THEORY OF DISEASE = ТЕОРИЯ БОЛЕЗНИ
Authors/Creators
Description
A.I. Gozhenko
THEORY OF DISEASE
2017
A.I. Gozhenko
THEORY OF DISEASE
Monograph
Odessa - 2017
UDC: 616-02.001.1
BBC: 52.522
G 57
Recommended for printing
Scientific Council of the Ukrainian Research Institute of Transport Medicine of the Ministry of Health of Ukraine
(Protocol No. 1 January 15, 2017)
Reviewers:
Trakhtenberg I. M. , Corresponding Member of the National Academy of Sciences of Ukraine, Academician of the National Academy of Medical Sciences of Ukraine, Doctor of Medical Sciences, Professor
Ataman A. V. , Doctor of Medical Sciences, Professor
Gozhenko A.I.
Theory of disease: monograph / A.I. Gozhenko. - Odesa: Phoenix , 2017. - 144 p.
The monograph summarizes modern ideas about the theory of the disease, which are presented on the basis of literature data and many years of research by the author, argues a number of methodological provisions that are subject to scientific discussion, contains conclusions that can be taken into account by practitioners. The main provisions of the theory of disease can be useful both for medical scientists and hygienists, specialists in the field of epidemiology of non-communicable diseases, clinicians, teachers and students of medical universities.
DOI https://doi.org/10.5281/zenodo.7738767
Foreword
The appearance of a new book by Professor A. I. Gozhenko "Theory of Disease" pleased readers who are interested in theoretical works in the field of medicine.
Firstly, because there was another opportunity to get acquainted with the opinion of the leading theoretician-pathophysiologist on the modern understanding of the main theoretical issues of medicine.
Secondly, because this is already the third work in which the ideas and provisions previously expressed in the works “Essays on the Theory of Disease” (2010) and “Basic Constructions of the Theory of Disease” (2015) are preserved and developed, which the author consistently supplements, clarifies, details his ideas and judgments, presenting the following work to the reader.
However, the third book of A.I. Gozhenko, along with the deepening of the previously stated provisions, is characterized by the appearance of new sections, for example, "Sanogenesis", "Teaching about death - thanatology", "Models of medicine", "General theory of disease and prospects for the development of modern medicine", significantly revised sections "Theoretical foundations and prospects for improving diagnostic and therapeutic technologies”, etc.
Moreover, the author not only formulates the principles and puts forward his judgments about the theoretical foundations of illness and health, but also demonstrates them on a much larger number of examples. In fact, it becomes clear that these are not individual examples, but a system that indicates that each theoretical position not only arose, but also “works” in medicine. Ultimately, the "Theory of Disease" presented to the reader becomes a significant part of the modern theory of medicine. Moreover, although the author does not set as his goal, but briefly but quite clearly in the new section presents a fundamentally new understanding of the models of medicine. This is especially important in our turbulent age of the development of medicine, which successfully develops based on biological principles, but already today steps further both technologically and philosophically.
Indeed, at present, medicine, as a field of knowledge and practice, is the most important component of the civilizational process. Therefore, the history of medicine, which has not yet been written in such a context, is the history of mankind in the philosophical understanding and development of its practical direction - public health. In the last section, the theory of disease is the theoretical foundation. To present it in a historical aspect, a huge number of opinions, achievements and ideas should be analyzed. Meanwhile, understanding the complexity and scale of the task, the author presents his own approach to the presentation of the problem, which is based both on the main historical milestones and existing knowledge, and on his own idea of the development of the theory of medicine. Moreover, it is important that the author's task is to present the theory in a format accessible to a wide range of physicians - from a student to a scientist, which is not only understandable, but can also be used as a working tool - theory for medical practice.
Theoretical ideas about the disease are addressed to everyone in medicine: from a student standing on the threshold of the temple of science and practice, a doctor and even a researcher, each of whom can use them both to form a methodology and a technique in medicine. And, indeed, it becomes clear the usefulness and significance of general biological, even philosophical approaches for medical science and practice.
In general, one should agree with the author's opinion that understanding and, especially, the use of general theoretical approaches in medicine can significantly increase the efficiency of the modern diagnostic and treatment process, especially at the present time of rapid progress in medical technologies.
Corresponding member of NAMS of Ukraine,
Professor A.I. Gubsky
Dedicated to Pathophysiology and Pathophysiologists
Author
AUTHOR'S FOREWORD
The rapid development of science is now the basis and condition for the development of civilization. This fully applies to medicine, the progress of which is obvious. At the same time, humanity sets new and new tasks for medical practice, which is designed to ensure the preservation of health and the maximum extension of human life. Moreover, the idea and understanding is being strengthened in society that it is the life of each person that is the goal and measure of civilization, because there is nothing more morally significant than this.
The scientific and technological achievements of civilization are largely measured and implemented by the success of medicine. It should be noted another global eco-ethical direction of the philosophy of civilization: the interaction of mankind with the environment, space, can also be measured by the interests of man, as an integral element and part, and one of the most complex - nature, at least on planet Earth. Thus, the humanization of science becomes the main direction in the development of modern civilization. The latter puts medicine, with its practical tasks of ensuring human health, to the very forefront of the development of science and technology. As a result, today there is a tangible progress in medical technologies, which are increasingly based on the achievements of fundamental sciences and, moreover, this connection is organic and quickly implemented in time.
The most important problems of modern medicine continue to be the prevention and treatment of human diseases. Undoubtedly, the prospects for progress in medical technologies depend not only on the achievements of fundamental sciences, but especially on understanding the essence of human life in its two main states - health and disease. In this regard, health, its maintenance, especially through its management, has recently become the main direction of medicine.
The need to deepen our understanding of the essence of the disease is also determined by the fact that many modern medical technologies use intensive methods of influencing a person. Transplantation of organs and tissues, the use of stem cells, genomic medicine, on the one hand, expand the biological capabilities of the body, but on the other hand, significantly change the evolutionary patterns of development of pathological processes and the formation of adaptive reactions that provide adaptation to the environment, and therefore determine human life and health . These and other issues that are associated with the emergence of modern medical technologies urgently require understanding and progress of our knowledge in the field of the theory of disease, the state of which has always been the basis for the development of medicine, the creation of its modern model.
Meanwhile, in recent years, predominantly analytical approaches to the study of human nature have triumphed in the biomedical sciences. Of course, it is the deepening of our knowledge about the elemental nature (structure, function, biochemistry, biophysics) of a person that is the basis for the creation of new medical technologies. However, one should also clearly understand the need to understand the behavior of individual elements and mechanisms in an integral biological system, which is the human body, the degree of self-organization of which forms the basis of its health, including the ability to recovery from illness.
Today, the classical ideas that it is necessary to treat the patient, and not the disease, should be filled with new theoretical content, it is necessary to create a new modern theory of the disease. Clearly realizing that it can be created only when a person as a biological system is fully known, we, at the same time, affirm that today it is possible and necessary to start building it, at least, forming the foundations of its creation. The author devoted his work to this task in the hope that the attempt to create a theory of disease will be used as the most important and necessary element of the foundation for building a modern theory of medicine.
Along with this goal, no less important is the task of equipping every doctor at the present time with modern ideas about the theory of disease, which are extremely necessary in a huge flow of medical information, especially in connection with the rapid progress of pharmacology, opening up new possibilities for managing the body in a state of health and illness.
The author is grateful to colleagues in science and medical practice, and, first of all, to pathophysiologists, communication and discussions with whom helped to formulate and present to your attention our ideas about modern problems in the theory of disease, which complete the cycle of work in this direction of the theory of medicine.
INTRODUCTION
Despite the validity of the statement of academician I.M. Trachtenberg about the complexity of formulating definitions, fundamental concepts are needed, because it is on them that knowledge is based, which is formed in a particular field of knowledge, to one or another historical stage in the development of science, including medical science [62] . In turn, fundamental concepts are also the prospect of improving the practical activities of mankind. Therefore, fully agreeing with the statement about the relative and complex nature of concepts that exist, including in medical science, we consider it possible and even necessary to present to the reader our vision of the modern understanding of the theory of disease - the totality of basic fundamental concepts in medicine. They are derived by biomedical science on the basis of the vast historical experience of medicine and form basic theoretical concepts that are constantly changing in connection with the development of science, and not only medical.
Knowledge about the essence and manifestations of diseases is so numerous and, at the same time, constantly replenished that it is very difficult to solve the problem of their complete analysis and generalization, but this is precisely the basis, the theoretical (methodological) basis for the development of modern medicine. The need for modern methodological concepts is especially felt at the present time, when there is a rapid development and introduction of new methods of diagnosis and, especially, treatment and rehabilitation. This allows not only to ensure recovery by influencing the mechanisms of the body, but also to significantly influence, influence and supplement them. Examples are methods of treatment using stem cells, transplantation of organs and tissues, genetic engineering. In these cases, the biologically formed mechanisms of illness and recovery are changed (completed). Therefore, the proposed methods and technologies should be based on a new methodological base, i.e. general theoretical understanding of the disease. Moreover, the more data on morphological, biophysical, biochemical and physiological changes in pathology accumulate, the more obvious the need for their synthesis in the system of general ideas about the disease becomes.
Of course, the improvement of our ideas about the elemental components of the disease at the same time often moves us away from understanding the state of the whole organism. Meanwhile, he is sick, i.e. is in a state of ill-health, namely the whole organism. It is important that such a conclusion at the same time deepens our understanding of the disease as one of the conditions of the body. We draw the reader's attention to the fact that the philosophy and methodology of cognition of pathology should be based simultaneously on two components: factual (symptoms, clinical data, laboratory, functional and instrumental examinations) and semantic (generalizing). Moreover, generalization should be carried out at different levels of the organization of the living - from the cell to the whole organism.
At the same time, the psychology and practice of understanding the disease often leads us towards the primary importance of the specifics of symptoms and individual morpho-functional and biochemical parameters characteristic of pathology. The latter, indeed, are important and necessary elements that characterize a diseased organism (markers, criteria), but they are not a disease as a state of the whole organism in the process of supporting life. Therefore, the thinking and psychology of a doctor should be based on basic general theoretical ideas about the essence of the disease, which form an idea of the pathology of the body, and then concretized to the level of a symptom, syndrome, nosology and disease of each patient. In turn, this is the theoretical basis for improving diagnosis and treatment.
The material presented in this book is aimed at the formation of a doctor, researcher and teacher of understanding the disease based on the patterns of development of pathology.
We hope that the proposed philosophy of disease will be a useful foundation for medical thinking in practical medicine and at the same time the formation of the methodology of medical science.
“Most of all I want to emphasize
the importance of theory. This is especially important
to do, because in our time
they are simply terrified of
abstract thinking in medicine.”
G. Selye
CHAPTER I
Theory of Medicine: Science, Education and Medical Practice
According to one of the most accepted definitions, “Medicine is a system of scientific knowledge and practical measures united by the goal of recognizing, treating and preventing diseases, maintaining and strengthening the health and working capacity of people, and prolonging life” [ ] . In our opinion, this is also an area of industrial, public and social human activity, aimed at the development of scientific and practical medicine. Of course, the most important part of medicine is medical education, which acts as a link between science and practice, providing training for a medical worker who carries out medical practice.
It should be noted that at present medicine is one of the most intensively developing areas of human practice. And this is not surprising, because a person becomes an object and a subject of civilization. Indeed, the entire development of science, technology, production, has as its main goal the maximum satisfaction of the needs of the individual and society as a whole. It goes without saying that the basic human need is health and longevity. Therefore, medicine is increasingly strengthening its position as the most important priority area of human activity.
In the modern world, the development of any human activity is based on the achievements of science. Accordingly, the science intensity of medicine is also increasing.
[37] . The avalanche of new information about the structure, function, biochemistry and biophysics of living organisms is growing every day. In understanding the essence of the living, medical science has moved to the molecular genetic level of knowledge. These achievements are associated with new technologies for diagnostics and treatment, the emergence of a huge variety of pharmacological preparations that make it possible to influence and control individual elements and mechanisms of a living organism [69] . At the same time, it becomes clear that the number of new facts does not always immediately lead to the formation of new ideas, their theoretical understanding and understanding of the essence of medical problems. How not to remember that back in 1845, A. I. Herzen wrote: “Natural scientists and physicians always refer to the fact that they are not yet up to the theory, that they have not collected all the facts, not all the experiments have been made, in total ... endless facts many and ... no matter how much you collect, you will not reach the end ... ”
Indeed, with the dismemberment of a single human organism into parts with a deepening of knowledge about its elemental components, the need to develop a theory of medicine increases proportionally [57] . We draw the reader's attention to the statement of G. Selye, taken as an epigraph to this chapter. Unfortunately, it can be stated that for more than half a century after this statement, little has changed in medicine, and scientists still pay insufficient attention to theory, preferring to engage in prestigious analytical research. However, the history of medicine shows that the emergence of new theoretical concepts has always served as a powerful stimulus for the development of medical science and practice, and the creation of fundamental laws and generalizations, i.e. new theory.
If we make a brief excursion into the history of medical theory, then in the development of the theoretical foundations of medicine, in our opinion, three main periods can be distinguished.
The first historical period, in our opinion, can be conditionally characterized as descriptive and speculative. Its length in time is quite large - from the moment when a person began to provide medical care, i.e. engage in medical practice, until the XVII-XIX centuries - the period of the beginning of active analytical scientific research on human nature.
The main information about this historical period has come down to us mainly from ancient Greece. The solidary theory of Democritus' disease, in fact, was the prototype of all subsequent theories of medicine, where the fundamental are structural (morphological) changes that determine the state of the body. In the same period of time, a humoral direction was also formed in the theory of the disease, the most prominent representative of which was Hippocrates, who explained the onset of the disease by improper mixing of the four basic fluids in the body. This interpretation later laid the foundations of the biochemical (humoral) direction in pathology.
It is important to note that in their reasoning, interpretations, ancient physicians proceeded from the described observations of a healthy and sick person as an integral object. In general, these views were defined as natural philosophy. However, the lack of specific knowledge about the structure and functions of the body did not allow scientists of that period to develop objective medical theories, and their reasoning was often predominantly speculative, which manifested itself both in brilliant conjectures and in idealistic delusions. New facts in medicine accumulated slowly, and theoretical thought, not having them, often formulated conclusions and theories that had nothing in common with reality. However, the great healers of the past, based on their clinical practice, sought to get closer to understanding the disease, developed medical theory, understanding its practical significance. Avicenna said especially clearly and specifically about the meaning of the theory: “Under the theory of medicine, we understand that part that teaches only the basic rules ...” [1].
In general, we can agree with Professor A.D. Pavlovsky, who wrote more than a hundred years ago, analyzing the history of thinking in medicine: “In its historical development, medicine has gone through the same phases as philosophy and natural science.”
With the introduction of new methods for studying the structure and function of the body, the number of facts that became the property of medical science increased dramatically, especially in the 19th century, and, as a result, the theory of medicine during this period can be characterized as analytical-materialistic.
Almost all theories of medicine of this period were based on specific materialistic positions, based on constantly growing analytical data on the structure and functions of the body. And, it was during this period that the foundations of all currently existing theories in medicine were formed. However, from the second half of the 20th century, and especially with the onset of the 21st century, it became clear that the theories existing in medicine began to lag behind the rapid progress in analytical research. We can return to the thought of A.I. Herzen and agree that there is no limit to the accumulation of new data.
In this regard, we believe that at present the time has come for the third stage in the development of the theory of medicine, the main content of which should be the creation of an anthropocentric synthetic theory of medicine . Meanwhile, although the need for new models of medicine and its theoretical understanding began to be realized already a quarter of a century ago, the problem still remains open [58, 59].
The essence of this stage, in our opinion, is to build a theory of medicine on a biological, evolutionary and ecological basis in integration with social and general scientific problems and prospects. The latter introduce new components into the biological essence and especially the existence of man, which can be successfully used in solving the issues of maintaining health, treating diseases and, in general, productive longevity.
Until now, the content (structure) of the disease theory itself is not clear. Many authors believe that the theory (model) of medicine is identical to the theory of disease, although according to another opinion, the latter is the most important, but not the only part of it. In any case, the need to create a modern theory of disease is an urgent need of clinical medicine. In our opinion, the factual data accumulated in medicine and the existing theoretical concepts may well be the basis for constructing a modern theory of the disease.
Thus, a brief excursion into the history of the emergence and development of medical theory allows us to highlight the main elements of the structure of the modern theory of disease.
1. The doctrine of health, which, based on the totality of the most modern data on the structure, biochemistry and functions of the body, is designed to describe a person as an integral biological system in the process of adapting to the environment in the absence of damage. The doctrine of health is a particularly important theoretical basis for preventive medicine, rehabilitation and recreation, moreover, these ideas serve as starting elements for comparison with the state of the disease. Moreover, with the expansion of the scope of medicine, with the formation of healthy medicine, the role of the doctrine of health is constantly increasing.
2. The doctrine of the disease, which should reveal the essence of another state in relation to human health - disease. In theoretical terms, the most important is the understanding of the unity of two human states - health and disease as interrelated forms of the existence of the organism and, at the same time, understanding their fundamental differences, the measure of which is the norm. The latter, as the boundary between health and disease, is the theoretical basis for diagnosing pathology.
3. The doctrine of etiology, as a science that describes the causes and mechanisms of the transition of the human body from a state of health to a state of illness. Knowledge of etiology is the main prevention and etiotropic treatment.
4. The doctrine of pathogenesis, as a science of the mechanisms of the development of a disease - a special form of adaptation to the environment in case of damage to the body. Understanding the pathogenesis not only allows you to understand the clinical symptoms, and, therefore, the diagnosis, the course of the disease, its prognosis, but most importantly, it is the basis of the pathogenetic therapy of the disease.
5. The doctrine of sanogenesis as a science of the mechanisms of recovery, which, together with an understanding of pathogenesis, makes it possible to predict and manage the outcome of a disease and a person's recovery and serves as the theoretical basis for restorative medicine (rehabilitation).
6. The doctrine of death, as a science of the mechanisms and essence of the transition of the human body, as a biological system, to a state characteristic of inanimate nature.
7. The doctrine of the theoretical foundations of prevention, diagnosis, treatment and rehabilitation.
8. The doctrine of clinical pathophysiology.
Such, in our opinion, is the modern structure of the theory of disease. Meanwhile, in clinical medicine, a specific object of medical practice is a sick person with one or another clinical form of the disease. A doctor starting to provide medical care to such a person must clearly understand the main provisions of the theory of the disease, which will allow him to identify the causes and mechanisms of the development of the disease among the individual characteristics of the patient, and the latter, in turn, make it possible to use the most effective and reasonable etiological, pathogenetic and sanogenetic methods of diagnosis and treatment that can ensure the recovery of the patient.
Emphasizing the fundamental importance of theory, including the theory of disease for medicine, we, as a rule, present the field of medicine as something unified, without structuring it. Meanwhile, it seems to us necessary in this regard to divide medicine into science, education and practical health care. In accordance with such structuring, the role of theory, its specific tasks in each part of medicine, should be considered separately.
Medical science creates the theory of medicine on the basis of obtaining and analyzing ever new facts about the structure, biophysics, biochemistry and functions of a person in a state of health and illness.
The following levels of organization of matter in living systems are known:
- structural (morphological);
- biochemical;
- biophysical;
- functional;
In fact, this corresponds to the levels of organization of matter, generally taking into account the characteristics of the biological form of matter. The former is often combined with the latter, denoting it as structural-functional (morphofunctional).
The knowledge of the human body in its basic states - health and disease - proceeded in the direction from the study of the integrative morphofunctional level to the biochemical one. At this stage in modern medicine, the main results have been achieved in understanding the physiology and pathology of a person, his main mechanisms, which is reflected in the enormous role that is given to the molecular genetic foundations of pathology. At the same time, it is well known that the chemical level of the existence of matter is based on the physical. Although some progress in understanding the role of the physical level of organization in biological systems has been achieved, examples can be the physical foundations of energy conversion in mitochondria (chemi-osmotic theory), the role of membrane potential in cell functioning, etc., it should still be noted that medical science, in this regard, is only at the beginning of the road.
On the one hand, this should be the sequence of knowledge - from the general to the particular, especially since the methodological possibilities for studying the physical level of the organization of the human body are significantly limited. On the other hand, historically, with an in-depth study of living systems, analytical approaches begin to prevail, allowing to determine the fundamental subtle mechanisms, which, at the same time, divides the whole organism into subsystems and separate elements, the knowledge of which does not guarantee an understanding of the functioning of the human body as a given integral supersystem.
A consequence of the development of such an analytical approach was the differentiation of theoretical scientific medical disciplines, which continued throughout the 20th century. However, by the end of the 21st century, it became clear that further analytical studies, which, of course, allow one to get an idea of the elementary, structural and functional components of the body, without a simultaneous integrative approach, do not provide an understanding of the functioning of the body as a single system. This served as the basis for the integration of theoretical medical disciplines. Thus, the concept of integrative medicine arose, which, in our opinion, is a new approach to the knowledge of the human body, which allows us to give a holistic view of the body as a single supersystem. At the same time, much less attention is paid to the role and mechanisms of the integrative approach.
Thus, the generalization of new facts, and then the creation of new theories crowns the process of scientific research in medicine. Each new theory opens up additional possibilities in cognition, becomes a program and an instrument of action, but does not linearly transform into new theoretical conclusions in accordance with the amount of data received. At present, in connection with the growing role of theoretical science, even the concept of "fundamental medicine" has arisen [39] . Thus, it is emphasized that theory is the foundation of all medicine.
In the process of scientific research, scientists, as a rule, are guided by existing theories that help them analyze the data obtained, although then at the same time they seem to “keep” them in captivity of existing ideas.
The creation of a new theory is always accompanied, to some extent, by the denial of previously existing ideas. The latter is not only epistemologically, but especially psychologically perceived as difficult. Therefore, a new theory is always a qualitative leap in the study and understanding of human nature, it is a personal intellectual breakthrough, including through the majority of conservatively minded individual scientists, and sometimes the entire scientific community. There are many examples of such theoretical breakthroughs in medical science. Suffice it to recall the theory of the general adaptation syndrome of G. Selye, in the emergence and creation of which the genius of the scientist relied not on a large number of fundamentally new scientific data, but on understanding, generalizing well-known, but not understood in terms of theoretical significance, factors [57, 83] .
Meanwhile, subsequently, it was on the basis of the theory of the general adaptation syndrome and the definition of the state of stress that world science took a big step into a new scientific analytics (hypothalamic-pituitary-adrenal system), and medical practice received powerful pharmaceuticals and medical technologies (steroid hormones and their analogues) .
This is a reality - scientists create new theories, use them, and then find themselves in their captivity. And only again subverting the ideas that have become classical, they develop new theories. It is impossible to circumvent these patterns of development of science. However, clearly understanding that in each historical period of the development of science, the truth, i.e. the existing theory is relative, we should strive in scientific research not only for deep analytics, but try to generalize new facts, comparing them with known postulates and previously described patterns. Based on this, it is certainly necessary at the stages of training a scientist to purposefully form such ideas about the role of theoretical generalizations in science.
All organizers of science, from the informal leader of a scientific school to the heads of research institutes and academies, should, if possible, create the necessary conditions not only for obtaining new facts and knowledge, but also for generalizing them, creating new theories.
Consequently, the role of the scientist's personality is the most important in science.
Historically, it so happened that the scientific school has always been considered the most important informal form of organization of scientific teams. The initial condition for the creation of a scientific school is the presence of a leader, who is an informal scientific and moral leader, around whom a group of students, associates, followers is formed in the process of scientific and pedagogical activity. Of course, the main thing is the research activity of the leader, who is helped, with whom his students, “children” in science, work and study [20] . The more intense and fruitful is the activity of the leader-teacher, the more his students are drawn into the orbit of his activity, interests, principles. Such qualities as love for science, combined with diligence and high moral principles, contribute to the formation of the worldview of students, their way of professional activity, and, sometimes, life in science.
The role of the teacher's personality in mastering by students the methodology of scientific activity and scientific thinking, scientific creativity cannot be overestimated [17] . In recent years, opinions have been expressed that such a phenomenon as a scientific school is losing its significance. Such judgments are based, first of all, on the fact that the concept of a scientific school is identified only with the process of learning, the transfer of scientific knowledge. Of course, in the era of a fundamentally new organization of information support for the scientific community, the role of one teacher, the leader of a scientific school, fades into the background in terms of training and information support. But, science is based not only on the knowledge of existing laws and facts, which are the basis of the modern idea of the laws of material existence, in our case, biology and medicine, although they are very important for work in science [40 ] .
Meanwhile, scientific creativity, research work, as a process of objective knowledge of new patterns, in particular, being a subjective process in medicine, is carried out and realized through individual scientific activity. At the same time, a complex of moral and ethical qualities in combination with the methodology of cognition is fundamental in the creative activity of a scientist. Their formation is possible in almost two different ways.
According to the most recognized way, this happens through personal transfer, teaching by a teacher, the leader of a scientific school, who implements the learning process in cooperation with the scientific school team.
The second is the possibility of obtaining the necessary information without its personalization, i.e. from the existing scientific information base.
Each of these ways of becoming a scientist has its own advantages and disadvantages.
So, of course, that the education of a scientist in a scientific school is the most systematized, purposeful, which, combined with the possibility of personal influence, is the universally recognized optimal way to enter science. Critics of scientific schools and their role in the organization of scientific creativity point out that in a number of cases, such qualities of a scientific leader as his authority in moral and ethical issues and the methodology of science hinder the formation of independent scientific creativity of students, limiting them, through the directed influence of the teacher's personality . Although one can agree with this at first glance, however, it is necessary to pay attention to the difference between formal leaders-heads of scientific teams and informal scientific leaders.
The most important condition and characteristic of an informal scientific leader of a scientific school is that the main and uniting students around the teacher are his qualities of a scientist and a person. Therefore, if such an informal leader leads a scientific team, the possibilities of such a scientific school increase. The main thing is that, in the end, a special moral climate is formed in it, in which young scientists acquire qualities that are extremely important for scientific activity.
There are several examples of the most successful scientific schools in Ukraine. Of course, in theoretical medicine, the most successful and effective was the scientific school of Academician A.A. Bogomolets, whose students academicians K.V. Gorev, V.P. Komisarenko, R.E. Kavetsky, N.N. Sirotinin and others became major effective researchers, successful organizers of science, who not only fruitfully continued the scientific direction of their teacher, but also created their own scientific schools.
In clinical medicine, a striking successful example was the cardiosurgical scientific school of Academician N.M. Amosov, whose students are still fruitfully developing cardiac surgery in Ukraine. Without citing other examples, one should pay attention to the fact that in the history of medical science there are also numerous cases when successful scientific researchers, leaders in science do not form their own scientific schools, i.e., apart from the scientific level, for the leader of the scientific school other qualities are needed. Unfortunately, in these cases of subsequent development, these teams do not have, at least, the direction of the leader, as a rule, stops its development or loses its effectiveness.
It should be noted that in the history of science there were effective scientific schools in different periods of history and, by the way, they even served as the basis for organizational administrative decisions in science. Suffice it to recall the scientific school of the ancient Greek thinker Plato, who walked with his students through the grove of the Academy, where his scientific school functioned. How not to pay attention to the fact that subsequently organized administrative forms in science were called the Academy.
According to the second approach to the formation of a scientist, his methodology is based on the existing modern knowledge base and methodology in science. With such training, a scientist is free from the personal influence of the authority of a leader in science, but at the same time, the process is random, which does not allow predicting and planning the development of the scientific community. In addition, with such a variant of the formation of the personality of a scientist, it is not possible to predict possible moral characteristics.
It can be concluded that the dialectics of scientific creativity presupposes success in combining the methodology and knowledge of modern science with the preservation of individual creative implementation in research work.
In this regard, special attention should be paid to the principles of organization and operation of administrative scientific structures (institutes, departments, centers, laboratories). Of course, the ideal solution is when the scientific team is headed by a scientific leader around whom an effective scientific school is formed. However, this is not always realistic.
At the same time, modern formal and informal leaders of science must clearly understand that although their task is to organize research work in a particular team, its successful implementation is largely, if not exclusively, based on the creative activity of each scientist. Therefore, not only a condition, but the most important tool is the education of scientists as effective researchers with the appropriate moral and ethical qualities. The existing cases of plagiarism, scientific copying, etc. testify to the importance of the latter. Consequently, every organizer of science is obliged to do everything possible to achieve the task of developing science, both through maximum support for scientific schools, and through other ways and means of training scientific personnel [5] .
At the very least, it is necessary for our leaders to be tolerant of new views, creating opportunities for their discussion, adoption or non-adoption of decisions only through free discussions, where the main arguments should be the facts and realities of theoretical views and proposals, the criterion for verifying which is, as you know, practice.
The situation is even more complicated with the theory of medicine in the second segment, in medical education. The subject in medical education is the teacher, the object is the student, the future doctor. Therefore, the subject in medical education is the same scientist, and everything discussed above applies to educators, for whom the significance of medical theory is even more significant. This is due to the fact that at the current pace of updating scientific medical information, a teacher of a higher medical school must not only ensure that students master the existing level of knowledge, but also prepare them for the perception of the data that will appear in medical science and practice in 5-10 years and beyond.
Consequently, in the process of teaching modern knowledge, a teacher of a higher medical school, along with teaching modern established knowledge, should strive to present predictable theories. This is possible on the basis of the modern conceptual apparatus of theoretical medicine, taking into account the forecast of the development of medical knowledge. Therefore, every teacher of the higher medical school should actively participate in scientific research, because only they are able to form the methodology of his scientific thinking.
It cannot be emphasized that the dynamics of the development of the personality of a teacher of a higher medical school should be based on the corresponding dynamics of the highest medical school, which implies the need for constant updating of curricula, and, in some cases, the very organizational structure of education. Unfortunately, the higher medical school in this matter clearly lags behind, at least in our country, the general progress of science.
There is no doubt that the student (future doctor) must, in the process of studying at the university, master, first of all, the theoretical foundations of medicine.
In this regard, at the beginning I want to remind you of two fundamental postulates of modern medicine.
