigs of this group two died on
the third day after the injection of the toxin; the remaining three
survived.
In the second group (the flashing of an electric light was used as
the conditioning stimulus), all five experimental guinea pigs died
18-24 hours after the injection of toxin. Of the five control ani-
mals, one guinea pig survived, while four died on the third day.
The investigations which were performed show that for the elabor-
ation of the conditioned defense reaction the strongest conditioning
stimulus is the sound stimulus (bell). N. A. Podkopayev also men-
tions this.
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The conditioned defense reflex was elaborated more quickly in the
animftle to the combination of the sound stimulus with the uncondi-
tioned stimulus (current) than to the ccMbination of light with the
same unconditioned stimulus. The conditioned defense reflex which
was elaborated in the guinea pigs to the use of the sound stimulus
was accompanied by quite an appreciable excitation and marked somatic
disorders. The latter also serve as indicators of the fact that a
disruption of higher nervous activity occurs in the animals in the
elaboration of the conditioned defense reflex to an electric current.
N. A. Podkopayev refers this stimulus to the group of disruptive
stimuli.
The experiments performed by us show, therefore, that a disruption
of higher nervous activity aggravates the course of diphtheritic in-
toxication and inhibits the development of antitoxic immunity from
the vaccination of animals with diphtheria toxoid.
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..,?????110.
ON THE QUESTION OF THE MECHANISM OF ACTION UP DIPHTHERIA ANTISERUM
O. Ya. ?atm and M. D. Speranskaya
Laboratory of Infectious Disease Pathology (lead -- O. Ta. Ostryy,
Doctor of Medical Sciences)
In our preceding investigations the significance of the patholo-
gical forms of stimulations of individual sensory zones of the tongue
was shown with respect to the disease mecha isms of diphtheria.
The tasks confronted us of elucidating the role of these zOnes in
the mechanism of the body's increase in resistance to the given dis.,
ease.
With this aim in view, an experiment was performed on 123 guineq
pigs weighing 240-250 grams, which were divided into four groups.
first control group was injected intravenously with one MLD of
diphtheria toxin.
If
The second group of animals was injected intravenously With one
MLD of diphtheria toxin and, immediately after this, with 0.001 anti,
toxin units of diphtheria antiserumalso intravenously.
The third group of animals was injected intravenously with one MLD
of diphtheria toxin and, immediately after this, with 0.001 antitoxin
units of diphtheria antiserum into the root of the tongue.
The results of this experiment are presented in the Table.
DEATH OF GUINEA PIGS FROM DIPMEERIA INTOXICATION FOLLOWINO THE INJEC-
TIONS OF DIPSTRERIA ANTISERA INTO Di .LENT S R11 AREA
No of
froup
4te of in-4
jection of
diphtheria
toxin
Dose of tSits
toxin
of in-,Doe.
jection of
diphtheria
antiserum
of 'Num-
serum
her
of
ani-
mals
Number of
which
them
Percent,.
age vbicl
died.
survived
died
1
Vein
3. MD
?
..
33
4
29
87.8
2
Vein
Same
Vein
0.001 AU
29
3
It
It
Tip of
tongue
If tl
4
n
n
Boot of
tows
ti il
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1
As seen from the Thble preiented, 87.8 percent of the animale in
the control group died. The intravenous adninisttation of 0.001
antitoxin units of diphtheria antiserum, just like the injection of
it into the tip of the tongue, decreases the mortality rate of the
aninale (to 58.6-571 percent) but to an appreciably smaller degree
than the injection of the same dose of serum into the root of the
tongue (33.3 percent).
Thus, one and the same dose of seium exerted different effects de-
pending on the site of injection of it. This difference cannot be
explained, under the conditions of our experiment, by an unequal re-
sorption of the serum into the blood. In injecting the serum into
the blood its effect was the sane as when it was injected into the
tip of the tongue, although in the latter case the absorption time
of the serum was lengthened. Moreover, the same dose of serum, when
injected into the root of the tongue, where the resopptive capaci-
ties do not differ essentially from those which are in effect after
the injection of the serum into the tip of the tongue, showed a
significantly greater effect, increaeing the survival rate of the
animals by 25 percent compared with the two preceding groups.
The facts obtained give us cause to consider diphtheria antiserum
not only as an agent which neutralizes the toxin, but also as a spec-
ific stimulus of the sensory nerve apparatus. This stimulation is
the primary link of the reflex process which alters the reactivity
of the body to a,pathological stimulus.
Such a conception finds its confirmation in those experiments
where novocaine was injected into the root of the totilgue. Under
these conditions also, It was possible to prevent the deaths of the
animals from diphtheria in a significant percentage of the cases,
even though a letha, dose of diphtheria toxin had been injected in-
to the novocainized zone of the tongue. TO. Ya. Oetryy and M. D.
Speranskaya, On the Role of Pathological Stimulations of the Sen-
sory Nerve Apparatus in, the Disease Mechanisms of Diphtheria in Ex-
periment (published in this collection)).
These data speak for the fact that it is possible to increase
the resistance of the body to diphtheria by nonspecific and specific
stimuli (novocaine, diphtheria antiserum) if they are Injected into
a definite seasory zone. By the same token, the question comes up
again as to the evaluation of the mechanisms of action of eels= pro.
phylaxis and therapy in a number of toxic-infectious processes.
Fran the experimental data presented it follows also that the
sits which proved to be most reactive with respect 'to diphtheria tox-
in simultaneously Was also the most effective for the action of spec-
ific serum.
.55'.
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The rules and regulations noted make it possible to outline new
perspectives in the research for effective forma of experimental
therapy of this disease.
?56??
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,????mIM.
ANASIMICAT., INVESTIGATIONS ar THE NERVOUS SYSTEMS aF ANIMALS INFECTED
WITH ANAEROBIC INFECTIONS UNDER common MAIMED BODILY REACTI-
vrn
Ye. A. Skvirskaya
Laboratory of Histopathology of the Nervous System (Head -- Pro-
fessor M. L. Borovskiy).
Ibie problem of our investigation was the anatomical study of the
nervous system reactions in the pathological process which develops
in animals after they are infected. withanaerobic infections.
According to the data in the literature, many infectious diseases
are accompanie*1 by extensive anatomical changes in the nervous system.
They have been noted in tuberculosis, typhus, septicemia, leprosy,
pneumonias, etc, (B. I. Lavrent'yev, M.L.0 Borovskiy, S.S., Vaylt,
L.I. Falin, V. F. Lashkov and others).
In the literature devoted to the study of as gangrene, data have
been presented. chiefly concerning the anatomical changes of the peri-
pheral tissues and of the neryous system directly at the site of
involvement. There are onlY individual indications of changes of
neural elements above the focus of involvement (A. N. Chiatovich,
A. A. Polyantsev).
Different data have been obtained concerning the changes in the
central nervous system in gas gengrenee A. A. AraPavslid not find
any anatomical changes in the central nervous system specific for gas
gangrene. A. V. Smol'yeanikov found characteristic nervous system
changes and came to, the conclusion that they are of decisive signif-
icance in the cause dt death of 'experimental Fuorialn from gas gang-
rens.
In selecting the methods of investigation we were guided by the
data on the development of neural dystrophic processes obtained in
A. D. Speranskly's laboratories.
By using the method of an additional influence on the body, we
attempted to change the anatomical reactions of the nervous system
and of the organs to the infectious agent, and, by means of anatomic-
al and electrophysiological study of the various central and. peri-
pheral nervous system centers to reveal the nature of these changes
and come to =understanding of their significance for the course and
outcome of the disease.
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Guinea pigs weighing 300 grams were infected with gas gangrene (The
infectitet was accomplished. b,y R. Ya. Zensanovich), by the injection
of a bacterial suspension of B. perfringens in a mixture with 0.3. cu-
bic centimeter of 110 percent calcium chloride into the right gastro-
cnemius asuic3.e. The right tibial. nerve on the side of the inOlvemen.t
was transacted before or atter infecting the animals. In different
experiments, different variants of this operation were used, namely:
a) transection of the nerve, b) transaction of the nerve and injec-
tion of 0.95 cubic centimeters of 70 percent alcohol into its peri-
pheral segment, a) transection a the nerve, injection of one to two
drops of vitamin 33, into its peripheral sigment and. subEsequent sutur-
ing of the nerve ends.
3:n the experiments where the operation was performed. on tha,nerve
after the infection, the times of the operation were varied: iiamedi-
atel,y after the infection, one hour after the infection, three hours
atter the infection, and. six hours after the inflection.
Guinea pigs served, as controls. They were divided into three
groups, namely, those in which; 1) only nerve trauma was produced,
2) only calcium chloride was injected. into the muscle, and. 3) trauma
of the nerve was produced and. calcium chloride was injected. into the
Muscle. In addition.; a series of experiments was performed. for de-
termining the rheobase and. chronaxie of the tibia3. nerves in the
infected, guinea pigs and guinea which bad *imply been injected with
calcium: chloride intananwscularly.
The following were subjected. to anatomical investigation: gastro-
ezemius muscles, skin of the thighs and. feet and, their neural struc-
tural:, sciatic nerves, intervertebral gent, a on the side of the in-
fection and on the opposite side, the 1 4,? ?acral end sometimes also
the cervicothoracic segments of the sp cor4 and. in apart of the
animals,. the anterior two fifths of the cerebral cortex.
The preparations were stained by the Nissl, Pd.ltshovskiy or Campos,
Bhovskly.Gross in the Lavrentlyev modification or 14a,rk modifica-
tion methods, and, for fate
In-the first stage of the work the problem was redueed to establish-
ing the 'nature of the netvous system changes in the fatal an& non-
fatal eases. Ten guinea pigs were investigated; of this number, sev-
en died, at different periods (freer one to fcirty days) after the in-
fection and. three survived and. were killed after six and. a half
Months; Through a comparison of the histopathological changes in
the spinal cord, intervertebral ganglia and peripheral segments ef
the nervous system and. also of those in the muscles .and, skin of the
animas which died and of those which survived, the following was es-
tablished. In all of the animas which died. after being infected
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OD.
with anaerobic infections dhanges were found in all the peripheral
nervous system sections studied by us and in the spinal cord both on
the side of the infection and on the opposite side (Pig. 1).
Fig. 1. Decomposition of nerve fibers in fasciculi of the left
gastrocnemius muscle of guinea pig which died a day after being
infected without nerve trauma (staining by the Bil,shovskiy-
Gross-Lavrent'yev method).
In the animals which died, severe necrotic and imflammatory pro-
cesses predominated. It should be noted here that severe, often ir-
reversible nerve cell changes were found, in the spinal cords of the
guinea pigs which died. Rarefaction and dissolution of the Nissl
substance, coaree vacuolization, shrivelling of cells, deformation
of their nucleoli, deposition of glia around the ganglion cells,
neuronophagia, and also ghost cells were seen.
In the guinea pigs which died two days after ,,eing infected with-
out additional nerve trauma, the changes in the cervical and. thoracic
segments of the spinal cord were expressed to a greater extent than
in the lumbosacral area. In all the animals which died after that,
more severe changes were seen in the sensory cells of the posterior
borne and in the internuncial neurons than in the motor cells of the
anterior horns.
The involvements of the motor cells of the spinal cords in animals
Wash died at short intervals after being infected. have the character
of so-called reversible changes and are expressed to a greater extent
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as????????????...."..
-
on the side of the involvement than on the opposite side; in gama
pigs which are sick for a long period of time, the changes are severe,
irreversible and are expressed approximately to the same degree on
both sides. Inflammatory foci were seen in the area of, the poster-
ior horns in certain guinea pigs.
In animals which died following the infection, where the latter
had been preceded. by trauma of the tibial nerve, in contrast to the
cases where infection Was caused without accompanying trauma, Waller-
inn degeneration (Fig. 2) rather than necrosis was found in the right
tibial nerve below the Site of the transection. Various anatomical
.1
'
Fig. 2. Wallerian degeneration of nerve fibers of the right tibial
nerve in a guinea pig which died. .threedays after being infected;
the infection was preceding by transectionce this nerve and alcoh-
olization if its peripheral segment. The alcbhol-triated nerve fi-
_Jbersareepreserved (stain., ng by the Billshovskiy-Gross-Lavrent,yev
method).
-
changes, including also signs of irritation, occurred in the contra-
laterial neural structures of the spinal cords of thesd animals. The
anatomical Changes in the contralateral intervertebral ganglia and
sciatic nerve were somtiMes expressed to a greater degree than on
the side of the involvement.
Microscopic stuay of the nervous systems of the surviving experi-
mental animals, which were then killed six and a-half months after
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being infected, revealed milder anatomical changes in the peripheral
system -- intervertebral ganglia, sciatic nerves, terminal neural
apparatus of the gastrocnemius muscles -- than in the guinea pigs in
the same series of experiments which had died. There were no changes
in the spinal cords of these animals.
The presence of a neuroma at the site of transaction of the right
tibial nerve and also neurotization of the peripheral segment of
this nerve and of the right gastrocnemius muscle in the surviving
animals permit us to draw the conclusion that regeneration of the
peripheral nerve is possible under the conditions of gas gangrene.
It should be noted that the, severity and character of the anatomic-
al Changes at the peripheryare associated with the severity of the
involvement of the nerve cells of the spinal cord and probably depend
on the state of the latter and of the higher centers of the central
nervous systems
A guinea pig which died after 40 days and also the surviving gui-
nea pigs may serve as examples of such an association. In the for-
mer, severe degenerative changes and marked signs of irritation of
the neural structures ol the contralateral muscle (Fig. 3) were seen.,
which coincided with the severe inflammatory process in the inter-
vertebral ganglia and, with severe disease of the ganglion cells in
these ganglia and in both halves of the spinal cord; the motor nuclei
were also involved here.
In the surviving guinea pigs the changes in the peripheral ner-
vous system were expressed to a much vdaker degree than in those which
died; the signs of irritation of the neural structures of the contra-
lateral muscle could be characterized as quiescent; the microscopic
picture of the intervertebral ganglia also attests to the former exis-
tence in them, apparently, of a noe quiescent pathological process.
In those 'guinea pigs, there were no changes in the nerve cells or in
the ntroma of the spinal Cord.
Study of the skin of these 10 infected guinea pigs showed that its
neural structures are better impregnated with silver than the normal.
This attests to the presence of some kind of physiological condition
of the cutaneous neural structures different from the normal, and ap-
parently reflecting the latered reactivity of the body as &whole.
We have also observed. appreciable ;ethological changes of these
nerve structures in the skin of degenerative and reactive character,
on the side of the infection as well as on the opposite side. In the
nerve fibers there were seen an inequality of the calibers, vari-
cosity, separation of the fibers, federal vacuolization, cork-screw
shaped convolutions and fragmentation of the axis cylinders. Along
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with these changes of the axis cylinders there were noted periaxonal
changes which were expressed unequally in different animals; they con-
sisted in an increase of the dimensions of the nuclei of the neuro-
lemma, near which reticulated structures were found. The latter
sometimes were of oval or cylindrical forms. Within them or along-
side them, the axis cylinder could be found; it maintained its in-
tegrity. It may be supposed that these reticulated structures arose
from the myelin sheath and the neurolemma.
In the neural apparatus of the encapsulated and, non-encapsulated
terminal corpuscles changes of the axone calibers and signs of vari-
cosity were found; no degenerative changes were observed. It could
be noted thereby that the character and intensity of the changes of
the neural structures of the skin depend on the duration and sever-
ity of the pathological process developing in the body and on the
outCome of this process. With a brief course of the disease and a
fatal outcome, degenerative changes of the cutaneous neural struc-
tures predominate, and these are expressed to a greater extent on
the side of the infection. With a prolonged course of the disease
and a fatal outcome, the signs of irritation of the axon's predomin-
ate; these are expressed both on the side of the infection and, on the
opposite side. In the surviving animals the changes of the neural
structures of the skin were expressed to an appreciably milder de-
gree, are encountered less often than in the animals which died, and
have the character of signs of irritation on the side of the infec-
tion as well as on the opposite side.