The first is that the human body, being a structurally and functionally heterogeneous system, is, meanwhile, a single whole. Consequently, in pathology, when one or another organ is primarily damaged (disturbed), the whole organism is included in the disease process - the person as a whole is ill. Thus, the changes inherent in the disease are systemic, even intersystemic, i.e. organismal. Hence, it is necessary to treat the disease as a general condition, and not only direct medical efforts to eliminate individual organ or systemic disorders.
Secondly, it is not a person who is sick in general, but a specific genetically and phenotypically individual person, which predetermined an important postulate traditional for domestic medicine - it is necessary to treat the patient, not the disease. These provisions are the general result of the integration of theoretical thought and clinical practice. Moreover, the latter, in fact, is a paradigm of domestic clinical medicine, which must not only be carefully preserved, but also developed, which is extremely important in the current pursuit of standards and protocols in medicine.
Both provisions predetermine a systematic, holistic and at the same time individual approach to the disease and the patient at all stages of medical activity. In this regard, the formation of an adequate methodology of medical activity is the most important condition for the effective work of medical practice. At the same time, I consider it important to pay attention to the fact that in his practice, the doctor is also a researcher. It is he who sees the fullness of the clinical picture of the disease, genotypically and phenotypically individualized. And, if he subsequently takes into account these observations and conclusions in his clinical practice, we usually talk about the doctor's intuition. However, it is especially important when a doctor seeks to analyze his clinical experience and project it into a deepening understanding as a general phenomenon, which is the first step of his scientific work. It should be noted that clinical practice is not only a criterion of truth for existing knowledge, but, at the same time, the main engine of knowledge in medicine. It was practical medicine that often outpaced science and encouraged it to learn new things. Therefore, clinical practice is the main driver of the development of medical science.
Meanwhile, the preparation of a doctor for practical activities in a higher medical school today is organized in such a way that by the end of the university, the doctor is theoretically not fully prepared to carry out his practical activities, based on the general theoretical provisions he has learned.
Let's look at the organizational and didactic structure of education in universities. In the first and second years, future doctors study a healthy person, based on a predominantly analytical approach: the morphology, physiology, biochemistry and biophysics of the body are studied separately. This is accepted in the pedagogy of medical universities in our country due to the extreme complexity of a person, as a result of which it is almost impossible to understand the body as a whole, without knowledge and analysis of its individual components. Already in the third year, a number of disciplines are taught, among which pathological physiology, pathological anatomy and pharmacology are of fundamental general theoretical importance. For it is their study that is aimed at forming ideas about the theoretical foundations of the disease and the principles of its treatment. Pathological physiology occupies a special place among them, designed to give an idea of the etiology, pathogenesis and outcomes of the disease [2, 3] . Such an integrative position of pathological physiology led to its classical definition as the philosophy of medicine. However, pathological physiology itself as an academic discipline is heterogeneous and is divided into the following main sections: nosology, typical pathological processes, pathophysiology of organs and systems, clinical pathophysiology - each of which has its own educational tasks [2, 3, 7, 9, 31, 32, 42 ].
Pathology education, i.e. those conditions, the prevention, diagnosis and treatment of which is the goal of all practical medicine, begins with the study of the nosology section. This is usually the shortest section of pathological physiology, which precedes the study of specific diseases, i.e. mechanisms of etiology, pathogenesis and sanogenesis of all clinical nosologies. Of course, the historically verified approach is correct to precede the study of specific diseases by considering the general principles of the emergence and development of pathology in general. However, the practice of teaching, personal experience indicates the presence of significant difficulties in the implementation of this approach in the future. The psychological consequence of the need to study and understand the general principles of pathology without knowing the specific mechanisms and individual diseases is the switching of the student's motivation with a reorientation to the study of predominantly specific pathology, individual diseases, which also begins to be carried out during this period of study.
The study of the theoretical foundations of medicine ends by the end of the third year, after which the subsequent clinical information is studied up to the end of the university. However, by this time of training, the main provisions of nosology are either simply forgotten or not always correlated with a specific pathology, i.e. they don't fully work. It seems that they are practically not needed either for clinical practice, or even for research work in the field of medicine. At best, only certain general theoretical phantoms of the educational level remain in memory. As a result, the laws of the medical theory of disease are little or insufficiently used by doctors and even scientists consciously. The latter is evidenced by the fact that in the scientific press there are practically no works devoted to the development of the theory of the disease, and the discussion of these issues at scientific conferences is episodic and attention to it is insignificant, even at congresses and conferences of pathophysiologists. Moreover, when analyzing scientific publications, it is difficult to find works in which the described changes in the body are considered on the basis of, for example, the general theory of pathogenesis.
If certain issues of medical theory are not used in sufficient volume, are not in demand in practice, then the question arises - should they be studied or taught? This issue has been resolved in a number of countries, when, after studying general pathophysiology in the third year, clinical pathophysiology is studied in the last year of study, and certain special sections are taught in internships and even in continuing education courses for doctors. Probably, our higher medical school should study and use this experience. And then every practicing doctor could better understand the most complex and diverse kaleidoscope of changes in the body during illness. Moreover, it is not so important whether it will be a course in clinical pathophysiology or clinical pathology, but it is essential that the doctor's training provides for the need to study the issues of the theory of medicine as a significant analytical tool for future clinical practice.
In practical (clinical) medicine, the conscious use of medical theory is extremely limited. The organization of the treatment and prevention process based on modern standards (protocols) does not seem to require, and sometimes even excludes, theoretical understanding of the content of clinical practice. However, this is not the case for the following reasons. First, the individuality of each patient (genotypic and phenotypic) implies the need for an individual clinical approach. Second, the development of new diagnostic and especially pharmacotherapeutic technologies implies the need to rely on the fundamental concepts of the theory of medicine.
Thus, the question of whether the theory of disease is necessary for medicine, despite its paradoxical nature, is currently quite appropriate. To answer it, it is advisable to consider the elements that are the basis for constructing a theory of the disease.
“... a conclusion for the medicine of the future:
isn’t it time
to make a healthy person an object of medicine ...”
I.V. Davydovsky
Chapter II
The doctrine of health
Despite the fact that the main goal of medicine is to maintain health, not much attention has been paid to the theoretical and practical aspects of this state of the human body. Only by the end of the 20th century, interest in the state of health increased in medical science and practice.
Health is the main value of a person, and public health - of the entire population. WHO defines it as: "Health is not only the absence of disease or infirmity, but a state of complete physical, mental and social well-being." Consequently, the theory of health is the fundamental basis of medicine and has many components - from individual somatic and psychological characteristics of the human body to its social. We will initially focus on the biological essence of health, which consists in the ability of the organism to adapt to the environment within the limits that are characteristic of the species. In this regard, we consider it as follows - in the form of a pyramid (Fig. 1).
The basis of this pyramid of health, of course, is the human genome, which provides the genotypic potential of adaptation, the implementation of the latter occurs under the influence of living conditions, the impact of environmental factors, which ultimately form the phenotypic potential of adaptation [2, 63] . The latter, as a rule, reaches a maximum during puberty. It should be noted that the creation of the most favorable conditions for antenatal and postnatal development, and then in the period from childhood and throughout subsequent life, contribute to the formation of the maximum genotypically possible phenotype. It should be emphasized that the phenotype is formed under the influence of external factors. But the parameters of the impact of these factors must be within the limits of the evolutionarily active ones, under the influence of which the corresponding functional capabilities of the physiological systems and the organism have developed, as one system as a whole, more precisely, a supersystem .
Fig.1 . Spatial-temporal structure of human health
I - genotypic adaptation potential
ІІ – phenotypic adaptation potential
ІІІ – occupational health
І V – age potential
Hence, one of the most important conclusions is that, especially during the period of age development, the human body not only can, but must also be affected by environmental factors, which, through the training effect, include (realize) the genotypic potential of health, its level. Leading researchers of the last century have shown that an optimal and stable environment does not contribute to the formation of a phenotype with maximum adaptability. An example is clinical and experimental studies that the development of an individual in optimal stable temperature conditions does not contribute to the maximum adaptation and development of its functional features. Thus, the maintenance of children and offspring of animals in conditions of temperature fluctuations leads not only to more successful thermoregulation, but also to a high level of development of more effective immunity [64].
In the future, as a result of both genome-conditioned aging and constant impact, including negative ones, of the environment (environmental factors and anthropogenically dependent ones, including both socio-biological and occupational factors), adaptive capabilities are constantly decreasing, and the body in under these conditions is either in a state of health, when the action of environmental factors does not cause damage and does not exceed the adaptive capacity, or, when they occur, the human body adapts through a state of illness [26] . In general, a decrease in the adaptive capabilities of the body is gradually observed, i.e. the level of health decreases, which causes aging and, ultimately, the overall life expectancy of a person (Fig. 1).
Thus, the formation of health at the antenatal stage of development provides for a set of measures aimed at ensuring the stability of the human genome, which can be based on a set of measures to reduce the impact of mutagenic factors on humans and society as a whole. In the period after birth, the health strategy should be based on optimizing the action of environmental factors, especially on reducing the number of damaging factors. The formation of a population and individual healthy lifestyle is the main task of preventive medicine, which contributes to the quality and duration of life, forms the labor and social potential of society.
Traditionally, health issues, or rather, the conditions for its preservation or violations in medicine, were dealt with by hygiene. However, it should be emphasized that the main task of this science at present is to study, first of all, the nature of the influence of the environment on a healthy person.
The best example is the following definition, given in the textbook "General Hygiene" edited by Academician E.I. Goncharuk.
"Hygiene is a science that studies the patterns of influence (positive or negative) of external and environmental factors on people's health, as well as the physiological household and industrial activities of people on the external and environment."
As a result, all known tasks of hygiene are aimed primarily at finding out how certain factors act on the body.
At the same time, the need to take into account the influence of not only various factors, but also the state of those on which they act, led to the need to differentiate the very concept of "health". Thus, in the previously cited textbook, the following definitions are used: "general biological health, population health, individual theoretical health, individual health."
In our opinion, this and other attempts are due to the fact that health is considered, as a rule, as a static state of the body. At the same time, we have previously proposed a spatio-temporal model of health [25]. In Figure 2, you can see that the influence of various factors on the human body differs in different periods of life. The combination of these two components - genetic and environmental - form the health phenotype.
The need to take into account the interaction of the external environment and the human body predetermines the complexity of defining the concept of health, which served as the basis for the classical statement of I.M. Sechenov "An organism without an external environment that supports its existence is impossible, therefore, the scientific definition should also include the environment that affects it" [36] .
The foregoing allows us to adhere to the opinion that health is a biological pattern that is realized in individual health, as a genetic and phenotypic characteristic within the limits of species adaptation possibilities .
At the same time, it should be emphasized that the definition of "health" of a person, which was proposed by WHO experts, is not able to cover the entire period of a person's life, given its age dynamics. Indeed, the concept of complete well-being as an integrative characteristic of health is naturally not identical for each age period of life. The latter suggests the need to take into account spatio-temporal changes in a person when assessing the state of health.
For this purpose, we have proposed the concept of a "spatio-temporal" human continuum (STC), as a chain of continuous biosocial events that accompany and form the individual structure and speed of a person's life cycle. Visualization of PVC is shown in fig. 2.
The above diagram shows that in different age periods, the role of the influence of the main factors (determinants) on PVK differs significantly, which is extremely important not only for understanding the state of health, but also for the implementation of preventive and clinical medicine measures.
Meanwhile, in medicine, at present, one of the main criteria for health is the incidence, which in civilized countries is constantly decreasing, which causes an increase in the life expectancy of the population. Accordingly, a system of medical and other measures aimed at maintaining health is being implemented. In science, even special areas have been formed, which are called valeology or sanology.
Without setting ourselves the task of a detailed presentation of the problems of sanology, we refer you to the works of G.L. Apanasenko, who was a leader in the development of this science in Ukraine. In this section, we focus only on those aspects that need to be considered from the standpoint of a subsequent understanding of the disease. This is necessary, since the idea has long been established in medicine that in the definition and understanding of the disease, the starting point is its difference from another state - health. Moreover, the idea that health and disease are two different forms of human life has been firmly established [ 11, 51 ] .
Figure 2. Spatio-temporal model of health.
At the same time, life itself is considered as the ability of living matter, in this case the human body, to maintain existence in the environment. Thus, the main condition for such existence in a constantly changing environment is the preservation of the relative constancy of the organism.
Therefore, adaptation can be considered the main goal and way of existence of biological systems, including humans. However, in evolutionary terms, considering biological organisms as the highest, at this historical stage, form of development of matter, it should be clarified that life, as a form of existence of matter, initially did not oppose inanimate nature. Moreover, it was formed in it and on its properties. We now have a better understanding of the chemical level of organization of living systems. And, as a result, we consider water, hydrogen, carbon, metals with variable valence (primarily iron) and other chemical elements in their complex interaction to be the mandatory constituent elements of biological systems.
This allows us to express an even more, in our opinion, interesting opinion - the organism in the process of evolution initially did not adapt to the environment, it arose and coexisted on it. The environment was absolutely necessary for him, the organism and the environment were one. This is well illustrated by the example of chemical coexistence - a constant supply of energy and compounds (nutrients) that provide structural integrity are absolutely necessary for the human body. Less we understand the relationship of biological systems with the natural environment at the physical level of the organization of matter. But here, too, we can give an example that such interaction seems to be an indispensable condition for life. Thus, deprivation of the animal organism from external magnetic fields leads to morphofunctional disorders in the brain in the experiment [19, 34]. Therefore, in this example, one can see the connection and dependence (necessity) in the interaction of the body with electromagnetic fields, as opposed to existing ideas about only the negative impact of electromagnetic fields, from which the body needs protection (for example, the problem of the influence of mobile phones on the body, fault zones of the earth's crust) .
Consequently, at the stage of the emergence of life and biological systems, the latter were formed as part of this environment, using all its properties to form a new type of existence of matter, the only and most important property of which was the ability to temporarily maintain stability and temporarily resist entropy. This property allowed the emergence of life in the form of biological organisms with the ability to exist up to self-reproduction in a certain range of space and time. Mechanisms have emerged to ensure this temporal stability, primarily based on the formation of nucleic acids and proteins, as the initial elements of living systems, followed by structural and functional implementation in the form of cells, and then various living systems (organisms), which ensured the coexistence of living organisms. and the environment.
However, the evolution of living organisms in the future was associated with a change in the environment of their existence. First of all, this is due to the release of biological organisms from the primary aquatic habitat, where they originated, to land. The change in the habitat was accompanied by the emergence and development of the necessary mechanisms for interaction with the new natural environment. At the same time, two directions of development should be distinguished in the strategy of adaptation of living organisms to the environment: the first is the desire to preserve the basic properties of living matter and biosystems: the use of hydrogen, oxygen to provide energy, by using the chemical transformation of solar energy and aqueous solutions for protein systems, genetic mechanisms for information transfer.
The second vector of development was the emergence of special special systems for the adaptation of living organisms to new conditions of existence. For example, one of the biological branches in evolution led to the emergence of mammals, including humans. The specific mechanisms for providing these biological systems (organisms) include structural and functional organization, which ensures temperature stability, homeostasis, and many other conditions, up to the emergence of higher nervous activity.
These mechanisms began to provide a new level of interaction between humans and other mammals to the environment - adaptation , and not just coexistence in the form of only interaction.
Consequently, adaptation is only one of the forms of interaction between biological systems and inanimate nature.
At the same time, for a person, the degree of adaptation to the environment is a measure of his health , which, as a rule, decreases with illness. It is also important for a person to adapt not only to the biological environment, but also to the social one, which, however, mainly depends on the structural and functional state of the person, i.e. its biological parameters. At the same time, social adaptation also depends on the psycho-emotional state, which is determined not only by biological parameters, but also by mental characteristics, and the latter are largely determined by the information-intellectual component, the role and significance of the latter is especially important for a modern person and, especially, in the future.
Thus, the idea has long been formed that the main criterion for the existence of an organism in a state of health is the degree of stability, i.e. degree of freedom, while a healthy person is the most stable, which is achieved by adaptation [8] . However, the opposition of the human body to the environment is a relative concept, because the second condition for the existence of all biological systems and organisms is the need for constant communication with the environment. Indeed, in biological terms, the human body is an open system that is "fueled" by the environment: providing oxygen, energy-plastic and informational components. Only with such interaction with the environment is the existence of an organism possible, and only with such interaction is the relative stability of the organism maintained. This stability ensures the relative permanence of existence (metabolism, physiological functions and morphological stability). Thus, the relationship of the organism with the environment is the main condition of life, and its stability is based on maintaining the relative stability of the organism.
It is important to note that ensuring the permanence of the existence of the organism is based on the work of functional systems [4] . The latter, meanwhile, were also formed in the process of evolution of living organisms in historically existing environmental conditions, i.e. in the process of evolution. Consequently, all the possibilities of the functional systems of living organisms are ultimately determined by the properties of the environment. As a result, in living systems, including the human body, mechanisms (physiological systems) have been formed and are functioning that ensure its existence in the environment. At the same time, there are mechanisms for adapting the organism to all factors with which biological systems interacted in historical development, in evolution. This leads to the conclusion that in the human body there are mechanisms of adaptation to all environmental factors (temperature, barometric pressure, ionizing radiation, etc.), however, the power of these mechanisms and their functionality reflect the evolutionarily established quantitative relationships with specific environmental parameters.
The reactions of adaptation to the environment in a healthy person can take place in two phases. In the first phase, in response to the influence of one or another environmental factor (its change), an increase in adaptive functions occurs due to an increase in the work of functioning mechanisms by intensifying the functions of existing structures. They are called urgent adaptation mechanisms, as they are activated directly in response to a particular impact. However, if the effects on the human body are long-term and the power (structural-functional) of the existing morphological structures is not enough to maintain sustainable adaptation, long-term adaptation mechanisms are activated, which are based on intracellular hypertrophy, when the number of intracellular structures increases or the number of cells increases due to hyperplasia.
For the first time, such dynamics of adaptive reactions was described by F.Z. Meerson, who believed that the trigger mechanism in both reactions is an energy deficit, the criterion of which is a decrease in the intracellular ratio of ATP/ADP + AMP, which triggers complex multifactorial intracellular regulatory mechanisms [43, 60] . Ultimately, due to an increase in the functional activity of an organ (system), the adaptive capabilities of the organism increase, despite the changing environment, and the increased capabilities ensure the internal stability of the organism, i.e. his adaptation.
However, if the functionality of physiological systems is insufficient, then in the main executive organs (and tissues) the energy deficit increases, and it also triggers the next long-term adaptation by increasing the number of functioning structures based on the activation of regeneration and even proliferation. Thus, morphological conditions for increasing the function of an organ (system) are formed.
The presence of adaptation mechanisms, in general, ensures the adaptation of the human body to the environment. It should be noted that the adaptation of modern man has a number of features. First, much more often a person changes climatic and geographical habitat zones, which implies complex sometimes extreme acclimatization processes [10, 36] . However, even greater questions are posed to the human body by its production environment and professional activity [ ] . Nevertheless, the adaptation of a modern person will always be based on a biological basis, taking into account the characteristics of anthropogenic modification of the environment [36] . The level of individual adaptation of each person is the level of his health at each stage of his life cycle. The above indicates that human health has a biological nature, which was formed in the process of evolution, i.e. in the course of the historical development of biological systems, including the most complex supersystem - man. The level of health and adaptive capabilities of each person are determined by his genotype. The individual characteristics of the genotype, if they reflect the evolutionarily established species characteristics and adaptation possibilities, largely determine the state of health and characteristics of a person, therefore, his existence in the environment, with the subsequent formation of the phenotype.
In medicine, it is generally accepted to determine the level of health according to the characteristics of the genome of a population, an individual with implementation in the phenotypic characteristics of each person. The practical implementation of this approach is a prospect for the future, however, genomic diagnostics of functionality and hereditary diseases is currently taking the first steps in this direction. Meanwhile, it should be emphasized that the implementation of the genotype in the human phenotype depends on many factors and, most importantly, on the degree of training of adaptive functional systems. Therefore, although in the biological plan health is an integral characteristic of the evolutionary developed adaptive mechanisms of a person, in the medical plan health is presented not only as a general biological, but also as a population, group and, finally, individual ability to adapt. The need for such a differentiation of the concept of health is due to the needs of medical practice. For the latter, health is not only a definition of the state of the body, an indicator of sustainability in the environment, but also the fact that the state of health is the opposite of disease. In this case, the diagnosis of the disease is carried out on the basis of a comparison of the characteristics of the body with indicators characteristic of health.
Of course, the goal of medicine is human health. All existing medical technologies are aimed at ensuring human health. And, first of all, they are aimed at ensuring the health of a particular individual. However, according to this indicator, the population as a whole is also assessed - population health, and its criteria, in contrast to determining the individual level of adaptation, differ significantly. First of all, these are the integration characteristics of the population: life expectancy, morbidity, infant mortality under 1 year, maternal mortality, and a number of others. Characteristics of population health is extremely important, as it largely indicates the level of medicine and well-being in society.
Along with the assessment of the health of the human population as a whole, it is customary to study the characteristics of individual groups of the population, for example, occupational health, which characterizes the state of health of people working in conditions of influence on the body relative to specific production factors, i.e. anthropogenically modified environment, which, in turn, allows a deeper understanding of the etiology and pathogenesis of a number of diseases. The latest in medicine has led to the separation of occupational and professionally caused diseases into separate groups [24, 41].
In turn, understanding the features of the occurrence and development of diseases allows more differentiated development of technologies for their prevention and treatment. Sometimes they are distinguished as specific types of health associated with the characteristics of age - maternal and child health, or with the provision of a particular biological function - reproductive health. Such concretization and differentiation of the concept of health, of course, makes it possible to obtain additional specific characteristics of population health and, accordingly, to deepen the understanding of the state of individual health, the causes and mechanisms of its change.
It should be noted that all features of population health characteristics are primarily due to genetically determined properties, for example, racial characteristics. Thus, adaptation to ultraviolet irradiation of representatives of the European and Negroid races differs significantly depending on the degree of protection of the integumentary tissues by melanin. Other features of the ability to adapt are due to the formed acclimatization mechanisms in the population living in different climatic zones, that is, in fact, are largely due to the phenotype. Group health characteristics are also determined by both gender and age differences. Thus, for practical medicine, determining the state of health of a particular person is of great importance, for which it is necessary to take into account both the biological mechanisms of adaptation and the peculiarities of character and degree of adaptation inherent in various groups of the population. At the same time, group and individual characteristics of health should always be within the limits of biologically established adaptive mechanisms that determine the evolutionarily formed boundaries of the ability to exist in the environment. At the same time, a significant modification of the natural environment at the stage of formation of the noosphere significantly affects a person [12] . Accordingly, taking into account these characteristics, it is possible to determine the state of health of each individual person, or to diagnose his ill health, i.e. disease.
Thus, understanding the fundamental characteristics and mechanisms for the implementation of health, as the main state of the existence of the human body in the environment, contributes not only to a deeper understanding of the fundamental foundations of life, but also equips medicine with a diagnostic algorithm and principles of health management, both ways to identify and treat diseases, and and ensuring human longevity.
"...health and illness are
different directions of the life process"
V.V. Podvysotsky
Chapter III
Doctrine of illness
A key issue for medical science and practice is disease as a state of the human body that is qualitatively different from health [14, 17, 20, 54, 55] . Explicit and numerous differences of the organism in the state of illness from the quantitative and qualitative indicators of the state of health, which were recorded by clinicians, have long prompted the definition of the general essence of the disease. Moreover, for a long historical period, doctors and scientists unsuccessfully searched for “something” new in the disease, not inherent in the state of health, i.e. its qualitative difference from health. Indeed, the essence of the disease was considered in a wide range of concepts from completely idealistic to erroneously materialistic. However, there has always been a statement that something new, not inherent in the body, is introduced into the body during illness. Only a little over 100 years ago, medicine came to the recognition that the human body in a state of illness is qualitatively identical to a healthy one in terms of its morphological elements, biochemical processes and functions. In this regard, it is impossible not to quote the words of the brilliant scientist, theoretician of medicine R. Virchow, who wrote that nothing new arises in the body during an illness, and those disorders that are recorded are only phenomena inherent in the body in a state of health, but “ at the wrong time, in the wrong place, and in the wrong quantity. The genius of this conclusion also lies in the fact that it was formulated by a pathologist who created pathological anatomy, describing the numerous morphological features of the organism inherent in the disease, i.e. at first glance, he had many grounds for judging the qualitative characteristics of the organism during illness. However, it was he who formed such a fundamental conclusion, which is today the theoretical basis of medicine, primarily the diagnosis of a disease.
Over the past 50-60 years, we have not been looking for certain qualitative differences in diseases at the level of the constituent elements of the body (morphological, physiological, biochemical). At the same time, the conclusion that a sick person differs from a healthy person qualitatively is just as obvious, i.e. health and illness are qualitatively different states, the criteria for distinguishing between which are the properties and characteristics of the whole organism. The search for this qualitative criterion of the state of the organism in case of illness, ultimately, ended with the fact that such is currently a reduced level, the degree of adaptation of the organism to constantly changing environmental conditions, which is the main condition for the existence of the organism, i.e. life, in a state of illness. In a state of health, the adaptive structural and functional capabilities of the human body allow it to maintain its constancy, independence from significant, diverse, constantly changing environmental conditions. At the same time, these possibilities of adaptation are not unlimited and in a state of illness they decrease.
In historical terms, the human body has been formed in certain external conditions over tens of thousands of years as a complex, relatively stable biosystem, thanks to the emergence and development of its functional systems, which provide adaptation to real environmental factors. Consequently, the organism is adapted only to those influences and factors and their parameters that affected it in the process of evolution. Obviously, the emerging mechanisms of adaptation (adaptation) are not unlimited in power. In reality, these mechanisms make it possible to adapt to such parameters that took place in evolution, and their functional margin of safety usually does not exceed two times.
It should be emphasized that the provisions that are absolutely understandable at the present time were initially very revolutionary, because they really changed the theoretical basis of both diagnosis and treatment. First, it became clear that all the differences between a sick person and a healthy person are purely quantitative. The latter saved medicine from attempts to search for qualitatively new morphological structures and functions in patients and pointed out the need to identify and take into account quantitative differences, which was the basis for diagnostics in the clinic. Secondly, it became clear that the first and main manifestation of the disease is a decrease in the degree of adaptation of the body to environmental factors. It should be emphasized that this postulate is the basis of the principle of functional diagnostics, when certain functional loads are presented to the human body in order to identify a disease, which makes it possible to determine the possibilities (limits) of adaptation. Moreover, in this way, not only diseases are detected in the peak stage, but also in the initial, and even in the prenosological period.
Ultimately, the position was formulated that, in general biological terms, a disease is a form of human life activity in case of damage [ 3, 11, 14, 78, 79 ].
The biological theory of disease is based on the recognition that the basis of the occurrence of the disease is damage (violation), which limits the adaptive capabilities of the human body to exist in the environment. Moreover, damage, etiology initiates a number of changes, rearrangements that provide the disease process, which is referred to as pathogenesis. Despite the huge variety of causes that can lead the body from a state of health to a state of illness, the mechanisms of etiology and especially pathogenesis are less numerous, due to the limited number of mechanisms of the organism itself. The latter has long been reflected in the thesis that the body creates its own disease. And this, in turn, predetermines a certain uniformity of many diseases, which, it would seem, is unexpected, due to the initiation by various reasons, as opposed to the expected absolute specificity of each disease. There is still a specificity of diseases, and it is determined not only by the characteristics of the cause, but also by what tissue or organ is damaged and how the body can react to it.
Moreover, the specificity of each of the diseases manifests itself, as a rule, in the early stages, which is precisely determined by the specificity of the action (interaction) of the cause with the body. However, as a particular disease becomes chronic, the degree of specificity decreases and universal changes and manifestations of the disease, which are determined by typical mechanisms of pathogenesis, come to the fore. An example is heart failure, chronic kidney disease, chronic pneumonia, acute renal failure, and others, when there is a loss of specificity and the disease acquires typical features, as a result, the prevalence of typical mechanisms of pathogenesis.
In the medical and social terms, the disease is a limitation in the adaptation of the individual (subjective discomfort, restrictions on the ways and forms of life), and in the social - disability.
Thus, the disease can be considered as a special state of adaptation of the organism to the environment, therefore, a sick person also adapts [14, 17, 70] . The adaptive mechanisms that have arisen in the course of evolution are genetically programmed and are transmitted hereditarily. Consequently, adaptation, as the basic principle and condition of life activity, is common to both health and disease.
Meanwhile, the main difference between health and disease is also adaptation, or rather the degree (level) of this adaptation [70] . Indeed, a sick and healthy person adapts to the environment, however, in a state of health, the body adapts within the boundaries of evolutionarily formed limits due to appropriate adaptation mechanisms. For example, a healthy person adapts to the most frequent temperature fluctuations within, say -40 ° C - + 50 ° C, maintaining life within a certain time frame, then with an illness, almost any, including time and temperature limits of adaptation decrease. Therefore, illness is life, but with more limited possibilities of adaptation in comparison with health. These restrictions begin with a change in the psycho-emotional state, a decrease in adaptation to environmental factors and, as a result, lead to restrictions in social production activities.
Limitation of adaptation to physical environmental factors is a decrease in the ability to endure a decrease in the partial pressure of oxygen, temperature fluctuations in the environment, changes in the parameters of the electromagnetic field, radiation exposure, chemical, including water-salt and food loads, and other environmental parameters. We believe that there is no need to separately highlight the social aspects of health, because this is a direct consequence of physiological limitations, including neuropsychic mechanisms of adaptation, which ultimately leads to a decrease in working capacity and the possibility of social adaptation.
The foregoing allows us to propose the following definition of the disease:
“A disease is a person’s vital activity in case of damage, the compensation of which, due to genetically predetermined and phenotypically implemented adaptive reactions, provides a person’s adaptation to the environment, which is limited in comparison with the state of health.”
Consequently, the disease arises in response to damage to the body and at the same time provides an adaptation to it, i.e. it is life in sickness [80] . Once again, it must be emphasized that, based on an understanding of the essence of the disease, practical medicine is oriented in diagnostics to the search for quantitative (morphological, functional, biochemical and biophysical) differences in the disease, which characterize the features and limits of the body's adaptation. Therefore, in the treatment of patients, there should be a focus not only on combating pathological phenomena, but more on supporting, correcting adaptive (compensatory) mechanisms that ensure adaptation to the environment in conditions of damage. Here it is necessary to pay attention to the concept of "compensation", i.e. a device aimed at eliminating the functional and morphological consequences of damage. Moreover, compensation occurs due to the same adaptive mechanisms, which, however, do not increase the possibility of adaptation, but provide the replacement of certain dysfunctions that have arisen during damage.
At the same time, it should be emphasized that general biological ideas about the disease in clinical medicine should be specified in the quantitative characteristics of biochemical, biophysical, physiological processes and morphological parameters. This is required, first of all, by diagnostics aimed at identifying the disease by searching for quantitative differences from the state of health. The totality and degree of quantitative differences are used to determine the degree and physiological "price" of the adaptation, which is the basis for the clinical diagnosis of human pathology. It is interesting that even attempts were made to mathematize the entire set of quantitative changes, up to considering them on the principles of physical laws, for example, from the standpoint of Ohm's law [6].
Between health and pathology, the measure is the norm. This is one of the most important and complex concepts, both in theoretical and especially in practical medicine [62, 69] . The norm is both a population and an individual characteristic, and this creates significant difficulties in clinical diagnosis. Even more difficult is the solution of the problem of determining the general level of adaptation of the organism in case of illness, its quantitative assessment, i.e. determination of its difference from the norm.
The biological commonality of the two basic states of a person - health and disease does not currently cause discussion. However, it is equally vital to distinguish between these concepts, especially for practical medicine. With the establishment of criteria for distinguishing between these conditions, the subsequent treatment of the disease begins. Due to the fact that human disease is a dynamic state, its establishment is based on identifying differences from the state of health, as relatively more stable and sustainable. In medicine, traditionally, a number of quantitative characteristics of a healthy person are taken as criteria for this condition, as its norm. Thus, the norm in medicine is the boundary between health and disease.
A clear definition of the norm of health is essential for practical medicine. Meanwhile, the concept of the norm is one of the most debatable. In practical medicine, in the diagnosis of diseases, a number of difficulties arise due to the variability of many, especially functional and biochemical parameters due to the presence of genotypic and phenotypic characteristics of each person. As a result, the norm, as a rule, is presented as a certain possible range of changes in indicators [17, 62, 77]. In this case, the lower and upper limits of the norm must be established. However, in the relevant reference publications for many indicators, albeit slightly, but still differing indicators of the norm are given. It is the need and, most importantly, the desire to define clear boundaries of the norm, as the most important condition for diagnosing diseases, that has given rise to a number of methodological approaches to their definition. The most commonly used in the clinic is a statistical approach, when the parameters of a particular phenomenon, process are determined on a sufficiently significant number of subjects, and the average values characteristic of the entire sample, population are calculated.
It became clear that many of the parameters studied are significantly dependent on a number of other characteristics of the body. So, quite a long time ago, the concepts of age and gender norms were established, in which many parameters have a certain degree of fluctuation. Subsequently, it was found that the more homeostatically significant one or another parameter is in the body, for example, blood plasma osmolality, the less it depends on other indicators, the more stable it is. Others, on the contrary, are more closely related to the physiological characteristics of the organism, for example, the number of erythrocytes and, especially, leukocytes in the blood are less constant values.
Later it was found that, to an even greater extent, most of the quantitative indicators of the organism's vital activity depend on its functional state at the time of the study. This served as the basis for the development and use of two fundamentally different approaches to the study of most of the biochemical and functional characteristics of the body. The most common is the first approach to studying the indicators of an organism, which consists in studying its characteristics in conditions of relative rest, i.e. minimizing impact on the body.
Indeed, the bulk of laboratory and functional studies are performed in the morning on an empty stomach, if possible, in the absence of physiological and psycho-emotional stress. At the same time, it was found that in this case, the values of the parameters of the functioning of the organism in conditions with the minimum possible requirements for adaptation are established. Therefore, if the parameters of the functioning of a particular system or organ are studied during such studies are normal, then this only indicates that the body can function fully under conditions of such relative rest.
Most of the indicators that characterize the norm are determined under given rest conditions. However, in real conditions of life, there is a constant change in the external parameters of existence, which is most often accompanied by the need to activate, increase adaptive reactions. This can only be achieved by activating the functions of organs and systems. The latter is determined mainly by the presence of reserve capabilities, i.e. functional reserves of the body. In clinical and laboratory conditions, they can be detected only by presenting the body with appropriate standardized functional loads. This approach is the fundamental principle of functional diagnostics, i.e. revealing the limits of adaptation of the organism.
The foregoing confirms that health is a state of vital activity of an organism with constant adaptation to the environment. The degree of change in the indicators of biochemical and physiological processes that provide it is adequate to the change in the parameters of the internal and external environment in which the human body is located. Therefore, the normalization of life parameters implies their mandatory gradation: rest conditions, standard and maximum functional loads. We have already noted the first ones, the second ones are determined under the conditions of one or another functional load and differ from the third ones in that the maximum possibilities of adaptation are determined with the help of the latter. With the help of such loads, the initial periods of diseases or the presence of hidden consequences of past diseases are revealed, i.e. the result of incomplete recovery, and hence the limitation of the adaptive capabilities of the organism.
The foregoing does not exhaust the complexity of defining the norm, especially in practical terms. This is due to the fact that the main object of medical practice is a specific examined patient and a doctor who evaluates the obtained indicators, decides whether they correspond to the normal values of the data of a particular person. Even with the maximum standardization of the research conditions, there is a certain scatter in the values of the indicators, and often there are difficulties in establishing the norm. One of the reasons is the presence of group differences in the population, which requires adjustment of normal values.
So, the indicators of lipid metabolism differ in the inhabitants of the Far North from the inhabitants of the southern regions of the world, the indicators of pigment metabolism and other characteristics of the body also differ. These differences are genetically fixed and reflect the evolutionary ecological biological component of the characteristics of adaptation to natural environmental conditions, i.e. to its climatic and geographical features. At the same time, there are also group differences in the norm, which are not genetically determined, although they are also determined by specific regional environmental conditions. These, for example, include higher concentrations of hemoglobin and erythrocytes in residents of high mountains. This example reflects the state of acclimatization in individuals who fall into the conditions of middle and high mountains, regardless of their group genetic affiliation. In essence, this is a phenotypic realization of genetic capabilities necessary for adaptation to specific long-term conditions of adaptation [10] .
Of course, the difference in the parameters of vital activity in the process of adaptation to the environment must be taken into account in practical medicine, which is expressed in terms of population, regional and group norms. However, practical medicine encounters even greater difficulties in connection with the assessment of metabolic and functional parameters in patients in the process of individual diagnostics. In this case, it has long been established that fluctuations in indicators are sometimes very significant individually. Their changes, especially near the limits of the norm, served as the basis for the introduction of the concept of a “gray” norm, i.e. the zone of fluctuations of indicators at the boundaries of the average statistical norm. If we exclude the influence of group membership by correcting the boundaries of the norm, then genetically determined individual fluctuations remain. Given the vast array of genetic differences, the question arose as to whether it was even possible to establish the boundaries of the norm. However, we emphasize once again that this is extremely important for practical medicine, because the norm is a measure that allows you to determine the boundaries of two states of a person - health and illness, i.e. this is the most important diagnostic criterion.
The main way to solve this problem should be considered a systematic, organismal approach to assessing the state of health. Indeed, if the main criterion of human health should be considered a sufficient degree of adaptation of the organism to the environment, then with all the importance of individual characteristics of the organism, the limits of its adaptation are more important. If the degree of adaptation is adequate to biological needs and capabilities, then the established indicators of metabolism and function can be attributed to indicators whose fluctuations are within the normal range. However, at the same time, the degree of adaptation is determined not only at rest, but also during stress tests, including at maximum physiologically permissible loads. Consequently, the main criterion for the normal state of an organism is its health as an aggregate dynamic characteristic of the whole organism, which determines its adaptive capabilities.
In our opinion, attention should be paid to the fact that all physiological, biochemical and other indicators can be relatively conventionally divided into two functionally different groups: indicators of homeostasis and adaptive functional indicators. The former include those that, as a rule, are indicators of the composition of the extracellular fluid.
It must be recalled that the evolution of living organisms was carried out in two stages. At the first stage, life originated in a certain environment of the primary ocean [13, 48] . At least, this refers to the stage of formation of multicellular organisms as a self-governing community of cells that exist in stable conditions of the extracellular fluid. The formation of the intracellular environment may have occurred in a potassium-rich environment (according to Yu.V. Natochin), in potassium lakes [46]. However, in the subsequent coexistence of cells and the formation of multicellular systems (organisms) took place in the conditions of the Primary Ocean. A feature of this stage of evolution was that the conditions of the Primary Ocean were extremely stable, which later became the most important and indispensable condition for the existence of living organisms. This is primarily the constancy of the concentration of sodium, potassium, magnesium, calcium ions, pH and osmolality in the intracellular and extracellular environments of the body [49] .
Subsequently, primary organisms with their main structural equivalent (the cell) could no longer exist in a different ionic environment. Therefore, when reaching land, multicellular organisms “preserved” their environment in the form of an extracellular fluid, the parameters of which are among the most stable in the human and animal body, which, according to many scientists, is the first and main criterion for the adaptation of living organisms. In this regard, a whole hierarchy of physiological systems was subsequently formed in the human and animal body, aimed at maintaining the constancy of the internal environment.
This phenomenon of stability of the internal environment is called homeostasis. Homeostatic functional systems are the most accurate and powerful in the body, because the existence of the organism as a whole depends on their work under conditions of two types of changing influences, external (environmental) and internal (physiological-metabolic). Hence, the limits of the norm of these indicators should be considered the most accurately controlled and constant. Basically, these are physicochemical constants (ion concentrations, pH, etc.). Of the other physiological indicators, they apparently include the partial pressure of oxygen in peripheral tissues, i.e. near cells and indicators of temperature homeostasis.
Meanwhile, in the scientific literature, the term "homeostasis" is often used in a much broader context due to the fact that it includes a large range of relatively stable parameters of metabolism in the extracellular fluid. It is well known that the first candidate, after the characteristics of water-salt homeostasis, which is homeostatically is glucose. In this connection, the terms "energy", "protein", "oxygen homeostasis" and a number of others also appeared. There is no doubt that the concentrations of these metabolites are quite effectively regulated; they are, as it were, homeostatized, being relatively stable. Meanwhile, in our opinion, such an opinion is erroneous, because these are, first of all, metabolically dependent parameters that accompany (provide) certain functional responses of the body. It should be noted that a theory was proposed that largely explains the principles of the formation of functional responses - the theory of functional systems by P.K. Anokhin [4]. However, this progressive theory considered the organization of exclusively physiological functions, regardless of their dependence and relationship with metabolic provision.
Thus, the parameters of metabolism are initially associated, as it were, with the aquatic environment of the primary ocean, but their action is realized to a greater extent in the regulation and provision of cells, and therefore they depend on metabolism. In turn, metabolic processes are predetermined by the state and needs of the functions of organs and systems. Therefore, the parameters of metabolism must necessarily correspond to the functional needs, which largely determine the state and indicators of metabolism. The totality of these interrelated mechanisms can be defined as a functional-metabolic continuum (FMC) [21]. It goes without saying that PMC is based on the functioning of regulatory systems and, in most cases, with the help of their activation, the function is turned on. However, in general, regulation is a way to control function and metabolism, their conjugation. Ultimately, it is the functional response that is the goal of adaptation.
It should be noted that the concept of "continuum", as a term denoting the presence of a close permanent connection in the body, was originally proposed in medicine to refer to the existing relatively stable functional relationships between organs. Thus, the most famous is the presence of a continuum between the heart and kidneys - the cardio-renal continuum, which has received full recognition [21].
The physiological functional relationship existing between these organs becomes the basis for the formation of pathophysiological interactions under pathological conditions. So, at present, clinical and pathophysiological mechanisms and manifestations of cardio-renal syndrome are being effectively developed. Even earlier, the concept of hepatorenal syndrome was established in the clinic, the concept of pulmonary-renal syndrome is being discussed.
Therefore, FMC is the regulation of all other metabolic parameters associated with the function of cells and tissue-organ formations, and therefore, despite the importance of some of them, especially glucose, they should not be attributed to homeostasis, since the change in these parameters directly depends on functional needs, and they should be considered as part of functional and metabolic relationships.
At the same time, despite the variability due to functional and physiological reasons, the FMC system is quite effectively and constantly regulated. At the same time, it should be emphasized that it is not a strictly constant constant of the extracellular fluid that is maintained, but the concentration of the metabolite that is adequate to the needs of the function in a given period of adaptive reactions of the body.
Thus, FMC is a system for maintaining optimal (in relation to the state of the physiological functions of the body) parameters of the internal environment of the body. Conditionally, these parameters can be divided into:
– substrates (exchange);
- end products of metabolism;
– regulators;
The substrate level is (provides) the energy and plastic needs of the body, which include:
- glucose, ketone bodies, amino acids, lipids, which, in general, can be defined as an energy PMK;
– amino acids, proteins, nucleic acids, as plastic PMK;
If the presence of the above FMCs is beyond doubt, then the situation is more complicated with the other two, which involve maintaining the regulatory level and metabolism of end products of metabolism.
- vitamins, K + , Ca + , H + - regulatory PMK;
- urea, bilirubin, NH 3 , CO 2 , H 2 S , CO - FMK antitoxic or catabolic.
At the same time, it is conditionally possible to distinguish the levels of providing PMC:
- cellular;
- tissue-organ;
- systemic
As well as executive support systems for FMK:
- cell;
- liver - kidneys;
– functional systems (support organs).
It should be emphasized that there is a certain priority of PMK in ensuring:
- brain, heart, lungs (vital organs)
- liver - kidneys (providing organs)
- muscles (executive organs)
The presence of the FMC system is a condition for adequate dynamic provision of the function of cells, organs and functional systems through metabolic changes in the internal environment.
The main principles of the functioning of the PMC should include the conjugation of regulatory and executive bodies.
It should be noted that FMC, on the one hand, indicates the existence of stable relationships between metabolism and function, but on the other hand, depending on the characteristics of adaptive reactions in relation to various environmental parameters, the mechanisms and parameters of FMC can change in a certain way adequately to the needs of the body.
In this regard, it is logical to state that the interaction of tissues, organs and systems is carried out, in many respects, through the internal environment of the body, more precisely, through the extracellular fluid, both homeostasis, and by maintaining the metabolic support necessary for a particular function, which and ensures the appropriate functioning of all cells that form more complex structures of the body - organs and systems.
In this regard, questions about the principles and mechanisms of functioning of the internal environment of the body are of particular interest. At the same time, it is clear that the systematic nature of providing PMC involves the participation of a number of organs and functional systems with corresponding changes in the parameters of their functioning. The general scheme of the functioning of the FMC can be imagined as follows (Fig. 3).
The trigger mechanism for the functioning of FMC is a change (often activation) of the functions of organs and systems. It should be emphasized that during the development of certain adaptive reactions, their functional support implies a physiological response, as a rule, simultaneously from several organs and systems. A striking example is the concept of vital organs, which primarily include the heart and lungs, which are associated with most adaptive reactions.
Fig.3 Block diagram of the functioning of the FMC
An increased function, as a rule, is a consequence of the inclusion of the relevant regulatory systems, and the latter simultaneously affect the metabolism of both functioning organs and those that provide an increased function due to the mobilization of metabolic reserves - this is primarily the liver, fat depots, although their range may increase. An example is the sympathoadrenal system, which not only increases the external work of the heart, but also increases the level of glucose and lipids in the blood. Similarly, in many respects, glucocorticoids work under stress, which can then also mobilize the metabolic reserves of the lymphoid and connective tissues.
A change, more often an increase in the concentrations of metabolites (energy, plastic, regulatory), in the extracellular fluid is the source of increased functions of cells, organs and systems. It is important to note that the metabolites themselves can have an additional regulatory and functional effect on cells. It must be emphasized that this metabolic modulation is, in fact, the theoretical basis of metabolic therapy. Among numerous examples, starting from the level of glycemic maintenance, we would like to draw your attention to the fact that recently, for this purpose, arginine preparations have been successfully used to correct, for example, endothelial dysfunction and a number of other metabolites.
An example of FMC is the energy continuum, which is the fastest in terms of turn-on time and the most significant for the body. This is due to the fact that energy PMC provides the most significant need for energy in the cells of organs and tissues. The criterion for the energy sufficiency of each of the cells is the content of ATP in the cell, which is controlled by its energy potential, i.e. ratio:
ATP
------------- .
ADP+AMP
An increase in the function of any cell is always accompanied by a decrease in the energy potential, which is a signal of the need to increase ATP production, primarily by mitochondria, and then glycolysis.
Accordingly, this requires an oxygen-substrate supply. Conventionally, two levels can be distinguished in such reactions: cellular-tissue and organ-systemic, which, as a rule, are switched on sequentially. The cellular and organ level is realized due to the regulation of microcirculation and vascular permeability in functionally activated cellular and tissue structures. The systemic energy supply of the function of organs and systems is based on the metabolic component of the energy FMC, which is carried out by increasing the level of glucose in the extracellular fluid, which is achieved by mobilizing liver glycogen, and then gluconeogenesis (liver, kidneys) with a simultaneous increase in lipids (ketone acids) in the extracellular fluid. body, FFA, lipoproteins), which occurs due to mobilization from fat depots and metabolic transformation in the liver, kidneys. Ultimately, hard working organs (muscles or others) receive the required amount of substrates. At the same time, adequate changes occur in the organs that provide oxygen delivery to the intensively working organs - an increase in the external work of the heart, respiration, the release of erythrocytes from the depot, combined with an increase in microcirculation in organs with an increased function. The organization of such a metabolic support of the function, i.e. by means of energy FMC is carried out due to the inclusion of systemic regulations - the sympathoadrenal system, glucocorticoids, insulin, glucagon, thyroid hormones and local ones: histamine, bradykinin, prostaglandins, NO and others [21, 25] .
Therefore, energy PMC is necessary to fulfill the functional needs of the body through the formation of stable interorgan and intersystem connections that provide adequate needs for the implementation of the function by creating the necessary level of metabolites in the blood. They are similar to the reactions of homeostasis by the desire to maintain certain constants of the extracellular fluid, however, the difference is their rather variable functionally dependent nature, due to which individual indicators of FMC differ significantly (change) due to the needs of a particular function.
Thus, FMC stereotype is a consequence of the desire for the same type of result - sufficient substrate metabolic supply, and the variable character reflects the ambiguity of the parameters of the function that is maintained.
It should be noted that there is a second way to change the level of blood metabolites - their intake from the external environment through the digestive organs. Of course, the deposition organs, primarily the liver and adipose tissue, significantly modulate the rate of entry of food metabolites into the extracellular environment, but this pathway is significant not only for long-term functional adaptation, but even for urgent functional responses. It is also successfully used in diet therapy, or it can even lead to pathology, for example, with prolonged alimentary hyperglycemia and hypercholesterolemia with symptoms of obesity, atherosclerosis. Consequently, disturbances in the energy FMC can lead to the formation of complex pathophysiological syndromes, of which the metabolic syndrome is the most significant [21, 25] .
At the same time, the range of stable relationships in PMC is significantly larger than in individual interorgan continuums. If stable functional relationships between individual organs are fixed in the latter, intersystemic and even organismally significant connections function in PMC.
For example, as in the case of providing energy homestasis by maintaining the required level of glucose. Of course, the need for glucose is significant and the need for its relatively stable level in the extracellular fluid is different - especially brain metabolism depends on its concentration, but all cells need it. But, not only glucose is an energy substrate for cells, but also lipids (from ketone bodies to fatty acids). Accordingly, the provision of the needs of the cells of organs and tissues in energy substrates depends on the ratio of these two energy-metabolic (carbohydrate and fat flows).
In our opinion, the energy PMC is one of the basic and most important in the life of the body.
Thus, the regulation of the state of the internal environment of the body involves at least two methods of homeostasis and FMC, through which the necessary conditions for the existence and functioning of cells, both individually and as part of organs and tissues, and the body as a whole, as a single supersystem, are provided.
All other indicators to some extent reflect the state of the function and exchange, which change in the process of adaptation and therefore they are rather unstable. The exception, perhaps, is the level of glucose in the extracellular fluid, although in our opinion, in the process of evolution of homeostasis, they are secondary and physiologically determined, i.e. their appearance is caused by the emergence of secondary metabolic and functional systems and functions, the implementation of which requires the stability (adequacy) of the supply of energy substrates.
Indeed, the most stable of this group of indicators of metabolic homeostasis is the level of glycemia, and although its normal limits are allowed with fluctuations of about 50%, it is still a fairly clearly regulated parameter that is controlled at various levels. Of the other indicators of metabolism, apparently, the most significant and stable is the value of the oncotic pressure of the blood plasma, which is determined by the amount of protein, especially albumin, in the blood plasma. The role of this parameter is taken into account more often according to the physiological effect, i.e. according to the volume of circulating blood, since there are still no ideas about the mechanisms of regulation of the level of protein in the blood, at least in relation to the stability of oncotic pressure. The remaining indicators of metabolism - fat, vitamin, and their characteristics in the blood, depend to a greater extent on the intake and metabolism of these substances in the body. Although there is an optimal zone of their indicators, necessary for the function of the body, they are definitely not homeostasized (regulated), and, therefore, the boundaries of their norm are quite wide. For example, they largely depend on the nature of human nutrition. Even wider are the limits of fluctuations in the body of indicators of the end products of metabolism. Meanwhile, their control is necessary, although very often carried out secondary to them. For example, an excess of end products of metabolism (urea, creatinine, uric acid, bilirubin, etc.) is considered as an important sign of pathology. The stability of these indicators often reflects a complex of metabolic and physiological reactions to ensure the vital activity of the organism. Consequently, the stability of these indicators in terms of concentration in the blood is secondary and they are not directly homeostatic values.
It should be noted that these indicators are not only criteria for the function of organs and systems, but also play a certain functional, regulatory role in the human body. This became obvious, for example, after the appearance of works on the antioxidant action of urea, uric acid, bilirubin, which gives us reason to deepen our understanding of the biochemical constants of the body and their role in life. Today it can be firmly stated that each compound at the stage of intake, metabolism and excretion from the body has a number of properties, including regulatory ones, therefore certain limits of their concentration are maintained in the body either at homeostatic or at the metabolic levels.
Even more difficult is the assessment of the biophysical parameters of the organism's vital activity. The functioning of organs and systems of the body as a whole is accompanied by the emergence of a number of electromagnetic fields. Evaluation of a number of characteristics is widely used in the diagnosis of the disease, for example, analysis of ECG, EEG. However, their role in the life of the organism at the physical level of the organization is not well understood. The exception is data on the role of the cellular membrane potential of rest and action, control signals of the conduction system of the heart, and locomotor nerves. Meanwhile, each molecule, cell, tissue, organ in the body is characterized by a number of physical parameters, which are often constantly changing. The latter, at first glance, either contradicts the concept of homeostasis or indicates that physical phenomena are not controllable and do not play a significant role in the organization of living matter into a single organism. And, as a result, the normalization of most physical parameters is currently impossible. Meanwhile, in order to understand their role, we proposed the concept of electromagnetic homeostasis, according to which the body has a system for maintaining electromagnetic homeostasis, the parameters of which remain at certain values [19].
However, the real theoretical content of this concept is currently absent. Another argument for the possible physiological role of the physical level of the organization of matter is the ideas of ancient Chinese medicine about biologically active points, meridians. One can only suggest that the most important condition for the existence of the human body is the relative stability of chemical (biochemical) and also physical (biophysical) processes, the indicators of which are considered and used in diagnostic processes on the basis of their normalization. In this regard, attempts to create quantum medicine as one of the promising areas of modern medical science and practice should be recognized as promising.
In historical terms, the origins of modern medicine can be seen in the medicine of ancient Greece. By this time, contemplative medicine had reached its maximum development, which was based on the description and awareness of the properties of the body as a whole, which reached perfection in oriental medicine. It is important to emphasize that in this case, in most medical systems, a person was considered as a single object. Starting from Ancient Greece, an analytical approach begins to form and develop in medicine, which is aimed at understanding the structure and functions of the whole, its elements, and at the same time determining those changes that develop in pathology, underlie the disease. So already Hippocrates says that in diseases there is an incorrect mixing of the basic fluids of the body. These ideas laid the foundations of humoral pathology, according to which the disease is determined by those disorders that occur in the liquid phase of the body.
Almost at the same time, a second direction arose in medicine - solidary - Democritus: atoms, their improper mixing is a disease. It subsequently developed especially successfully and is an excellent illustration of the triumph and success of the analytical approach in medicine. Let me remind you of its main milestones: Virchow's cellular pathology, Pauling's molecular pathology and, finally, at the present time, genomic pathology - genetic diseases. It should be noted that the emergence of these very different approaches is due to the complexity of the organization of the body.
In this case, the organism should be considered as a supersystem that has a number of levels of structural and functional organization.
In this supersystem, the cell is the basic fundamental structure in the human body. Cells, as an elementary structure, make up all tissues and organs. Any cell has three main structural and functional elements: the nucleus (control), functional executive elements (contractile elements, secretory apparatus, etc.), and energy-providing structural and metabolic elements (mitochondria, glycolysis).
The second level of organization is tissue as a structural and functional association of parenchymal cells that perform specific tissue functions, connective tissue, microvasculature and innervating elements.
The intended purpose and the corresponding structural and metabolic features are derivatives of the function of the corresponding tissue.
A further higher level of structural and functional organization is the organ, as, in fact, a highly specialized and organized tissue.
The third level of organization is the system level. Each functional system arose in the body to perform certain physiological functions.
These include the nervous, endocrine, immune, cardiovascular, respiratory, digestive, genitourinary, reproductive and blood systems, and the musculoskeletal system.
It should be emphasized that the work of all functional systems is aimed at adequate provision of cells, organs and tissues of the body. However, it must be emphasized that there are two principles for providing (regulating) cells: direct or targeted, in which the functions of the system are implemented on each cell (organ) or indirect. Specific (targeted) regulation of cells is based on nervous, endocrine and humoral regulation.
First of all, homeostasis refers to mediated, as one of the most important conditions for the existence of an organism. It has been established that the most important condition for the existence of an organism is the constancy of the internal environment in which all the cells of the organism are located. In fact, the extracellular fluid is, as it were, an external environment for each of the body's cells. Therefore, its stability is a prerequisite for the functioning of cells. In recent years, we have proposed to single out the functional-metabolic continuum as one of the subsystems of homeostasis that provides the metabolic needs of cells, which, first of all, includes the regulation of glycemia, the level and composition of lipids, blood amino acids.
It is important to note that the totality of all systems ultimately provides the adaptive capabilities of the organism, which are aimed at adapting to the environment with the maximum possible stability. It should be noted that adaptation always has a specific and non-specific component. For example, adaptation to temperature fluctuations in the environment, to physical activity, etc., of course, has its own specifics, which is expressed in the greatest activity of the corresponding functional systems, however, as a rule, general reactions always occur, for example, each specific work (function ) is provided by an increase in energy costs, which explains the practical mandatory participation in all adaptive reactions of the cardiovascular system. In addition, it should be noted the wide interaction between various functional systems of the body in the process of physiological adaptation, which is often specified in special interorgan relationships between organs that play a major role in adaptive reactions. For example, there has long been an idea of a close functional relationship between the liver and kidneys, kidneys and heart, which were later defined as hepatorenal and cardiorenal continuums.
In fact, this is the selection of the most significant interacting functional elements (organs) of different functional systems in the process of adaptation to the environment.
Interaction (structural and functional) ensures the existence of the organism as a single supersystem. At the same time, the achievement and state of adaptation is determined by the correspondence of the biological parameters of homeostasis. The main ones are, in our opinion, the constancy of temperature and osmolarity of the internal environment of the body.
As long as the organism, as a biological supersystem, adapts to the environment within the boundaries genetically predetermined by evolutionary development, a person is in a state of health, i.e. one of the life forms.
The second form of vital activity of the human body is disease , i.e. adaptation in case of damage, when the adaptive capabilities of the organism (supersystem) are reduced.
The successes of scientific medicine are indisputable, the theoretical significance and practical results are impressive. And at the same time, at the same time, traditional medicine continues to exist, and in recent times (the second half of the 20th century) and even flourish, certainly empirical and contemplative. Why? Of course, there are psychological roots of this phenomenon, which is primarily associated with a person's desire for longevity up to immortality. This is facilitated by the sometimes growing imbalance between the psycho-emotional (spiritual) and somatic status.
However, it should be noted that each direction existing in science and practice must have its own objective epistemological basis. In our opinion, such a basis is that with the development of the analytical direction, in scientific medicine, they began to move further and further away from a person as an integral phenomenon. And, only in folk medicine, in its various varieties, a priori, a person has always been considered as an integral system. This led to the fact that, despite the extremely insufficient scientific base of such areas, they continued to exist and even develop.
At the same time, in scientific medicine there were also conceptual approaches of an integrative plan, in which attempts were made to create a holistic view of the essence of health and disease. The most significant was and, in our opinion, continues to be the concept of homeostasis. The main idea was proposed by the father of experimental medicine Claude Bernard 125 years ago. His main conclusion is: "The constancy of the internal environment is the condition of a free and independent life." Thus, maintaining the constancy of the internal environment, the body adapts to the external environment, its changes. Under the internal environment, he understood: water, oxygen, temperature, chemicals needed by the body, plus reserves. The biological essence of this direction was that in a constantly changing environment (external to the body) environment, the internal environment remains relatively stable and each cell is always in constant conditions of functioning. Thus, the human body adapts, that is, it realizes the main condition of life. Of course, this stability is relative, because "every living system has its limits of adaptation."