41771!, Alta&
:
? s,-,? =
46.
eftwv7,0011:
"
Fig. 3, Aeu#oma. Of motor nerve ending of left gastrocnemius mus'
of guinea pig Which died 40 days after being infected., which was
precoam4y a transaction of the right tibial nerve and alcohol.tre
mutt of its petiPheial eigmeat (staining by t1*Bil,shovskiy-Gros
,Lavrent'yev method).
C1=IIM?mm.M=I/01
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r-e,-.-7V"e?rn,=2"17..m. .e?-..-77m-Ters-nr
-
4
The next stage of our work was conditioned, by the need for differ-
entiating the nervous system changed produced. by the microbial few-
tor from. the changes produced. by supAimmaktaryprodedures -- nerve
trauma, injection of Calcium chloride into the muscle and the combina-
tion of nerve trauma with the injection of Calcium chloride into the
muscle. In all, 18 guinea pigs were investigatedl of which 12 guinea
pigs were infected; same were subjected to additional nerve and
some were not. Six guinea pigs were subjected only to the supplement-
ary procedures without being infected. The guinea pigs were killed
seven and 21 days after these procedures.
In the presence of 'nerve trauma alone, only degenerative and regen-
erative processes occur in the traumatized nerve; no Changes were
found in the central nervous system. Changes of the neural structures
of the muscle on the opposite side were also absent. The solution of
calcium Chloride, in the same concentration which we used for injec-
tion into the muscle, produces not only necrosis of the muscle tissue
but also degeneration of the neural structures of this muscle, degen-
eration of the nerve innervating it, so-called reversible and irre-
versible changes in the intervertebral ganglia and signs of primary
irritatien of the motor nerve cells of the spinal cord (Fig. 4). The
Fig. 4. Degeneration of the right tibial nerve after the injec-
tion of calcium chloride into the right gastrocnemius muscle
(staining; by the Bilishovskiy-Gross-Livrent'yev method).
coMbination of the two procedures mentioned led to an intensification
of the signs of primary irritation of the nerve cells of the spinal
cord.
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; rf n?F '???
Pathological changes of the nervous system of the infected gui-
nea pigs differed from those which had. not been infected, but which
had. been subjected. tothe effect of calcium chloride. Thus, in the
guinea pigs which had been infected, without additional nerve trauma,
an inflammatory process was found. in the pia roster and. in the cdre-
bral cortex, expressed to a greater extent on the left than on the
right (Pi. 5).
*. - '.'1?PdAtk ir ? ..? ' 1 -
? :-..,,...%?
4i- ? : 14 4c C
??.,
? ??
:V - ,:k ? ?
,;.14..
1?40:-.0'.
,?i".
; . Mf w, ; on' ?-?1'N
-,...n ? ; ??????41 d' S 4i' .0...
iv. ..... 4.1*
e. : It er
4s, ? iio ..r,
le*
,
.12-e,'?
-er
?.*
44,
Fig. 5. Inflammatory changes of the pia meter of the cerebrum
of a guinea pig which had been infected without nerve trauma
(Nissl stain).
Signs of primary irritation in the intervertetre ganglia occur
sooner in the infected guinea. Trigs than in the guinea pigs in which
.nerve trauma had been produced. by the injection of calcium chloride
into the muscle. The inflammatory process in membranes of the in-
tervertebral ganglia and. also the so-called reversible and irrever-
sible changes in the nerve cells of these ganglia were sometimes ex-
pressed to a greater extent on the so-called healthy side than on the
side of the Intervention in the cases of the guinea pigs which had.
been infected without supplementary influences as wall as in the gui-
nea pigs which had been simply injected intramuscularly with calcium
chloride. ,The regeneration of the traumatised nerve was delayed in
the infected animals in comparison with those which had not been in-
fected.
Signs of irritation in the opposite wastrocnemius muscles of in-
fected guinea pigs with settere involvements of the infected, pews were
expressed to a much greater extent than in the remaining animals.
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Certain observations point to the role of the time factor in the
development of the pathological process in the experimental guinea
pigs.
Thus, in guinea pigs which had been operated siri hours after the
infection, neurotization of the nerve and muscle were expressed
better than in the other infected animals and approximately the same
as in guinea pigs which had been subjected simply to an operation on
the nerve. Hence, the conclusion may be drawn that under certain
conditions of infection, regeneration of the traumatized nerve is
possible. With an operation on the nerve after the infection (es-
pecially after six hours) a lessening of the anatomical changes is seen
in the intervertebral ganglia and improvement of the process of regen-
eration of the traumatized nerve compared with what occurs in other
animals investigated.
For studying the functional state of the nerve innervating the in.-
fected muscle and that of the corresponding nerve of the opposite
side, the rhbaase and chronaxie of this nerve were determined in
guinea pigs which had, simply been injected intramuscularly with cal-
cium chloride (control).
Determinations of the rheobase and of chronaxie were made atter
three and six hours, then at one, three and five days after the pro-
cedure. These determinations showed a decrease and then a loss of ex-
citability of the nerve innervating the involved muscle, in the ex-
periment as well as in the control; the excitability was not restored
for the entire period of the observation.
In the opposite nerve, a decrease of the excitability was noted dur-
ing the first few days in the experiment as well as in the control.
However, in Oontrast to the experimental animals, in the controls the
negnitudes of the rheobase and chronaxie were afterwarda restored al-
moat to normal.
These facts indicate the fact that infection of the body produces
more constant 'reflected changes than does the injection of calcium
chloride intramuscularly*
As seen from the data Obtained by us, calcium chloride, when inject-
ed in certain concentrations into the muscle produces pathology not
only in the muscle tissue but also of the nervous system, which appar-
ently alters the reactivity of the body. Such an alteration of the
reactivity of the body facilitates the development of disease under
conditions of introduction of anaerobic infections.
Certain agents used by us, however, exerted favorable effects on
the outcome of the disease.
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11.?=0.????.....110
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411..to
By additional procedures it was, therefoie, possible to alter the
reactiVity of the body., under some conditions, in the direction of
intensifying its "physiological measures" against disease, and under
other conditions, contrariwise, in the direction of ireakening these
"measures".
As has been indicated. above, In guinea:Edge sick with anaerobic in-
fections, the cutaneous nerual structupes wore demonstrable with much
greater prominence than in the healthy animals. Making use of this,
we managed to Obtain abetter conception of the structure and distri-
bution of tee neural apparatus of the akin of the thigh and, foot in
gui ea pigs and to coantruct an outline of their inntivation.
While we do not have the opportunity to present the data Obtained
in detail, we shall discuss only certain, we believe, new facts in
this connection.
It was shown that the innervation of each section of skin is char-
aeterized. not only by a certain number api structure of the neural
formations but also by a definite linkage of them. We observed the
gro!iping of certain *Ural Apparatus and also the linkage of the en-
capsulated corpuscles with the free terminal branches. In all the
investigated areas and in all the layers of the skin small noa-
capsulated balls were found, which were formed along the courses of
bunangs of nerve fibers by concentric rings of the nerve fibers
which made up these bundles. We have not found any descriptions of
neural structures like these amall balls in the literature avail-
able to us.
The following hypothesis may be expressed concerning the function
of these balls. They serve, possibly, just like other neUral struc-
tures, for the transformation of neural excitation' Or else for its
intensification. If this hypothesis is correct, then, in addition to
the peripheral nerve structures which transform an external stimu-
lation into neural excitation, it is possible to accept the existence
also of structures which transform the neural excitaticnImbich is
already progressing along the neural pathways of the skin.
.66.
4,????1??=?.1.1.
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grs,
al...??????????""..
.001
BIOCHEMICAL CHANGES IN TEE CENTRAL NERVOUS SYSTEM FROM VARIOUS TOXIC-
INFECTIOUS PROCESSES
H. Sh. Promyslov
Physiological analysis of the mechanisms 02 disease and recovery
can be made substantially more profound by including, in the analysis
those biochemical changes which occur, thereby, in the central ner-
vous system.
Unfortunately, at the present time the number of investigations
which might disclose the biochemical essence of the change in react-
ivity of the body in the.toxic-infectious processes is still inade-
quate.
At the same time, it is hard. to imagine that the profound changes
which occur in these processes are without pertinence to the trophic
function of the nervous system, or that they do not produce appreci-
able biochemical changes in the body.
I. P. Pavlov ascribed great importance to physico.chemical invest-
igation for obtaining knowledge of the essence of the processes which
occur in nerve tissue. it can hardly be disputed," he wrote, "that
an accurate theory of all neural phenoamna will be obtained. by us on-
ly through a study of the physico-chemical process which occurs in
nerve tissue; knowledge of its phases will give us a complete ex-
planagon pf all the extarnalumnifestations of nerve activity, their
sequence and associations." (I. P. Pavlov, Collection of His Works,
1949, Vol III, p 346).
We Studied the changes of the nitrogenous substances of the brain
and spinal cord after the actions of various toxins on the animal
body. The experiments were performed on rabbits.
Changes of the nitrogen metabolism of the brain usuaUy are
identified with changes of protein metabolism. However, such an
identification is not justified, especially in the investigation of
nerve tissue, Nerve tissue, specifically brain tissue, contains 60
percent lipids; the spinal cord, 70 percent. The nitrogen of all
the lipids comprises 14 to 1, percent of the total nitrogen of the
brain and 23 to 24 percent of the total nitrogen of the spinal cord.
Therefore, we studied three separate fractions of the brain tissue:
a trichloracetic extract, protein nitrogen and lipid nitrogen. It
was established thereby that the changes produced by the toxins in the
brain and. spinal cord are distinguished by specific qualitative and
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quantitative characteristice in the presence of a developing patho-
logl.cal process.
In contrast to the action of diphtheria toxinp.which produces a
diminution of the proteins in the brain as well as in the spinal
cordl the action of tetanus and gas gangrene toxins lead to diminu-
tion of the nitrogenous lipids only in the brain. With generalized
tetanus and gas gangrene, no disturbances of the metabolism of nitro-
genous sOstances are seen in the spinal cord. It should be noted_ al..
so that in local tetanus we did not find any changes in the nitrogen
balance either in the brain or in the spinal cord. In addition, a
lethal dose of tetanus toxin produces unitypical qualitative changes
in the brain, regardless of the ate of injection and of the clinical
picture of tetanus. At the same time, the quantitative relation-
ships, which are expressed in observable changes, are varied.
Because the basic nitrogenous lipids of nerve tissue are phospho-
lipids and cerebrosides, we decided to clarify the question as to
which of these compounds is diminished in general tetanus and which,
in gas gangrene.
With this .aim in view, we determined the phosphorus and nitrogen
of all the lipids of the brain and for purposes of chare,cprizing
them we took the relationship of phosphorus to nitrogen in normal
rabbits Aladin rabbits which had. been injected. with lethal doses of
tetanus toxin and B. perfringens toxin, It was found, In doing this,
that the quantity of phosphorus of the cerebral phospholipids does
not change in the experimental animals comparied with the normals;
the relationship of phosphorus to nitrogen, however, increases.signi-
ficaatly. This made it possible for us to draw the preliminary con-
clusion that in generalized, tetanus and gas gangrene a decrease oc-
curs in the cerebrosides of the brain.
In order to convince ourselves of the accuracy of this conclusion
we worked out a method of determining the bilain cerebrosides. Sep-
aration of the brain tissue lipids was accomplished. by successive sin.
hour extractions with ether, acetone, and a 1:1 mixture of chloro-
form-with methyl alcohol, respectively. Then, the solvent was dis-
tilled. off, and the lipids were sUbjected to hycrolysis. After this
the galactose was determined quantitatively by the calorimetric meth-
od. The determination was carried out by means of enthrone, with
which galactose gives a blue coloration in concentrated sulfuric acid.
The auantity of galactose found multiplied by 4.6 (the conversion fac-
tor) gave the quantity of cerebrosides of the brain.
These determinations confirmed. our preliminary conclusions. In
effect, in generalized tetanus and gas gangrene a decrease occurs in
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the cerebrosides of the brains of rabbits.)
It is interesting that the latter investigations showed the pre-
sence of a larger quantity of qdrebroeides in the spinal, cords of
rabbits than in their brain; nevertheless, the quantity of care-
brosides in the sicpel cord did. not undergo any cbanges in either
tetanus or gas gangrene.
The established fact is Of interest also with respect to the fact
that the biological role qr the cerebrosides has still :labia clari-
fied in the processes Of Metabolism in nerve tissue.
Until recently, investigations were limited simply to noting
the fact that cerebrosides are contained in nerve tissue in large
amounts.
Thus, two lines of metabolic disturbance of nitrogenous com-
pounds were established. by us: 1) in diphtheria -- where a decrease
in the cetebral protein nitrogen is seen, and 2) in tetanus and gas
gangrene -- where decrease is seen of the nitrogen of the cerebral
cerebrosides.
It seems to us that consideration of these facts aids in estab-
lishing the fact that diphtherial-tetanus and gas gangrene are din-.
eases in which the developments of the pathological processes are in
each case specific and clearly definable involvements of the brain.
However, these involvements in tetanus and gas gangrene are qual-
itatively unitypical in their biochemical expressions.
Evidently, the generality Observed here characterizes only the
type of functional and organic change in the central nervous system
which reflects the unity of the reactive Changes connecting the van..
ous nosologic forms according to the characteristics of their dys-
trophic processes; these processes have been shown here to be inde-
pendent of the Characteristice of the causal agent itself. In other
words, we have before us a group reaction, not an individually spec-
ific reaction.
Only the finding of a basic link in all the varied. biochemical
processes occurring in the centratnervous system can bring us closer
to an understanding of all the mechanisms which underlie disease
and recovery. The finding of this link will aid.us in solving the
problem indicated here.
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ON THE ROLE OF THE HIGKER CENTERS OF THE CENTRAL NERVOUS
SYSTEM IN COMPENSATING FOR DISTURBED vbrant's 07 TIIE BODY
S. I. Frankehteyn
Laboratory of Comparatiye Pathology (Head -- Professor S. I. Frank-
shteyn)
"The more perfect the nervous system of an animal and the more
centralized it is, the more its highest center is a director and dis-
tributor of the entire activity of the body, despite the fact that
this does not come out clearly and openly." (I. P. Pavlov, Completh
Collection of His Works, 1951, Vol III, p 409).
This statement by I. P. Pavlov contains a broad. program of cooper.
ative-evolutionary investigations. It should, howevdr, be recognized
that the role of the higher centers of the nervous system in regula-
ting the functions of the body has been investigated very systemat-
ically only with respect to the motor function, where the signific-
ance of these centers is manifested in particularly distinct form.
The removal of the cerebrum in fish, amphibians (frongs), and. rep-
tiles (turtles) does not produce any constant changes in the motor
function: decerebrate fish continue to swim, frongs continue to
swim and dump, and turtles continue to crawl.
Beginning with the birds, compensation of the motor function dis-
orders produced by the removal of the cerMxnumbecomes quite dif-
ficult. In pigeons an& roosters, for example, the removal of the
fore-brain produces distinct disturbances of motor function: de-
cerebrate birds move about very slowly, loos their abilities to take
wing by themselves, alight awkwardly when thrown up into the air.
Removal of the cerebral cortex in reasnals is compensated with
still greater difficulty. In dogs, decortication produces marked
disorders of motor function. Coordination is notably affected
thereby; the animals walk by throwing their paws forward, at a high
level, lose their equilibria when pushed, cannot run, permanently
lose their capacities or differentiated movements of the front paws
.- the ability to dig holes, hold, bones, etc.
Disorders of motor function produced by the removal of the cere-
bral cortex in Monkey* is even more poorly compensated..
Thus, in the process of evolution, by virtue of the ever greater
centralization of the nervous system, the possibility Of replacing
functions of some of its parts by those ofobbers becomes more and more
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111????==liP
limited..
The capacity of the higher centers of the nervous system to regu-
late the entire activity of the body, and not lust the functions of
movement and those of the higher sense organa, is suggested. by a stu-
dy of the role of these centers in the process of evolution and in the
regulation of the so-called vegetative functions: cardiac activity,
respiration, digestion, urinary excretion, etc. These questions have
been subjects of investigation in the group directed, by us for the
period of the past few years.