The next stage in the development of this direction was the work of Walter Cannon. In 1929, Cannon defines homeostasis as similarity and likeness plus constancy. The main thing is that he drew attention to the physiological mechanisms of the stability of living systems. Complicated and clarified the concept of the internal environment: H 2 O, NaCl, Ca, O 2 , internal secretion, t °, H + , as well as mechanisms that ensure structural and functional unity - heredity, regeneration, repair, immunobiological activity. Already during this period, ideas about the mechanisms of maintaining homeostasis are formed. He gave a special role to the sympathetic nervous system, which is responsible for the urgent mobilization of protective forces (servo reflexes).
In 1976, a book was published edited by P.D. Gorizontov "Homeostasis", in which the author puts forward and develops the position of the body as a self-regulating system (cybernetic principle). Substantiates the ultrastability property of the organism due to the multi-contour, duplication, hierarchy of control, self-regulation. The book ends with the statement: "Homeostasis is one of the most important problems of modern medicine."
What is the most important in the concept of homeostasis? First, its biological significance, the explanation of the meaning (method) of the existence of the organism - maintaining the constancy of the internal environment. Secondly, this is an indication of the main (selection of them) characteristics of this process: stability ↔ variability, i.e. dynamic stability.
In historical terms, the next 20-30 years were spent mainly on the analytical development of the problem: clarifying the parameters of homeostating, their mechanisms. And so, in the 60-70s, the terms appeared: osmostat, lipostat, glucostat, aminostat, etc. Thus, individual parameters of homeostasis are singled out and their mechanisms are clarified. With a careful analysis of this period, it becomes clear that it is mainly analytical in nature: the whole, the homeostasis of the internal environment of the body is divided into separate elements and subsystems. The main thing, however, was the application of the cybernetic principles of the functioning of homeostasis systems.
Meanwhile, the end of the 20th century was marked by integrative trends in the development of the concept of homeostasis - ideas about energy and even reproductive homeostasis appeared. At present, the current state of the problem is presented as follows. The life of an organism is a constant adaptation to the environment. Biological adaptation has the essential feature that it is carried out with the preservation of its internal stability. This stability is still relative and dynamic, i. it has limits and fluctuates, although it is constantly homeostatized. This is the body's homeostasis.
What is homeostatic? In our opinion, homeostasis is carried out at different levels:
I level - organismic - spatio-temporal unfolding of the organism (dynamic stability), i.e. life (embryo, adulthood, aging, life expectancy). Now there is enough data to assert the existence of such a systemic organization.
Level II - biological functions of the body - energy homeostasis, reproductive homeostasis, etc.
III level - functional subsystems: cells, liquid medium and their components.
Thus, any assessment of the state of the body should be based on the state of homeostasis, and each parameter should be compared with those homeostatic tasks that the body is solving at this time.
We believe that the current state of development of the theory of homeostasis allows us to come to the following definition: "Homeostasis is a spatio-temporal, stable-dynamic regulated state of the organism in the process of its adaptation to the environment, providing the maximum possible conditions for the existence of the organism in a state of health or illness."
Such a definition and understanding of homeostasis positions it in the broad sense of the word and phenomenon, i.e. determining the stability of the whole organism. In the classical "narrow" sense, after all, the state of dynamic stability of the internal environment (extracellular fluid). Perhaps in the future other terms will be proposed that will be able to separate these two conditions of the phenomenon, to “separate” them in a conceptual sense. However, at present it is expedient, in our opinion, to use both an extended and a concretized concept of homeostasis.
In clinical practice, maintaining homeostasis is the most important and mandatory task of treating the disease. The significance of such therapeutic measures is especially pronounced in resuscitation, where measures to stabilize homeostasis, in fact, predetermine the possibility of survival.
In general, homeostasis as a state of the body should be considered as one of the main properties of health. Homeostasis is also maintained in the state of illness. The only thing is that the “price” of such adaptation in case of illness is higher; higher functional costs of the body to achieve it. And according to those changes in functional characteristics that occur during the disease, it is diagnosed.
Thus, the disease is a qualitatively new condition, in which, however, the relative stability of the internal environment is preserved. This allows the human body to adapt to changing environmental conditions, although the degree of adaptive capacity is limited, which distinguishes disease from health.
The complexity of the organization of life and, at the same time, the great adaptive capabilities of the body in case of illness are due to the fact that the body as a supersystem has a spatio-temporal organization.
A supersystem (supersystem, supersystem) is defined as a system of a higher level of hierarchy for a certain system under consideration, which is one of its elements.
The supersystem also combines many similar systems with similar characteristics, their elements can be interchangeable, they can have informational links with each other (not necessarily direct).
These two definitions, which exist in the literature most often to define social structures, give us reason to use the concept of a supersystem to characterize the human body. In this regard, one could schematically introduce supersystem of the human body as follows (Fig. 4).
Subsystem Subsystem
Systems:
cardiovascular Regulatory
system
(CNS, immune)
respiratory
Rice. 4. The human body is like a supersystem.
Such a schematic representation of the organism as a supersystem does not fully take into account the spatio-temporal organization of a person, however, it gives a general idea of the complexity of the supersystem, its subsystems and individual systems, which at the same time form a single whole, the functioning of which provides the possibility of adapting to the environment, i.e. .e. maintaining its relative constancy in changing external conditions. This possibility determines the essence of life, under the most realized genetically existing conditions, it is defined as health, and with a decrease in adaptive capabilities due to disturbances in the elements of the supersystem, it is defined as a disease.
A distinctive feature of the human supersystem is its plasticity, i.e. the ability to change the structural and functional organization due to structural and functional duplication, when the performance of individual functions is partially duplicated by other systems and their elements. In addition, each system, as a rule, has additional strength and stability due to the fact that the number of available elements is initially excessive in relation to some average system function. A particularly clear demonstration of this is the presence of paired organs: lungs, kidneys, adrenal glands, sex glands, as well as an excess number of cells in organs, their reservation (spleen, bone marrow, lymph nodes).
The features of the human body as a biological supersystem should also include, on the one hand, the specificity of individual functional systems, and, on the other hand, their interaction and interdependence.
Consequently, the specificity of each of the functional systems is relative, which is largely due to the participation of the same organs in the work of these systems, primarily the heart, lungs, liver, etc. Such interaction is the basis for the development of compensatory reactions in pathology accompanied by disturbances in one or another functional system.
All of the above makes it possible to explain, on the one hand, the possibility of increasing the volume of functions in a state of health with an increase in the adaptive capabilities of the body, for example, during acclimatization, and, on the other hand, the ability to develop a disease. So, depending on the degree of damage, the involvement of certain organs in the pathological process, the possibility of compensating the function, the onset, development and outcome of the disease can differ significantly, and the clinical picture will be determined by the features of pathogenesis, which, in turn, will depend on how and due to which systems the compensation of primary impaired functions, their initial state, and structural and functional capabilities at the time of damage will occur.
Despite the complexity of the clinical and pathogenetic picture in the dynamics of the disease, two fundamentally different periods can be distinguished. In the first period, as a rule, compensatory reactions are formed that provide a sufficient level of adaptation under stationary conditions of existence, which is referred to as latent, or it is often called pre-illness. But, as the disease progresses, when the structural and functional capabilities of the body's subsystems are insufficient to adapt to the environment even in stationary conditions, it is defined as the period of the disease itself.
The subsequent progression of the disease, in fact, is expressed in a decrease in the functionality of the entire supersystem, although the latter is always determined and expressed in a change in certain specific structural and functional elements, which manifests itself in symptoms and syndromes.
Moreover, the human supersystem is always genotypically and phenotypically individual, therefore, the general patterns of the development of the disease, determined by its etiology, are implemented taking into account individual structural and functional features, which was previously defined as the human constitution [47] .
At the same time, the temporal dynamics of the structure of a system or a disease determines the possibility and necessity of its change.
One of the most important in theoretical and practical medicine is the question of the evolution of the disease. It is due to the fact that the clinic of modern diseases sometimes differs significantly from the classical clinical picture. So, for example, it is well known that a number of major diseases appear at a younger age, “a heart attack has become younger”, or proceed more aggressively, etc. Morphologists have noted for a long time that the modern pathomorphosis of diseases must be taken into account in clinical practice. First, the recognition of differences in the clinic and morphology of modern pathology raises a number of questions, the main of which are the following. Recognition of the increasing role of the influence of changed environmental factors on a person, which led to the formation of the concepts of "environmental diseases" [35]. Moreover, this made it possible to substantiate the ecological model of medicine [30] . Secondly, this is a significant change in the phenotype of modern man. Indeed, in the conditions of the existence of a fairly conservative genome, its phenotypic implementation has changed significantly as a result of significant differences in the modern lifestyle: dietary habits, psychosocial stress, etc. As a result, acceleration, earlier puberty, change in the rate of aging.
What causes these changes, why does the evolution of diseases take place? Answering this question, it should be noted that there are indeed significant changes, firstly, in the etiology of diseases. This is mainly due to a deep modification of the environment, in which there are significant changes in its properties, mainly anthropogenically caused.
So, for example, evolutionarily the human body is adapted to the values of ionizing radiation within the natural background and the appearance of intense sources of radiation due to anthropogenic technogenic transformations caused the emergence of such a nosology as radiation sickness. The increase in the environment of heavy metals was the cause of a number of intoxications, the latter also occur with the appearance of new chemical compounds (pesticides, herbicides, etc.). As a result, the concept of eco-dependent pathology even arose [35] .
At the same time, when discussing the possible pathogenic role of chemical compounds, it should be remembered that the first and main condition for their influence on the human body is the effective concentration of these substances. So, biological organisms, including humans, are adapted, i.e. they have mechanisms of interaction with all chemical compounds of the natural environment, but within their ecologically existing concentrations. An increase in the content can lead to pathology, up to poisoning [27] . No wonder Academician I.M. Trachtenberg focused on the fact that each substance can be a poison, it's all about its quantity [61, 63]. It should be especially noted that a number of drugs can also cause pathology, the effects of which largely depend on the dose, the age of the patient, and a number of other conditions. This is the main cause of the group of so-called iatrogenic diseases.
It is important to note that in addition to the physical and chemical modification of the biosphere, human activity is also accompanied by biological modification. An example is the epidemic of HIV infection, this also includes multi-resistant forms of bacteria that cause the development of specific clinical forms of infectious diseases, which is very well known in the tuberculosis clinic, where multi-resistant forms of mycobacteria are an important problem. It is impossible not to mention the interaction of the body of a modern person with genetically modified organisms, although this issue is at the stage of discussion and study.
The consequence of a wide modification of the environment is also the simultaneous appearance of many changes or other influencing factors. This leads, in some cases, to the occurrence of several diseases in the population at the same time, which is called comorbidity (polymorbidity, multimorbidity).
It should be noted that not just a combination of known pathologies, but their significant changes due to the interaction of various links of pathogenesis, which are often "included" in various diseases. And this, as a rule, reduces the adaptive capabilities of the body and changes the traditional clinic of pathology. In addition to changing the structure of etiology, altered environmental factors affect the course of the disease, i.e. their pathogenesis.
Secondly, it should be noted that the cause of the evolution of diseases can be not only changes in the environment, but the nature of the person himself. Although the biological evolution of modern man ended quite a long time ago, the phenotypic structure of the health of the population of modern society has a number of features. Thus, it is well known that the aging of the population is observed, which changes the structure of pathology, based on the characteristics of the adaptive capabilities of older people. This should include the phenomenon of acceleration, and a number of others.
Thus, changes in the working and living conditions of a modern person increase the stratum of the population with an overstrain of adaptation systems, especially due to increased psycho-emotional stress, the main consequence of which is stress and suppression of the immune system. As a result, the human response to the impact of a number of other pathogenic factors changes.
Thus, the structure and content of the pathology of modern man is really changing. At the same time, a fundamental question arises that a change in the structure of pathogenic effects causes new diseases in humans, or changes the course of already known historically established forms of pathology.
In our opinion, all changes in the pathology of a modern person, despite sometimes very significant differences, are only variants of clinically and pathogenetically known diseases. This is due to the fact that diseases, as a form of adaptation of the organism in case of damage, are genotypically completely predetermined by biological laws and the possibilities of the structural and functional organization of a person. The human body can adapt (react) only within the limits of its biological capabilities. Features of the etiological effects and phenotype can only influence the typical biological mechanisms of the disease, not canceling or replacing them, but only modifying them.
It must be emphasized that the definition of the disease, its diagnosis is the first step in medical activity. Indeed, for successful treatment, the doctor must determine the disease, and only then, at least, understand how it arose and develops. Of course, the etiology and pathogenesis of individual human diseases are different, but they have common patterns, which will be the subject of the following chapters.
"... it is well known that etiology is
the weakest branch of medicine"
I.P. Pavlov
Chapter IV
The doctrine of etiology
The patterns and mechanisms of the onset of a disease, as the transition of an organism from a state of health into a disease, are the content of the doctrine of etiology - the most important section of the theory of disease. Aitia - reason, logos - teaching, i.e. Literally, this is the science of the causes of diseases. However, in all modern textbooks and manuals, this definition sounds somewhat different: "Etiology is the science of the causes and conditions for the onset of a disease." More than two thousand years of experience in medicine allows us today to assert with confidence that every disease has its own cause. Hence, in medicine, the search for the causes of the disease has always attracted the attention of scientists and practitioners of medicine, and, by the way, of the whole society. Without conducting a detailed historical analysis of the development of the doctrine of etiology, four main periods can still be distinguished:
- idealistic (theological);
- natural philosophy;
- scientific and materialistic;
- modern biomedical.
Aware of the significant abstractness and schematic nature of such periodization, we still believe that in this way it is possible to focus on the main stages in the development of a scientific and medical understanding of etiology without going into a huge amount of existing historical information. It should be noted that until the middle of the 19th century there were much more diseases with unknown causes than with known ones. This was due to limited knowledge due to insufficient objective research capabilities and, accordingly, specific data. However, the occurrence of diseases in previously healthy people has always assumed the presence of any causes that cause them. Without dwelling on this period, when views on the causes of diseases were largely idealistic and even theological in nature, we note that, starting from ancient Greece, the search for the material causes of diseases has always been in the focus of medicine. However, the insufficient methodological possibilities of medical science did not allow us to find out many causes of diseases. An example is infectious diseases, which were the most frequent and massive in the population, constituting the main cause of morbidity and mortality of patients, regarding the causes of which various, sometimes opposite views were expressed - from idealistic to completely materialistic. In general, it should be noted that despite the natural-philosophical nature of most of the ideas of this period about the causes of diseases, the best minds of that time sought to establish material causes, for example, Hippocrates' ideas that the basis of diseases is the wrong mixing of the basic four fluids organism.
The situation changed radically in the 19th-20th centuries, when, in connection with the discovery of bacteria, and then viruses, their role in the occurrence of diseases was studied. The revolutionary nature of these scientific discoveries consisted in the fact that the material causes of many previously mysterious diseases that claimed millions of lives became known. The idealistic or natural-philosophical views were replaced by the time of searching and understanding the real causes of diseases. Although there were still diseases, the causes of which have not yet been established (mental, oncological diseases, etc.), the opinion has already been firmly established that each human disease has its own material cause, which is responsible for its occurrence, and efforts should be directed to the knowledge of which medical science. Consequently, the triumph of the scientific-materialistic period in the doctrine of etiology began, the successes of which laid the foundations of modern effective medical practice, because the prevention and treatment of diseases began to be largely based on preventing the action or eliminating the causes of diseases.
In theoretical terms, the discovery of the causes of diseases served as the basis for the creation of the first scientific theory of etiology - monocausalism, according to which each disease is caused by a specific material cause, the presence and action of which always causes a disease. The avalanche of new scientific discoveries of the causes of diseases at the end of the 19th century and in the first half of the 20th century expanded the understanding of the etiology of diseases. However, exaggeration of the role of cause and monocausalism, as a theory, faced a number of factors and phenomena that were difficult to explain. So, it turned out that the presence of a pathogenic microorganism in the human body does not always cause the corresponding disease. And yet, in fact, monocausalism was the first real theory that armed classical medicine with a materialistic concept, although at the same time a number of questions arose that could not be answered based only on the theory of monocausalism. This is evidenced by the phenomenon of bacteriocarrier, and finally, vaccination, which prevents the development of the corresponding disease when the microorganism re-enters, although the pathogenic properties of microorganisms are preserved in full. All this and much more could not be explained from the standpoint of monocausalism, which put an equal sign between cause and effect, i.e. etiological factor and disease. Probably, it was at this time that the brilliant IP Pavlov said the phrase taken as the epigraph to this chapter. It became clear that it is necessary to rethink the existing theory of etiology - monocausalism. In this regard, it should be emphasized that medical practice always encourages and provides material for theoretical generalizations, which subsequently contribute to a deeper understanding of the essence of the disease, are the basis for improving medical technologies, and contribute to the development of medicine. The same medical practice subsequently gives new material (observations, facts, phenomena), which do not always fit into the framework of the existing theory, and this logically leads to the need to revise the current ideas, because each specific truth is relative.
With regard to the etiology of diseases, it became clear that for their occurrence not only the cause, but also a number of factors, which were called conditions, became clear. In etiology, the theory of conditionalism appeared, according to which the presence of a number of operating factors - conditions - is necessary for the occurrence of a disease. From the point of view of clinical practice, such an interpretation expanded the theoretical ideas of doctors and drew their attention to the need to take into account a number of factors and conditions necessary for the onset of the disease, i.e. for the action of the cause of the disease. This, in turn, requires reconsideration of both prevention and treatment of diseases, not limited to etiotropic (causal) directed measures.
Along with the positive impact of conditionalism on medicine, the exaggeration of this theory of etiology led to negative consequences, the main of which was a decrease in understanding of the determining role of the cause in the onset of the disease, balancing the causes and conditions in this process. If the conditions and causes are equal, the random nature of their action, it is possible to diminish the role of the cause up to its complete loss, due to the fact that the role of each of the acting causes and conditions is comparable, which is unacceptable. Thus, medical practice itself overcame the shortcomings of the theory of etiology - monocausalism, but conditionalism did not give an understanding of how the onset of the disease occurs, i.e. no new interpretation of the etiology has been given. This period includes the book published in 1962 by the outstanding pathologist IV Davydovsky [ 29] . Perhaps, after the work of V.V. Podvysotsky and, especially his student A.A. Bogomolets, this book was the most significant phenomenon in Russian theoretical medicine.
Analyzing the state of the doctrine of etiology at that time, speaking about its shortcomings, I. V. Davydovsky writes: “Millions of removed appendices, tonsils, gall bladders, stomach ulcers, etc. Today, only an ocean of thoughts and hypotheses opposes, and all the same attempts to discover the “etiological factor” as the root cause, with the help of which the secrets of diseases would be immediately revealed.” The author draws the reader's attention to well-known nosologies (appendicitis, cholecystitis, tonsillitis), for the diagnosis and treatment of which various technologies have been developed, the pathogenesis of which is based on inflammation, and meanwhile the cause of the development of the disease is not fully understood.
Indeed, even 50 years after the publication of this book, we can almost completely repeat this idea [ 62, 82] . Thus, important ideas about the decisive role of the cause, the significance of the conditions (external and internal, facilitating and hindering) that contribute to its action still did not lead to an understanding of how certain diseases arise. However, it should be noted that I. I. Davydovsky indicated the direction of the search for truth in this matter. This is evidenced by another of his thoughts, expressed in the book “You cannot think of a cause otherwise than as a connection between a cause and an action”, which indicates that etiology is not only the action of a cause, but also its interaction with the body.
In our opinion, the lack of progress in the development of the doctrine of etiology was due to a fundamental mistake, which still exists in the scientific literature. Recall that the classical definition of etiology is as follows: "etiology is the study of the causes and conditions for the occurrence of diseases" [ 9, 75] . We have already drawn attention to the fact that this definition notes that the occurrence of a disease is due only to the action of causes, which is facilitated or counteracted by the existing conditions. It should be noted that with this interpretation of etiology, the body is assigned a purely secondary role and, in general, passive in relation to the action of the etiological factor. At the same time, according to I.V. Davydovsky, there is no connection between the cause and the action.
We have proposed a broader idea of the essence of etiology, taking into account the active participation of the organism. According to him, etiology is the study of the mechanisms of disease occurrence [ 14, 16, 20 ] . The mechanism of etiology is not only the action of the cause, but it is the interaction of the cause, including the conditions, and the effect - the human body [ 76] . Such representations are in full accordance with the theory of causality [ 16 ] . Within the framework of this view of etiology, we propose to distinguish three variants of the mechanism of disease occurrence.
The first is the action of causes that cause direct damage in the body (cells, tissues, organs) (Fig. 5).
Rice. 5. Etiology - the mechanism of direct (first type) damage.
The latter is due to the fact that the cause has such properties that exceed the body's ability to adapt and the possibilities of mechanisms that are not enough for the development of adaptive reactions, and therefore external influences cause damage (destruction) - this is the action of mechanical factors, temperature, acids, alkalis and others. Of course, with this variant of etiology, conditions play a role: temperature gradient, duration of action, concentration of acids and alkalis, etc. But even with such a mechanism for the occurrence of diseases, the body takes part in etiology, although the role of its properties has less effect on the final result (damage) than the actual factors. Properties such as skin moisture (its elasticity, degree of mechanical damage, on which electrical conductivity depends) and many other properties affect the nature and extent of the cause, but their values are not very large.
The second mechanism of etiology should include those cases when the cause itself does not cause direct damage in the body, but as a result of its interaction with the body, damage is formed (occurs), which is secondary to the direct action of the cause (Fig. 6). In essence, this is self-harm.
Figure 6. Etiology - the mechanism of indirect (second type) self-harm.
A striking example is allergic diseases - no matter what violations are observed with them (from skin rashes to the development of allergic shock), they are all caused by non-damaging direct effects (action) of the allergen (cause), but are the result of the immune response to the allergen entering the sensitized organism (conditions). Interaction with the allergen of antibodies or sensitized T-lymphocytes leads to the release and action of biologically active substances, complement activation, etc. [ 81] . And only they cause local or systemic disturbances, i.e. essentially self-destructive in the human body. Therefore, the decisive conditions that determine the development of protective (elimination of the allergen), or damaging, when the destruction of the antigen is accompanied by significant damage in the body, which exceed the degree of protection and lead to the onset of the disease (damage). It should be emphasized that the primary etiologically dependent damage, in fact, almost always occurs when any cause interacts with the body. It should be noted that the recognition of such a mechanism in the occurrence of diseases is a vivid example that demonstrates the active participation of the organism in the mechanisms of etiology. At the same time, the properties of allergens are of great importance, on which it largely depends whether the human body will react to them or not. In clinical practice, this contributed to the emergence and improvement of allergy diagnostics based on the search for allergens that cause sensitization. It should be noted that in the final result, the interaction is indeed influenced by many conditions, both external and internal, but necessarily interacting with each other. Moreover, self-harm is almost always present (participates) in the etiology of diseases, whether it be an infectious pathology, hypothermia, overheating, etc., although its meaning is different.
The third mechanism of etiology should include those diseases when the cause (etiological factors) does not cause either direct or indirect damage in the body at the time of action, but intense adaptation reactions occur, which result in the development of rather complex adaptation reactions, and then subsequent disadaptation (Fig. 7). And already they, after a certain, sometimes very remote period, lead to the appearance of delayed violations, i.e. diseases [ 72, 74, 81, 83] .
Figure 7. Etiology - the mechanism of indirect dysregulatory (third type) damage.
Almost all the so-called diseases of civilization, especially hypertension, can be attributed to such diseases. This mechanism for the occurrence of diseases was proposed by G.M. Kryzhanovsky and was called dysregulation pathology [38]. It is important to note that in the case of the etiology of dysregulatory reactions, it is necessary to include the intensity and, especially, the duration of exposure to external conditions. At the same time, to the internal, the state of the regulatory systems - parasympathetic or sympathetic tone, etc.
In our opinion, the recognition and definition of etiology as a mechanism for the occurrence of diseases directs the scientist and doctor not so much to identify the cause and eliminate it, but to a large extent to study the mechanisms of interaction between the cause and the human body, which contribute to or hinder the existing external and internal conditions. Hyperbolization of external factors in the etiology of the disease has led to the concept of so-called environmentally dependent pathology [ 35 ]. Although the influence of the changed environment is really great in the occurrence of diseases at the present time. However, the term eco-dependence to a greater extent indicates the structure and role of one or another factor of the changed environment, and not the emergence of a fundamentally new pathology. It is important to emphasize that the mechanism of etiology is always based on the active interaction of the human body with the cause. Namely, in many respects, the possibility of interaction is determined by how the human body reacts, which can be realized in adaptation (health) or damage (disease). Moreover, in both cases, the body adapts to the environment. However, this, along with the classical principle of etiotropic therapy - the elimination of the causative factor, necessitates the modulation of the body's response in order to ensure that each interaction is not accompanied by the occurrence of secondary damage, i.e. the development of the disease. Or this damage would be minimized. It should be noted that mankind empirically came to this conclusion quite a long time ago. A striking example is the prevention of so-called colds by increasing the body's resistance, especially by hardening methods. At the same time, the mechanism of interaction of infectious agents with the human body changes, and the very possibility of infection or the effect of temperature fluctuations on the body is not eliminated. The successful practice of immunization is also evidence of the importance of modulating the mechanism of etiology of many infectious diseases. In this case, not only the possibility of action on the body of an infectious agent is not prevented, but also its interaction with the body. However, this interaction, immune recognition and elimination of a foreign agent occurs faster and with much less damage in the human body.
Finally, an example is an injury that causes shock, while pre-anaesthesia in surgery allows for surgical interventions in which tissue damage occurs, but shock does not develop.
Recently, more and more often in the literature, when considering the etiology of pathogenesis, the term etiopathogenesis is used. Moreover, these are mostly clinical works, although theorists also use this term. Questions arise about whether such a definition is justified, why it arose, what is positive about it. The previously considered questions of the history of the theory of medicine give us grounds to assert a priori that none of the new theories, which are later even rejected, none of the new concepts arise without the presence of objective reasons. In our opinion, the emergence of the term etiopathogenesis was initially due to the fact that factual medical material on the study of the causes and mechanisms of the disease led to an important conclusion about their relationships. Of course, this important understanding was the result of disagreement with the understanding of the mechanisms of the disease from the position of monocausalism, when the presence of a cause and its action triggers the disease, and then pathogenetic mechanisms work. However, an increasing amount of experimental and clinical data indicated that there are various relationships between etiology and pathogenesis. This is especially true for the second mechanism of the occurrence of diseases, when it is extremely difficult to draw a line between etiology and pathogenesis.
This is due to the fact that the cause is often present for a sufficiently long period of the disease, and sometimes throughout it. At the same time, it is sometimes almost impossible to separate the effects of the action of the cause and the mechanisms of pathogenesis. Nevertheless, in our opinion, this term should be used with caution. This is due to the fact that with this approach there is no need to identify the mechanisms of the onset of the disease and the subsequent links of pathogenesis. This may lead to the fact that the value of measures aimed at the prevention of diseases and their etiotropic treatment may decrease, meanwhile, these are effective ways to influence the onset of the disease.
In conclusion, we consider it necessary to emphasize once again that without the interaction of the etiological factor and the body, the disease is not possible, although damage is possible, sometimes incompatible with life up to destruction, but the disease, as a form of adaptation, can develop only due to the mechanisms of interaction with the body. Therefore, our research in this direction should be aimed at understanding how this or that agent interacts with the body, which is accompanied by damage and the launch of the disease. Modulation of this interaction is the basis of prevention and even etiotropic treatment.
“From the modern point of view, the disease
does not create anything new in the body”
A.A. Bogomolets
Chapter V
The doctrine of pathogenesis
Currently, the disease is not considered as a stationary state, but a dynamic process that takes place over time, which sometimes lasts for many years and decades. This process ensures the adaptation of the organism to the environment, i.e. life in a state of illness. The process involves development, but in this case it is necessary to determine the driving force for the development of the disease. Of course, the connection and close dependence of the disease on the etiology suggests that such a driving effect can be the presence and constant action (interaction) on the body of the cause. This, it would seem, the most logical mechanism for the development of the disease, as a result of the constant presence and action of the cause, turned out to be the rarest and most insignificant. Such diseases can, perhaps, partly include some parasitic diseases, and a classic example in pathophysiology is scabies, when the disease is almost completely predetermined by the action of the cause - the scabies mite. Its action causes illness, removal - recovery. However, most even parasitic diseases are more complex processes, where damage by parasites to the human body is often combined with the appearance of secondary disorders that occur during the development of the pathology, complicating the course and outcomes of the disease.
The second possible explanation for the dynamics of the disease process is also the presence and action of a cause, but interaction with the organism is necessarily added to this. This interaction changes in the dynamics of the disease, mainly due to changes in the human body, which change the nature and even the form of the interaction of the human body with the cause. There are many more such diseases, and, first of all, these are chronic infectious diseases. A prime example is tuberculosis. Indeed, if in the process of treatment it is possible to achieve sanitation of the body from tubercle bacillus, then we can talk about recovery from tuberculosis, no matter how significant the consequences of the disease are, up to pulmonary heart failure. At the same time, depending on the state of the body, primarily its immunity, the disease can manifest itself in a variety of clinical forms from primary tuberculosis to miliary, etc. Moreover, a chronic inflammatory process in the lungs can continue even after sanitation from mycobacteria. In this case, fibrosis, respiratory failure and other pathological changes support the dynamics of the pathological process in the lungs with the development of eventually pneumosclerosis.
However, it turned out that even more diseases develop according to this type of relationship with etiology, when the interaction of the cause with the body with the onset of primary damage is only the first impetus, and subsequently the disease develops without the participation of the cause, solely by the mechanism of self-development. An example here is any stress-induced, autoimmune, tumor and other diseases - myocardial infarction, especially by the mechanism of non-coronary necrosis, hypertension, glomerulonephritis, etc. At the same time, the recognition of a very close relationship led to the emergence of the concept of etiopathogenesis.
Etiopathogenesis is a term that, in fact, corresponds to the II and III mechanisms of etiology. It is in these cases that it is almost impossible to draw a line between etiology and pathogenesis.