The investigations mentioned herh have been carried on in two di-
rections. On the one hand,- we studied the compensation of the fUnc-
tional disorders produced by the operation of decerebration itself;
and on the other, the capacity of decerebrate animals to compensate
for functional disturbances produced by the effect of extraordinary
stimuli on the body.
For the investigation of the mechanisms of compensation we util-
ized the method of conditioned reflexes, along with the method of
decerebration.
In approaching the comparative investigation of, therole of the
higher centers of the nervous system in the processes of compensa-
tion it is important to take into account the Characteristics of the
brain structure at various stages of evolution.
In fish) amphibia, reptiles and, birds, the fore-brain is repres-
ented chiefly by the subcortical nuclei, which graduolly 'become more
and more prominent, attaining very large dimensions in. birds. The
layer which covers these nuclei is represented in fish by epithelial
cells; in amphibians, by a thin layer of nerve cells. In the rep-
tiles, this layer is increased in size, but in, birds it again under-
goes a certain reduction with a simultaneous increase in size of the
subcortical
Only in the mammals, especially in the highly developed ftrimaln,
i0 this layer represetned. by a very well developed cortex, which we-
dominates over the other parts of the brain.
Therefore, by removing the fore-brain in fish, amphibia, reptiles
and birds we are removing a homologous structure represented chiefly
by the subcortical nuclei. In meamals, complete removal of the
fore-brain (that is, of the cortex and subcortical nuclei) is im-
possible, because this operation leads to the rapid deaths of the
animals. In the procesS of decortication the subcortical nuclei are
to some degree injured and afterwards undergo partial tieganeratiort,
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but this, to be sure, is nbt equivalent to their complete withdrawal
as in removal of the fore-brain in animals of the lower classes.
wising this circumstance into account, it is impossible to identi-
nr tie copse minces of in mamas with the consequences
of removal of the fore-brain in representatives of other classes.
In the comparative investigations of the role of the higher cen3
tars of the nervous system in the regulation of cardiac activity we
made use of the method of electrocardiography, which made it possible
to judge objectively the activity ofthe heart, although this is not
a completely exhaustive functional Characterization of it.
If the fore-brain of a fish is removed (the experiments were done
on crucians), no 'changes of the rhythm nor any qualitative character
istics can be noted in the electrocardiogram.
Investigations of the electrocardiograms of frogs before' and after
removal of the fore-brain showed, that, after brief (over the course of
several minutes) periods 9f slowing, and sometimes of increased fre-
queney, of the cardiac activity, sinus arrhythmia occurred.
In addition, *n increase in the size of the electrocardiographic
waves, and, in a nuMber of experiments, splitting of the P wave, is
noted, which give evidence of the lack of simultaneous involvement
of both atria by the excitation process. The changes mentioned are
brief and disappear on the second day.
More marked disturbances of cardiac activity, up to complete cess-
atien of the heart, occur only when the brain is transacted at the
level or the optic lobes, which was shown by I. V4 Seehenov.
Electrocardiographic examinations before and after decerebration
in reptiles -- swamp turtles and lizards (agamas and monitors) --
showed that a very brief retardation or acceleration of cardiac
activity and an increase in the size of:the waves occur in them.
However, these disturbances are quitecp.takly compensated iLthese
cases also.
Very distinct and. constant cardiac activity changes occur be?
ginning with the claim Ares.
Electrocardiographic investigations showed that the removal of
the cerebral hemispheres in pigeons and roosters produces a, marked
retardation of cardiac activity, in individual experiments going
down to 80-100 beats per minute (instead of the normal 300?350).
Tea to fifteen days after the operation, the bradycardia becomes
't ?
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somewhat less definite, but is maintained throughout the entire life
of the decerebrate animal.
An analogous regular increase in the part played by the higher
centers of the nervous system is also noted with respect to the reg-
ulation of respiration.
After the removal of the hemispheres in frogs, their respiratory
movements slow up for several minutes; sometimes, they accelerate.
In some experiments, periodic respiration can be seen on the second
day after the operation, but then the respiration returns to normal.
The phylogenetically older respiratory movements of the submaxillary
muscle of the frog are altered to a lesser degree, after this opera-
tion, than pulmonary respiration.
Removal of the hemispheres of reptiles (especially, turtles), as
our experiments showed, produces very brief, rapidly compensated
changes of the respiratory movements.
Hera again, just as in the case of the cardiac functions, perman-
ent respiratory disturbances following removal of the hemispheres
develop only in birds. Observations existing in the literature
(0. P. Molchanova, B. I. Bayandurov and Pagel' and others), which
have also been confirmed. by our experiments, show that removal of
the hemispheres of birds produces permanent retardation of the res-
piratory movements and. a decrease in metabolic rate, which continues
until the animaldie.
In general, the same rules and regulations have been established
by us also with respect to the function of digestion. Roentgeno-
scopic examinations of the evacuatory function of the gastro-intest-
inal tract and a study of the rate of digestion showed that distur-
bances of these functions are also brief following decerebration of
the frog, but are expressed to a greater extant than are disordgrs
of respiration and of cardiac activity. However, atthr one to two
days, these disturbances are also eliminated.
In birds, following the4removal of the cerebral hemispheres the
functions of the gastrointestinal tract are inhibited markedly and
for a long time, as are also the functions of the heart and. respir-
ation. Roentgenographic investigations showed that the inhibition
of the motor function extends not only to the crop (as has been
noted previously in the literature) but also to the entire gastro-
intestinal tract and continues until the animal dies.
Finally, we have obtainedetalogous data in the study of diuresis.
After the decerebration of frogs, the output of urine is only slight-
ly altered; in birds after the same operation, the urine output is
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qrf
decreased. by two to three times.
Thus, the investigation of the condition of certain vegetative
functions in representatives of various classes of vertebrates
showed that the disturbances of activity of the internal organs pro-
duced. by the removal of the hemispheres in fish, amphibians and rep-
tiles are very brief and are easily Compensated. Distinct and per-
manent changes are seen. only starting with the class of birds.
Birds, in contrast to all the preceding classes, are warm-blooded..
In order to understand the tremendous significance of this fact in
the process of evolution, it is sufficient to remember that 95 per-
cent of the energy obtained from food, in the case of the warm-blood-
ed animal in a resting state, goes into the maintenance of a con-
stant body temperature, and only five percent of the energy is spent
for the maintenance of the work of the heart, gastrointestinal tract
and other systems of the body. This explains the ability of the low-
er classes, which do not have constant body temperatures (fish, am-
phibia and reptiles), to survive without food for months, and some-
times even longer.
A constant body temperature ,ie a tiemendotis step forward in the
adaptation of the body to changing environmental conditions.
For purposes of beat output, in addition to certain adaptations
of the integument (feathers, wool, swaat glands, etc.), systems
which were built pp at earlier times (respiration, circulation) con-
tinue to be utilized. Thus, for the occurence of homoeothermism the
functions of the body had to be made, to a greater degree, sPbserv-
ent to the central nervous system.
This, it seems to us, has also made possible the fact that, be-
ginning with the class of birds, the importance of the higher ner-
vous system centers as directors and distributors of the entire body
activity is manifested in particularly distinct fashion.
The more the nervous system regulates the actiirity of the organs
at the periphery, the more it itself must be under the influence of
impulses from the periphery, because only with the fulfillment of
this condition is central regulation of the activity of the body pos-
sible.
I. M. Sechenov directed attention to the ntiark sensation." which
is conditioned by impulses from the muscles. The possibility of the
passage of impulses from the internal organs to the highest centers
of the central nervous system has been shown by the experiments of
I. P. Pavlov, K. K. Bykov and others. Our experiments permit us to
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entim,rmAmik
assert that in the process of evolution-this stream of impulses
should dhow itself most distinctly beginning with the class of birds.
From this point of view, we cannot help but express wonder at the
fact that to date only the role of exteroceptive stimulations is be-
ing taken into account in the evolution of the brain. Thus, the de-
velopment of the fore-brain is made dependent on the olfactory organ;
of the mid-brain, on the visual organ; and of the hind-brain, on the
auditory and vestibular organs. Our data permit um to assert that,
in any case, beginning with the class of birds the interoceptors
assume great importance in the evolution of the brain, and particul-
arly of its anterior segments.
Experiments on the investigation of the state of the vegetative
functions after the removal of the fore-brain have been conducted by
us mainly with the aim of further study of the reactions of decor.-
brats animals to excessive stimulations.
However, as has been shown, these experiments are independently
interesting, because they demonstrate graphically the ever increas-
ing importance of the higher centers of the nervous system in the
regulation of the vegetative functions. This also is at the basis
of the different degrees of recovery of those functional distur-
bances which are caused by the operation of decerebration itself.
The reactivity to excessive pathological stimulations is altered
in accordance with the role. assumed by the fore-brain, as our exper-
iments have shown.
The Choice of the form of the excessive stimulation requires spec-
ial discussion, the utilization of biological and chemical stimula-
tions in comparative-evolutionary investigations is made difficult
because of the varied swiss sensitivities to these stimuli. #iis is
why we used localized tissue inuury, that is, the method which as
widely used in his investigations by the founder of comparative
pathology, I. I. Nochaikov. This form of stimulation waslilso used
by 14 Y. Sechenov, I. P. Pavlov and N. Ye. Vvesdenskiy for the invest-
igition of the mechanisms of pat.hological reactions.
/.?
? la our investigations, we used, along with localised thermal in-
jury of the tissues, diphtheria and tetanus toxins, intoxications of
the animals with mercuric Chloride, injections of turpentine into
the tissues and disruptions of the coronary circulation of the heart.
The most marked difference in the reactions of the normal and de-
cerebrate animals to exeessiVe.stimulatio0 is seen in the class of
birds. It is manifest:0d chiefly in the fact that the functional re-
actions of decerebrate birds to .excessive stimulation are, as a rule,
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more weakly expressed and rapidly cease.
Thus, the acceleration of cardiac activity after various myocardi-
al injuries, which in the normal pigeon continues for several days,
is expressed more weakly in the decerebrate pigeon and lasts a total
of several hours.
Lung injuries, which in normal birds produce increases in the res-
piratory rates and of metabolic rates, can in decerebrate birds, on
the other hand, produce a retardation of respiration and a decrease
in metabolic rate.
The injection of turpentine into the tissues, which in normal
birds produces a distinct increase in theiemperature, increase in
frequency of cardiac activity and respiration, evokes weakened and
rapidly abating reactions in decerebrate birds. Fuactional disord-
ers after mercuric chloride intoxication are expressed to a milder
degree in decerebrate birds than in normal birds.
The fact attracts special attention that weakening of the function-
al reactions is accoMpanied by a general diminution of resistance to
excessive stimulations..
Using the sane strengths of excessive stimulations, normal birds,
which respond with marked functional reactions, remain alive, while
decerebrate birds, in which these reactions are weakened, not uncom-
monly perish.
From these experiments it follows clearly that functional reac-
tions can have protective natures, and that theirtecurrences depend
on the higher centers of the-nervous system.
In connection with the data obtained by us, the work of P. A.
Paratynskiy is interesting; this work was carried out at the end of
past century according ito the suggestion and under the direction of
I. P. Pavlov. The author studied the effect of narcotic agents on
decerebrate fregs andiigeons. Be showed that these agents equally
affect frogs f.rom which the Cerebral hemispheres tem, been removed
and normal frogs. In decerebrate birds, however, the functional re-
actions were weakened (specifically, no stage of excitation occhred
after the narcotic agouti), and the resistance to narcotic agents de-
creased markedly. Therefore, our data coincide with those of the
'investigation presented.'-
We have already mentioned, that in mammals only the removal of the
cortex is possible under conditions of the chronic experiment, be-
cause complete removal of the fore-brain, that is, of the subcortical
ti???????./1.0.
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nuclei also, rapidly causes the deaths of the animals. This fact in
itsle is clear-cut proof of the high degree of centralization which
is present in the nervous system in this stage of evolution and of
the importance which it assumes for the regulation of the entire ac-
tivity of the body.
Preservation of the subcorticanuclei in the process of decortica-
tion of mammals permits them to adapt themselves better to the defect
than can birds in which the fore-brain is removedes a whole. This is
why in mammals in which the cortices have been removed, disturbances
of the vegetative functions are expressed more mildly than in de-
cerebrate birds.
As I. P. Pavlov has shown in his salivary gland experiment, in ani-
mals in which the cortex has been removed the conditioned reflex re-
gulation of vegetative functions is impaired. Unconditioned regula-
tion is preserved: food stimulation of the oral cavity continues to
produce salivary excretion reflexly. It was shown by the experiments
of Zeleniy that six to seven months after decortication the excre-
tion of gastric juice in response to a mock feeding is restored. In
time, the evacuatory function of the stomach is restored, as is also
the periodicity of hunger. Thus, in mammals in which the cerebral
cortex has been removed there is no permanent inhibitiomof the evacu-
atory function which is seen in birds after complete removal of the
cerebral hemispheres. After the removal of the cortex in dogs, the
normal rates of cardiac activity and respiration are recovered in
the first few days.
Investigations which have been conducted in our laboratory have
shown that in rats, rabbits and cats removal of the cortex does not
produce any distinct electrocardiographic changes. In dogs, a cer-
tate lability of the waves is noted.. lioweVer, this, apparently, de-
pends oaths changes of position of the diaphragm following the remov-
al of the cOrtex. More distinct changes of the electrocardiograms
appear after the removal not only of the duperficial but also of the
basal parts of the cortex; here, the function of the hypothalamic
area is distrubed to some degree.
Our inveatigations shoved, that in dogs iii which the cerebral cor-
tex had been removed the metaboliC rates not only did. not decrease
but they even increased somewhat, which may?be astociated with their
increased motor activity. The amount of urine excreted, its composi-
tion and specific gravity showed no deviations from the normal in
dogs in which the cortices had, been removed..
Therefore) with respect to the functions of the heart, respiration
and diuresis of dogs in which the cortices had been removed, the per-
menent inhibition characteristic of birds In which the hemispheres
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have been rani:Wed was not found.
With the aim of a comparative study of the reflex reactions of nor-
mal dogs and dogs in which the cortices had. been removed, we under'-
took the investigation of their olfactory reactions to painful stimu-
lations of the skin by electric currents.
The latter produces a stormy motor reaction, shortness of breath,
defecation and urination in operated dogs. These undonditioned ref-
lex reactions are expressed to -a somewhat greater extent in them than
in normal dogs. After turning off the current, the dog jerked its
head and trunk for some time; shortness of breath lasted somewhat
longer in it than in the normal, and there vas greater inhibition of
hunger periodicity.
The difference in the reaction of the decorticate dog to electro-
cutaneous painful stimulation depends also on the absence of its high-
erenalyzers. The normal dog tries to rip off the electrodes, gnaw
through the electric wire, tear itself away from its straps. AL dog
which has been deprived of its cortex is not able to find the plasm
where the painful stimulation is being applied; it turas its muzzle
in the opposite direction., gets hold of one of its front ;laws (the
electrodes are attached to the hind extremities) and, begins to bite
it, sometimes drawing blood.
In the normal dog, as is well known, even after the second or third
application of the painful stimulation, a conditioned. reflex reac-
tion is elaborated to the situation, to the experimenter's touching
the induction coil, etc. In strength, the conditioned olfactory re-
action, motor as well as vegetative (shortness of breath, anuria,
etc.), does not lag behind. the unconditioned reaction.
Quite naturally, in the decorticate dog no conditioned olfactory
reaction occurs.
A clear picture should be Obtained of the correlation of the con-
ditioned and unconditioned reflex regulations of mammals for analyz-
ing their reactions to excessive stimulation and for analyzing the
role of the cerebral cortex in the compensation for distruhance of
functions.
Removal of the cortex in dogs disturbs the conditionel reflex re-
action, particularly, coordination. Against this background, addi-
tional injuries of the nervous system or of the motor apparatus can
altogether deprive the animal of the capacity of standing or walking
(E. A. Asratyan). thconditioned reflex reactions (for example, ol-
factory reactions to electrocutaneous stimulation) in decorticate
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dogs, on the other hand, are not only preserved, but can even be in-
tensified by virtue of the elimination of cortical inhibition. The
same thing is seen with respect to the reactions of decorticate ant-
to other excessive stimulations also.