An important conclusion of the considered role of etiology (cause) in the dynamics of diseases is the position that, along with the extremely important role of etiology, from which any disease begins, human diseases subsequently develop to a large extent, and in many cases completely independently, therefore, they develop themselves. These mechanisms of disease development are called pathogenesis. The very term pathogenesis (pathos - disease, genesis - origin) indicates that we consider the disease as a process, and not a set of disorders that initially arose as a result of interaction with the cause. However, a detailed analysis of the problem immediately raises the key question of what is the driving mechanism for the development of the disease (pathogenesis) in cases where the cause ceases to act (interact), what causes more and more pathological changes in the body. The regularity of such a question becomes all the more obvious if we analyze the initial stages of the development of the process.
The consequence of the mechanisms of etiology is the occurrence of damage, the initial, key link in the onset of the disease, which occurs according to type I or II etiology. This, in turn, leads to the development of a number of body reactions aimed at eliminating damage and compensating for the resulting functional disorders. Compensatory reactions are adaptation to damage, which ensures the adaptation of the organism in conditions of damage. Moreover, each of the body's reactions in response to damage is always primarily adaptive in its essence, i.e. protective. There is not a single reaction in response to damage, initially pathological in its essence and qualitatively different from the mechanisms of adaptation in the norm. In this case, if the defense reactions manage to compensate for the damage, and the action of the cause has ceased, then the disease must also end, recovery should occur. Indeed, acute diseases develop in this way, for example, acute non-communicable diseases (altitude sickness), although in these cases the development of pathological processes can still take place. However, practical medicine shows that many of the diseases become chronic and develop over a long period, sometimes for a lifetime. Moreover, it is interesting that their development really depends on the primary damage, the more significant it is, the greater the likelihood of chronic disease. At the same time, in almost all cases, protective reactions initially compensate for the primary damage, although more often not completely.
In those cases when compensatory mechanisms are insufficient and even limited adaptation does not occur, the disease ends in death. However, clinical observations indicate that in the course of the development of the disease, more and more disorders appear, which often determine the severity of the disease and its outcomes. When analyzing this issue, the key is to determine the mechanisms for the occurrence of secondary disorders (damages) in the course of the development of the disease. Quite quickly it was established that they are not directly caused by the action of the cause, its interaction with the organism. The analysis of this problem eventually led pathophysiologists to the key concept of pathogenesis - the unity of the mechanisms of damage and protection in the dynamics of the disease. It was found that in all cases of pathogenesis there is a possibility that each protective and adaptive reaction of the organism itself in response to initial damage can become damaging, i.e. becomes a source of secondary disorders (damages) in the body of a sick person. Such a probability is realized in those cases when there is a significant, excessive activation of protective reactions. Consequently, the higher, the stronger the protection, the greater the likelihood of subsequent damage, in response to which then compensatory protective reactions occur, and the process becomes cyclical. Thus, in the theory of medicine, the concept of the unity and struggle of opposites of reactions of protection and damage as the main mechanism of self-development, self-propulsion of the disease appeared, and then became established. [17, 20].
Consider the course of the disease from these positions. The etiology of the disease lies in the fact that the interaction of the cause with the body, if this is not accompanied by damage, first leads to the inclusion of adaptation reactions (Fig. 8) as a whole, despite the influence of external factors, the body adapts, is in a state of health, i.e. adjusted within the normal range. With an increase in the degree (strength) of external influences, the development of primary damage is possible, in response to which adaptation reactions to damage are again activated in the body, defense reactions, the purpose of which is to compensate for the violations that have arisen.
Rice. 8. Adaptive mechanisms of a healthy person,
where A is adaptation, H is the norm, E is etiology
The higher the intensity of protection, the more likely it is that the defense reactions themselves cause a new, secondary (pathogenetic) damage, self-damage (Fig. 9).
Rice. 9. Disease outcomes
I - full recovery
II - incomplete recovery
III - recovery with an increase in the adaptive capabilities of the body
IV - death
E - etiology, A - adaptation, N - norm, D - death
In response to it, other reactions of a primarily protective nature are triggered, which compensate for previous violations, but they themselves can also become damaging. At the same time, primary, etiotropic disorders can be completely compensated, eliminated, and only their own protective reactions and mechanisms act as the cause of subsequent disorders. In this case, the development of the disease occurs later in most cases, regardless of the causes and mechanisms of their occurrence. The most striking example is autoimmune diseases, when the initial antigenic provocation (infectious or non-infectious) is not present in the course of the disease at subsequent stages of the disease, and the disease progresses (glomerulonephritis, hepatitis, etc.). In fact, there is not a single chronic disease in the development of which chains of protective-damaging reactions were not included. Consequently, pathogenesis is a mechanism for the self-development of a disease as a process of interrelated and interdependent, sequential reactions, each of which, having arisen as an adaptive protective one, itself becomes damaging, causing the next protective reaction with similar dynamics, being the next link in the pathological process, i.e. pathogenesis.
If this or that violation is not compensated, the outcome is ultimately death. The subsequent analysis of the dynamics of pathological processes showed that not all of its links are equivalent. It turned out that individual links of pathogenesis are decisive for the subsequent development of pathological processes. Such a link in each pathological process is called the main link of pathogenesis, since it is this link that predetermines the further development of the disease. In this connection, the definition of such a link is an important pathophysiological and clinical task. This already classical concept of pathophysiology, meanwhile, raises a number of questions. The main one is that, in principle, any link in the emerging chain (pathogenesis) of the disease is predetermining for the subsequent development and, therefore, its elimination (normalization) should lead to a “break” in the pathogenesis chain. Meanwhile, the experimental and clinical data do not allow us to agree with this. The answer to the question can be found in the following analysis of the known concepts of pathogenesis - the role of general and local in pathogenesis. The idea that no matter how local the pathological process (local damage) is, the whole organism is always involved in the process of the disease to one degree or another.
The physiological basis of such a development of the disease is that the human body is not a collection of individual organs and systems functioning in isolation, but is a functional whole (supersystem); changes in its parts are always accompanied by conjugated reactions of adaptation (defence). In pathology, this means that not only local, but also general numerous mechanisms are involved in the process of damage compensation. However, understanding that defensive reactions can always become damaging, pathological, we can conclude that the disease is not the development of only one single pathological process. At the same time, a whole network of interrelated, interacting processes can arise, aimed at adapting not one organ or system, but the organism as a whole to the pathogenic influence of the environment.
For the first time, this idea was clearly expressed in the guide to pathophysiology by A.I. Zaichik and L.P. Churilova [32] , about the same, about the branched types of pathogenesis, A.V. Ataman, pointing out two types of their dynamics - divergence and convergence [7] . Of course, the role of various branches of pathogenesis in the network of pathological processes in compensating for damage is different in terms of their influence on the dynamics of the disease. Consequently, the main predetermining mechanism for subsequent pathological processes includes the most important, i. main links. The main ones are because in the dynamics of the disease, the role of individual links of even the main pathological process often changes, which means that the main link is not always constant throughout the disease. At each stage of the development of the disease, its main links of pathogenesis are possible.
The established classical concept of a vicious circle also testifies to the complex dynamics of pathogenesis. It turned out that the pathogenetic chain itself is not always a linear developing process. Often, starting from some link, it subsequently returns to it, causing even greater damage, i.e. there is, as it were, a closure of the pathological process according to the type of a circle, and since in this case disturbances in the body increase, this circle is called vicious. This once again indicates a complex spatio-temporal configuration of pathogenesis, which is very conditionally (schematically) presented in Fig. 10.
Rice. 10. Disease as a pathological supersystem. (E - etiology)
The theoretical position about the pathogenetic chain as a single basis for the dynamics of the disease must, in our opinion, be replaced by the recognition of a pathological system, which, in fact, should be considered as a pathological supersystem. The need for a systematic approach in understanding the vital activity of a healthy organism was first noticed by P.K. Anokhin, having created the theory of functional systems [4, 46] . In principle, it is quite applicable to the state of the disease. It should be emphasized that this is a rather simplified scheme; in fact, many functional systems are simultaneously included in the adaptation process in the body, changing in time and space, representing a certain space-time continuum.
Consequently, today the problem of analyzing pathology from the standpoint of the theory of functional systems is common. This should aim to search in the dynamics of the disease not one single link, but also others that arise both primarily in relation to the mechanism of etiology, and secondarily in the course of self-development of the disease. In general, it can be argued that pathogenesis has a complex spatio-temporal organization involving many pathogenetic chains that arise sequentially and also in parallel and interact in time (disease dynamics) and space (disease structure).
Thus, a disease is an extremely complex process of adaptation of an organism to the environment with the involvement of many of its parts (organs and systems) in a dynamic self-developing process of protection (adaptation), which also causes numerous disturbances with the formation of a dynamic state of temporary adaptation [20, 69 ] . More precisely, this is not one pathogenetic process, but a combination of them, developing in time and space (Fig. 10). The scheme presented in this figure is rather conditional, but it demonstrates the principles of the organization of pathogenesis, each link of which can be expanded and detailed for each specific disease.
It should be noted that in this case, not all mechanisms of pathogenesis are accessible to clinical observation, or they manifest themselves in some generalized form of adaptation, while complex and diverse pathophysiological mechanisms are hidden behind these external manifestations, because the general is not a combination of the particular (its parts). Therefore, in pathophysiology, the concept of the internal mechanisms of pathogenesis and their external (clinical) manifestations has been established. Clinical observations of the development of the disease in the presence (influence) of concomitant diseases or comorbid pathology indicate a more severe course of the underlying disease under these conditions, the severity of the clinical picture of which reflects the complex and diverse nature of the interaction of pathogenesis mechanisms.
At the same time, in the practice of clinical medicine, a lot of data has been accumulated on the influence of environmental factors on the course of diseases, which can be schematically represented as follows (Fig. 11).
Fig.11. Influence of external conditions.
E - etiology, VU - external conditions
According to this scheme, additional exposures affect the subsequent development of the disease. In this case, they prevent recovery, but can also worsen the course of the process. It is important to note that although for clinical practice the understanding of the influence of external conditions on pathogenesis is generally recognized, however, in the theory of pathophysiology, this has not been given sufficient attention.
Unlike the conditions that affect the realization of the action of the cause, the factors that affect the pathogenesis do not belong to the etiology of diseases. The influence of external factors on the development of the disease is especially significant in the case of the so-called professionally conditioned pathology. It is known that this group of diseases is not caused by conditions that affect the human body in the course of its production activities, however, the frequency and severity of the outcomes of this pathology are much higher in certain professional groups. An example is the high morbidity and mortality from cardiovascular diseases, for example, among transport workers and representatives of other professions with a high psycho-emotional load. At the same time, these diseases cannot be attributed to occupational ones, since the factors inherent in the profession do not cause diseases, although they significantly negatively affect their course (development).
Factors contributing to the development of eco-dependent and occupational pathology may be physical, chemical, biological, or psychological in nature.
If physical, chemical and biological factors directly affect the body and modulate the mechanisms of etiology and pathogenesis, then psycho-emotional influences contribute to the emergence or development of exclusively dysregulatory disorders (Fig. 12). Consequently, professionally caused diseases are not special nosological forms, their high frequency and severity are due to the negative influence of external conditions on pathogenesis [ 41] .
In fact, the above fully applies to the so-called diseases of civilization. Indeed, the nosological structure of pathology in modern civilized countries is significantly different. But the leading ones are diseases of the cardiovascular system, oncological, the etiology of which corresponds to known nosological forms, although their frequency, severity, course features are due to the influence of external modern environment factors on the pathogenesis of classical pathologies.
However, it has been known for a long time that the action of environmental factors may not cause clinical signs of pathology for a considerable time, although certain changes in the human body are allowed. Thus, the concept of prepathology arose , that is, some kind of transitional state from health to illness, which prompted the development of various diagnostic approaches to identify initial pathological changes in the human body. It should be noted that the result of this was the idea regarding the state of "virtually healthy", as well as the prenosological state. However, the above requires us to search for those changes that occur in the human body before the development of pathology, and determine their mechanisms.
Modern data, in our opinion, suggest the existence of at least two conditions, relative to the prenosological period. It should be noted that in modern society, the degree of direct etiological pathogenetic impact of negative physical and chemical factors of the environment and the production environment, which are, in fact, damaging, is constantly decreasing, which is associated both with environmental preventive measures and with the improvement of technological processes in production. and improvement of living conditions.
Meanwhile, the change in the structure and content of labor in modern production is characterized, along with a decrease in the degree of negative impact of natural physical factors, at the same time, an increase in the action of anthropogenically dependent physical and chemical factors, and, most importantly, an increase in psycho-emotional stress, that is, labor intensity. Therefore, in our opinion, in those areas where the factor of psycho-emotional stress grows in workers, violations occur mainly according to the stress mechanism [25] .
At the same time, changes in the body develop in several stages.
The first stage is a compensated and dysregulatory state . And only at the second stage - decompensation . It most often occurs due to the action of physical, chemical or psycho-emotional factors. Although this may cause cell damage, some of which may disappear, the overall function of the organ or tissue remains sufficient, at least to maintain adaptation under conditions of stationary rest, and often damage may not occur (Fig. 12).
Rice. 12. Etiology and pathogenesis of occupational pathology
The development of adaptive reactions at this time occurs first due to the intensification of the functions of existing cells and tissues, and only then the formation of long-term adaptive reactions according to the mechanism of hypertrophy and hyperplasia (FZ Meyerson 1970-1990). A good example is the results of our research, which studied the effect of heavy metals on the kidneys. In these experiments (1980-2015) it was shown that in the kidneys heavy metals always cause primary damage, in particular, this initially concerns the proximal renal tubules. But depending on the degree of damage, either acute kidney damage occurs with an outcome in acute renal failure, although in most of the works cited, due to compensatory reactions, kidney function was restored. That is, compensation first hides damage that is not clinically manifested and this condition corresponds to the concept of “practically healthy”. If, in the further dynamics, adaptive reactions turn into damaging ones and secondary mechanisms of kidney damage occur, the formation of chronic kidney disease occurs with progressive phenomena in subsequent renal failure. We proposed to identify this state of compensation to use the definition of functional renal reserve and, if it decreases, even in the absence of pathological changes in kidney function, to diagnose the presence of disorders, pathologies [22] . Thus, we can detect pre-nosological changes in the kidneys, that is, diagnose pre-pathology of the kidneys. These experimental data allowed us to develop a diagnostic test for clinical practice and determine the functional renal reserve in patients with toxic nephropathy, hypertension and diabetes mellitus, which made it possible to identify hidden compensated kidney disorders before the appearance of clinical signs of their pathology in these diseases [22 ] .
That is, prenosological conditions, in the examples given, are, in some cases, compensated phases of pathology development arising from the damaging effects of physical and chemical environmental factors, to identify which it is necessary to apply the methodology for determining the maximum functional capabilities of organs and systems by diagnosing functional reserves . An example is the methodology and methodology developed by us for determining the functional renal reserve.
For preventive medicine, this can make it possible to identify the very initial phases of the damaging effects of environmentally unfavorable and professionally hazardous factors, and for clinical practice, to diagnose early clinical manifestations of the disease and monitor them in the future.
More complicated is the mechanism of formation of disorders in the body under the influence of psychological factors, psycho-emotional stress, which do not have a direct damaging effect on the human body. It is very important, because it is precisely such professional factors that become leading in modern production, and, in general, in modern society.
Yu.I. Kundiev and A.M. Nagornaya. The consequence of this stress is the development of stress as an important main chain in the pathogenesis of many occupational diseases. That is why the motto of the World Day for Safety and Health at Work in 2016 was: “Stress in the workplace: a collective challenge”.
It should be noted that stress in the workplace arises not only as a result of psycho-emotional stress, but other factors, especially physical factors, play an important role in its development: electromagnetic radiation, noise, changes in light and temperature conditions, vibration, etc., which are the cause increase in receptor-mediated information overload, therefore, there is a summation of various influences on the human body.
It is important to emphasize that all researchers came to the conclusion that the action of these factors, as a rule, does not cause primary damage in the body. However, at the same time, changes in the functional state of people exposed to extreme or long-acting psycho-emotional factors were still recorded. To understand these violations, G.N. Kryzhanovsky (2000-2005) put forward the theory of dysregulatory states, when damage does not occur in the human body, but the state of regulatory systems changes, which first leads to the appearance of functional deviations that reflect adaptive processes, subsequently causing the development of pathological dysregulatory states [ 38 ] . That is, the psycho-emotional load and, especially, overload by the dysregulatory mechanism of etiology cause changes in regulatory systems and dysregulatory pathology. In general, psycho-emotional overload is more often considered as psycho-emotional stress. At the same time, hyperactivation of the hypothalamic-adrenal system is considered to be the main dysregulation, which causes an imbalance in adaptive and damaging reactions, which was continued in the concept of allostasis (B. Mc. Ewen, S. Luсpien, 2002). Therefore, it is believed that periodic psycho-emotional overloads change the function of regulatory systems and form trace reactions, which are considered as an "allostatic load", which is the price for adaptation.
However, it should be noted that the state of allostasis develops as a result of damage during psychoemotional stress, when even endogenous signal damage molecules (alarmins) appear. That is, according to the concept of allostasis, psycho-emotional stress also causes damage at the molecular level. In view of the increasing role in human pathology, it is important to apply a method of reducing the intensity of stress, i.e. stress-limiting technologies [ 53] .
However, in a work environment, stress in the workplace rarely causes direct injury. Probably, the phenomenon of allostasis occurs not so often, as evidenced by the development of occupational diseases, mainly after 10–15 years of professional activity [41]. Meanwhile, dysregulation disorders arise and start the process of adaptation with the transition to dysregulation.
Such an approach can be taken as the basis for the violations that occur in workers in production with high labor intensity. What can explain, for example, the progression of cardiovascular pathology, pathology of the gastrointestinal tract, suppression of the immune system, the development of vegetative-vascular dystonia, psychopathy up to the development of professional burnout with significant professional psycho-emotional stress.
It is important to note that, in our opinion, the formation of trace reactions due to regulatory overstrain is facilitated by the fact that psychoemotional overloads are accompanied by a decrease in somatic accompaniment. It is known that regulatory activation under normal environmental conditions was formed in animals and humans in the course of evolution as the beginning of complex activation with the development of adaptive reactions in the form of an increase in the functional response with an increase in muscle work, the function of the cardiovascular, respiratory systems, liver, kidneys, blood and etc., the implementation of which should be provided by metabolic changes that provide the energy-plastic needs of adaptive reactions.
Earlier we noted that the above prompted us to develop the theory of the functional-metabolic continuum as a system that provides adequate energy-plastic support for the functioning of the body during adaptation and activation reactions [21] .
In turn, on the basis of the proposed theory of FMC, those changes that occur in the process of violation of adaptive reactions were considered. So in fig. 13. shows how, when FMC blocks (1 and 2) appear, the system is transformed with the formation of changes in metabolism and their effect on organs.
Rice. 13. Block diagrams of FMC functioning in case of regulatory-somatic imbalance.
According to these ideas, each altered functional adaptive reaction is accompanied by metabolic disorders, which not only provide the possibility of implementing physiological functions, but act as links in pathogenesis.
It is important that the regulatory mechanisms not only trigger somatic adaptation, organize its energy-plastic support, but after the cessation of regulatory activation, for example, the end of the action of extreme factors, regulatory trace reactions (hypercatecholaminemia, an increase in glucocorticoids), metabolic changes (hyperglycemia, hyperlipemia), may negatively affect somatic organs, the function of which should decrease when the regulatory signal disappears, but at the same time, intensive metabolism continues even after the state of complete restoration of the initial functional state of the organ sets in. That is, after intensive work, somatic organs still use (react) to regulatory and metabolic changes, which reduces trace reactions and possible allostatic load. Meanwhile, modern work is characterized by a growing imbalance between the regulatory and somatic load, that is, increasing psycho-emotional stress occurs in conditions of minimal somatic activation. As a result, there is an imbalance of regulatory activation with the state of somatic realization , which contributes to the long-term existence of trace reactions and the accumulation of these changes in the form of violations of the FMC up to the formation of an allostatic load and is a payment for adaptation, with hard work, as one of the important factors in the formation of professional dependent pathology. The general scheme and sequence of these violations is shown in fig. 14.
Of course, often the mechanisms and influences of the first and second groups are combined, combined, but it is always possible to identify the leading mechanisms for the formation of professionally dependent pathology and diseases of civilization.
Therefore, the correction of the leading factors of eco -dependence and professionally caused pathologies is the basis for prevention, early diagnosis and rehabilitation, which in general can provide an appropriate level of professional health, including professional longevity and, finally, life expectancy, as a summary characteristic of health. It should be noted that everything related to professionally conditioned pathology, in fact, manifests itself in the diseases of civilization.
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Psycho-emotional tension (stress) ↓ |
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Activation of the sympathoadrenal system ↓ |
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Activation of the hypothalamic-adrenal system ↓ |
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Activation of the PMK metabolic chain ↓ |
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Imbalance of FMK and symptomatic accompaniment ↓ |
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Metabolic trace reactions (hyperglycemia, hyperlipemia) ↓ |
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Progression of atherosclerotic vascular disease |
Rice. 14. Psycho-emotional stress (stress).
Indeed, the literature provides information that in developed countries the frequency of diseases of civilization reaches 75%. Of course, professionally caused diseases are only a part of them. However, in all cases, psycho-emotional overload is considered as the most important condition and mechanism for the development of diseases of civilization. It is important to emphasize that this entire group of diseases does not have a specific etiology. In fact, this is a consequence of the influence of the external environment in the form of stress factors on the pathogenetic links of known nosological units with a specific etiology. In most cases, attention is paid to the fact that these effects work according to the mechanism of stress-realizing factors as important links in pathogenesis [25]. However, it should be noted that in this case, as a rule, there is no initial damage due to the mechanism of acute stress, which is most clearly manifested in the fact that the effect of these external stress factors is realized after many years. Such dynamics requires an explanation of how the adaptive mechanisms of the general adaptation syndrome exacerbate the severity of, for example, cardiovascular pathologies. To explain this phenomenon, as already mentioned, we proposed a hypothesis of regulatory-somatic imbalance as one of the mechanisms for the development of diseases of civilization and professionally dependent pathology.
Regulatory-somatic imbalance is one of the most significant conditions that are inherent in the modern way of life in civilized countries. On the one hand, this is due to a change in the structure of loads on the human body, when psycho-emotional stress becomes predominant. At the same time, a powerful activation of neuro-hormonal systems that are aimed at adapting to the environment is not accompanied by an adequate somatic response. As a result, there is an imbalance of the biologically evolutionarily formed type of response and adaptation of the human body. The resulting redundancy in the activation of regulatory systems leads to the fact that neurogenic, hormonal and humoral reactions can become damaging. Examples are the effects of an excess of catecholamines: from "catecholamine" myocardial necrosis, hypertensive crises to mobilization hyperglycemia and hyperlipemia. For clarity, we can also cite the suppression of immunity, which occurs with an excess of glucocorticoids under stress. It can be argued that the excess concentration (activity) of any hormonal-humoral regulator or functional activity of the nervous system can cause negative consequences, which, however, manifest themselves, as a rule, only with significant hyperactivation of these regulatory systems. However, it can be safely assumed that even less significant phenomena of regulatory-somatic imbalance are unfavorable for the human body. To a large extent, they are implemented through violations that occur in the PMC.
At the same time, due to the mechanisms of intersystem and interorgan adaptation, they are initially compensated to a large extent, which implies the nature and methods of evolutionary established adaptation mechanisms, which are one of the reasons for the adaptive stability of the human body. However, with systemic and permanent phenomena accompanied by a regulatory-systemic imbalance and violations of the FMC, negative changes occur in the body, which reduces its adaptive resistance, i.e. there is a decrease in the level of health, and, in some cases, is one of the causes of the formation of diseases. The latter include professionally conditioned pathology, and, apparently, diseases of civilization. For example, a higher level of cardiovascular pathology in persons with chronic psycho-emotional overstrain, which is especially characteristic of persons engaged in operator work, cannot be explained otherwise than by a regulatory-somatic imbalance. The significance of this professional imbalance is extremely high, because the main civilizational trend of changing labor processes is precisely the decrease in the physical component and the increase in operator functions. This helps to increase productivity, but also reduce the physical intensity of labor.
At the same time, it must be emphasized that with positive subjective sensations that usually occur in a person with a decrease in physical activity, as a rule, psycho-emotional stress even increases and a regulatory-somatic imbalance is formed. The changes resulting from this are manifold, but it can be noted that one of the metabolic effects of regulatory activation is hyperlipemia, which is part of the metabolic support of the somatic activation reaction, which uses energy substrates, in this case, lipids. If somatic activation is absent or minimal, then the time of existence of hyperlipemia increases and, consequently, the possibility of infiltration or the vascular wall increases, which, with other mechanisms of violation of the FMC, can contribute to the progression of atherosclerosis, one of the most important mechanisms for the occurrence and progression of cardiovascular pathology (Fig. 14).
The foregoing allows us to once again emphasize the importance of the position on the role of external factors, their influence on pathogenesis. Thus, along with the endogenous mechanisms of pathogenesis, which predetermine the self-development of the disease, external influences influence the implementation of internal pathogenetic mechanisms, acting as modulating factors. If external influences increase the damaging effect of pathogenetic mechanisms, they should be attributed to conditions affecting the pathogenesis of diseases.
Consequently, the development of the disease is based on the internal mechanisms of pathological processes, the implementation of which is influenced by external factors that should be attributed to the conditions of pathogenesis.
Thus, at present, the main mechanisms and patterns of pathogenesis have been identified, which make it possible to understand the dynamics of the development of the disease and their internal logic. In general, it can be argued that the modern paradigm of the disease should be considered self-development and self-propulsion of pathology as a way to achieve adaptation of the body in conditions of damage and pathogenesis (disease), is the only possible form of adaptation of the damaged organism to the environment, evolutionarily formed and genetically fixed .
It should be noted that in the second half of life, it is necessary to take into account the fact that the dynamics of the disease is combined (summed up) with the general phenomena of regression (aging) of the body, which collectively reduce the adaptive capabilities of the body up to a decrease in life expectancy [ 64 ] .
However, the pathological process is not the only form of response of organisms and the development of pathology. Earlier, we paid attention to the fact that the severity of the development of the disease depends on the degree of primary damage, because it predetermines the need to include certain compensatory reactions and their severity, and, consequently, the further dynamics of the disease. In cases where the damage is insignificant and more often local, then not a whole process may develop in response, but one or more reactions, which are called a pathological reaction. Completion of the pathological process, along with the presence of a sufficiently persistent violation (limitation) of functions, leads to the development of a pathological condition, which is characterized by low dynamics or even its complete absence.
Usually, three main periods can be distinguished in the development of the disease: latent, incubation for infectious diseases, the period of pronounced clinical manifestations (peak period) and the outcome of the disease or the transition to a chronic disease. The general result of acute (rarely chronic) diseases is: complete or incomplete recovery, death. The presence of almost the same periods in a variety of diseases also indicates that there are general principles for the development of various diseases due to common mechanisms of pathogenesis.
The latent period of diseases is characterized by the fact that in most cases damage does not occur at this time, or its degree is insufficient and does not cause external manifestations, as a result of the fact that the body does not actively interact with the cause or, in case of infectious diseases, the infectious agent enters the body into depending on its pathogenicity, it is often not initially accompanied by any (minimal) clinical manifestations until there are no significant injuries, or they are completely compensated. However, already during this period, changes in the body begin due to the fact that antibodies or sensitized lymphocytes are produced to antigenic determinants of bacteria or viruses, and even earlier reactions of nonspecific phagocytosis are activated. It is the formed immune reactions that determine the subsequent interaction with viruses or bacteria, and are most often those mechanisms of damage (self-harm), i.e. diseases develop according to the second mechanism of etiology, in which, along with the destruction of a foreign agent (cause), an additional, sometimes basic damage occurs, which is accompanied by pronounced clinical manifestations already in the second period of the disease development. As a rule, most diseases develop in this way, which are especially related to acute infectious diseases.
Another reason for the latent period of the disease, which is more often characteristic of chronic, especially non-infectious diseases, is that with the development of minimal damage that is not clinically detected on its own, the development of defense reactions, adaptation initially leads to almost complete compensation of functions, and therefore to maintaining the ability to maintain the required level of adaptation. At least, this is true for stationary conditions under normal loads on the human body, and only an increase in the degree of damage, which reaches the limit of the adaptive capabilities of protective reactions, leads to the manifestation of subsequent functional failure with the development of one or another clinical picture of the main period of the disease. In addition, protective reactions, reaching their maximum, become damaging.
The outcomes of diseases, in turn, depend on the ratio of the degree of damage (primary and in the course of the further development of pathological processes) and the compensatory possibilities of protective reactions. Severe injuries, in which the protective mechanisms do not provide compensation, lead quickly enough to death. So, in the case of significant damage (disturbances) arising under the influence of the interaction of the cause and the organism, the degree of which cannot be compensated for by defense reactions, the latter, reaching their maximum severity, cause secondary damage in the body (shock in case of injury, etc.). Since the primary damage (violation) cannot be compensated, its combination with the secondary aggravates the severity of the pathology, while the adaptation of the body can only be ensured to a very limited extent, and its degree is constantly decreasing, damage (disturbances) are growing, which ultimately can lead to the impossibility of adaptation of the body with subsequent death, or to the chronicization of the disease. In the second case, if the primary violations are compensated by defense reactions, then the pathological process develops in the direction of increasing (normalizing) adaptive capabilities, which leads to recovery.
Depending on the degree of normalization of primary disorders (caused by causation) with the restoration of damage, either a complete recovery occurs, when after the illness the adaptive abilities of the body are completely restored, or in some cases, especially after acute infectious diseases with the formation of immunity, i.e. even with their increase in the adaptive capacity of the organism (Fig. 8). However, this or that damage often leads to disturbances, especially morphological ones, which, under normal conditions of the organism's existence, are compensated only due to the reserve capabilities of organs and tissues, i.e. interorgan and intersystem compensation, while recovery occurs, but not complete. Its distinguishing feature is a decrease in the maximum adaptive capacity of the body. Thus, incomplete recovery is always due to the fact that the primary etiotropic damage is accompanied by the death of a part of the tissue (organ) - as a result of which the number of its structural and functional units decreases. The complexity of pathogenesis predetermines both the difficulties of diagnosis and, especially, the treatment of diseases.
The presence of modern powerful pharmacological agents in the doctor's arsenal requires the development of such a treatment methodology, when the main thing is not to eliminate all manifestations of pathology, but to regulate pathogenesis in order to promote recovery after damage and increase the body's adaptive capabilities to the environment (natural and anthropogenic). However, we must once again note that in almost every modern scientific work, where certain changes are given that are identified in the disease, each of them is considered solely as an indicator of pathology. Indeed, as a rule, this is a criterion for the presence of a disease, but not only as a manifestation of damaging reactions, moreover, such manifestations initially indicate protective reactions. At the same time, the modern pathogenetic approach is almost completely absent, where the pathological process is considered as a chain of sequentially replacing each other protective and damaging links, each of which is in two states only at different times, which affects the tactics of treatment - there is a desire to eliminate all changes. in the body, i.e. always pathogenic.
This approach is always wrong and this can be demonstrated by numerous examples: it is not advisable to always completely normalize elevated body temperature in infectious diseases (influenza, etc.), strive to quickly reduce edema in the pathology of the cardiovascular system, normalize blood pressure with a decrease in glomerular filtration, or reduce the level of leukocytes during infection, inflammation, etc. Therefore, it is always necessary to analyze and clarify the essence (protective or damaging) of various links of pathogenesis in each specific period of pathogenesis development and their clinical manifestations.
One of the most important in theoretical and practical medicine is the question of the evolution of the disease. It is due to the fact that the clinic of modern diseases sometimes differs significantly from the classical clinical picture. So, for example, it is well known that a number of major diseases appear at a younger age, “a heart attack has become younger”, or proceed more aggressively, etc. Morphologists have noted for a long time that the modern pathomorphosis of diseases must be taken into account in clinical practice. First, the recognition of differences in the clinic and morphology of modern pathology raises a number of questions, the main of which are the following. Recognition of the increasing role of the influence of changed environmental factors on a person, which even led to the formation of the concepts of "environmental diseases" [35]. Moreover, this made it possible to substantiate the ecological model of medicine [ 30] .
What causes these changes, why does the evolution of diseases take place? Answering this question, it should be noted that there are indeed significant changes in etiology. We have already noted that this is mainly due to a deep modification of the environment, in which significant changes in its properties occur.
So, for example, evolutionarily the human body is adapted to the values of ionizing radiation within the natural background and the appearance of intense sources of radiation due to anthropogenic technogenic transformations caused the emergence of such a nosology as radiation sickness. The increase in the environment of heavy metals was the cause of a number of intoxications, the latter also occur with the appearance of new chemical compounds (pesticides, herbicides, etc.).
At the same time, when discussing the possible pathogenic role of chemical compounds, it should be remembered that the first and main condition for their influence on the human body is the concentration of these substances. So, biological organisms, including humans, are adapted, i.e. they have mechanisms of interaction with all chemical compounds of the natural environment, but within their ecologically and evolutionarily existing concentrations. An increase in their content can lead to pathology, up to poisoning. No wonder Academician I.M. Trachtenberg focused on the fact that each substance can be a poison, it's all about the quantity [61, 63]. It should be especially noted that a number of drugs can also cause pathology, the effects of which largely depend on the dose, the age of the patient, and a number of other conditions. This is the group of so-called iatrogenic diseases.
It is important to note that in addition to the physical and chemical modification of the biosphere, human activity is also accompanied by biological modification. An example is the epidemic of HIV infection, this also includes multi-resistant forms of bacteria that cause the development of specific forms of infectious diseases, which is very well known in the tuberculosis clinic, where multi-resistant forms of mycobacteria are an important problem. It is impossible not to mention the interaction of the body of a modern person with genetically modified organisms, although this issue is at the stage of discussion and study.
The consequence of a wide modification of the environment is also the simultaneous appearance of many changes or other influencing factors. This leads, in some cases, to the occurrence of several diseases in the population at the same time, which is called comorbidity (polymorbidity, multimorbidity).
It should be noted that this is not just a combination of known pathologies, but their significant pathological changes due to the interaction of various links of pathogenesis, which are often "included" in various diseases. And this, as a rule, reduces the adaptive capabilities of the body and changes the traditional clinic of pathology.
Secondly, it should be noted that the cause of the evolution of diseases can be not only changes in the environment, but also in the person himself. Although the biological evolution of modern man ended quite a long time ago, the phenotypic structure of the health of the population of modern society has a number of features. Thus, it is well known that the aging of the population is observed, which changes the structure of pathology, based on the characteristics of the adaptive capabilities of older people. This should also include the phenomenon of acceleration.
Changing working and living conditions of a modern person increase the stratum of the population with an overstrain of adaptation systems, especially due to increased psycho-emotional stress, the main consequence of which is stress and suppression of immunity. As a result, the human response to the impact of a number of pathogenic factors changes. It should be noted that in order to explain the characteristics of a person's reaction to certain pathogenic effects, the concept of "reactivity" was often used earlier.
The reactivity of the organism is the property of the organism as a whole to respond with changes in vital activity to the influence of the environment. In practical medicine, the term "organism reactivity" was widely used for the purpose of a general, often quantitative assessment of the state of the patient's body. The state of increased reactivity is defined as hyperergy, and reduced - hypergy. In fact, these and other features of reactivity are genotypically determined, and therefore, at present, there is a desire to clarify the causes of deviations and features of reactivity. The main way is to study genetic polymorphism, which largely determines the characteristics of human reactivity. At the same time, the features of the genotype to varying degrees can be realized in the phenotype, which largely depends on the influence of the external environment, fitness and other living conditions.
In turn, it is on the reactivity of the organism that its stability depends - resistance . Resistance of the body - the resistance (resistance) of the body to the effects of various environmental factors. Therefore, resistance largely depends on reactivity.
Nevertheless, it should be noted that at present such generalizing definitions as "reactivity" and "resistance" are largely specified in relation to the features of the mechanisms on which they depend.
Thus, the structure of the pathology of modern man is really changing. At the same time, a fundamental question arises that a change in the structure of pathogenic effects causes new diseases in humans, or changes the course of already known historically established forms of pathology.
In our opinion, all changes in the pathology of a modern person, despite sometimes very significant differences, are only variants of clinically known diseases. This is due to the fact that diseases, as a form of adaptation of the body in case of damage, are genotypically completely predetermined by the biological laws of the structural and functional organization of a person. The human body can adapt (react) only within the limits of its biological capabilities and mechanisms. Features of the etiological effects and phenotype can only influence the typical biological mechanisms of the disease, without canceling or replacing them, but only modifying them.
Meanwhile, only such an approach will make it possible to create a modern pathogenetic therapy based on the methodology of managing pathogenetic chains, when the object of action is not single "pathological" elements, but their functional consequences and, ultimately, the general state of the adaptive systems of the human body, which is controlled by selective influence. on various protective or damaging mechanisms.
It is necessary to emphasize that general biological ideas about the disease in clinical medicine should be specified in the quantitative characteristics of biochemical, physiological processes and morphological parameters. This is required, first of all, by diagnostics aimed at identifying a disease by searching for differences from the state of health, both at the level of individual quantitative indicators, and especially an integrative assessment of the level of the nature of the body's adaptation.
“... the key to recovery from an illness,
success in the fight against it lies primarily
and mainly in that reserve energy
that can detect all living things ...”
V. V. Podvysotsky
Chapter VI
The doctrine of sanogenesis
One of the most important theories for clinical medicine is sanogenesis. Sanitas - health, genesis - origin, development, i.e. recovery mechanisms, or rather, the mechanisms of health formation. The logic of medical thinking really perceives the statement that a person's recovery, of course, occurs due to the inclusion of certain special recovery mechanisms (reserve energy). Meanwhile, in domestic theoretical medicine, this is one of the most discussed issues. Although more than 40 years ago, Professor S.M. Pavlenko formulated the position on sanogenesis as a mechanism of recovery, theoretical thought has not advanced a single step during this time, moreover, this position has been subjected to devastating criticism and was initially rejected by most pathophysiologists. What caused such rejection among medical theorists?
Historically, it was by this time that the position on the driving mechanism for the development of pathological processes, the unity of damaging and protective mechanisms of pathogenesis, was finally firmly established in pathophysiology. It became clear that every defense mechanism is potentially damaging. Along with a truly fundamental significance, for the theory of disease, this automatically raised the question that if damage and protection are so organically combined in pathogenesis itself, is it necessary to single out outside pathogenesis, or rather pathological processes, there are still some mechanisms that are only mechanisms of recovery, i.e. exceptionally protective. It seemed that in this case, the fundamental principle of pathology collapses by itself, i.e. the unity of damage and protection, and hence the very possibility of explaining the mechanism of the development of the disease of its self-propulsion, self-development of pathogenesis.
However, by the end of the XX century. there is a need, based on the fundamental concepts of pathogenesis, to deepen and expand the existing understanding of the disease. This was due to the needs of practical healthcare. It was necessary to define the concept of premorbid states, clarify the mechanisms underlying recovery, rehabilitation, etc. There were such directions as adaptive, regenerative, rehabilitation medicine. For their understanding and development, it is not enough just to understand the unity of damaging-protective mechanisms as the only basis of pathogenesis, or rather the dynamics of the disease. Since, for example, in the period of rehabilitation or recovery or during prophylactic treatment, damage phenomena may often be absent. Moreover, the methods of treatment used in this case relate to methods of stimulating adaptive capabilities in healthy individuals, however, they cannot always be attributed exclusively to valeological effects in a healthy person, because in many cases rehabilitation is a way to stimulate the recovery capabilities of the body after an illness with symptoms of incomplete recovery from - for the resulting morphofunctional defects. It should be noted that as early as the 19th century, prominent pathologists turned to the theory of these issues. An excellent example is the work of Professor V.V. Podvysotsky, published by him in 1894 "On the reserve forces of the body and their significance in the fight against the disease." In it, he writes that “in a living organism it is necessary to recognize the existence of a double series of reserve forces: ready-made and again growing, newly formed” [52]. Analyzing in detail the development of diseases from the standpoint of the inclusion and formation of new reserve forces, V.V. Podvysotsky comes to the conclusion that "... that the guarantee of recovery from an illness, success in the fight against it lies primarily and mainly in that reserve energy that can detect all living things ..." It is now clearly established that this is how called reserve forces, this is nothing more than the functional reserves available in each organ (system). In fact, our great predecessor draws attention to the complexity of the dynamics of the disease, to the fact that simultaneously with the development of pathological processes, many protective mechanisms are turned on, which in themselves often do not cause damage, but in turn significantly and positively affect the mechanisms of the development of the disease. promoting recovery. However, the subsequent period of the development of the doctrine of the disease was characterized by theoreticians' predominant attention to the course of pathological processes as the basis for the development of the disease, rather than to the protective adaptive mechanisms of the body [ 2, 20 ].
And only in the mid-70s, Professor S.M. Pavlenko, an attempt was made to theoretically substantiate the mechanisms of recovery. The concept of sanogenesis was formulated: “sanogenesis is a dynamic process of protective and adaptive mechanisms (of a physiological and pathological nature) that occurs at the stage of pre-disease, developing throughout the entire disease process and directions for restoring the self-regulation of the body” [50 ] .
At the same time, however, such a position was perceived mainly only as a new attempt to divide the mechanisms of the disease into exclusively damaging or protective (sanogenetic), which served as the main reason for the official denial of sanogenesis among theorists as an independent and important theoretical direction in pathophysiology. Subsequently, despite the complete denial by most pathophysiologists of the presence of only protective, i.e. sanogenetic mechanisms in clinical medicine began to use the term sanogenesis more and more and began to study the mechanisms of recovery. Such a discrepancy between the needs of clinical practice and the position of theorists could not exist for a long time, and, indeed, by the end of the twentieth century, attempts to substantiate the presence of sanogenetic mechanisms reappeared. Moreover, the reason was not only the needs of practical medicine. So, when considering pathological processes, difficulties arose with understanding the mechanisms of recovery only from the position of unity and struggle of opposites - damage and protection. After all, if he agrees that the primary mechanism of recovery will be only a decrease in the degree of damage, then as a result, the severity of protection will also decrease, which will also reduce the subsequent damage. Consequently, a kind of "fading" of pathogenesis may occur, but it is absolutely not clear how the initial level of adaptation before the onset of the disease should be restored, without the presence of additional protective, but not damaging mechanisms. All the more impossible with such an interpretation is the recognition of an increase in the degree of adapted capabilities of the body after an illness, the previously cited example of an increase in immunity after an acute infectious disease, for example, influenza.
Previously, we have shown that the main reason for the insufficiency in the interpretation of the development of the disease is the identification of the entire pathogenesis with one single pathological process [20] . If only one single pathological process would develop in the human body during a disease, in which protection and damage would alternate sequentially and interconnectedly as a change in the subsequent same links of pathogenesis, then no other, including sanogenetic, mechanisms simply could would be. However, in our opinion, the disease is a much more complex spatio-temporal structure. First, the pathogenesis itself is not so much linear, but much more complex linear-network character. This provides the necessary (possible) level of adaptation of the patient's body with those injuries that occur in organs and tissues. At the same time, not all adaptive defense reactions reach such an intensity as to cause damage, but they can induce other mechanisms of adaptation (defense) with the formation of sanogenetic chains. Taken together, such an adaptive “unloading” of the main pathogenetic chain, in turn, reduces the degree of activation of defense mechanisms, which means their possible transition to damaging ones, and, consequently, the severity of secondary damage [ 67] .
Defense mechanisms and chains of protective-adaptive reactions, which are not themselves damaging, can be considered as sanogenetic , and the process of adaptation itself with the help of compensation systems should be defined as sanogenesis (Fig. 15). Thus, the structure and dynamics of the disease includes both pathogenesis and sanogenesis , which are very difficult to change in time and space, forming a regular, but largely individual (spatio-temporal) picture of the disease [ 15] .
Rice. 1 5. A - adaptation, E - etiology, P - pathogenesis, B - disease, N - norm, C - sanogenesis.
Moreover, it should be emphasized that in chronic diseases and, consequently, with prolonged adaptive overloads of individual organs and systems, the intensity of sanogenetic reactions can reach such values that they themselves can also become damaging in the future , but this in no way requires us to initially attribute such mechanisms to pathogenetic. It can be argued that an overstrain of physiological adaptive responses can also lead to damage. So, long-term sports overload, adaptation to which is one of the main mechanisms of adaptation and training, is implemented largely due to myocardial hypertrophy, which, with prolonged existence, can lead to myocardiosclerosis, the latter is the next phase in the development of hypertrophy, regardless of whether it occurs in pathology . or under conditions of physiological overload. And only its degree determines the subsequent dynamics of the process. Therefore, as long as the mechanisms of sanogenesis provide adaptation to the disease, contributing to its positive dynamics, i.e. recovery, they are the opposite of pathogenic processes.
Thus , the recognition of the presence of complex and diverse sanogenetic mechanisms, which largely compensate for the occurrence of damage in the body, not only expands our understanding of the disease, but, which is very important, is an important element of clinical, including, mainly, rehabilitation medicine. About the last V.V. Podvysotsky said the following: “out of the huge mass of therapeutic agents that were offered at various times for the treatment of diseases, only those whose action consists ... in strengthening the weakened protective and reserve forces of the body remained intact and strengthened ...” [52] .
Successful treatment of many diseases in which damage occurs initially, during recovery, especially requires rehabilitation measures that are based on the principles of sanogenesis. For medical rehabilitation, sanogenesis is essentially the underlying theory. Therefore, the attention of theorists and clinicians should be focused on the problems of the complex interaction of pathogenetic and sanogenetic mechanisms in the spatio-temporal dynamics of the disease, on the management of which the treatment and restoration of health should be based.
Indeed, in our proposed formulation of the concept of sanogenesis, it is emphasized that the level of health is formed due to the same mechanisms. Consequently, the level of adaptation of each person, including a healthy one, may differ and not coincide, more precisely, not fully realize the genetic potential. Thus, the phenotype, which determines the level of health, i.e. the degree of adaptation to the environment is based on the genotype, the degree of implementation of which is determined by the loads that a particular person, his adaptation system, is subjected to in ontogenesis. It should be pointed out that a change in environmental conditions that require the activation of physiological functional systems that provide this adaptation and the activation of the function of one or another adaptive system involves the intensification of the work of its structural and functional elements, primarily cells. It is known that if the intensification of cell function exceeds its functional capabilities, then the overall result of such a deficiency is an energy deficit, which is manifested by a decrease in the energy potential, which is expressed in a decrease in the ratio of ATP/ADP+AMP. Energy deficiency includes a number of adaptive reactions at the cell level: activation of glycolysis, increased consumption of glucose, etc.
At the same time, this mechanism is a trigger in the activation of the cell genome with a subsequent increase in protein synthesis of functioning structures, which leads to hypertrophy, and sometimes hyperplasia, followed by an increase in the number of functioning structures, which increases the adaptive capabilities of the organism within the limits determined by the genotype. This principle is widely used in various beauty technologies and controlled muscle development, and, in general, in rehabilitation medicine.
At the same time, in classical pathophysiology, an understanding has been formed that damage, from which the development of any pathological process begins, simultaneously activates the phenomenon of regeneration, as one of the main recovery mechanisms. An example is inflammation, the basic pathological process with local damage to any organ and tissue, which in its development goes through three stages: alteration, exudation, and only then proliferation. However, it has long been established that already during the first stage, when the main changes in the inflammation zone are the development of primary or secondary alteration, regeneration processes are also activated, and the phenomenon of damage is associated with regenerative, through decay products, cell death. Meanwhile, despite the fact that the phenomena of alteration and proliferation occur in conjunction, however, death, decay significantly predominate during this period over recovery, therefore the first stage is considered as alteration.
Therefore, under conditions of pathology, with the death of a part of the functioning parenchyma, it is necessary to turn on sanogenetic mechanisms. However, at the cell level, the primary stimulating mechanism, since and in the state of health is energy deficiency, as a result of an increased function in working structural and functional elements, a reduced number of which, in pathology, tends to compensate and provide the necessary adaptive level of functions.
In addition to pathophysiological understanding, these data are also the theoretical basis of restorative medicine. As a result, regenerative medicine technologies are divided into those that are used during the development of the disease (pathogenesis) and those that are used after recovery, i.e. in the absence of any mechanisms of the disease, but in the presence of certain morphofunctional disorders. Sanogenesis during this period is close in organization to the mechanisms of increasing the level of adaptation in healthy individuals.
In accordance with this, there is a distinction between rehabilitation at the hospital stage and restorative technologies, which, as a rule, are used at the sanitary-resort stage, and if the former are based both on pathogenetic correction in combination with sanogenetic stimulation, then the latter are based solely on the activation of the mechanisms of sanogenesis.
In this case, initially after the disease, there is one or another deficiency of the structural and functional elements of the tissue (organ), where the initial damage occurred, to compensate for which the protective mechanisms of pathogenesis were directed, but did not fully compensate for the functional deficiency.
Restorative medicine technologies during this period were originally based on increasing the function of existing structural and functional elements of tissues (organs), i.e. according to F.Z. Meyerson, there is an intensification of functioning structures. Numerous stimulation technologies can be used for this - from classical massage to the most modern electrophysical effects. Their use leads to an increase in function, as a rule, immediately after exposure, which is simultaneously accompanied for the second time by an increase in blood supply to the organ (tissue), the function of which increases. However, such intensification, as a rule, is very short-term, and is limited by the functional limits of functioning structures. The same F.Z. Meyerson pointed out that a further increase in function is possible only with an increase in the number of functioning structures. Currently, this is used on the basis of the technology of multiple stimulation of functions, which has long been actively used in rehabilitation medicine. Moreover, it is extremely important that at the same time, an increase (restoration) in the level of adaptation occurs due to adaptive changes in the structure and function in the organs (systems) in which there were violations in pathogenesis (compensation) and simultaneously in other organs and systems that “unload” and complement adaptation after an illness.
Chapter VII
Theoretical Foundations and Prospects for Improving Diagnostic and Treatment Technologies
Medicine has come a long way of development and has achieved impressive success not only in understanding the disease, but also, which is especially important for humanity, in the diagnosis and treatment of diseases. It should be noted that the main achievements in medicine, as a rule, are initially predominantly the result of empirical achievements, which often outstrip their theoretical understanding. Meanwhile, the subsequent improvement of especially medical technologies, as a rule, is initially directly related to theoretical studies in the field of pathogenesis. Almost a century of successful use of nitrates is a classic example, but only the establishment of the mechanism of action and the role of nitric oxide over the past 15 years has transformed pharmacotherapy in cardiology.
Meanwhile, if in the field of development and improvement of diagnostic technologies, everything is basically clear: on the basis of technological and informational progress, methods for identifying markers of damage or predisposition to the disease will be improved . This is especially true for advanced genetic diagnostics, or the determination of the functional state of organs and tissues, which will make it possible to identify pathology and establish its degree according to the state of function and activity of adaptive mechanisms, and therefore, to evaluate healthy, diagnose and characterize the disease. Consequently, in modern diagnostics, they practically do not look for qualitatively new structural biochemical and physiological properties inherent only in diseases, but mainly reveal their quantitative deviations from the norm. How can one not remember here that R. Vikhrov also pointed out that in pathology changes are detected in the wrong place, amount and time, i.e. they are quantitative, not qualitative. Despite the apparent fundamental simplicity of such a methodology, it has quite a lot of complexities, which we mentioned in the section on the norm. Without repeating what was said earlier, one should still pay attention to the ongoing attempts to find qualitatively inherent diseases, phenomena, signs. So, recently there is a fairly large number of works on the detection of markers of pathology. More often these are enzymes, proteins, etc. Despite the fact that in some cases their detection is practically useful in diagnosis, however, it should be noted that these are still not qualitatively new characteristics that are not inherent in a healthy person. Apparently, in this case, too, we are talking about quantitative differences between illness and health, it’s just that in the state of health these indicators are usually less significant, but at the same time they are related to the characteristics of a healthy organism. An example is the detection of α- fetoprotein and its role in the diagnosis of liver diseases, lipocaine - kidneys, etc. Although these indicators are successfully used in diagnostics, they are also inherent in the state of health, they are only detected in different quantities, in a different place and time.
At the same time, it is necessary to pay attention to the fact that the identification and diagnostic value of such markers of pathology, as a rule, should draw the attention of the doctor (researcher) to the pathogenetic significance of such signs of pathology. This means that practically with the exception of such markers, which are the result of cell decay, damage, all the rest are the result of an active adaptive reaction of the body, which means that each response can be twofold protective or damaging.
In this regard, along with the improvement of a systematic approach that allows to determine the boundaries of the norm, taking into account genotypic properties and phenotypic features, the main direction in improving diagnostic technologies is the development of functional diagnostic methods. Indeed, it must be emphasized that most of the modern diagnostic technologies and techniques are based on the determination of quantitative indicators of function and metabolism in stationary states of the subjects. At the same time, most often, studies are carried out in conditions of maximum physiological functional rest, as a rule, in the morning and on an empty stomach. This principle is due to the fact that with such an organization of the examination, the patient's condition is minimally affected by environmental influences (factors) and, therefore, the functions of the body can be judged by indicators that reflect the functional state of the body, and not side effects of random unaccounted for influences. However, this does not take into account the fact that any influences, including pathological changes in the body, are initially compensated, while the main parameters of homeostasis and, often, the functional characteristics of organs and systems remain within the normal range, if protective mechanisms are able to provide the necessary level of adaptation. .
Under these conditions, there are two diagnostic approaches to identify existing changes (disorders) in the body. Firstly, it is the determination of those functional or biochemical indicators that indicate compensation reactions in the body. For example, if organic acids are formed in the body in the metabolism, then initially the pH of the blood does not change. But by the amount of titratable acids excreted by the kidneys, it can be concluded that a state of metabolic acidosis may develop in the body.
Secondly, if the maintenance of a normal state, function or metabolism occurs due to the intensification of existing structures and functions, then such reactions can be identified by determining the maximum functional reserves of these organs or systems. At the same time, if under conditions of functional rest, vital signs can be normal, then at maximum functional load, a decrease in functional capabilities can be detected, which usually indicates the presence of certain structural and functional disorders.
Such a diagnostic approach is the basis of functional diagnostics, making it possible to identify compensated stages in the development of pathology. Indeed, such approaches have been developed for diagnosing cardiovascular pathology, lung diseases, detecting insulin deficiency, and a number of renal dysfunctions. At the same time, there are practically no methods for determining the functional reserves of a number of organs: the liver, gastrointestinal tract, protein, fat metabolism, the functional state of the endocrine system, immunological protection. It goes without saying that the development of methods for the functional diagnostics of these organs and systems will make it possible to identify the early stages of diseases in the period of function compensation.
It is she who allows you to determine the functional capabilities of organs and systems, and, consequently, the adaptive capabilities of the body. The latter determine both the state of health and the degree of impairment, and, then, its recovery after illness. It should be emphasized that such technologies are essential to identify the initial stages of the disease, when the initially occurring disorders are largely compensated, although it is during this period of disease development that their therapy is especially effective.
More complex is the theoretical basis for improving treatment and prevention (treatment and rehabilitation) technologies. In fact, modern technologies for prevention, treatment, rehabilitation were created, improved, as a rule, not on the basis of theoretical awareness, but mainly as a result of empirical research and achievements, which often outstripped theoretical justifications, being an incentive for these studies. As a result, in historical terms, most of the treatment technologies used were originally symptomatic in nature. Symptoms, as external manifestations of the disease, served as the object of therapeutic effects from surgical to therapeutic methods. Of course, based on the understanding that symptoms are an external manifestation of the mechanisms of the disease, the technologies used did influence the etiology and pathogenesis of the disease. However, it must be emphasized that initially it was an empirically arisen, so-called symptomatic treatment, which was not directed at the main links of pathogenesis, and therefore was not always effective enough.
At the same time, at the present time, it can be pointed out that all existing preventive, treatment and rehabilitation technologies are based on three main parts of the disease theory: the doctrine of etiology, the doctrine of pathogenesis and sanogenesis and, in fact, are etiotropic, pathogenetically or sanogenetic justified. It is on them and their combinations that modern prevention and clinics are based. Etiotropically directed technologies provide either prevention or reduction of the impact of the etiological factor and, concomitant with its effect on the body, conditions with simultaneous modulation of the body's response to them. Such a scientific and practical approach was the basis of the prevention system in our country and the world. In our country, the etiotropic direction has successfully developed in hygienic science and practice, which was realized in the creation and work of the sanitary and epidemiological service. Control over the environment and, especially, the working environment, living conditions made it possible to ensure a sufficiently high level of population prevention in the country. However, already in 1961 I.V. Davydovsky writes: "etiology, based only on the knowledge of today's external factors for, random, irrespective of human nature, cannot be the true basis of preventive medicine" [ 29] . Genius I.V. Davydovsky refers us to the previously substantiated in the chapter on etiology, the position that the mechanism of the onset of the disease consists in the interaction of the cause with the human body [ 84] . And, therefore, the prevention of diseases should consist in the fact that these interactions, which depend both on the cause and the condition of the person, are corrected in these two directions. At the same time, it was traditionally believed that the nature of these effects is largely determined only by the properties of the cause. For example, factors with temperature characteristics that cause protein coagulation should not contact (act) with the human body, although some people can walk on coals. Therefore, etiological factors with direct and damaging destructive effects should not come into contact with the human body or their effect should be limited. However, adaptation mechanisms have evolved to most environmental factors that interact with the cause, and therefore, when developing preventive technologies, impacts on the human body that affect the adaptation mechanisms should be simultaneously provided.
Of course, their ratio depending, first of all, on the degree of the damaging effect and the cause, can be very different. However, even with respect to damaging factors very significantly, preventive measures are possible that affect the human body: for example, to hypoxia through preliminary hypoxic training, a person can also be partially adapted even to ionizing radiation, antioxidants increase resistance, hardening increases immune defense, etc. d. Therefore, in these cases, it is possible to prevent diseases by modulating the state of the body in relation to interaction with the cause, at least partially, despite the predominant role of the cause in the occurrence of the disease.
For example, in the prevention of temperature damage, especially cold ones, hardening programs and others are necessarily implemented, which are included in anti-epidemic measures for the prevention of influenza and colds. Along with reducing the possibility of infection from patients, technologies of specific immunoprophylaxis (vaccination) are used in combination with effects aimed at increasing the nonspecific resistance of the organism, etc. If this is not taken into account, then a purely exogenous (etiotropic) population approach based on a system of restrictive and etiotropic measures is not only not always effective, but sometimes leads to a decrease in public confidence in such a prevention system, which, in fact, is little individualized and therefore not always effective. However, underestimation of the role and capabilities of etiotropic prevention, in turn, can lead to a situation where another threat of loss of an important etiotropic part of the prevention system arises, an example is the transformation that led, for example, to a sharp decrease in the functions and capabilities of the sanitary and epidemiological service in Ukraine, in particular, immunization population, and hence the entire system of population anti-infection prevention.
As for treatment and rehabilitation technologies, here, as a rule, complex etiotropically directed and pathogenetically substantiated approaches are implemented. Without setting ourselves the task of even a brief review of existing technologies, we consider it necessary to emphasize once again that by now the understanding has been established that modern medicine, using all medical technologies, is based on the principle that the main task of these influences is to help body to recover, and in accordance with its existing genetic programs of adaptation. In the case of the use of etiotropically directed treatment technologies, along with various ways of influencing the causes of diseases, which helps to prevent or reduce the effect of the cause, effects on the human body are successfully used, which modulate its interactions with the cause.
This approach is based on the modern understanding of etiology, according to which the disease is not so much the result of an action, but to a greater extent, the interaction of the cause with the body. An even greater role is assigned to the body during pathogenetic therapy, when the impact on the mechanisms of the disease, especially often pharmacotherapeutic ones, creates the conditions for the transition of pathogenesis into sanogenesis, i.e. conditions for self-healing. The body not only creates its own disease , but also recovers itself , although often it needs help in this. This brilliant statement is the result of scientific understanding of the essence of the disease.