In response to localized injury of the stomach mucosa in dogs de-
prived of the cerebral cortex, vomiting and incessant contractions of
the hunger type appear, which are seen also in normal dogs when the
same procedure is performed. As our preliminary data show, these
disorders apparently may be protracted in dogs in which the cortex
has been removed.
Circumscribed myocardial injury in decorticate dogs produces btu"-
ically the same functional cardiac changes as in normal dogs. How-
ever, during the period when these disorders are completely compen-
sated in the normal dog, they can reappear in decorticate animals. -
Thus, a convulsive attack produced by an electric current in a de-
corticate dog provokes disorders of cardiac activity but does not
cause them in the normal animals which, in the past, suffered from
the same myocardial injury.
Our investigations showed that fever produced by turpentine in
a decorticate dog is eXpressed to a greater degree than in =mai
dnimals. These data correspond completely with the results obtained
by P. N. lIeselkin.
In decorticate mammals, the reactions to excessive stimulation, as
a rule, are not only maintainards but can ev4in be expressed more vig-
orously, which is evidenced by a series of investigations which have
been carried out in various laboratories.
In summarizing everythingithich has been said, the conclusion may
be drawn that .the cerebral Cortex plays a great part in equilibrat-
ing the reactions of the body with excessive stimuli eating on it. ,
Removal of the cortex, as a rule, produces *protracted-course reac-
tions, whereby a disturbance 'of the compensatory capacity of the '
operated animals is most often seen.
AA attempt to establish the significance and show the specific
characteristics of various centers of the central. nervous system,
particularly the cerebral cortex and subcortical structures, in the
defense reactions of the body presents considerable difficulties, in
view of the profound interconnections ithich exist between the indi-
vi4ua3. divioions of the nervous system. These attempts, naturally,
come up against both contradictions and exceptions. However, the need
for establishing some kind of general orientative rules and mule-
tions is increasing every day as the investigation develops.
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L.;
Comparative investigations of the reactions to unitypical stimula-
tions in animals with varying degrees of development of various cen-
ters of the central nervous system can prove to be very fruitful for
the establishment of such rules and regulations. TO be sure, it is
essential to take into account ecological and other characteristics
of various species of animals -- problems which require particular
elucidation.
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...????""'"""m
ON THE ROLES OF DItnatiNT BRAIN CENTERS IN THE REGULATION OF
THE GASEOUS EXCHANGE
E. S. MaiIYan
Laboratory of Comparative Pathology (Head Professore S. I.
Frankshteyn)
In birds, as is well known, the subcortical nuclei reach maximal
sizes. In connection with this capacious development of them, the
rudimentary cortex in birds is expressed to an even smaller degree
than in animals of the preceding class -- the reptiles, and is al-
most completely absent anatomically. In birds, under conditions of
the chronic experiment, the hemispheres may be completely removed,
whereas in mammals only the removal of the cortex is possible. Re-
moval of the cortex together with the sUbcortical nuclei leads to
the rapid death of the animals, and attempts at isolated removal of
the subcortical nuclei inevitagly are associated with the simultan-
eous involvement of the cortex.
In connection with this, the study of the after-effects of remov-
al of the hemispheres in birds and decortication of manuals are,
undoubtedly, of interest in the study of the interrelationship of
the cortical and subcortical structures in the regmbrWaa of the
actiitity of the body. It goes without saying, here, that it should
be taken into account that this comparative method has serious
shortcomings, because the subcortical structures of birds cannot be
regaided as being completely indentical with the subcortical struc-
tures of mammals. However, by virtue of the fact that the uniform-
ity of functions of the corresponding centers of the central ner-
vous system has been clearly shown in various species of animals by
comparative-physiological investigations, the use of the comparative-
physiological method in solving the problem of the interrelationship
of the cortical and subcortical structures can be considered justi-
fied.
The present investigation is devoted to the study of the changes
of the gaseous exchange in birds in which the hemispheres have been
removed and in decorticate dogs.
Data in the literature on this subject are limited. In investi-
gations conducted. by B. I. Bayandurov and his co-workers (F. G. Popov,
KOdryavtsem) a marked drop intim quantity of excreted carbon di-
oxide was found in pigeons aftr the removal of both hemispheres
(gaseous exchange was determined. by the Pashutin method). A certain
time after the operation, an increased excretion of carbon dioxide
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1
oCcurred, but at the same time the weight of the animal also in-
creased. In calculating the excreted carbon dioxide per unit of
weight a long-lasting decrease in its quantity was noted; the res-
piratory quotient was unchanged thereby.
The investigations of 0. P. Molchanova in this direction, which,
however, were conducted under other methodological conditions (gase-
ous exchange was determined by the Reguaud method), showed the same
rules and regulations: the gaseous exchange in, pigeons which had
been deprived of both brain hemispheresias often decreased; the res-
piratory quotient was unchanged.
Along with the decrease in the gaseous exchange in birde after
decerebration the rate of the respiratory movements is also slowed.
In dogs following decortication, as was shown in the old observations
of ranilevskiy, the rate of the respiratory movements is returned to
normal.
The methods of removal of the hemispheres in birds au& of decorti-
cation in dogs used. by us did not differ., from the generally-accepted
methods. She investigation of the gaseous exchange in dogs was ac-
complished by means of a special mask supplied. with respiratory
valves. Preliminarily, for one to two months the dogs were trained
to breathe in the mask. The expired. air, after passing through the
expiratory valve, entered gas meters which made it possible to de-
termine the pulmonary ventilation. After certain time intervals (20.
30 minutes), tests of the embalad air were taken, which were analyzed
in a Holden apparatus. Ow tho bases of the ventilation data and the
qualitative composition of the exhaled air, the oxygen consumption and
the carbon dioxide excretion were determined per unit of time, and
the respiratory quotient was calculated.
The investigations were conducted in the morning hours, fasting,
over a rerLod of fran one to two hours.
She decorticate dogs were investigated under the same experimental
conditions. Application of the respiratory mask caused, at first, a
motor excitation in them, which quieted down after a certain time
(different times for different dogs from five to 45 minutes).
The gasedus exchange was determined when the animal appeared to be
in a completely relaxed state. Investigations of gaseous exchange
in decorticate dogs were made at various periods after the opera.
tion -- a month or more.
In investigating the gaseous exchange in birds, we utilized gas
meters,5 in contrast to preceding authors, which made possible the
simultaneous determination of the pulmonary ventilation as well as
a more detailed analysis of the gaseous exchange. Because the use
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of the respiritory mask in birds is technicOly almost impossible to
accomplish, we had to resort to tracheotomy, which was conducted und-
er local anesthesia and under aseptic conditions. The upper outlet
of the tracheotomy tube was connected with a respiratory valve,
whdch substituted for the mask. Tracheotomy itself, as is well
known, produces a decrease in pul onary ventilation, but because
both decerebrate and normal birds were studied under the same con-
ditions in our experiments this factor was equalized out.
We set about the inverstigatione the gaseous exchange in decere-
brate roosters 12-14 days after the operation, at which time the
after-effects corzected with the operative procedure itself had been
eliminated.
The experiments were jperformed on five adult roosters (li to two
years of age) of approXlmately the same weight (i4 to two kilograms).
The data obtained are presented in Table 1 and. Table 2.
Table 1
GASEOUS EXCHANGE IN BIRDS BEFORE REMOVAL OF CEREBRAL HEMISPHERES
No of
rooster
,Ventilation
in cc.
In expired air.
% utiliza
tion of 02
02 consump-002 ex..
tion per !oration
minute t Iper min
ute
spiratory
uottent
% c02.!
!
i
% 02
1
330
i
5.7 t
14.65 6.45
21.29 18.81
0.88
270
5.4
13.85 7.15
19.31 14.58
0.76
2
300
5.53
14.75 6.75
20.25 16.59
0.82
290
5.48
14.13 7.17
20.79 15.89
0.76
3
330
5.63
13.2 7.3
24.09 18.58
0.77
zoo
5.1
13.68 7.44
29.76 20.4
0.65
330
5.48
13.55 7.5
24.75 18.08
0.73
390
4.58
14.38 6.69
26.09
17.86
0.68
14.
po
5.35
14.0 6.97
34.85
26.75
0.77
500
5.4
13.85 7.15
35.72
27.0
0.76
450
5.65
13.6 7.4
33.3
25.43
0.76
5
350
3.83
15.93 5.33
18.7
13.41
0.72
380
3.6
15.85
5.09
19.3
13.68
0.7
I
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GASEOUS EXCHANGE IN BIRDS AFTER REMOVAL OF C
124-404:
Table 2
RAL HEMISPHERES
No of
Rooster
Ventilation
in cc.
In expiredeir4-utiliza-
.02
tion of 02
consump4a2
tion per
minute
excre -.Respire -
tion per tory Quo.
minute tient
% CO2
% 02
1
200
5.1
14.1
6.91
13.02
10.2
0.74
200
5.25
13.73
7.34
14.68
10.5
0.72
2
220
5.05
14.05
6.98
15.36
11.11
0.72
230
4.98
,14.45
6.5
14.95
10.45
0.69
210
4.35
15.0
5.96
12.51
9.14
0.73
3
290
3.55
15.93
5.01
14.53
10,29
0.77
190
3.95
14.9
6.2
11.78
7.51
0.64
130
4.23
14.83
6.21
8.07
5.5
0.68
140
4.0
17.78
6.34
8.88
5.6
0.63
4
160
4.4
14.48
6.61
10.58
7.04
0.67
190
4.9
14.15
6.9
13.11
9.31
0.71
200
4.63
14.93
5.98
11.96
9.26
0.77
190
4.63
14.48
6.55
12.45
8.79
0.71
5
250
4.5
14.15
7.0
17.5
11.25
0.64
200
4.95
--
--
**a
-9.9
--
250
5.25
14.05
6.93
13.06
13.13
0.95
From the Tables it is seen that the removal of the hemispheres in
roosters does not produce any particnipr changes in the compositiozi.
of the expired air. The percentage of oxygen utilization, that is,
the quantity of oxygen absorbed from 100 cubic centimeters of ventila-
ted air is no different in decerebrate roosters from that in normal
roosters, but the total consumption of oxygen per unit time is de-
creased considerably. While the normal rooster Consumes an average
of about 20-25 cubic centimeters of oxygen per minute (minimal quan-
tity in the experiments was 18.7 cubic centimeters of oxygen), the
decerebrate roosters, under the same conditions, use a total of only
10-15 cubic centimeters. Such a decrease in the oxygen consumption
per unit time was caused. by a decrease in pulmonary ventilation of
the operated. birds (from 300 cubic centimeters to POO cubic centimet-
ers and less). The carbon dioxide excretion is significantly de-
creased in exactly the same way with no change in the respiratory
quotient. Such a decrease of oxygen consumptibn and, carbon dioxide
excretion attests to a decrease in the iteasity of the metabolic
processes in the bodies of the birds folloging the rmnaval of both
hemispheres of the brain.
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Different results were obtained in the study of the gaseous ex-
change in dogs after the removal of the cerebral cortex (the inves-
tigations were performed on three dogs two months to a year after the
decortication operation).
In dogs with intact nervous systems the oxygen consumption per
kilogram of weight ranges, on the averages from five to seven centi-
meters per minute. The alcilven consumption in decorticate dogs
ranges approximately within the sane limits. In two decorticate dogs
the oxygen consumption per kilogram of weight was equal to 4.95-7,2
cubic centimeters of oxygen; in the third, somewhat higher -- uto
8.5 cubic centimeters (possibly this was connected with the frequent-
)..y Observed motor excitation resulting from the development of the
poet-operative scar). Al]. the other indices of gaseous metabolism
(oxygen content and CO2 content in the expired air, the percentage
of oxygen utilization, ventilation of the lungs) were practically un-
changed after the removal of the cerebral cortex.
These preliminary data indicate that the intensity of the oxidative
processes in decorticate dogs is not decreased. As our further in-
vestigations showed, the sifipificance of the cerebral cortex in the
regulation of the gaseous exchange is manifested particularly dis-
tinctly when there are additional influences acting on the decorti-
cate dogs, particularly pathological changes of the lungs. Evident-
ly, the cerebral cortex plays a part chiefly in the adaptation of
respiration to the constantly changing conditions of the environment,
whereas automatic regulation of respiration (mintAmante of it at
the level which is average and usual for the given animal), as our
experiments on birds also showed, can be accomplished by the sub-
cortical structures.
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THE INFLUENCE OF THE FORMATION OF DEFENSIVE CONDITIONED REFLEXES
AND OF DISRUPTIONS OF HIdIER NERVOUS ACTIVITY ON ItE STATE OF RE-
ACTIVITY IN RABBITS
L. A. Pronin
Laboratory of Age Physiology (Head -- Professor I. A. Arshavsk.iy)
Studies devoted to disruptions of higher nervous activity which
have been accomplished in I. P. Pavlov's laboratory, especially the
work of M. K. Petrova$ show the tremendous influence of disturb-
ances of the activity of the cerebral cortex in altering the phy-
siological functions of the intact body.
Studies carried out previously have shown theeffect of various
experimental forms of the pathology of pregnancy in animals on the
development of the fetus =don the physiological condition of the
newborn (I. A. Arshavskly, 1950$ 1951; I. A. Arshavskiy and. I. S.
Caleyeva, 1951; I. S. Galeyeva, 1950, 1951).
The purpose of the present work consisted of studying the effect
of the formation of conditioned reflexes and disruptions of ner-
vous activity on natural physiological immunity in rabbits.
The method of work =rabbits usingeonditioned reflexes has not
been adequately worked out; in the literature, we were able to find
only a few studies on this subject 01. A. Golubev, 1926; A. N.
Bregadze, 1929-1935; V. I. Elimova$ 1948; O. V. Malinovskiy, 1952;
A. A.Volokhov, 1952). Apart of the studies mentioned were devoted
to the study of the motor food conditioned reflexes; another part,
to the study of the defensive conditioned reflexes. V. I. Klimova
used, pin pricks of the rabbit's pew as the unconditioned stimulus.
A. Bregadze used. an electric current) placing the electrodes on
the hind paw; however, the details of his method are not known.
We found= data in the literature concerning disruptione of
higher nervous activity in rabbits. Therefore, we shall discuss in
greater detail the method of operation with the motor defensive con-
ditioned reflexes and the method of creating disruptions La the
nervous activitein rabbits.
The conditioned reflexes in rabbits were elaborated in a spec-
ially constructed chamber measuring 70 x 45 x 66 centimeters (for
this purpose we used the method accepted. in the laboratory of A. A.
Volokhov). On the front side of the chamber there is a glass,
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5
duuble-wing door, through which the experimental rabbits are Observed.
The chamber walls are double and, are made of plywood.; several layers
of asbestos are placed. between them for the purpose of better sound-
proofing. Abell, rattle, siren and two light bulbs are built into
the roof of the chamber. One light bulb of 25 candlepower served
for constant illumination; the second, of 60 candlepower, was used
for elaborating conditioned reflexes. A, metronome was placed. by the
side of the chamber.
First, the rabbit was permitted!to become accustomed to its DAV
sixivoundings, for which it was simply placed in the caaditioned-ref-
lex chamber for 23-30 minutes on the first day; on the second day, it
was again placed in the chamber for 20-30 minutes, and the electrode
was put on its ear; only on the third day was the elaboration of con-
ditioned reflexes begun. The conditioned reflexes were elaborated
to the effects of sound and visual stimuli. The experiment consisted
of six to 10 associations (per day); there were one to three-minute
interruptions between the associations. The various intervals between
the associations were haphazard in order to avoid, a conditioned re-
flex for time, which might interfere with subsequent work on condi-
tioned.reflexes. Differentiations and inhibitory conditioned reflexes
were also created in the rabbits. The unconditioned stimulus was an
induction current of a strength adequate to obtain a threshold re-
action. The reinforcement lasted a secomi following five to eight
seconds of the isolated. action of the conditioning stimulus. In or-
der to avoid the souml of the induction coil, we used the alternating
current from the citpcircuit, the potential difference of which was
decreased to five volts by a transformer. Tae alternating current
does not need a breaker, and therefore, the induction coil works
noiselessly.
The base of the rebbit is ear was stimulated by the current, for
which purpose special electrodes were assembled. in the form of a clamps.
The latter hung free on the ear and. did. not fall off when the rabbit
moved or shook its ears.
The reaction was considered.positive when the rabbit phi;ok its ear,
tapped. with its hind paws, moved or adducted its ears. DdliAlly, sev-
eral components of the reaction could be seen which were accomplished
separately or together in various combinations.
Disruption of the higher nervous activity was produced. by: the "con-
fusion" of the negative and:the positive stimuli (Cho positive stim-
ulus was given immediately after the negative conditioning stimulus)
or by a "double exchange" of the negative conditioning stimulus for
the positive one and of the positive conditioning stimulus for the
negative one, and also by an overstrain of tbe nervous system by high-
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powered stimuli au automobile siren for a strong induction current.
In the latter case$ the electrodes were placed an the hind, paw of the
rabbit and sometimes on the ear. The stimulus acted from three to
fifteertminutes. If= disruptioa was obtained the first time, and
there were no changes of conditioned-reflex activity on another day,
then t1 experiments were repeated the next day. Sometimes, the
stimulus was used several days straight; however, despite this, in
some rabbits no disruption could. be obtained..
The character of the disturbance of the cortical activity from the
creation of nervous system disruptions was evaluated by the change
in the positive conditioned reflexes and differentiations.
For evaluating the change in the reactivity state we selected the
determinations of one of the indices of natural physiological im-
munity, namely, the complement titer. The complement titer was de-
termined in the following way. Three to five cubic centimeters of
blood were taken from the margirutl vein of the rabbit's ear and
placed in a thermostat at 37? C for 30 minutes. Then, dilutions of
the serum to be examined were prepared (0.25, 0.12, 0.06, 0.05, 0.04,
0.03, 0.02, 0.01 cubic centimeters) in 0.5 cubic centimeters of phy-
siological solution. One cubic centimeter of the hemolytic system
was added to each test-tube, and then, one cubic centimeter of the
physiological solution (the physiological solution was prepared. us-
ing thoroughly boiled distilled water). Thus, the total volume of
liquid in which the reaction occurred was 2.5 cubic centimeters.
The mixture was shaken up carefully*, after which the test-tubes were
placed in the thermostat for an hour. Complete hemolysis was de-
signated by three plus-signs; incomplete by two, and. hardly notice-
able -- by one plus. The smallest quantity of soros which gave
visible hemolysis was taken as the complement titer. The experi-
ments were performed on 63 .rabbits; 30 of them were gravid.
She motor defensive conditioned reflexes were elaborated. in the
rabbits to different degrees; in some of them, they were practically
not formed at all.
We noted that conditioned reflexes are formed much more rapidly
to a bell and a rattle than to the beat of the metronome; as a rule,
there was no orientative reflex to the metronome. We connect this
with the fact that a tap is a customary soundlbr rabbits, because
they often tap with their hiud legs when they are troubled. However,
despite the absence of an orientative reflex conditioned. reflexes
are, nevertheless, formed. to the metronome.
Conditioned reflexes to the bell and the rattle are sometimes
elaborated after the first one or two combinations. The conditioned
-88.
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reflexes thereby begin to manifest themselves, as a rule, on the
first day, and. on the third to fourth day they become permanent. Con-
ditioned reflexes to the tap of the metronome appear only on the sec-
ond to third. day, and. become permanent still later.
Differentiation giscriminatiog in rabbits is elaborated. well and
is very stable. It is elaborated. best and quickest to different fre-
quencies of the metronome. It shoulilbe noted that there was no res-
ponee reaction to the conditioning stimulus in the first different-
iating combinations. It appears the differentiation has occurrel sud-
denly, but after several combinations the same response reaction begins
to appear to the differentiating stimulus As to the positive condi-
tioning stimulus, and only after several combinations does the reac-
tion to the differentiating stimulus again disappear, this time for
the last time. Mese data eorrespond with the data of A. N. Bred-
adze (1929), who first noted, this fact. The elaboration of differ-
entiation indifferent rabbits occurs at different times. In some
rabbits it is impossible to obtain complete differentiation.
We are not in agreement with the opinion of A. N. Bregadze (1935)
that in motor defensive conditioned reflexes to an electric current
the differentiations are poorly formed and readily destroyed. Our ex-
periments on 48 rabbits (A. N. Bregadze performed them on two rabbits)
showed that differentiations are rapidly obtained and, as a rule, are
permanent.
Rabbits, like dogs, can be divided according to nervous system
types. In our dxperiments04hree groups of rabbits could be distinct-
ly outlined. The first group consisted of those in which both posi-
tive and negative conditioned reflexes (differentiations)were well
elaborated. The majority of rabbits belong to this group; they cor-
respond to Pavlov's strong vell-balenced type.
She second group of rabbits corresponds to the strong unbalanced
type of nervous system. Positive conditioned reflexes are elaborate&
well in them, but differentiations are obtained. with great difficulty
=dare often lost. Rabbits of this group are more sensitive to the
current; therefore, for reinforcement they should. be given weaker
current. After disruption of higher nervous activity, their differ-
entiations are most often lost.
The third group is made up of rabbits in which conditioned re-
flexes are formed with great difficulty or are not formed altogether.
Sometimes, signs of "exhaustion" of the nervous system are seen in
them, as in higher nervous activity disruptions, where the first one
or two combinations give good conditioned reflexes, and then the con-
ditioned reflex activity is colipletely absent for a long period of
time.. Differentiations are obtained well and rapidly in this group
of rabbits; they are permanent and are elaborated, beginning with the
89
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????????m?mf?MI...
first combination without being changed afterwards. Usivelly, these
rabbits reactpoorly to reinforcement by current; therefore, the cur-
rent has to be intensified. Disruptions of the higher nervous act-
ivity in them most often occur with inhibition ? the positive con-
ditioned reflexes disappear.
We first produced. higher nervous activity disruptions by a strong
induced current, but the disruptions were obtained rarely by this
method., and cases were even observed. where the conditioned reflex
activity became better expressed. We believe that the intensifica-
tion of the conditioned reflex activity and the difficulty of obtain-
ing disruptions from a strong induced current in our experiments de-
pend on the fact that we also used the induced current in the capaci-
ty of an unconditioned reflex, that is, reinforcement. It might be
supposed that in the case of food conditioned reflexes the strong
induced current would produce disruptions of higher nervous activity
were better, but not always obtained to the autdhobile siren. Usu.-
immediateXy, after the stimulation with the siren positive con-
ditioned reflexes disappear; sometimes, paradoxical phases are seen.
However, on a different day, the conditioned-reflex activity may be
restored, and in certain, rabbits is even better expreased than before
the disruption. If the disruption is not Obtained the first time,
then it is sometimes obtained after repeated dailyAapplications of
the siren.
Sometimes, the disorders of the conditioned-reflex activity occur-
red. when, we proceeded, with the elaboration of differentiation and
used, right away, a large number of differentiating conditioning sti-
muli (more than the number of positive conditioning stimuli).
Disruptions of higher nervous activity are obtained, also with
"confusion" of the negative and. positive conditioning stimuli or with
a "double exchange." We created. the "confusion" in.the following wayl
a negative conditioning stimulus was used, atter which immediately,
without interruption, a, positive conditioaing stimulus was administ-
ered and a reinforcement with the currant. Three such combinations
were made, one after the other. "Double exchange" -- is the rein-
forcement of a negative conditioning stimulus amino reinforcement of
the positive one: this was don) three times Ina row, whereby posi-
tive and negative conditioning stimuli were alternated.
The disruption of higher nervous activity were obtatied best with
combinations of "confusion", "Aouble exchange" and the action of a
high-powered stimulus (in thes4 cases, the automobile siren, was used).
Uswoly we began with "confusions"; if there were no signs of condi.
tioned-reflex activity distktbances on the second day, "double ox-
chane" was used. Cu the thiridety, in case of necessity, the siren
was used. Under these conditions, as a rule, a single siren stimula-
tion for three minutes was adequate.
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Forty three rabbits with disruptions of the higher nervous act-
ivity were observed, by us. In the presence of disturbances of cere-
bral cortical activity we found paradoxical phases, inhibition of
the conditioned reflexes, and, much less often, loss of different-
iations. The behavior of the rabbits is markedly altered during the
disruptions. Some animals becomes more excitable: they are in con-
stant movement, shake their ears, tap with their feet, gnaw the cage,
throw the calmp with the electrodes off their ears (although they
never did this before the disruption), gnaw through the electric wires
from the electrodes, and often show shortness of breath. Other rab-
bits, on the other hand, become quiet, hide in some corner (always
in the same one), usost13y far from, the -place where the conditioning
stimuli are locatedl and they assume strained. positions. Inhibition
of the positive conditioned reflexes is usually noted in such rab-
bits. She unconditioned stimulus also acts with less effect; the cur-
rent has to be intensified. From time to time, marked changes in be-
havior occur in these animals. They begin to move, to shake their
ears almost contin.uously, to tap with the feet, etc., like the rab-
bits of the preceding group. Such a state sometimes occurs after re-
inforcement with a strong current and dometimes even:without obvious
causes. The conditioned reflexes nay be restored thereby, and, on
the other hand, differentiations maybe lost. The threshold for cur-
rent stimulation is reduced.. Such an excitation state can last for
several minutes or for several days and. is again replaced. by an in-
hibited state*
The complement titer was determined in 12 rabbit* first before
working with conditioned reflexes, and then at the time of the ela-
boration of the conditioned reflexes, and in seven rabbits after
the disruption of higher nervous activity had occurred (see Table,
page 93).
First of all, we directed attention to the feet that the elabora-
tion of conditioned reflexes in itself, which is usually of protec-
tive significance to the body, is a factor which increases its react-
ivity.
In the normal; control rabbits the complement titer ranges from
0.04 to 0.05 Cubic centimeters of serum. Because of the elabora-
tion of conditioned reflexes to the action of the stimulus which
produced a protective, defensive reaction in the body Cin our ex-
periments, the shaking reflex in response to stiTulation by an in-
duced current), the complement titer was increased inane out of
twelve rabbits. The increase was particularly well marked at the
time of elaboration of the conditioned reflexes, at that time reach-
ing; 0.03 cubic centimeters of serum. In three rabbits the comple-
ment titer did not change in response to the elaboration of the con-
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Elm ?,110
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ditioned feflexes.
It maybe supposed that this fact discovered. by us is of essential
importance in the understanding of the mechanism of protective re-
actions of the body to the effects of various environmental stimuli.
Participation of the brain, partioninmly in the formation of the
conditioned reflexes to the effects of stimuli which produce defens-
ive reflexes in the body, induces, so to speak, a mobilization of the
adaptative protective capacities of the body as a whole with respect
to its various indices.
As a matter of fact, the ear-shaking reaction of the rabbits in re-
sponse to stinulatios by an induced current woUld seem in itself to
be adequate for the accomplishment of the necessary protection;
nevertheless, we see that as time associations are formed to this re-
flex, the body mobilizes also its other protective capacities, which
is expressed specifically in an increase of the natural immunity,
With the disruption of the higher nervous activity a fall in com-
plement titer was seen, whereby in four rabbits it fell below the
initial level. On the average, the complement titer dropped to 0.06
cUbic centimeters of serum, that is, it was determined in an eight-
fold dilution.
Disruptions of conditioned-reflex activity affect markedly not only
the condition of the natural immunity but also the state of the en-
tire body. If the disruption is long maintained, dystrophic distur-
bances are noted in some rabbits : the fur loses its previous lustre,
becomes dishevelledl and. tufts of hair fall out in places4 In one
rabbit with a disorder of conditioned-reflex: activity, trophic ul-
cers developed on the anterior extremities, and the nails fell gut.
The ulcers persisted. for several months and crippled the paws to such
an extent that the rabbit could not use them for locomotion (Fig. 1.).
It had also chronic rhinitis, which also rersisted for several month.
The nervous system disruption was produced in this rObit at the be-
ginning of May 1952; the Ulcer developed afters. month, first on one
paw, and then on the other. Soca afterwards, the rhinitis was added
to the picture. The ulcer and. the rhinitis persisted for six months;
there was no tendency to recovery shown (for this reason the rabbit
was killed).
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01110===...MMIIM
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Fig. 1. Trophic Ulcers on the Front Paws of a Rabbit as a
Rssult of a Disruption of Nigher Nervous Activity.
COMMENT TITLES IN RABBITS
Quantity of serum in cUbieineters
Tine of
investigation
Before elab-
oration of
conditioned
reflexes
In the pro-
cess of
elaboratioa
of the cook,
ditioned Art
fleXa
,No of 4
rabbitl 0.12 4 0.0614 0.051 0.04 0 0.03 ? 0.02
1 , ,
1
2 ?-ti
it + 4-1 -1"fil +-f+
3 .-r-c-..1-i 4-i--k? -
4
5 1,- 4. + 1- +.-1- . -H-
6 ..f. 4 + +-H- ?i 4- i-
7 -t"44 + -t-i- t -1- -i-
8 t -t-+ -i-i- 4- + + -f
9 + 4-1-1-1--1.-qi --
10 --N 1 -t-+ 11 1- -f. -4
11 t + ?i? +-H-1 -4-
12 i- 4- -i. 4-4- 4 1
13 +4+ -1-44-1 -I---t-+
14 +-i-+ 4+1-11-++
15 ?-f-t- +++ +4,-*
16 .f. -}i. i-+1- *+,
17 1--t? -I- -r-f- + 4 -ir 1-1
18 -{-4--f- 4 4- 4 + ti? I
-93-
WOO
MEN
mpan.
IMO
?????
alma
MOP
mem.
.00
fate
OW.
IMMO
4.1?10
ilm1?1
?????
??1?10
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COMPLEMENT TITERS IN RABBITS
(Cont)
Time of IRO of
investigationipribbit
Quanti
of serum in cub:_c
centimeters
0
??T.
? soe
. 0.0
? 0.03
-0.
With disrup-
tic a of high-
srnervous
activity
19
20
, 21
22
2
24.
25
26
27
28
29
30
31 1
-4. + i
t+-4-:-I--i--t?
t-4-1-
'-t--1-i-i+++
4?i--1-1+-t-+
++4-+++
4. .4--t-
4...1-.1.
4.. +. +.
4t--1-1-
+-.-
4-1-+
+ +. 4.
?-1*- t +
-1--1-+
4?f?f-
4. 4- .I-
+---
-1-++
-I- + i-
.1-1-1-
--+ 1...
+ 4-. 4-
1-4-4-
+1-+
+++
+?f-+
?
? + 4-
?
?
4-i-
.4-?4-.4-
?-1-1-
?t-t--t-
4- +?I-
+++
4-41-
1-4-4-
+ + -fr.
++1-
.???
++
++.f-
++
4-4- -fr
+"1-11""4-
?4-?
++.4:::
?i?f-
+ ? .4. - -t-
i-4-1-
Om.
?
? +4-
?
.H-
1-4
?
4- -c
4a.
?
?
?
In the majority of rabbits, the development of various pathological
processes were observed as a result of the disruptions of higher ner-
vous activity; tropic ulcers of the extremity, rhinitides, pneumon-
ias,-skin abscesses, etc. (Fig. 2).
? .'1./C:V,C=Fr
Fig. 2. Chronic Itit4tis.in the Rabbit as a?Result Of a Dis-
ruption of Higher Nervous Activity.
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She data obtained stimulated us to perform special experiments in
which the resistance of the rabbits was determined to the sUbcutane-
ous administration of staphylococcus toxin in connection with the
elaboration of conditimeidelense reflexes in them, and also in the
presence of dieruptions of higher nervous activity.
Ifanadult rabbit is given a lethal dose of toxia eacutaneous-
ly, a typical inflamatmyreactioa occurs thereby whieh counteracts
the action of the toxin and prevents the death of the animal. The
adult rabbit does not die even when two, and in inlividual. cases even
three, lethal doses are given to it subcutaneously (I. A. Arshavakiy,
1947).
Conditioned reflexes were elaborated in three rabbits. In the
process of elaboratioa of the conditioned reflexes each of them was .
given staphylococcus toxin subcutaneously in the ear in equal doses.