The degree of influence on the mechanisms of the disease is diverse, and methods, especially pharmacotherapeutic ones, are constantly being improved. This, first of all, is a consequence of deepening our understanding of the mechanisms of pathogenesis. However, it must always be remembered that the essence of influencing the mechanisms of pathogenesis is not to eliminate them, but only to reduce the damaging effect while strengthening the protective effect, because each link in pathogenesis can be both protective and damaging. We consider it necessary to pay attention to the fact that the quantitative differences diagnosed in pathology do initially indicate the development of protective adaptation reactions. And, only later, these defense reactions can become damaging. And only a doctor, as an analyst and researcher of a particular disease, should and can determine this limit, and only depending on the role of these reactions in a particular case, apply treatment. This is extremely important, because against the background of the introduction of modern treatment protocols, as the basis for a high level of standards in medicine, the doctor is ultimately obliged to individualize, personalize them in a particular patient - this is medical art.
We consider it necessary to draw the reader's attention to the fact that in clinical practice, as a rule, all types of treatment used are divided into symptomatic and pathogenetic. In fact, such a division is based on the importance of the applied interventions in relation to the development of the disease. However, from the position of pathological physiology, all effects on the body should be classified as pathogenetic, because each of the symptoms is an external manifestation of pathogenetic mechanisms. In our opinion, pathogenetic, according to the currently accepted criteria, is the effect mainly on the main links of pathogenesis, while all the correction of symptomatic manifestations is a therapeutic effect on other links of pathogenesis, including all its branched chains that do not predetermine the development of pathology, but participate in its development. .
It should be emphasized that all etiotropic (in terms of influence on the human body) and pathogenetic treatment technologies contribute to the implementation of genetically programmed programs of the human body, the implementation of which ensures the adaptation of the human body in a state of illness. We remind you once again that the body itself creates its own disease (according to existing endogenous programs), and modern medical technologies only contribute to the implementation of these programs. Currently, much attention is paid to this, for example, in cardiology, the concept of endogenous mechanisms of cardioprotection has been formed, the maintenance of which is an important direction in the treatment of heart diseases [45].
At the same time, in recent years, new technologies have been successfully introduced into medical practice: stem cells, genomic medicine, transplantology, the concept of regenerative medicine, etc. [ 65] .
However, apparently, attention should be paid to the fact that at the same time, a fundamentally new direction in treatment technology is also gradually being formed, which, in our opinion, can be called external . programmable biocontrol of the body [23] . Indeed, if in most traditional and modern technologies we help the body, on the basis of its biological (endogenous) programs, adapt to illness and even recover, i.e. recover, then the proposed concept is fundamentally new, in which an attempt is made to generalize the already existing elements of new technologies and substantiate the possible prospects for its development based on external control of the body [18] .
The human body was formed as a complex whole, as a multisystem formed from many specialized elements (organs and tissues) integrated into one single supersystem due to a complex system of subordinate hierarchical regulation. At the tissue-organ level, the task is to integrate management between the elements of the local system, which includes cells (parenchymal connective tissue) and the microcirculatory bed (arterial, venous, lymphatic vessels and capillaries). Integration of all elements of the system is carried out due to metabolic regulation, as well as cellular hormones-cytokines, biologically active substances (to a greater extent associated with the microcirculatory bed). Due to the functioning of these three regulatory subsystems, tissue-organ control is carried out. At the same time, there are systems of central regulation, the task of which is the differentiated control of organ-tissue structures and systems of the body, which is aimed at ensuring the optimal level of adaptation of the body as a whole to the environment.
Under conditions of normal functioning, this is a state of health, and in case of damage, it is a disease. The body's regulatory and integrative systems include nervous, hormonal, immune, cellular, and, to some extent, humoral. All of them play a different role in the regulation of individual tissue-organ subsystems, depending on their significance in the functioning of the entire supersystem. Thus, the vital organs are quickly involved in maintaining the body's homeostasis. One way or another, under physiological conditions, there are typical adaptation reactions that have arisen in evolution at the level of the cell, tissue-organ elements, the functional system, and, finally, the organism, which are genetically determined. Equally clearly organized at all levels of the body are the mechanisms of adaptation in the event of damage, i.e. in pathological conditions. So, at the cellular level, this is activation, necrosis and apoptosis, at the tissue-organ level - inflammation, at the systemic level - stress, pre-immune response (systemic inflammation), shock. On this basis, depending on the degree and localization of damage, typical reactions and adaptations develop - typical pathological processes, in fact, endogenous bioprograms of adaptation in health and disease.
According to modern classical approaches to treatment, it is necessary to ensure the optimal development of reactions (typical pathological processes) of protection. The need for optimal influence on the development of typical pathological processes comes from the theory of pathogenesis, according to which each adaptive mechanism, being excessive in intensity, can become damaging, therefore, the optimal treatment is one that supports the defense mechanisms in pathogenesis, but at the same time controls (limits) their possible damaging pathogenic action. At the same time, in case of severe injuries in terminal conditions, especially in conditions of resuscitation, a different approach to managing the body's adaptive reactions has long been used. A classic example is pain relief, especially general pain relief. Thus, all the achievements of modern surgery have become, in many respects, possible due to the introduction of general anesthesia into clinical practice. Meanwhile, with the help of anesthesia, the evolutionarily developed mechanisms of systemic adaptation to severe damage, primarily stress and shock, change fundamentally.
On the one hand, for example, shock is often the main cause of death in patients with severe injuries, because the vitally important adaptive reactions that develop in this case are simultaneously damaging. However, there are simply no other adaptation mechanisms for such damage in the body; they did not arise in the process of evolution. It is the mechanisms of stress and shock that provide adaptation in case of severe damage to the body. And, only in those cases when medical workers ensure the stabilization of systemic hemodynamics, homeostasis, the nervous system can be "turned off" or partially reduce the activity of systemic integrative, primarily nervous mechanisms for regulating the development of adaptive biological reactions of the human body in case of severe damage. In fact, it becomes possible to "reprogram" the biocontrol of the organism's vital activity in case of damage on the basis of controlled and managed external regulation and maintenance of vital functions. Consequently, genetically programmed biofeedback can be supplemented and sometimes replaced by new external programmable biofeedback under shock conditions. In fact, such medical technologies of the future can be hybrid biocontrol systems of the body using both external and internal programmable control systems and elements of functional systems or organs. Of course, biomonitoring of vital activity is an obligatory technological condition, which allows, based on the principles of biofeedback, to ensure the functional support of the body, maintaining homeostasis and all adaptation through external control. It should be emphasized that external programmable biocontrol is not limited to anesthesia, for example, the technology of hibernation, controlled coma, etc. is based on the same principle. In general, it will be possible to change the structure of biological reactions of adaptation in case of damage in order to more effectively restore the disorders that have arisen. An example is the technology of programmed sensory deprivation developed by us as a variant of external programmable biocontrol [1, 23]. It has been proven that sensory deprivation creates conditions for effective correction of autonomic nervous system dysregulation in patients with long-term consequences of closed craniocerebral injury [23].
It is important to note that if the central nervous system is “turned off” in the developed technology, then another example is when, in order to achieve optimal conditions for the functioning of a damaged kidney, its hormonal-humoral defense mechanisms are turned off. In a series of works performed by us, it has been shown that if the mechanisms of regulation of sodium homeostasis in the kidneys are “turned off”, then new conditions can be created for the kidney, under which, despite severe damage to the tubular epithelium (acute kidney injury), acute renal failure does not develop and, thus Thus, it is possible to prevent a lethal outcome [22].
In general, external biofeedback makes it possible to prevent severe damage to an organ or tissue, despite the fact that the programmed biological adaptive responses are disrupted.
The problem of external programmable biocontrol becomes especially relevant with the use of stem cells in medical and rehabilitation technologies. Stem cells are most promising in cases where, as a result of the development of pathological processes in tissues (organs), the number of cells decreases, especially due to necrosis. It is known that the typical reaction of the body to local damage is inflammation - a phase-developing typical, predominantly local pathological process to damage.
The self-organization of the inflammatory process lies in the fact that when damaged, alteration develops (primary, and then secondary), followed by exudation, and then proliferation. However, although with the latter, the cellular composition is restored, the number of parenchymal cells, as a rule, decreases, and the tissue defect is filled mainly with proliferating connective tissue. Several reasons are responsible for the fact that when the damaged tissue is repaired, the complete normalization of the cellular composition does not occur. These include, firstly, a change in blood supply, and secondly, an insufficient number of stem cells in the regeneration zone. Of course, what is attractive is the possibility of increasing blood flow in the area of damage, which will ensure the delivery of oxygen, metabolites and even stem cells there. Or it is possible to inject stem cells directly into the area of tissue (organ) damage (defect). Moreover, the introduction of stem cells into the necrosis zone in the acute period of the disease really turned out to be very effective, for example, in myocardial infarction. However, in the case of the development of a typical reaction of a tissue (organ) to damage, inflammation, the situation becomes more complicated.
Modern technologies separately allow this to be done, however, in this case, a situation arises that contradicts the biological essence of inflammation: limiting the damage zone from the body as a whole to localize the tissue area in which it is necessary to destroy the foreign etiological agent and sanitize the damage zone from decay products of one's own cells. In fact, inflammation is the main local protective biologically formed typical pathological process. In case of local damage, the body cannot defend itself in any other way, it does not know how. At the same time, in the process of development of protection, damage occurs, the main of which is secondary alteration, the degree of which in many cases exceeds the primary alteration. The prospect of controlling inflammation is to reduce secondary alteration and stimulate regeneration, especially of the parenchyma. Indeed, the existing modern therapeutic techniques can make it possible to fulfill these tasks. At the same time, attempts to influence the development of inflammation by even effectively influencing individual mechanisms turned out to be not only ineffective, but sometimes extremely dangerous. For example, the powerful anti-inflammatory effect of glucocorticoids in local infectious processes (abscess) can lead to generalization of infection, sepsis. However, in the future, inflammation management may become a promising treatment technology. Its implementation is possible on the basis of external programmable biocontrol. In this case, fundamentally two problems will be solved: first, the partial “disconnection” of an organ/tissue from the body, i.e. removal (limited) from under the systems of bioregulation and the second - ensuring full local regulation at all stages of the development of the pathological process, i.e. implementation of external programmable biofeedback by increasing blood supply and introducing stem cells.
In fact, the medicine of the future, in order to preserve and restore the human body, can (will) not only “help” its own genetically determined reactions of protection and restoration, but, in some cases, can take the path of more active external control, provision and even replacement of its elements.
The theoretical foundations of rehabilitation are even less developed. It is known that any damage to organs and tissues in pathology is accompanied by the death of some part of the parenchyma. Its restoration is part of the disease (pathological process), however, as a rule, it never leads to a complete restoration of the structure. As a result, after the disease, there is always a decrease in the functionality of the organ (tissue). In the second period of the disease, when recovery processes begin to prevail over damage, there is a need to restore functions.
All technologies in regenerative medicine can be conditionally divided into those that are performed before and after the completion of pathological processes.
The theoretical basis for the restoration of functions are two mechanisms: urgent and long-term adaptation. The former are based on strengthening the function of existing structures, i.e. function intensification, while long-term adaptation is based on the inclusion of a morphological reserve due to hypertrophy and hyperplasia.
The sequence and mechanisms of urgent and long-term adaptation are genetically determined. Moreover, the strengthening of the function leads (starts) the mechanisms of the formation of a morphological reserve, which are always based on the release (formation) of growth factors that stimulate both hypertrophy and regeneration.
All growth factors can be conditionally divided into tissue and blood. Tissue cells are formed either during the decay of cells, or with a significant activation of the function. During the decay of cells, substances are formed that stimulate regenerative processes. However, during the period of completed pathological processes in tissues, the only way to stimulate the morphological reserve is to activate the function.
In this regard, in cases where rehabilitation is carried out during the period of the completed pathology process, and the pathogenetic mechanisms of the disease no longer “work”, the only consequences of the disease are a decrease in the amount of functioning parenchyma, which is usually replaced by connective tissue (the main consequence of proliferation) in subsequent morphofunctional insufficiency. . At the same time, there are violations of microcirculation, which is mainly associated with the formation of connective tissue. Thus, the metabolic supply of the parenchyma is limited, which reduces the possibility of recovery. Rehabilitation measures during this period of the disease, its completion - the outcome, as a rule, consist in methods of stimulating the function with a simultaneous increase in microcirculation. Moreover, the activation of the function is the leading one, because with its increase, metabolites and biologically active substances also appear that have vasodilating effects, which contributes to the restoration of microcirculation (decrease in pO 2 and pH, increase in CO 2 in tissues, ATP breakdown products, bioactive substances of mast cells , bradykia, etc.).
The primary stimulation of the function most traditionally occurs by mechanical action on the tissues, i.e. massage, in which mechanical effects on cell membranes cause their depolarization, deformation of structures and, accordingly, an increase in the work of ion pumps using ATP. These and, possibly, other cellular responses to mechanical action, the essence of which is to stimulate the restoration of the initial functional state of the cell, one way or another, occur with energy costs, the consequence of which is a decrease in the energy charge of the cell, which is expressed in a decrease in the ATP / ADP + AMP ratio. A decrease in ATP and an increase in its decay products is an integrative signal for the activation of energy metabolism (an increase in the rate of oxidative phosphorylation), the activation of glycolysis, which is also facilitated by insufficient supply of O 2 due to microcirculation disorders.
All this stimulates the function of microcirculation. Moreover, the latter also increases due to the same effects on mast cells, nerve endings, nerve conductors and other tissue elements. However, with repeated massages, it can be assumed that functional insufficiency gradually increases, as a result, energy deficiency increases, which itself is a signal to the cell nucleus about the need to turn on the morphological reserve by activating DNA synthesis, and then protein, with an increase in the number of intracellular elements functioning in the cell and organelles. With subsequent massages and an increase in functional insufficiency, the phenomenon of hyperplasia may also occur in a number of tissues, i.e. increase in the number of cells as a result of cell division [18 ].
Functionally activating influences in rehabilitation medicine should also include electrophysical influences, and even temperature ones. Along with the activation of tissue function, all of them, as a rule, are accompanied by an improvement in microcirculation, which can be both primary and secondary in relation to local effects.
In rehabilitation medicine, external programmable biocontrol technologies can also be used. Thus, we have developed the technology of activation-regenerative stimulation, which consists in the fact that massage stimulation of the face area is immediately combined with the introduction of activated platelets or even stem cells into the activation points [18]. Thus, both activation of the function and stimulation of regeneration are carried out simultaneously. Consequently, the internal biological program of the sequence for providing an increase in function is changed, which is corrected by external control.
It should be noted that there are also systemic mechanisms that affect the function of a tissue (organ). These are, first of all, neurogenic, neurohormonal, hormonal, which are realized through either the influence on the zone of damage (impact), or through systemic metabolic reactions. Therefore, in order to achieve the maximum rehabilitation effect, it is necessary either to activate urgent, or better, long-term adaptation reactions.
As a result, all modern technologies of rehabilitation medicine involve the use of course procedures. This is empirically substantiated as a way to achieve the maximum possible recovery of function based on the formation of long-term adaptation mechanisms.
Thus, the arsenal of medicine of the future can make it possible to solve many issues of preserving and prolonging life, which are currently practically impossible. It can be confidently stated that further progress in medicine will also be based, first of all, on the knowledge of the mechanisms of the disease (etiology, pathogenesis, sanogenesis), and on their basis, i.e. the principles of the functioning of living systems and, first of all, the human body, which will continue to be the case for organizing their management in the treatment process.
Chapter VIII
Doctrine of death
The doctrine of death or thanatology - (from the Greek - θαν ατος - death, λοgoς - teaching) a section of theoretical and practical medicine that studies the state of the body in the final stage of the pathological process, the dynamics and mechanisms of dying, the immediate causes of death and its clinical, biochemical and morphological manifestations - this is the most accepted definition given on the Internet in Wikipedia.
Interestingly, the term "thanatology" was introduced by the outstanding domestic pathologist I.I. Mechnikov [18]. It should be noted that among the problems of thanatology there are biological, clinical, social, spiritual and even ethical aspects.
From the standpoint of the theory of disease, we are primarily interested in the biomedical problems of dying. In this regard, attention should be paid to the fact that death is the final stage of the existence of the human body, at which it becomes impossible to adapt to the environment, as the main condition for life, the existence of a biological individual. This outcome of life is based on the constant entropy of the living system, i.e. a person who is partially certain time compensated through physiological adaptation reactions in a state of health or illness. And only when adaptation stops, the organism comes into balance with the environment - it ceases to exist as a biological system, i.e. dies.
An interesting question is about two possible mechanisms for the termination of adaptation: genetic and phenotypic. According to the first, life expectancy is genetically limited and one of the possible reasons is the shortening of DNA telomeres.
Previously, evidence of a genetically predetermined human lifespan was the Hayflick limit, according to which a cell is capable of dividing about 50 times, after which even in tissue culture in vitr o, after exhausting which, she dies. Subsequently, it was shown that the Hayflick limit is due to the shortening of telomeres. At first, A.M. Oleinikov expressed this hypothesis, and in 2000, the Nobel Prize was awarded to Elizabeth Blackburn, Carol Greider, and Jack Szostak for the experimental proof of the mechanisms of protection of chromosomes from terminal underreplication using telomeres and telomerase. Currently, this phenomenon is considered as the most important genetic cause of biological aging. Moreover, in wildlife, examples of even self-destruction of organisms are well known. At the same time, there is still no direct evidence of the predetermining and even more so the only significance of the genetic mechanisms for limiting life expectancy.
The second mechanism for reducing and stopping the adaptation of the organism to the environment, and, consequently, dying, is phenotypic, i.e. death occurs as a result of an increase in morphological and functional disorders, with a decrease in the functional capabilities of physiological functions, as they arise and progress in the form of a disease, and the latter is a process of adaptation to damage, with the final outcome in death, i.e. cessation of adaptation.
Thus, adaptation through disease is, in fact, a stage (process) of the human body dying.
At the same time, attention should be paid to the fact that the adaptation of the body is provided by a complex set of physiological systems that determine the possibility of adapting the human body as a complex biological supersystem that functions as a whole, which implies the participation of many, more precisely, all of its elements in adaptation. to the environment. At the same time, the significance of individual physiological systems and organs in temporal adaptation differs significantly. Thus, the most important life support systems of the body are the cardiovascular and respiratory systems, as a result of which their main executive organs (heart and lungs) are referred to as vital organs, on the work of which, first of all, the existence of the organism as a single biological system depends. However, regulatory systems, primarily the central nervous system, are even more significant for the existence of an organism.
Such an understanding is necessary because modern medicine uses a lot of technologies with an impact on both vital and less systemically important organs and tissues, which allows you to save life, the existence of the system, as with a decrease in the number of structural and functional elements (removal of the kidney, lung , limb amputation) up to organ replacement (temporary cardiopulmonary bypass), and permanent (mechanical heart). Although with such treatment technologies the adaptive capabilities of the body are reduced, however, adaptation, although limited in time and space, is preserved, which is a way to prolong life in case of illness.
In the future, the possibilities of modern medical technologies, apparently, will steadily increase due to the modulation or even replacement of individual organs (elements) of the body, both due to biological material (transplantation of organs and tissues) and artificial organs and systems. Ultimately, the goal of such technologies is to preserve the ability of a complex biological supersystem, which is a person, to adapt while maintaining a non-equilibrium state with the environment.
It should be especially noted that the death of a personality differs significantly from the death of an organism, while the death of the cerebral cortex, which determines the existence of a personality, may not lead to the death of the entire organism as a biological system. Consequently, the death of an organism in time is not a one-time process due to the fact that its individual systems, organs, tissues and, finally, cells, on the one hand, have different stability, and on the other hand, their significance for the existence of the organism as a whole, different. Ultimately, the epicenter of death is always cell death, which occurs by the mechanism of destruction, necrosis, apoptosis, or autophages, which terminates its existence [28]. The beginning of cell death is its damage under the influence of any impact, the degree of which exceeds the possibility of adaptation, including its recovery after damage. The main pathogenetic mechanism of cell death is its energy or genetic (regulatory) deficiency. The degree of the latter, in addition to damage, is determined by the functional activity of the cell - the more intense its function, the more energetic, plastic and regulatory dependence, and the less the stability of such a cell. These two mechanisms, as a rule, are coupled: in case of energy deficiency, mitochondria swell and cytochrome C comes out of them, which triggers the genetic mechanisms of self-destruction (death) of the cell. Although direct DNA damage is also possible (ionizing radiation, etc.).
Thus, the process of dying is a rather complex and multi-stage phenomenon from a person to a single cell and vice versa. The need for such an understanding is extremely important: a differentiated approach to ensuring the vital activity of an organism is based on the fact that in order to ensure the existence of an organism as an integral supersystem, it is necessary, first of all, to ensure the work of important organs (brain, heart and lungs), i.e. those that are of decisive importance for the functioning of the entire supersystem (organism). And only then it is necessary to correct other organs and systems, as parts of the entire supersystem. At the same time, understanding the non-simultaneity of the death of various cells allows the use of organs, tissues and individual cells in transplantation, with an increase in the possibility of modern medical technologies to prolong and save human life.
Such ideas about the non-simultaneity of the termination of existence (death) of an organism, as a supersystem and its individual components, allows the wide use of various technologies with the use of artificial elements, which mainly provide (replace) the function of the corresponding biological elements and ensure their function. In fact, for an organism, as a supersystem, each of its elements, first of all, must provide a function. And here the range is extremely wide: from artificial heart valves (mechanical function) to sensory systems (hearing, vision) and, possibly, entire organs (heart, kidneys), etc.
One way or another, in the complex and even dramatic phenomenon of human death, the biological essence is the cessation of the organism's adaptation to the environment in the transition from a non-equilibrium to an energy state in equilibrium with the environment.
"The patient must be treated,
not a disease"
Ya. Mudrov
Chapter IX
Clinical pathophysiology
This chapter was written for two main reasons. Firstly, by the desire to once again draw the attention of theorists and clinicians to the need for pathophysiological research in the clinic, and secondly, to pay attention to the possibilities and role of the pathophysiological approach for the formation of a doctor's clinical thinking and his successful professional activity. In our opinion, clinical pathophysiology can be the most important tool for using the achievements of fundamental medicine in solving the problems of clinical medicine. For the first time in Ukraine, we drew the attention of our colleagues pathophysiologists to the relevance of clinical pathophysiology in 2000 at the III Congress of the Ukrainian Scientific Society of Pathophysiologists in Odessa.
The result of heated discussions was the decision to open a scientific discussion on this issue on the pages of the Physiological Journal, in which our article appeared [ 23 ]. However, unfortunately, this discussion ended. At the same time, in this and our subsequent works, it was shown that although the experimental method, as the basic methodology in pathophysiology, made it possible to solve many issues of etiology and pathogenesis in modern medicine, however, it is practically impossible to understand the complex interacting and mutually influencing mechanisms in the human body only on the basis of experiment. Maybe. Simulation and study of individual mechanisms of pathology in the experiment provided a powerful breakthrough in medicine in the twentieth century. However, the dialectic of scientific knowledge is such that the concentration of the researcher's attention on individual mechanisms of the disease often leads him away from understanding the disease as a whole. Moreover, the desired condition for the experimental modeling of pathology is precisely the desire to access and understand individual "mechanisms", which was largely the result of the analytical modeling of pathology.
Having studied individual mechanisms, we began to move away from the disease as a holistic phenomenon, especially in a particular patient, where the main patterns "work" in the individual conditions of the body, and the latter are genetically and phenotypically very heterogeneous. Meanwhile, the epigraph of the chapter takes the classic statement, which is generally recognized that it is necessary to treat the patient, and not the disease, especially its individual links. And this implies the need to study in each particular patient the peculiarities of pathogenesis inherent in him, i.e. it is necessary to study the general patterns of the development of the disease in a particular patient. Consequently, every doctor at the stage of especially diagnosis acts as a clinical pathophysiologist.
Studying human disease on experimental models of pathophysiology, theoretical medicine, in general, having received enormous opportunities in understanding the individual mechanisms of pathology, however, began to simultaneously separate from the whole, from the disease as a holistic state of a person, and only clinical pathophysiology can overcome these difficulties and lead to the desired result. understanding the pathogenesis of the disease in the patient.
It should be noted that one of the reasons why theorists do not work directly with a person is the questions of bioethics and the methodological possibilities of science. Of course, not only the complexity, but also the need to fulfill one of the main medical ethical precepts “do no harm” in previous historical periods sharply limited the possibilities of clinical pathophysiology. However, significant progress in diagnostic technologies over the past 25-30 years has led to the emergence of fundamentally new opportunities, both in diagnostics and in human research. Moreover, it should be emphasized that acute vivisection methods, which , by the way, are currently being successfully replaced by in vitro studies , the cultivation of individual cells and even tissues, including those of humans, have made it possible in most of the main analytical research approaches in the clinic far ahead of experimental science. In our opinion, the time has come to combine the possibilities of experimental and clinical pathophysiology, which will certainly increase the effectiveness of scientific research in the field of medicine. Moreover, having such an approach will make it possible to bring a real theoretical basis under an absolutely justified desire to treat not individual pathogenetic mechanisms, but a disease and even a patient.
We would like to draw attention to the most important role of the pathophysiological approach to the patient and its importance for the successful professional activity of a doctor. Thus, the teaching of theoretical questions of medicine ends by the third year of study at a higher medical school. Moreover, for didactic reasons, and in many respects, in connection with the way of thinking of theoreticians-experimenters, training is carried out element by element, in a fundamentally schematic plan. This, indeed, allows us to assimilate a large number of individual mechanisms and principles of the formation of pathology. However, training does not reach the creation of a holistic view of the disease, and even more so the emergence of its pathological features. In many respects, it is also because the clinical worldview (basic, educational) of students is formed only by the end of their studies at the university. And, as a result, the theoretical knowledge gained in junior courses remains only in the form of a general outline of the problem, at best, its "reference" points. Recently, a huge mass of important new knowledge about the mechanisms of diseases has “piled up” on the doctor’s thinking, many pharmacological preparations have been proposed for their correction, which poses a large number of problems for doctors in understanding and, especially, the ability to manage the disease. Therefore, it is clinical pathophysiology that can become a theoretical basis for a practicing physician, forming his integrative theoretical thinking.
In addition, during this clinical period, pathophysiology and theorists do not interact effectively with clinicians, even in the highest medical school and science.
Meanwhile, there are a large number of problems, the understanding of which from the standpoint of pathological physiology, theoretical medicine is essential for modern clinical practice. Let's look at a few examples. Describing the course (development) of a disease, pathophysiologists usually provide students with an understanding of the phases of the disease, highlighting the classic periods: prodromal (incubation), peak period and outcome.
At the same time, a pathophysiological analysis of these periods is not carried out in the full modern sense. So, for example, from the standpoint of pathophysiology in the first period, a person is not yet sick if he is in the incubation period, when, for example, pathogenic microorganisms are already present in the body, but there are no clinical manifestations of the disease. In this case, the analysis of the problem from the standpoint of the modern doctrine of etiology suggests that, despite the presence of pathogenic microorganisms in the human body, their interaction with the host organism has not yet occurred. After all, the presence of a cause is the basis, the condition for the occurrence of a disease, but a disease as a consequence can arise only as a result of the interaction of the cause with the organism.
A completely different mechanism of the prodromal period of the disease, for example, in the case of chronic intoxication. The etiological factor interacts with the body, which is accompanied by damage, but at the same time, the adaptation that occurs due to the inclusion of compensatory mechanisms of the body ensures the vital activity of the body within sufficient limits of adaptation. An example is damage to nephrons of any etiology and their subsequent death, and this ultimately leads to chronic kidney disease, which often reveals itself only in the form of a decrease in glomerular filtration, although the latter occurs only after the death of 50% or more of the nephrons. Thus, the period of the peak of the disease is a state of imbalance between damage and compensation, with the former predominating. The outcome of any disease ultimately depends on the degree of functional insufficiency of the organ, tissue or system, which is again determined by the amount of damage and the possibilities of compensation. When the latter are insufficient, the level of adaptation decreases, and when it does not provide adaptation in optimal environmental conditions, death occurs. And if the compensation mechanisms are sufficient to adapt to the conditions of damage, then there is a basis for recovery, the nature of which depends on the degree of compensation and the level of adaptation achieved.
Of interest is the pathophysiological analysis of the concepts of acute and chronic diseases, which are usually based in the clinic on the temporal characteristics of damage and their clinic. At the same time, it should be noted that the clinical picture and its features are ultimately determined by the relationships that arise between damage and compensatory reactions with the achievement of a certain level of adaptation to the environment. So, acute diseases therefore quickly manifest themselves due to the fact that the damage, as a rule, is of such a degree that the insufficiency of adaptation mechanisms is immediately revealed. The latter is manifested in the clinical picture. In chronic diseases, the degree of damage in many cases is balanced for quite a long time by the formation of adaptive reactions, as a result of which the clinical signs of pathology develop much more slowly.
The complexity of the disease of a particular person is also determined by the fact that in the body often, and with age, as a rule, various diseases can simultaneously develop simultaneously. These are concomitant diseases and comorbid ( with -together and morbus -disease) pathology. For clinicians, the relationship and interdependence of these diseases is very important. From the position of a clinical pathophysiologist, the development of several diseases in the human body will always change the nature of pathogenesis, and hence the disease as a whole. The theoretical basis for this is the understanding of the body as an integral system, complexly participating in adaptation to the environment in a state of health and illness. And this means, in turn, that adaptation, especially under conditions of damage, significantly changes the course of other diseases due to the interaction of different systems in the same adaptive reactions or one system in different adaptive reactions. The whole complexity of the clinical picture is due to the peculiarities of interdependence and mutual influence of the mechanisms of pathogenesis in cases of comorbid and concomitant pathology. Of course, the pathophysiological analysis of such complex conditions is extremely necessary for the clinician, especially since in each case, along with general patterns, significant individual features of pathogenesis will appear due to genotypic features and phenotypic state.
Of course, in our opinion, for the formation of clinical thinking and practice, first of all, clinical pathophysiological analysis can serve as a support. In fact, clinical pathophysiology makes it possible to implement the achievements of fundamental medicine in clinical practice.