Avail expressed inflammatory reaction was seen in all the rabbits
at the site of injection of the min; this reactionwas expressed to
amore marked extent than the reaction in ,the control rabbits. Of
the three rabbits, only one died, on the second day. In four rab-
bits, conditioned reflexes were elaborated, after which a disruption
of nervous activity vas produced. Against the background of the
disruption, each of them was given staptylocopcus :toxin in equal
doses under the skin of the ear. The animale of ibis group respond-
ed with less definite signs of inflammatory reaction at the site of
injection of the toxin ccerpared with the controls. Three of these
rabbits died at one, five and seven.days? respectively, after the in-
jection of the toxin; one rabbit survived.
The data obtained permit us to conclude that the cerebral aortae
plays the leading part in the mechanisms which determine the con-
ditions of reactivity and resistance of the body to the effects of
various pathogenic stimulations of the environment. Individual Oti-
? chich act on the body, cannot produce disease-type reactions
in cases of well-balanced nervous systems.
14.. 1C. Petrova (l945) writes: "Pathogenic microbes always and
everywhere surroumi us, but pathology occurs onlar when the nervous aye-
tem, its physiological and physico-ch.emical processes, ,are altered;
this occurs sometimes so unnoticeably that often, accoaing to the
statement. of I. P. Pavlov, lit is difficult to say where physiology
ends and pathology begins?". 04. K. Petrova, Om the Bole of the
FUnationalW Weakened Cerebral Cortex in the Occurrence of Various
Pathological Processes in the Body, Medgie, 1945).
We have found that disruptions of higher nervous activity of grav-
id female rabbits retard the growth and. development of the fetus.
The corresponding material is being presented in another special work.
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? " "
In conclusion, we believe it essential to note certain advant-
ages of rabbits as experixontal animals in connection Iiith the re-
solution of problems connected with various subjects of physiology
and. pathology of higher nervous activity. Tele rabbits are more
easily kept under laboratory conditions, and less time is spent per
rabbit (using our method) in working with conditioned reflexes than
on the dog when working with food. conditiceekreflexes. This per-
mits the performance of experiments on Bevel _eel rabbits during the
course of the day. We believe that in pathology, where a large num-
ber of animals is often required. for the experimental resolution of
eerteln pathoph,ysiological problems of higher nervous activity, rab-
bits are VerY suitable as experimental animals.
I. ? MOP .4 OW r
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ON THE ROLE OF
11}I DV
MECHANISMS IN THE PROCESS OF CARBOHYDRATE
METABOLISM DURING A DISTURBANCE OF LIVER FUNCIIIION
I. P. Tetreshchenko
Laboratory of Experimental (Pathology (mmd of the Laboratories --
Professor S. I. Lebedinekaya)
A study of the role of the nervous system in the metabolic process in
the body is one of the essential links in the investigation of the problem of
nerve trophism.
Normal existOnce of the body is, possible only when its metabolic processes
correspond to the functional state of the body. This is why the study of
nerve trophism and. of its disturbOlces of of first-rank significance for the
understanding of many concrete mechanisms of adaptation of the body to 0
conditions of its existence.
In the numerous works of I. P. Pavlov and his students it has been shawl
that reflex and conditioned-refla)c stimulations can become the sources of al-
teration of various metabolic processes. Pakticularl,y abundant data have been
obtained in this connectioa in the laboratories of IC. N. BYkov and A. D.
Speranskiy.
The present work is devoted to a clarification of the significance of
reflex: mechanisms in carbohydrate metabolism during a disturbance of liver
function. The dynamics of the blood sugar were studied as one of the indices
of carbohydrate metabolism.
The liver function disturbance was produced by thermal stimulation of a
localize& section of the livers which was achieved by the injection of three
cubic centimeters of Tdatii. t,a temperature of 60-900C into the hepatic tissue.
This procedure has undodbted advantages over the other forms of stimulation
(infectious or chemical) for the study of reflex mechanisms of compensation for
Zile- disturbed. liver functions. With this methods the liver as a whole is
'not excluded, and other systems participation in the carbohydrate metabolism
are not injured.
-Thetaugar content in the blood, was determined, in the majority of experi.-
mantes at fives 151 and 30 minutes, and also at one and two hours.
In the first series of experiments, 14 rabbits were used. Sevencof them
were subjected to liver damage; as a control, the remaining animals were in.-
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jected with three cubic centimeters of hot water subcutaneously each in the
area of the left hypochondrium.
HYperglycemia was seen in all the experimental rabbits after the injury
to the liver; this was determined as early as five minutes after the injury
and most often was best expressed after 30 minutes. The degree of hyper-
glycemia thereby reached 78 milligrams percent in some cases; am the average
it equaled 44 milligrams percent, and only in one case was it less than 25
milligrams percent.
At the and, of two hours after the liver injury the level of thesagar
content in the blood approached. normal in the majority of mlimo (gig. 1).
17J
Fig. 1. Blood Sugar Content with Inuury to Liver of a Normal Rabbit.
In a portion of the control rabbits (five nramals) an increase in the
sugar content in the blood, was also seen; however, it did. not in, any ease
achieve the sane degree as in the experimental rabbits.
For purposes of studying the mechanisms of this hyperglycemia, the blood
sugar content in the next series of experiments was investigated after injury,
to the liver following the &nervation of it (maximal disruption of innerva-
tion). Denervation of the liver was attained by means of the transection of
the hepatogastric ligament and also, as much as possible, of the hapatoduo-
denal ligament. The hepatic artery, portal vein and also the cam= bile
duct passing through the hepatoduodenal ligament were carefully dissected
out, freed from the surrounding tissues and treated. With 96 percent alcohpl.
Zn addition, the suspensory ligament and the triangular ligament were trans,
acted..
Eight rabbits were subjected to the experiment. The liver injury WAS pro-
duced one to eight days after the disruption of tbe liver innervation.
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It should be noted that in itself the disruption of the liver innervation
in a number of cases led to hyperglycemia, which continued for several
days. N. B. Medvedeva also observed hyperglycemia in such cases.
Of the eight experimental rabbits of this series, the blood sugar content
in six rabbits was normal at the time of injury to the liver; in two rabbits,
it was increased (157 and 166 milligrams percent).
Injury of the liver under conditions of maximal disruption of innervation
produced only a brief increase of the blood sugar, which was replaced by
hyperglycemia after 15-30 minutes (Fit 2). The decrease in blood sugar
lb
o9.9
0,10
110
110
AlloatrJew.ye
.14
114
JO oeve,vo
41
O I Ji rl.
o t 301
,
.,,
L.
sgem,s,.. JO 50 .90 120 150 le 210 20
..vaiirinat
2P,S 27/0
Fig. 2. Blood Sugar Content with Injury to Denervated Liver Lobule.
attained considerable magnitudes in this process; on the average, the
quantity of sugar dropped to 57 milligrams percent and, in one case, even
by 89 milligrams percent.
In this series, only one rabbit was an exception; in it, hyperglycemia
was seen, possibly in consequence of the less complete disruption of inner-
vation than in all the other rabbits of this series.
Thus, the results obtained in this series of experiments speak for a
reflex mechanism of the hyperglycemia which was observed in the first series
of experiments after injury to the liver under normal conditions, because when
the injury to the liver was accomplished in the presence of a disrupted
innervation, the blood sugar curve assumed a completely different appearance.
The hyperglycemia which occurs here may associated with stimulation of the
parasympathetic nerve plexi found in the liver tissue.
It might be supposed that stimulation of the sympathetic division of the
nervous system might have definite importance in the mechanism of hyperglycemia
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which was observed following liver injury. As is well know, there are many
indications of this in the literature.
Experiments with the use of ergotamine were performed for purposes of
experimental verification of this theory.
The ergotamine was injected intravenously in a dose of one milligram per
kilogram of weight. Injury to the liver section was produced by the usual
means at 40, 45, 60 and 70 minutes after the injection of the ergotamine.
The investigation of the blood sugar content showed that in the presence
of liver damage 40 and 45 minutes after the ergotamine injection hyper-
glycemia is still seen in the rabbits, which reaches approximately the same
level which was seen in the animals of the first series of experiments.
In the presence of liver injury, 60-70 minutes after the injection of
ergotamine hyperglycemia is no longer observed (Fig 3) which maybe explained
by the action of ergotamine on the sympathetic nervous system.
e le10
.4 IN RI
.., 120 I
o I
o, t
N 100 gotedelfut
o
t., JpeofwAvY0
V
j 80 . copeweemm
t., Deem/
1
0 JO 80 90 110 1.50 le0
t.-
giehis I itaHrinar
17.9
Fig. 3. Blood Sugar Content with Injury to Lobule of Liver of Normal
Rabbit under conditions of the Use of Ergotamine
Thus, the data of this experiment indicate that the changes of the con-
dition of the sympathetic division of the nervous system can influence the
blood sugar content after liver injury.
However, the data of modern physiology do not permit us to regard the
changes of blood sugar content observed as the results of the isolated effect
of the sympathetic nervous system on the processes of carbohydrate metabolism.
The sympathetic nervous system itself is under the regulating and correct-
ing influence of the higher centers of the nervous system--the cerebral cortex.
The next series of experiments was devoted to the study of the roe of the
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KM I NI.M?amg.II
cerebral cortex in the accomplishment of the compensatory mechanisms under
conditions of a disturbed carbohydrate metabolism.
Twelve animals were subjected to experiment. The liver injury was pro-
duced at various intervals following the bilateral removal of the cerebral
cortex. It should be noted that in connection with the methodological
difficulties of operation in removing the cortex its basal sections were
preserved. In all these cases, it was noted that the operation itself
leads to an increase of the blood sugar, reaching, sometimes, 180 milligrams
percents.
Injury to the liver one to three days after the removal of the cortex
in four out of six rabbits led to a further increase of the blood sugar
level (which in one rabbit reached 296 milligrams percent), and in two rab-
bits, to decreased of 34 and 45 milligrams percent, respectively.
In view of the fact that the treatment of the data obtained MRS made
difficult by the presence of a high blood sugar after decortidAtion, we
afterwards injured the liver at later periods.
It turned out that six days after the decortication the blood sugar con-
tent in all six rabbits exceeded the normal, reaching 161 milligrams percent.
The liver injury led to an increase in the blood sugar content by 102 milli-
grams percent. Three hours after this, the sugar content had still not returned
to the initial level.
In later experiments, we used liver injuries performed three weeks after
the removal of the cortex. At this time, the blood sugar content had be-
come normal.
In all five rabbits following the localized injury of the liver, hyper-
glycemia was observed which reached much higher degrees than it did with
liver injuries in normal animals (Fig 4). Here, in individual cases, the
blood sugar increased by 151 milligrams percent) on the average, the blood
sugar content increased by 119 milligrams percent.
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270
250 .
"4 210
'00
170
150
MO
110
28.1
204
/74,
173
A
/
/52
410
252
?20
,
ga,modeme
fleVe/la
0 6 :10
60
90/20
8,478,HR e Afamrifia,r
Fig. 11... Blood Sugar Content with Injury of Liver of Decorticate
Rabbit and in Rabbit with au Intact Cerebral Cortex.
wombeftimweiwom.01.4.44.1.04.1or
de coiticate rabbit:
rabbit with intact cortex.
Let us recall that with liver injuries in normal rabbits the blood. su-
gar content never rose more then 78 milligrams percent, and on the
average it increased, by 1/2k milligrams percent.
It should be noted also that in AnimOn with intact cerebral cor-
tices, two hours after the liver injury the blood sugar content had
already returned to normal; in decorticate animals, the quantity of
sugar in the blood at this time never returned. to the initial level.
Thus, in decorticate rabbits the disturbance of carbohydrate meta.
bolism from localized liver injuries reached, higher levels than in
normal rabbits.
Ibis permits us to draw the conclusion that the cerdbral cortex
is important in the compensation for disturbed, carbohydrate seta-
bolimn.
It should. be iftmodbered that, aside from the liver other systems
of the body also participate in the metabolic processes; the rune-
tit= of these systems are als0 regulated by the higher centers of the
nervous system. Disturbancesin the regulation of these systems un-
conditicnally also find, their reflections in, more profound blood su-
garcontent Changes which were observed in our experimento.
The material obtained, in the present wollt attests to the import-
ance of reflex mechanisms in the processes of carbohydrate metabolime,
and.ofthe important role or the cerebral cortex in compensating for
the disturbances of this metaboliam.
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? .?
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ON THE MECHANISM OF ACTION OF PENICTILTN ON ASEPTIC INFLAMATION
A. M. Chernukh
Laboratory of Specific Pathophysiology and Experimental Therapy
(ibeel - A. H. Chernukh).
Until now, the mechanism of the therapeutic action of penicilli
in various diseases has been studied without taking into accouat the
date of Pavlovian physiology. Therefore, the opinion has been offer-
ed. that antibiotics affect only the fuactional states of the microbes
up to the destruction of their structures. This opinion is tesed on
various experiments which ha Ve been performed in. vitro. Physiolog-
ical reactions occurring in the coeplex intact aniroaU body in re-
sponse to the injections of antibiotics have as yet not been studied.
It is believed, that the antibiotics "can in principle disturb also
the processes which occur in the host organism" (4. D. MasWovskiy).
The so-called side-effects of the antibiotics comes to attention
here.
The clarification of the problem of the effect of penicillin on
non-microbial, aseptic inflamantion assumes greater importance.
The data in the literature are inadequate on. this subject. Only
the work of N. V. Lazarev ard L. S. Salymmoa ana the articles of M.
P. Yermolayera have been pubgehed. on the study of the effects of
sulfonamides anapenicil3i.n on aseptic inflammation.
The experiments of L. S. Salyamon show that aseptic inflammation
of the aural conchae of rabbits produced by burning, freezing, smear-
ing with croton oil and allergic inflammations can be markedly weak-
ened or even completely suppressed by means of treating the animals
with sulfonamides. Penicillin therapy did. not lead to any positive
therapeutic results.
It should be noted that the criteria of the course of the in-
flammatory reactions in the given case were only the temperature of
the aural concha and. edema of the ear. No histological examinations
were performed. The animals were aservedally 72.-94; hours.
All thisstimulatedus to undertake the study of the nechanism of
action of penicillin under such methodological conditions which
would permit us to observe thq apiem5s for a, long: time ant to per-
form not only a clinical but also a histological anelysis of the in-
flammatory focus. The experiments were performed on 51 'white rats
weighing 150-180 grams. Wtth the aim of producing the aseptic in-
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lmurtoryfbeus, 0.3 cubic centimeter of turpentine was injected in
the muscles of the right shin.
After three days (not counting the day of injection of the turpen-
tine) end following the formation of local inflammatory infiltrate,
all the animals were divided into five groups.
First group the control al rats). The animals were not stbject-
ed to any procedures.
Second group (10 rat). The anlivals were injected, with peaciliFft
(sat= Salt) in physiological solution into the muscles of the left
shank;,
Third group (10 rats). The animals were injected, with physiolog-
ical solution only into the muscles of the loft shank.
Pburth roi (10 rats). %be ammls were injected. with penicillin
diluted, with .5 percent novocaine solution in the muscles of the
left shank.
Fifth group (10 rats). The Pvtrvon were injected. with 0.5' percent
novocaine solution into the muscles of the left shank.
The memos of the second, third, fourth and. fifth groups received
the injections on the fifth, sixth, seventh, eighthand ninth days of
the disease.
The blood count was investigated in the animals before and after
treatment. Systemetic observations were performed on the inflammatory
focus and the function of the extremity.
On the 10th, 21st, 32r4 and 42nd days, the ailing rats were kill-
ed. according to the calculation that at each of these times several
nnirAln of each of the various groups were killed.
At autopsy, the muscles of the right and left shanks were taken
for histological examination. Staining of the preparations was ac-
combplinhed by the Van Wasson and, hematcoxylin-eosin methods.
The control animals (11 rifts) were injected with 0..3 cubic centi-
meters of turpentine into the depth of the right gestroonemius
muscle.
On the second day after the injection of torpentine, the right
hind paw was sosiel'ehat swollen, hyperemia of the skin appeared, and
on the third day, a tender thickening was felt in the depth of the
gastrocnemius msucle of the right hindpaw the inflammatory in..
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filtrate. In connection with this, a limitation, of active and. pass-
ive movements of this extremity was noted. (in consequence of the
formation of an inflamatory contracture of the muscle). On the 10th
day, the thickening- of the muscles reached from one to two centi-
meters in diameter. Mree days after the turpentine injection a
significant change in the blood count was noted --an increase in
the percentage of transitional for and. of mononuclear cells (from
the normal 2-5 percent to 20-25 percent).
An autopsy of the rats at various periods of the disease, inflam-
matory changes, extensive infiltrates and also abs ceases (from one
to two centimeters in diameter) were found, in the area of the muscles
of the right shank with scar formation in the surrounding tissue and
the formation of a capsule.
In the rats of the second. group, the state and. bet tion of the
right hind paw during the first five days after the injection of tur-
pentine corresponded to that described. in the control group of ani-
mals. Edema, an infiltrate, and. limitation of movements (active and.
passive) appeared in, connection with the appearance of an inflame.-
tory contracture ofthe muscles. Changes of the blood. counts in
these anima,ls were no different from those which obtained in the con-
trols.
Beginning with the fifth day, this grou;p1:of rats was injected in-
tramuscularly with the sodium salt of penicillin which bad, been di-
luted. in phypioloacal solution (1,200,000 units per each injection)
three times a day (at 9 a.m., 12 noon and 5 p.m.). Me penicillin
was injected into the muscles of the left hind. =trendy which cor-
responded to the inflammatory focus gin the right side in 0.6 cub-
ic centimeter volumes.
After a day, a certain decrease in the infiltrate was noted, and. a
definite increase in the range of movements of the right paw.
Iio pencilLin injections were given for five days. As the total
course of therapy each rat received. 18,000,000 units of penicillin.
As a result, active and. passive movements of the extremities were
recovered. by seven rats on the 10th day of the dizeaae. A signifi-
cant decrease was noted in the size of the thio.kening (on the aver-
age, it decreased. to 005 centimeter in. diameter).
Autopsies of rats killed on the 30th, day showed .a conaideratie
hyperplasia of scar tissue. An extensive capsule was noted, vithin
which there was a small (cempared with the control) amount of granu-
lar pus.
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Afterwards, on the 21st day, only a small hard. thickening could
be palpated in the depth of the muscles. If there had been an ab-
scess, it usually was walled off by a strong connective-tissue cap-
sule.
Simultaneously with the recovery of the function of the extremity,
and. as early as at 14 days, normalization of the blood picture was
seen.
Bats of the third group, begianing with the fifth day after the
turpentine injection, were injected intramuscularly for five days
with 0.6 cubic centimeter each of physiological solution. The fur-
thers clinical course of the focal inflammation did. not differ from
that described in the control group of animals. Under the conditions
of this experiment, the foci of inflammation were even distinguished
by somewhat larger sizes, while the functional disturbance of the
extremity was prolonged..
Five days after the turpentine injections, the animals of the
fourth group were injected intramuscularly with the -8-64ii4 salt of
penicillin in 0.5 percent novocaine solution in a volume of 0.6 cubic
centimeter (em:h dose cootaia(ng 1,200;000 units three times a day).
The course of treatment, as in the other groups of antmalc, lasted
five days. In this time, each rat received 18,000,000 Inits of pen-
cillin.
It should. be noted that this form of treatment brought about the
elimination of the muscular contractures with particular rapidity.
They disappeared completely' in six rats as early as one to two days
after the onset of therapy; the inflammatory infiltrates were also
decreased. The figures of the blood count rapidly became normal.
On the 10th day, three rats were killed. In these animala, only
cicatricial Changes of the muscles could. be noted in the area where
turpentine had, beeninjected, and less often, there were small ab-
scesses (0.5 to 0.5 centimeters in diameter) with well-developed, cap.
sules and cicatricial changes of the surrounding muscles.
The same picture was found also at later periods.
The last, the fifth groilp, of anfrul3n was injected (three times a
day) with 0.5 percent novocaine solution five days attar the injec-
tion of turpentine.
As early as the second day of treatment the contractures of the
muscles disappeared. in the majority of animals, and free movements of
the extremities were recovered, although the inflammatory infiltrates
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decreased in size ill only three rats.
Autopsies of the animals showed that =der these conditions the re-
covery of the inflammatory focus progresses better and. quicker than
in the control group of rats, but not so well as in the second and:
especially, the fourth group.
The results of our experiments give evidence of the influence of
penicillin on aseptic focal inflammation, which effects a certain de-
crease of the inflammatory phenomena, decrease in the inflammatory
contractures and. particularly the stimulation of hyperplasia of the
connective tissue around the abscess formed.
Xt is particularly important to note the good therapeutic effect
in animals which were injected with penicillin diluted in 0.5 percent
novocaine solution. This coincides with the observations of A. *.
Vishnevskiy and his co-workers. However, our data give evidence to
the effect that the combination of penicillin with novocaine is ef-
fective not only because the penicillin acts etiotropieally on, mic-
robes and because novocaine acts pathogenetically in the inflammatory
process (??. A. Vishnevskiy believes). Apparently, the action of
pencillin for a normalization of the neural trophism of the tissues
of the inflammatory focus is also important here.
Our experiments give us the basis to believe that in suppurative
processes, penicillin intensified, the proliferation of connective tis-
sue, and consequently also the encapsulation of the suppurative focus,
which can lead, to the formation of latent suppurative foci. These
data are confirmed by the experiences of surgical clinics (Shlapo-
berskiy and others) end. are still the only basis for the use of the
combination.qr peniciLlin therapy with the obligatory incision and
drainage of 4 suppurative focus.
Certainly, here, account should be taken of the fact that, depend.
1143 on the dosage, penicillin can stimulate or suppress the'prolifer-
ation. of connective tissue. The latter has been shown by' Ye. A. Tim-
ofeyevskaya under tissue-culture conditions. The data of M. P. Yer-
molayeva can also be exPlained by this; by usingord.inary.penicinin,
she showed its suppressive effect on connective tissue, during the
formation of a capsule around a fpreiga body which had bean injected
into the tissues of a white rat.
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1
ON THE ROLE OF TOE NERVOUS SYSTEM IN THE AUTOTRANSPLANTATION
OF THE THYROID AND ADRENAL GLANDS
I. N. Shapiro
The role and, sigaificance of hormones, vitamins end other 'tumoral
factors of body activity are being at present evaluated from two
points of view which are different in principle.
One of them is based. cn the principles of the cellular pathology
of Virchow and. the cellular Veysiology of Fervorzt transliteration.
Fairborneil, according to vital the effects of various humoral agents
are the result of the direct contacts of the given agents with the
tissue substrates. The glands of internal secreticn are looked on
as a kind. of isOlated system itviependent of the influence of the en-
vironment and. of neural influences.
Another point of view is based on the teaching of I. M. Seehenov
and. I. P. Pavlov on the integrity of the complex organism and tbi
leading significance of the nervous syste in its activity.
This makes it pbssible to analyze ithd.,. evaluate the effects of vari-
ous factors of the external and. internal milieux as the results of
their indirect actions through a number of nerve tn)cs. The tterhirkg
of I. P. Pavlov regards all processes occurring in the complex organ-
isms of the higher animals and. men frcet the point of view of reflex
nervous activity.
Investigations, begun in his time, in the laboratory of A. D. Sper-
anskiy dealt with the role of the nervous system in the endocrine
regulations of the bodily functions.
Numerous data which have been accumulated at the preserCtime per-
mit us to believe that no gland. of internal secretion is autonomic in
its physiological functions in the body and, that they are all under
the direct regulating influence of the nervous syst4.
At the same time it has been ne0d that hormonal. factors can ex-
ert effects not only directly on tissues but also by means of spec-
ific forme of stimuli:I:W=0f the nervous system -- through its sensory
apparatus. Our investigations have estehlidhed that the survival, and
functional integrity of an aUto transplant depend primarily on the
site *fits transplantation.
The thyroid and. adrena glands served as the objectsibr our trans-
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plantations; these were selected. for the following reasons. The con-
ditions of survival and regeneration of autotransplants of the thyroid.
gland in various parts of the body have been studied.most. However,
in the experimental ievestigations and in clinical practice, the re-
sults of thyroid gland transplantation in the cases of its functional
abortion or inadequacy have been but little studied.
In our experiments, we also used as a starting point certain facts
of clinical endocrinology pertaining to the interaction of the func-
tions of various glands of internal secretion in the body. Such a
connection has been repeatedly established. between the thyroid and
adrenal glands.
Survival of the adrenal gland under conditions of auto-transplant-
ation with prolonged. maintenance of its functions has not been obtain-
ed. by anyone.
After the removal of both adrenal glands, animals die quickly, as
a rule. This permits us to determine more easily the functional inte-
grity of the grafted transplant, and, based on this, to evaluate more
readily the conditions of this "taking-boot process".
To acccmplish as complete as possible an adaptation of the grafted
gland to its new circumstances, we had. to review the technical meth-
ods used and to perfect several of them.
In the present report, we are presenting experiments demonstrating
the results of the graftings mentioned in connection with an altered
botreactivity.
We performed one Bevies of experiments with the simultaneous remov-
al of both adrenal glands and the autotransplantation of them into
the area of the lower poles of the kidneys and two contra series of
experiments.
From our own observations and from the data in the literature we
know that large grafted. pieces of the cortical and. meduns-ry layers
of the adrenal gland often undergo necrosis.
atking this into account, in all the seriea of experiments on
rabbits we transplanted the entire adrenal gland mass in. its finely
divided form. The finely divided. adrenal gland. was collected on a
tongue depressor, applied. in an even layer to the area selected, and
lightly rubbed. Into it. The removal of both adrenal glands and the
autotransplantation into the lower poles of the kidneys at the edge
of the vena cava vera performed simultaneously..
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Special attention was directed to the post-operative period. Im-
mediately after the operation the rabbits were placed in a special
cage with an air temperature of 21-220 C. The food of the animals
during the first 10 days after the operation consisted. of fresh cab-
bage, carrots cut in thin slices, beets and. hay or clover.
In all, 27 rabbits were operated in this series of experiments;
22 of then survived and were killed, at various time intervals atter
the grafting, while five rabbits died seven to thirteen days atter
the transplantation.
Our observations show that signs of weakness were not marked in the
first few days after the operation; the body temperature increased
slightly and, after four days it came back to normal. Re'fusal of food
was noted only for the first three days, although a complete diet was
not taken until the tenth day. The all in body weight continOed un-
til the 21st day after the simultaneous removal of both adrenal
glands and the autotransplantation of them.
At the autopsies of the rabbits, adrenal transplants were found of
different forme and. sizes. Thus, for example, in the first three
days after the grafting the transplant had the appearance of indiv's.
idual pieces which were not connected with me another. Thirty days
after the grafting, the transplant. wan found in the form of a lumpy
layer, which after one and. a half to two months presented an almost
smooth surface of yellow-pink color. After three months, lumpiness
appeared again on the transplant, which gradual4 increased and fused
into a common mass. At eight months to one year after-the grafting,
we lound transplants at autopsy which had the form of the normal ad-
renal (Fig. 1.)
oiL
r
e e
Fig. 1. Development of the Adrenal Gland Transplant after its
Grafting into the Area of the Lower Poles of the Kidneys (Diagram).
a - at 1-3 days; b at 30 days; c - at 3 months; d - at 5
months; e - at 7-8 months; f - at a year
Ou histological examination of these adrenal transplants it was
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found that degeneration of the cells of the cortical and medullary
layers of the adrenal gland. are seen beginning with the first day
after the grafting. Tae medullary layer is seen, three to seven
days after the grafting, in the form ofpoorly staining cellular ele-
ments, and decomposition of then brseen. Bundles of "old" nerve fi-
bers of different calibers are seen here as well as individual frag-
ments of these fibers$ which are encountered. most often near the
vessels among the tissue detritus of the medullary layer even 21-30
days after the operation. Areas of cortical-layer cells, more or
less intact, are found in the first seven to tan days after the
grafting. Anstable regeneration of themla seen 14 days after the
grafting. At this time, cells of the cortical layer are seen in
certain sections of the transplant, which are radially disposed. a-
long the courses of the blood vessels and which have cytoplasms me
nUelei of normal structures.
TWenty one days after the grafting, bundles of "old" nerve fibers
of medium and large calibers in the cortex are markedly and unequal-
ly stained. The fine newel fibers are, to the most part, not not-
ably Changed.
Three months after the antotrezusplzsitation, a significant portion
of the cells of the cortex of the transplant are distinctly seen. In
the layers of connective tissue which connect the individual sections
of the transplant, bundles of nerve ffters are found, directed toward
the cortical layer.
Ayear after the grafting, the transplant has an oval shape equal
to two thirds of the normal adrenal gland and consists of cortical
cells having normal structures and disposed haphazardly in the cen-
tral part of the trensplant (Figs. 20 3 and 4).
Fig. 2. Transplant of Adrenal Gland at 3 Months after Transplant-
ation into the Area of the lower Bole of the Right Kidney. Regea-
oration of Cells of the Cortical Layer. Ilematoxylin-Eosin Stain.
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Fig. 3. CorticeiSubstanee of Adrenal Gland. at 8 Months after
Autotransplantation into the Area of the Lower Pole of the Right
Kidney. Bematawlim-Eosin Stain.
Fig. 4. Transplant of Adrenal Gland at 8 Months After the
Transplantation in the Area of the Lower Ible of the Bight
Kidney. Bundles of Nerve Fibers. in the Cortioal Layer of the
Transplant. Stain by the Bil,shovbkiy-Gross Method.
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As a control, experiments were performed on rabbits with the sim-
ultaneous removal of both adrenal glands without transplanting them.
Thirty rabbits underwent the operation. They all died 24-63 hours
after the operation with signs of coma.
In order to clarify the role of theadrenal transplants, experi-
ments were performed on 20 rabbits with the removal of the adrenal
transplants at different time intervals following their simultane-
ous removal and transplantation into the areas of the lower poles of
the kidneys. Al). the memln died 20-30 hours after the removal of
the' transplants.
In the rabbits of this series, the same clinical symptoms of
adrenal insufficiency were found as in the rabbits in which both ad-
renals had been removed, without transplanting them, but these symp-
toms appeared sooner.
A year and. two months after the transplantation, in addition to the
definite cortical cells, a narrow strip of pens was found in one
section of the adrenal transplant going from the periphery to the
center. Their cytoplasms were stained (fixation Lithe Nisei/ meth-
od, staining with hematoxylin-eosia) a chestnut brown color, the
borders of these cells were not distinguishable, wile the nuclei
were larger than the cortical cell nuclei, and. theycytoplasms did. not
stain so well (Fig. 5).
Fig. 5. Transplant of Adrenal Gland at 1 Year and 2 Months
after the Transplantation in the Area of the Lower ftle of the
Right Kidney. Strip of Medullary Substance. Fixation in the
Visa' Method, Hematoxylin-Dsein Stain.
.113.
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.1Immelm?Oka.
It was of great Interest to elucidate how the operation perfornel
(removal and. autotransplantation of the adrenal gland) reflected it-
self on certain important funetions of the body.
For the resolution of this problem experimeats were performed on
the study of the physiological and, biochemical indices of the blood
under these conditions (slow content, adrenalin content and content
of adrenalin-like substances).
We shall not present the numerous investigations on thin subject
here. Let us note only that the most varied.opinions exist from
a complete negetion of the role ofadrenalia in the nativity of the
body (Gray, 1930; Stewart and Boger, 1517-1920) to the evaluation of
it as a factor which determines practically all human behavior (Can-
non, 1929-1932).
K. M. Bykov (1947) writes, ". ? .We are, for example, well informed
on the effect which adrenalin exerts on the blood, pressure, heart
rate: sugar content in the blood, development of fatigue in the iso-
lated muscle, movements of isolated intestines, etc. These data were
obtained after the injection of adrenalin into the blood or by study-
ing its effect on isolated organs. However, we know vary little
about the actual sigaificance of the elaboration of adrenalin in the
adrenal glands for the activity of the entire body." (K.. M. Bykov,
The Cerebral Cortex and the Internal Organs, Moscow, Medgiz, 19471
p 286).
He made determinations of the blood adrenalin content of rabbits
on isolated frogs' hearts. 'tieing perfusions of Binger's solution
and. after the cardiac contractions had acquired, a stable character
with respect to rate and amplitude, we injected three drops of nor-
mal rabbit's blood into the eannula.
The force of the cardiac contractions thea increased somewhat com-
pared. with the initial contractions (Fjg. 6)* Gn theLbackground of
the original, establienedematztetions, the blood. of a rabbit from
which both adrenal glandif had, been removed without traneplanting than
was injected. into the cannula. In these eases, the strength and fre?
quenay of the cardiac contractions decreased. considerably (Fig. 7).
i(ligiii(11001Pili Ili(
fig Kr , 1
Fig. 6. Action of Norrsal Etloda bin. the Isolated. Frog's
Heart.
Arbitrary designations: r Binger's solution injected;
kr - blood. of normal rabbit injected.
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__\1 1 11M
f)./1 A-Rf nr
Fig. 7. Contraction of Isolated Frog's Heart during the Injection
of the Blood. of a Rabbit from which both Adrenal Gelnds were
Simultaneously Removed Ona Day before the Blrperiment.
Arbitrary designations: r Ringer's solution injected;
kr - blood of rabbit, from which adrenal gland was removed,
injected..
If then, after perfusion of the heart, blood of a rabbit from which
both adrenals had been removed and an autotransplantation of them per-
formed is injected. into it, the strength and. 3?articularly the frequen-
cy of the cardiac contractions increased. markedly. e positive
chronotiropic and inotropic effects therefrom were considerably bet-
ter exprolsed than the effects from blood taken from the normal. rab-
bit. (Fig. 8)
Fig. 8. Contraction of Isolated. Heart of Frog during the Injec-
tion of the Blood, of a Rabbit from which Both Adrenal Glands were
Simultaneously Removed. Coe Day before the Dcperiment and. a 9re118-
plantation of them Performed in the Area of the Lair0., Poles of
the Kidneys*
Designations: r Ringer's solution injected; kr - blood, of
rabbit injected from which adrenal glands were relayed. but in
which transplantation of this tissUe was performed.
In subsequent experiments the content of the adrenalin in the blood.
of rabbits was investigated at?e.rious periods of time following the
removal of both adrenal glands and. tranopiantation of them.
It was established. that the strength of the cardiac contractions
(after injection of blood. from the rabbit five end seven days after
the operation) compared with the original curves is either the sane
or even a littleirrearled.
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Fourteen and twenty one days after the removal and transplenta-
tion of both adrenals, the strength of the contractions continuos to
be a little increased compared. with the reaction of the heart to the
blood of the normal rabbit.
Positive chronotropic and inotropic effects on the isolated frog's
heart also occur after the injection of blood taken from a rabbit 41
days after the removal of both adrenal glanda from it and autotransplant-
ation of them.
It must be supposed that a day after the removal of both adrenal
glands not only a disappearance of the adrenalin from the blood oe-
curs, but apparently also an accumOlation of acetylcholine-like sub-
stances which evidently also give increased chronotropic and inotro-
pie effects on the frog's heart.
We also need to dioeuse the following question.
The rabbit dies allay after the removal of both adrenal glands.
As our experiments have shown, deaths of the rabbits can be averted
in the majority of cases if, at the same time an the operation of re-
moving the adrenal glands an autotransplantation of them is at the
same time performed in, a definite area. As the material of our ana-
tomical investigations showy before the rooting adrenal glands estab-
lish a connection with the nervous system, a, progressive destruction
of the medullary substances and the cortical layer occurs in them.
Only the data obtained a, day after the removal of both adrenal
glands and transplantation of them might explain the destruction of
the medullary layers of the transplants of the adrenal glands and
the associated excessive excretion of adrenalin into the blood from
these adrenal glands.
How can we explain the feet that as early as several days after
the operation a content of adrenielinand adrenalinl.like substances is
establiphed in the tame of the rabbits operated on by the method
described above, which content approaches.norsal and even frequently
exceeds it?
It would. be natural to believe that the compensation for the func-
tion lost by the adrenal glands, particularly by their medullary
layers, is achieved by an intensification of the functioa of the
chramarfin system which remains.
, However, as follows from our data, this cagpaamation occurs only
1
1 in the event that following the removal of the adrenal glands they
I are transplanted in a certain spot only (in the area of the lower
poles of the kidneys). It =1st simply be graated here that campen-
1.0.?????0
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elation can occur quickly, because the transplanted adrenal gland con-
tinues, for a certain time, to secrete its hormones.
In the literature, there is mention of the fact that at autopsy
sometimes various pathological changes of the chromaffia cells are
accidentklly refold in the medullary layer of the adrenal glands,
which goes as far as the complete loss of the chromaffin reaction by
these cells..
It is characteristic that some of those who die with this picture
never suffered. from Addison's disclaim during life nor from any other
symptams of adrenal insufficiency which ordinarily acaompany destruc-
tions of the adrenal glands. In such cases, reference is useelly made
to the compensatory hypertrophy of the chromaffin tissue in the resi-
dual healthy imragenglia of 'the chrcaaffin system.
If the residual chromaffin system compensates for the adrenal
function whichtas been lost by the adrenal glands, then why do the
animals still die after the removal Of these organs?
From the investigations of the I. P. Pavlov school it follows that
the neural regulation of the, activity of the various systems of or.
pus is accarAished through the direct control of the cerebral cor-
tex and the adjacent subcortex. The fUnction of the adrenal or
chromaffin system can hardly be an exception.
In the further coufte of the investigation the problem was posed
to establish in, what wa,y a change of functioa.of the eerebrel cortex,
produced by means of pharmacologic agents, affects the adrenalin con-
tent and the content of adrenalin.like agents in the blood of normal
and experimental rabbits.
Smoression of the activity of the cerebra cortex and of the ad-
jacent subcortex was achieved. by us by means of chloral hydrate. We
attempted. to produce increases of the cerebral bortical activity by
means of caffeine and. bromides. Control experiments for the determin-
ation of the effect of chloral hydrate, bromides and caffeine were
carried on with the addition of these agents to a sample of blood al,-
ready taken or to Ringer's solution.
Chloral hydrate, by suppressing the activity of the c6rebral cortex
by the same token decreases its effect on the chromaffin system. As
a result, a decrease is seen in the adrenalin content and in the con-
tent of adrenalin-like agents in the blood, which was shown by ahio.
logical test.
At the same time, caffeine and. bromides, when injected in a defin-
ite dose into the body, increase the activity of the cerebral cortex,
threlka to which, possibly, the stimulant effect, on the chromaffin sys-
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?
tem is also increased. As a result, the content of adrenalin and of
adrenalin-like agents in the blood is increased.
Any different treatment of these results would, be simply incom-
prehensible, because the stimuli used by us in themselves exert a, weak
or even an opposite effect on the idolated frog's heart ccupared with
their effects In the body.
Therefore, it is seen from the experiments that in the vast major-
ity of cases when both adrenal glands are removed:from rabbits with-
out their transplantation, coppensatioa for their loaE function does
not occur. This is confirmed. by a decrease in the content of adron-
slin in the blood, by =increase in the hypoglycemia, emaciation,
fall in temperature, and high mortality rate of the Ftwilmftls*
Atter the removal of both adrenal glands and. autotrensplantations
of them into the areas of the lower poles of the kidneys (along the
border of the vena cava) the normal content of adrenalin and adren-
alin-like agents is rapidly established in the blood of the experi-
mental rabbits.
It may be granted that during the first one to two days after the
removal of both adrenal glands and. transplantation of them, the con-
tinuing excretion of the adrenalin into the blood might be explained
by an excess content of it in the tissues of the adrenal glands.
However, this explanation is not very probable. As amatter of fact,
injections of adrenalia into aniwP3s from which the adrenal glands
have been removed do not protect them from death at definite inter.
vals. Furthermore, transplantation of the adrenals in various other
sites rarely gives any emcees, despite the feet that the destrue-
tioa and resorption of the medullary layer of the adrmme gland in
both places proceeds almost equally. The idea arises involuntarily
that at the basis of all this lies a specific neural excitation which
is conditioned by the site of the transplantation.
The decrease in the blood sugar content is also referable to the
cllaical symptoms of removal of the adrenal glands. cats, guinea
pigs and rabbitp the concentration of' sugar in theblood decreases
by half.
We have not come across any observations dealing with the state
of the blood sugar in rabbits -following the simultaneous removal of
both adrenal glands and autotransplantation of them.
Our experiments on the determination ofplood sugar were performed
on 22 rabbits; five of them were controls with the simultaneous re-
moval of both adrenal glands, and 17 were experimental .with the
simsl-
tauoots removal of both adrenal glands and autotransplantation of them
Is
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into the area of the lower poles of the kidneys. The examination of
of the blood was made by the Bhgedorn-Jensennethod.
The blood sugar contengailthe blood of rabbits with simultaneous
removal of both adrenal without transplantation of them falls
to less than half on the day following operation. in the experiment-
al rabbits a day after the simultaneous removal of both adrenal
glands and autbtrensplantation of them into the area oflhe lower
poles of the kidneys, the Change of the blood sugar content was ex-
pressed to a smaller extent than in the control rabbits (Fig. 9).
In the next three days, a small rise is seen in thiexperimental ani-
mals, and then a fall in the blood sugar content, which is continued
for seven to ten days. Beginning 'with the 21st day the blood sugar
content begins to increase appreciably and reaches the initial level
three months after the operation.
120
,/ro
Blood
sugar in 1
mg. % 80
m
co
I 3 S 7 10 M 21 JO 66,
?pa/ noene 0,7epaqua
Days after operation
Pig. 9. sugar Content in Blood. of Rabbits After Simultaneous
Removal of both Adrenal Glands and. Autotransplantation of them
in the Area of the Lower Poles of the Kidneys.
Designations: experimentv- - - control (sim-
ultaneous removal of both adrenal glands).
Thus, the adrenal transplants during the first one to two days after
the operation create in the body the conditions of a sealer degree
of drop in blood sugar than in the control rabbits in which the ad-
renal glands were removed without autotransplantation.
Oae cannot help but direct attention to the fact that the begin-
ning of the significant increase in blood sugar content coincides in
time (21st day after the operation) with the cessation of weight loss
by the animals and the ingrowth of neural structures into the trans-
plant capsule from the surrounding tissues.
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Observations show that the restoration of the blood sugar to its
initial level occurs three months after the transplantation of the
adrenal glands, that is, at the time of formation of the new neural
apparatus and of regeneration of the cortical layer of the transplant.
420.
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TO OCCURRENCE AND DEVELOPMENT OF INDUCED TUMORS UNDER
CONDITIONS OF BODILY REACTIVITY WRICHIAS BEEN ALTERED
BY.ACCEZSORY STIMULI
S. I. Iebedinskaya
Laboratory of Experimental Pathology (Head -- Professor S. I.
Lebedinskaya).
For the past few years the problem of our investigations has been
the elucidation of the significance of nervd reflex mechanisms in the
occurrence and development of malignant tumors.
The application of accessory stimulations aerved. as the method of
nnelysis in our investiaatione, which, by changing the reactivity of
the body, exert influences on. the formation of tumors experimentally.
By this route it is possible to set about the elucidation of the rules
Pea regulaticcas of the occurr nee and development of malignant tumors.
The elucidation of those rules and regulations can in their turn
indicate the routes of the most effective methodsar influencing the
tumor process.
Certain foreign scientists (Boreal= and his co-workers), who have
been engaged in investigations of the action of accessory stimuli on
carcinogenesis, regard the actions of thesesbimuli as exclusively di-
sect ones, associating them with their permanent properties of in-
tensification or inhibition of tumor developmentp and of exerting
"co-carcinogenic" orluati-carcinogenic" effects* Thus, thelipstion
of the significance of the reactivity of the body in the tumor pro-
cess has been completely ignored. by these authors.
Our first investigations, however, (A. A.Soiov'yev, S. I. Lebedin-
skaya and. A.A. Solovi.yev), confteted in the laboratories of A. D.
Szeranskiy, showei that the effect ot accessory stimuli on the de.
velopment of tumors is not only connected with their qualities but
also depends on the conditions of their use.
The experiments showed that one and the same stimulus can, de-
pending on the Site of application, either intensify or inhibit tumor
development.
These data, along with others, permitted us to express a hypo-
thesis concerning the nerve-reflexamhcanism of action of the access-
ory stimUli, which alter the TUnctional state of the nervous system
and. which therefore affect the tumor process.
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Such a hypothesis is in accordance with data obtained by I. P.
Pavlov and his students in the study of higher nervous activity on
the effect of external stimuli on the conditioned-reflax activity of
anivnln and also with the experimental material of the laboratories
of A. D. Speranskiy on the effect of accessory stimuli on various
pathological processes.
FrOm the very beeortng of the work on conditioned reflexes in the
1aboratori4s of I. P. Pavlov it was noted that an extraneous (access-
ory) stimulus can, under certain conditions, disrupt the reactionl
and under other conditions, contrariwise, intensify this reaction.
The observed phenomenon can be explained., based on the teaching of
I. P. Pavlov, by the interrelationships between the excitatory and
inhititory processes which make up the activity of the body under
various concrete conditions.
A. D. Speremskly and his co-workers showed. with tbilise of extensive
experimental material that various accessory stimulations can also in-
fluence the pathological process, intensifying it under certain con-
ditions and inhibitittg it under other conditions. Stimulations pro-
duced by means of the use of accessory stimuli received the special
name of "counter-stimulations". Ibis conception:has as its purpose
the emphasis of '::he cOltsion of the two processes which occur sim-
ultaneously in the nervous system.
In the present report, our new material is being presented on the
study of the effect of accessory stimuli, under various conditions of
using them, on the occurrence of induced tumors.
It was noted ib.-our previous experiments on rats that with repeated
applidation of accessory stimulations to the skin, the intensifying
or weakening effect of these stimulations on the tumor process is man-
ifested maximally at a definite time after the injection of carcino-
genic stimulus, namely, between the 1.6th and 22nd weeks after the
start of the experiment.
In connection with these data, naturally, the necessity arose of
performing a new series of experiments purporting to study the effects
of accessory stimulations under conditions of their being applied. at
various times after the time of the subcutaneous injection of the sub-
stance which induces the tumor.
The experiments ware performed on 150 white f tr. ...rats weighing
115-130 grams each. In this series of experiments as well as in the
subsequent ones the tumor was produeed by the subcutaneous injection
of 0.5 milligrams of 9,10-dimethy1-1,2benzanthracene in 0.2 dubic cen-
timeters of apricot oil into one of the hind extremities. Cantharidin,
which had been tested. by us previously was used. in the capacity of an
accessory stimulus; as inpreceding experiments, it was applied once a
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wok to the skin of the opposite extremity.
The antmOs were divide& into five equal groups. In the first and
second groups the aceosory stimulus was applied for eight weeks be-
fore the injection of the 9,10-dimethy1-1,2-benzanthracene, after
whin the amazing was stopped. in the first group but continued. in the
second group until the end of the experiment, throughout the next
eight maths of the observation. In the third group, the application
of the accessory stimulus was begun after eight weeks; in the fourth
group, 16 weeks after the subcutaneous administration of a carcinogen-
ic stimulus. The fifth group of animals served as controls. In each
group there were 30 rats, which were kept in the experiment until the
end of the observations.
The results of the experiment showed that under the conditions mem-
tioned the application of an accessory stimulation exerts an intensi-
fying effect on tumor growth regardless of the time of its application;
this effect is dintinayabhed only by the time of its appearance.
In the first three groups of experimental animas the tumors appear-
ed one month and seven days earlier than in the control rats. In the
fourth group (where use of the accessory stimulus was begun later),
its intensifying effect could. be determined. beginning with 5i7 months,
at which time the nuMber of tumors in this group was two times great-
er than in the control group (Fig. 1).
Number ii,
of rats g?
with
tumors 5.
t3.
...... ?
........... I
31/2 41/4