Thus, the doctrine of clinical pathophysiology, which has been formed in recent years, will certainly deepen our understanding of the pathogenesis of many diseases and serve as an effective way to form clinical thinking among students and practicing physicians.
CHAPTER X
Models of medicine
At present time, medicine (from the Latin medicina , which is often translated as the art of healing) is seen as a system of scientific knowledge and practical measures united by the goal of diagnosing, treating, preventing and rehabilitating diseases aimed at maintaining and strengthening health, including working capacity, social adaptation, alleviating suffering from physical and mental ailments, prolongation of human life. Consequently, medicine, as the most important component of the civilizational process, is focused on ensuring the individual and population health of a person as a condition for its biological and social implementation. However, the main subject of medicine is the disease - its diagnosis, treatment, prevention and rehabilitation, because the absence of disease is health.
Thus, although the goal of medicine is to ensure health, the main subject and object is the disease. In this connection, models of medicine have always been built on the basis of the theory of disease.
Attempts to build a model of medicine have been made for a long time.
In the fundamental monograph by V.M. Dilman "Four Models of Medicine" [30] discusses in detail the ecological, genetic, accumulation and ontogenetic models. It should be noted that this work is the most significant in recent times. At the same time, it should be noted that the author actually considers not the theory of medicine, but the theory of disease, i.e. those leading causes and mechanisms that determine the emergence and development of diseases. And this is only a part of the tasks facing medicine, the purpose of which is health and longevity; to achieve the latter, medicine develops diagnostic, treatment, preventive and rehabilitation technologies. Undoubtedly, the merit of the author is the grouping of diseases according to the main criteria and mechanisms of development, which, in fact, is a reorientation from the nosological approach to the pathogenetic one.
At the same time, understanding the essence of health and the mechanisms of disease formation, i.e. states of ill health and all other possibilities and tasks of medicine are based. Consequently, the models of medicine, according to V.M. Dilman, are, in our opinion, the basis for the formation of only one biological model of medicine. Indeed, V.M. Dilman defined the main purpose of his very bright and deep work as a book about the causes of the main diseases of modern man, about the relationship between aging and disease, between norm and pathology, between external and internal causes of disease and death.
Consequently, the content of all the theories put forward by the author, in fact, represents, in his own words, "... four models of the emergence of the main human diseases ..."[30]. It is important to emphasize that the author does not put forward models of medicine as a broader concept, but considers possible theories of the disease, depending on their etiology and internal development mechanisms, i.e. pathogenesis. Of course, it is interesting to analyze the most general principles of the development of major diseases, with an attempt to separate the main mechanisms of their occurrence, however, in our opinion, such an approach at the same time naturally contradicts the natural integrity of the body. This understanding led, in our opinion, V.M. Dilman to the need to eventually introduce the concept of integral medicine, within the framework of which the relationship between the four main mechanisms of the onset of the disease, which in a real situation are really carried out simultaneously, is naturally shown.
We did not set ourselves the task of a detailed analysis of the work of V.M. Dilman, however, having come to the idea that the main content of it is the problem of the disease, they asked themselves the question of how the theory of disease differs from the model of medicine.
In this regard, it should be recalled that medicine solves the issues not only of the essence of health and disease, but also, in connection with this, develops technologies for diagnosing these conditions, preventing and treating diseases, as well as rehabilitation, i.e. restoration of the maximum possible adaptation of the organism to the environment.
Consequently, the theory of disease is always included in the concept of a model (theory) of medicine, being its most important component, but the latter is a broader concept that includes both theoretical and practical parts. Moreover, medicine is aimed specifically at achieving the practical goals of ensuring human health and longevity.
The historical analysis of medicine allows us to distinguish three stages of its development: from its inception to the middle of the last century, when medical problems were mainly considered and solved on the basis of human biology, which naturally transformed into the second stage, which continues to this day, when, along with medical biological problems , the role of social adaptation of a person began to increase, and this period, which can be defined as a socio-humanistic one, which, according to a number of authors, will subsequently be transformed into a post-humanistic (transhumanistic) period.
In this regard, we propose to consider three models of medicine :
1. Biological.
2. Humanistic.
3. Transhumanist.
According to this classification , the biological model of medicine provides for scientific and practical activities in medicine to ensure human health by controlling the physiological mechanisms of the human body based on the knowledge of their biological essence, followed by the development of therapeutic and preventive medical and biological technologies based on the regulation of vital processes. In fact, most of modern medicine, from theory to the most advanced diagnostic, preventive, therapeutic and rehabilitation technologies, is based on the principles of the biological model of medicine.
The humanistic model provides for the development of medical technologies that provide greater biological and social adaptation and freedom (opportunities) of the human personality. At the same time, medical and social activities and technologies complement and / or expand the social capabilities of a person based on his biological nature. Therefore, the theoretical basis of this model is also data on the morphofunctional biological characteristics of a person.
Thus, the socio-humanistic model of medicine is always, on the one hand, based on the biological nature of man as the basis of his existence. However, technologies developed within the framework of the biological model of medicine are increasingly being supplemented with technologies for external technological correction of health and / or longevity, based on the addition, correction of biological functions, sometimes even by replacing individual biological elements with technical ones.
An example of such technologies is the correction of vision (glasses, lenses), hearing (hearing aids), this includes all types of prostheses up to the exoskeleton, hemodialysis and all types of extracorporeal blood purification, organ transplantation and even the use of artificial organs. The list of such medical technologies is constantly expanding, however, in all cases, the personal result of increasing adaptation and, first of all, social, is achieved on the basis of supplementing and / or correcting to some extent the biological structure and functions by external technological means of any nature.
The line between biological and humanistic models of medicine is very difficult to draw. However, with the humanistic model of medicine, the priority is not only to ensure the maximum level of biological adaptation, but mainly to ensure the maximum possible social adaptation, although based on the biological essence of the human body.
At the present stage of development of medicine, the humanistic model, in our opinion, is the most acceptable, and is realized in the anthropocentric synthetic theory of medicine.
Anthropocentricity lies in the fact that the main object of medicine is a person, and each specific one. Hence the concept, which has arisen recently, of personalized medicine. Of course, it is appropriate to recall that personification is a modern development of a historically established one of the leading postulates of Russian medicine that it is not the disease that should be treated, but the patient. The synthetic nature of modern theory lies in the fact that it is based both on the foundation of the biological nature of man and uses other technological solutions, biosocial and social areas. Ultimately, such medicine ensures the existence of a person, both an individual and a person.
The transhumanist model of medicine is emerging at the present time and is based on the use of the achievements of science and technology to eliminate those aspects of human existence that are defined as undesirable, first of all, the elimination of diseases up to the prevention of premature death.
This, first of all, includes genetic technologies, mind uploading, exocortex, isolated brain, cryonics and many others.
The transhumanistic model overlaps and overlaps the humanistic one, but their fundamental difference is that transhumanist technologies not only supplement (correct) biological capabilities, but, in the end, can lead to a complete loss, replacement of the human biological nature. At the same time, medicine can actively participate in the formation of a trans-person and, finally, a post-person. Robots are already underway to cyborgize humans. Without going into a scientific analysis of these medical and philosophical problems, it can be emphasized that the main aspiration of this trend is aimed at the immortality of a person, but not the body, but the personality, i.e. spirit. The basis of this approach lies in the very duality of man: body and spirit. At the same time, the biological nature of a person is not a mandatory basis for the technology of transhumanistic medicine. We only note that the author is an adherent of the biological model of medicine, which is based on theories of health and disease.
Why such ambiguous rejection in medicine, society causes the phenomenon of death both in individual and population approaches? What is the essential basis of such an approach? It seems to us that this is based not only on the individual desire of a person for his biological immortality, which is based on the duality of a person, which includes biological and spiritual components. And, if the first is very carefully studied in modern medicine, resulting in different ways, but scientists still come to the recognition of the limited existence of life as a biological form of matter [44], the fundamental basis of which is the understanding of entropy as the fundamental law of the existence of matter. Then the second component, which includes emotions and reason, is the most complex and therefore less known. Moreover, the spiritual essence of a person is constantly developing on the basis of the spiritual heritage of previous generations, combined with the individual life experience of each person. Ultimately, as a rule, there is a discrepancy between the decrease in the adaptive biological capabilities of the body and the development of the mind and spirit of a person.
It should be noted that humanity has long been aware of this contradiction and evidence of this is the postulates of religion about the immortality of souls, which are inherent in all religions up to the concepts of reincarnation. Undoubtedly, the desire to overcome this duality of a person, which cannot be realized within the framework of the biological model of medicine, although only partially possible by extending life, anti-aging technologies, with an increase in the lifetime of the human biological structure itself, can only be supplemented with humanistic medicine technologies by replacing, correcting the function of individual organs and systems, but with the preservation of the existence of the organism as a biological supersystem, and therefore a person limited in space and time (genetically determined).
In fact, a cardinal attempt to separate the biological and spiritual essences of a person is the basic principle that is put within the framework of transhumanism.
It must be emphasized that the concept of spiritual essence is based not only on the mind, which determines intellectual activity, but also on the psycho-emotional state. At the same time, although emotions are an important part of spiritual life, they are formed on the biological basis of a person, the loss of which, in our opinion, will affect to some extent the essence of the psycho-emotional component of the personality.
Without going into the problems of transhumanism, which, according to some scientists, may be the theoretical basis of the medicine of the future or part of it, it is nevertheless worth noting that the technologies that can be used to ensure the existence of the individual, apparently, in essence and in form are unlikely can be called medicine in its current form, because for the latter the object is a person, as a biological supersystem.
Therefore, due to the fact that the main forms of human existence are health and disease, our work was devoted to the analysis of the state of the disease, the prevention, diagnosis, treatment of which, as well as rehabilitation are the main content of the biological and humanistic models of medicine.
CHAPTER X I
General theory of disease and prospects for the development of modern medicine
Summarizing the above, it should be noted that at present medicine is based mainly on the biological model, the key concept of which is the understanding of the disease as a special form of adaptation of the human body to the environment. The main reason for the appearance of the disease is damage (disturbances) that occur in the body in the process of interaction with the environment.
The evolution of the disease is largely due to the fact that modern external influences differ significantly in many respects from the conditions in which a person was formed during evolution. The need for close interaction, existence in the environment led to the formation of a complex biological supersystem, the elements of which and the systems of their interaction ensured interaction (use) with other forms of matter.
The main fundamental property that distinguishes biological systems, including humans, is the emergence of such forms of existence of life (a biological form of matter), which made it possible to temporarily reduce their entropy, and, therefore, create conditions for maintaining their temporary stability in the environment. These abilities are based on the emergence of a regulated metabolism, which provided the energy conditions for the existence of life in space and time through the formation of reproductive mechanisms.
However, such a relative independence of existence is simultaneously limited by the capabilities of educated biological organisms, by the mechanisms of adaptation that have arisen, which are genetically fixed and implemented in each individual person. The existence of a person in the environment due to evolutionarily formed mechanisms of adaptation is defined as a state of health. However, in the process of adaptation to the environment, the human body periodically interacts with biological, physiological and chemical factors, in relation to which the adaptation mechanisms are insufficient, which leads to disturbances (damage) in the human body.
Such a mechanism of interaction of the organism with the environment with the occurrence of damage is referred to as etiology. It is necessary to clearly understand that for any parameters of external influence, the human body always interacts with all factors, and therefore the damage that occurs in the body is always the result of the interaction of the body and the external environment.
The state of the body in case of damage is defined as a disease. At the same time, the disease is an active form of adaptation and existence in conditions of damage. Consequently, all changes determined in the human body are always external manifestations of adaptation, the difference of which is that the adaptation of the organism occurs due to a decrease in the possibilities of adaptation to other factors. Thus, all changes determined in the human body are always external manifestations of the mechanisms and process of adaptation. Its difference is that the adaptation of the organism occurs due to a decrease in the possibilities of adaptation to other factors of the external and internal environment. The consequence of this is that the overall level of adaptation decreases, which is the main difference between illness and health. Another consequence of adaptation through disease is its progression (development) through the mechanisms of pathogenesis. The basis of pathogenesis is that adaptive defense mechanisms, reaching a maximum, become damaging. This is the sequence: damage → protection → damage → progression of the disease (decrease in adaptation) → death.
This is the basic scheme of the development of the disease, however, in the human body in the process of the disease, however, in the human body in the process of the disease, both pathogenetic and sanogenetic mechanisms simultaneously work, forming a complex spatio-temporal structure.
The basis of the modern theory of medicine is a biological model, which is guided by the principle of the active interaction of the body with the environment, the management of which is the basis of practical medicine: prevention (prevention of damage), clinical (management of adaptation mechanisms in case of damage).
The complexity and problems of medicine of the future are due to the fact that a person actively modifies the natural environment, changing its properties quantitatively, and sometimes qualitatively (for example, the state of weightlessness), which significantly exceeds the evolutionary and genetically fixed adaptation mechanisms of the organism (in terms of values, a, sometimes, and the absence). The most significant modification of the environment in the process of civilization is a particularly significant social modification (desyncronosis, psycho-emotional overstrain), which does not fully correspond to the biological nature of a person, the latter, meanwhile, is conservative, because it is based on the genome.
The main consequence of such a discrepancy between social needs and biological nature is the emergence of diseases of civilization and, in general, a decrease in the health conditions of modern man. In this regard, when forming public and social health programs, it is necessary to base them as much as possible on the realization of the possibilities of human biological nature. However, in recent years and probably in the future, medicine will have to increasingly use technical means and methods for prevention and treatment: vision correction methods, hearing aids, artificial materials in dentistry, traumatology, orthopedics, and surgery. Enriched and specialized nutrition, and numerous other technical and technological solutions up to artificial organs. At the same time, although, in our opinion, this is a stage of transition to humanistic medicine, however, technical and technological solutions continue to be based on the implementation and / or addition of the properties of the biological nature of a person - this, apparently, is the basis of the vector of development of medicine of the future , because the transition to the ideas of transhumanism takes us beyond the boundaries of man and the entire evolution of the living and, accordingly, the entire civilizational process.
As a consequence, modern medical theory can be seen as anthropocentric synthetic . Anthropocentricity lies in the fact that all modern medical technologies (population and individual) are focused on ensuring the health of a person - society and each individual. Moreover, their goal is to preserve and strengthen health through the prevention, treatment and rehabilitation of diseases. And recently, the formation of health through genotypic correction and control, and, especially, ensuring its maximum phenotypic implementation. The latter is the theoretical basis for the creation and functioning of the public health system by managing the biological implementation of the human genomic program. Undoubtedly, the theoretical basis of the modern theory of medicine is the understanding of health and disease as two types of biological realization of the existence of an organism in the environment.
At the same time, more and more medical technologies include various technological solutions that complement or protect certain elements or processes of the body that allow the body to better adapt to the environment, i.e. ensure its viability. It should be emphasized that various psychosocial technological solutions are also becoming increasingly important, which contribute to the realization of the growing psycho-emotional and, especially, social needs of modern man. Essentially, medicine is becoming synthetic; using all possible technological solutions to ensure the most complete human existence in the environment.
It should be noted that the progress and creation of the medicine of the future will be based on the consideration and deepening of our understanding of the biological nature of man, the knowledge of not only the chemical, but also the physical levels of the organization of human biology and its psychosocial implementation.
At the same time, at the same time, there is an increasing shift towards the expansion of psycho-social adaptation, as the main trend in ensuring the most complete existence (content) of human life. Undoubtedly, the main goal of the medicine of the future is to ensure active longevity within biological boundaries and possibilities. It is extremely important, especially in society, in our opinion, not to cross the border of this, in general, humanistic model of medicine beyond the line when the psycho-social essence of a person loses contact with his biological nature. Then, firstly, the stage of posthumanistic medicine begins, and, secondly, a person (as a biological individual) may also disappear.
It is difficult for us to predict this stage of civilization, however, if it takes place, then it will no longer be the development of human society and man. And this is no longer included in the goals, objectives, and, in general, the content of modern medicine.
AFTERWORD
You, my dear reader, have read the book, thank you.
I really hope that it was for you at least something interesting, and maybe even useful. The book is written primarily for doctors, especially young, senior students, so that they can be more effective in their medical activities, based on a system of fundamental ideas about the disease. After all, it is on them that all clinical medicine is built. However, under the pressure of a huge number of new facts from the field of diagnosis and treatment of patients, which are urgently needed by the doctor, constantly updated and supplemented, one can not lose the principles of a systematic approach in the clinic. One of the important principles for the successful use of new achievements in medical science and, most importantly, in the treatment of a particular patient, his healing, is, in our opinion, the combination of a basic general theoretical (pathophysiological) approach, which will be useful in systematizing, ordering and, finally, application of all new knowledge in medicine with the individual essence of a person.
I hope that colleagues in medical science have become my readers. Let them forgive me that this book has not become a classic scientific monograph on the problem of the theory of disease. At the same time, I hope that recently they have not so often come into the hands of scientific publications in which the theory of disease would be comprehensively presented. Moreover, as you are convinced that this scientific problem has a lot, if not white spots, then certainly not fully developed problems. Finally, I think that some thoughts will allow you, dear colleagues, to take a fresh look at a number of scientific questions you are solving. The methodology of scientific research in medical science has not exhausted itself.
Of course, a sick person is the main object of medicine, and knowledge of the essence of diseases contributes to the formation of the theory of medicine, on the basis of which the development and improvement of medical practice is built - this is the historical path of the development of medicine.
However, a doctor, a researcher does not have the opportunity (time) for such an evolutionary path, so they must master the existing theory of medicine in order to conduct a successful medical practice and develop medical science.
If on this path our work will be useful to you, then the author does not expect greater satisfaction for himself.
The main provisions of the book offered to the reader's attention represent the author's philosophy in medicine. It was formed as a result of studying medicine, analyzing experimental and clinical experience accumulated over many decades of research work and, finally, creative communication on these issues with colleagues. The results of our discussions, experience, ideas and comments of my colleagues stimulated the author's creative thought in understanding the theory of disease. In this regard, I consider it my duty and pleasant duty to thank all those who contributed to my work.
Of course, I want to address special words of gratitude to the bright memory of my teacher in the field of pathophysiology, science, philosophy and life, Boris Andreevich Pakhmurny, years of work, under whose leadership I was formed as a pathophysiologist. Another teacher of mine, Professor Igor Konstantinovich Vladkovsky, aroused interest in the analysis of clinical material. Creative communication with academicians and professors: G.N. Kryzhanovsky, Yu.V. Natochin, N.N. Zaiko, D.D. Zerbino, Yu.I. I. Gubsky, G. M. Butenko, A. G. Reznikov, V. F. Sagach, V. N. Elsky, V. A. Mikhnev, A. V. Ataman, E. F. Barinov and many other my colleagues in the field of pathophysiologists contributed to the clarification of the basic concepts and provisions of the theory of disease, supported interest in working on the book. My thinking was practiced, and its results were tested in the scientific teams of the departments of pathophysiology of the Bukovina and Odessa Medical Universities, as well as the Ukrainian Research Institute of Transport Medicine, where colleagues and students (N.V. Krishtal, B.A. Nasibullin, S.V. Biletsky, A. A. Svirsky, A. L. Kukharchuk, I. L. Popovich, V. A. Lisobey, L. M. Shafran, Y. E. Rogovoy, A. S. Fedoruk, A. A. Avramenko, I. V. Savitsky, S.G. Kotyuzhinskaya, V.V. Shukhtin, V.S. Goydyk, V.N. Mikhalchuk, T.L. Lebedeva, N.S. Badyuk and many others) not only acted as listeners, but also in fact, they were co-authors of many ideas.
And, finally, the 45-year experience of teaching pathophysiology to students is invaluable, whose attention and patience always prompted the author to search for such forms of presentation of the theory of pathology that would provide depth and clarity of presentation of the material.
All the listed scientific and life experience allowed me to present this work to your attention.
A. Gozhenko
CONTENT
AUTHOR'S FOREWORD
INTRODUCTION
CHAPTER I. Theory of medicine: science, education and medical
practice
CHAPTER II. The doctrine of health
CHAPTER III. Doctrine of illness
CHAPTER IV. The doctrine of etiology
CHAPTER V. The doctrine of pathogenesis
CHAPTER VI. The doctrine of sanogenesis
CHAPTER VII. Doctrine of death
CHAPTER VIII. Theoretical foundations and perspectives
improvement of diagnostic and therapeutic
technologies
CHAPTER IX. Clinical pathophysiology
CHAPTER X. Models of Medicine
CHAPTER XI. General theory of disease and prospects for the development of modern
medicine
AFTERWORD
BIBLIOGRAPHY
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31. Z iiko A . I . General pathology / A. I . Z aiko, Yu.V. Bitsya - M., - Medpress-inform. - 2006. - 635 p.
32. Zaichik A.I. General pathology / A.I. Zaichik, L. P. Churanov. - St. Petersburg, ELBI - St. Petersburg. - 2005. - 655 p.
33. Zaporozhan V.M. Clinical pathophysiology: current state, problems and prospects for development / V. M. Zaporozhan, A. I. Gozhenko // Journal of Physiology. - 2000. - T.46, No. 6. - P.123-126.
34. Zaporozhan V.N., Gozhenko E.A., Shapranov R.A. Influx of the geomagnetic field on the structural and functional correlates of cerebral measles // Journal of Physiology. - 2002. - T.48, No. 3. - S. 16-22.
35. Zerbino D. D. Ecological pathology and ecological nosology — one of the priority directions in medicine / D. D. Zerbino // Journal of the Academy of Medical Sciences of Ukraine. - 1995. - V. 1, No. 2. - S. 323–328.
36. Kanep V. Human adaptation in extreme environmental conditions / V. Kanep, D. Slutser, L.M. Saffron. – Riga,
37. Karpin V. A. Foundations of the theory of pathology: philosophical and methodological aspects. Abstract dis. for the competition of scientists. degree of Dr. med. sciences: spec. 09.00.0 "Philosophy of science and technology" / V. A. Karpin. - Novosibirsk. - 2009. - 33 p.
38. Kryzhanovsky G. N. Dysregulatory pathology / G. N. Kryzhanovsky. - M .: Medicine, 2002. - 96 p.
39. Kundiev Yu. I. Fundamental science and wikis of health protection / Yu. I. Kundiev // Journal of the Academy of Medical Sciences of Ukraine. — 2011 . - T. 17, No. 1. - S. 3 -6 p.
40. Kulinichenko VL Modern medicine: transformation of paradigms of theory and practice: philosophical and methodological analysis / VL Kulinichenko. - Kyiv, 2001. - 238 p.
41. Lisobey V.A. Morbidity of transport workers / V. A. Lisobey. - Odessa, 2005. - 260 p.
42. Litvitsky P. F. Pathophysiology vol. 1 / P. F. Litvitsky. - M.: GEOTF-Med, 2002. - 751 p.
43. Meyerson F.Z. Adaptation medicine: the concept of long-term adaptation / F.Z. Meyerson. - M: Delo, 1993. - 138 p.
44. Mechnikov I. I. Etudes of optimism - 2nd ed. / I. I. Mechnikov. - M.: 1990.
45. Moybenko A.A. Endogenous mechanisms of cardioprotection as a basis for pathogenetic therapy of heart diseases / Ed. A.A. Moibenko, V.E. Dosenko, A.N. Parkhomenko. - Kyiv: Naukova Dumka, 2008. - 520 p.
46. Natochin Yu. V. Physical and chemical determinants of physiological evolution: from protocell to man / Yu. V. Natochin // Ros. physiol. Journal them. THEM. Sechenov. - 2006. - T. 92, No. 1, - S. 51-72.
47. Nazarchuk I.A. Human constitution and its role in modern medicine / I.A. Nazarchuk // Medical business. - 2015. - No. 3-4. - S. 25-30.
48. Natochin Yu.V. Physiological evolution of animals: sodium key to resolving contradictions // Bulletin of the Russian Academy of Sciences. - 2007. - T.77. - S. 999-1010.
49. Natochin Yu.V. Evolution of evolutionary physiology // Ros. Physical journal named after I.M. Sechenov. - 2008. - T.94, No. 9. - S. 977-988.
50. Pavlenko S. M. Nosology: textbook / ed. S. M. Pavlenko. - M. : Medicine, 1974. - 63 p.
51. Podvysotsky VV Fundamentals of General Pathology. Guide to the study of the physiology of a sick person / VV Podvysotsky. - St. Petersburg, 1891. (1st ed.). - 413 p.
52. Podvysotsky V. V. On the reserve forces of the body and their significance in the fight against disease / V. V. Podvysotsky. - St. Petersburg, 1901. - 18 p.
53. Popovich I.A. Stress-limiting adaptogenic mechanism of biological and luscious activity of water Naftusya. - Kiev, Computerpress, 2011. - 300 p.
54. Razumov A.N. Health of a healthy person (basics of restorative medicine / A.N. Razumov, V.A. Ponomarenko, V.A. Piskunov. - M .: Medicine, 1996. - 413 p.
55. Serov V. V. General pathological approaches to the knowledge of the disease / V. V. Serov. - M.: Medicine, 1999. - 303 p.
56. Sechenov I. I. On plant acts of animal life / I. I. Sechenov // Med. Bulletin, 1861. - No. 28. - S. 17-22.
57. Selye G. Essays on the adaptation syndrome / G. Selye. - M.: Medicine, 1960. - 254 p.
58. Speransky A.D. Elements of construction of the theory of medicine / A.D. Speransky. - M.: VNIEM, 1937. - 135 p.
59. Sukmansky O.I. Disease: anthropological aspects / O.I. Sukmansky // Integrative Anthropology. - 2016. - No. 2 (28). - S. 45-50.
60. Tverdokhlib V.P. General mechanisms of adaptation and prevention determine the health of a healthy person / V. P. Tverdohlib, D. V. Tverdohlib, Yu.I. Kazakov, F.Z. Meyerson // Bulletin of SUSU. - 2006. - No. 3. - S. 99-102.
61. Trakhtenberg I.M. A book about poisons and poisonings: essays on toxicology. - Kyiv: Naukova Dumka, 2000. - 366 p.
62. Trakhtenberg I.M. The main indicators of the physiological norm in humans. A guide for toxicologists / I. M. Trakhtenberg, V. A. Tychinin, R. E. Sova [and others]; ed. I. M. Trakhtenberg. - K .: Publishing house "Avicenna", 2001. - 371 p.
63. Trakhtenberg I.M. Popular toxicology / Ed. I. M. Trakhtenberg, N. G. Prodanchuk. - Kyiv: VD "Avicena", 2016. - 447 p.
64. Frolkis V. V. Aging, evolution and life extension / V. V. Frolkis, Kh.K. Muradyan. - K .: Naukova Dumka, 1992. - 336 p.
65. Amanda EIChemokine receptors: multifaceted therapeutic targets // Nature Reviews Immunology. - 2002. - No. 2. - P. 106-115.
66. Barley, NTJ The mathematical theory of infectious dis-eases and its applications: 2nd ed. — Hafner Press / MacMillian pub. Co., 1975. - 413 p.
67. Barta AG, Bartb VA, Stelandc A., Zaslavskiya ML Modeling disease dynamics and survivor functions by sanogenesis curves // J. Statist. Planning Inference. - 2005. - 132, No. 1-2. - P. 33-51.
68. Bhopal RS Concepts of epidemiology. An integrated intro-duction to the ideas, theories, principles and methods of epidemiology. - Oxford: Oxford University Press, 2002. - 317 p.
69. Brena RM, Huang TH-M., Plass Ch. Quantitative assessment-ment of DNA methylation: potential applications for disease diagnosis, classification, and prognosis in clinical settings. Review // J. Mol. Med. - 2006. - 84, No. 5. - P. 365-377.
70. Florey ED General pathology. - London: Loyd-Like, 1970. - 1259 p.
71. Gervais P. Allergologie et ecologie. - Paris: Masson, 1976. - 150 p.
72. Goldfain A., Highway B. Adverse events and the ontology for general medical sciences // Adverse Events Work Shop. — July 26, 2011. [Electronic resource]. Access mode: albertgoldfain@gmail.com .
73. Hutchinson M. Genetic basis of common diseases: the general theory of Mendelian recessive genetics // Med. hypotheses. - 2005. - 65, No. 2. - P. 282-286.
74. Kann MGProtein interactions and disease: computational approaches to uncover the etiology of diseases // Bioin-formatics. - 2009. - 25, No. 12. - P. 1536-1542.
75. Kazem S.-Z. The prototype resemblance theory of disease // J. Med. disease. - 2008. - 33. - P. 106-139.
76. Krieger N. Epidemiology and the people's health theory and context. — New York: Oxford University Press, 2011. — 394 p.
77. Rangel AOThe systems theory of living systems and rele-vance to CAM. Part I: Theory // eCAM. - 2005. - 2, No. 1. - P. 13-18.
78. Rangel AOThe systems theory of living systems and rele-vance to CAM. Part II: Theory // eCAM. - 2005. - 2, No. 2. - P. 129-137.
79. Rangel AOThe systems theory of living systems and rele-vance to CAM. Part III: Theory // eCAM. - 2005. - 2, No. 3. - P. 267-275.
80. Rangel AOThe systems theory of living systems and rele-vance to CAM. Part IV: Theory // eCAM. - 2005. - 2, No. 4. - P. 420-439.
81. Reumauxa D., Duthilleula P., Roosb D. Pathogenesis of dis-eases associated with antineutrophil cytoplasm autoanti-bodies // Human Immunol. - 2004. - 65, No. 1. - P. 1-12.
82. Schumacher A., Petron A. Epigenetics of complex diseases: From general theory to experiments laboratory // DNA Methylation: Development, Genetic Disease and Cancer Current Topics in Microbiology and Immunology. - 2006. - 310. - P. 81-115.
83. Selye H. The stress without distress. - New York, 1974. - 171 p.
84. Suzuki J. Ecological model and systems theory [Electronic resource]. Access mode: http://www.hawai.edu/dyson/ Ecological%20model%20web%201-21.01.htm.
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Influx of the geomagnetic field on the structural and functional correlates of cerebral measles // Journal of Physiology. - 2002. - T.48, No. 3. - S. 16-22. 35.Zerbino D. D. Ecological pathology and ecological nosology — one of the priority directions in medicine / D. D. Zerbino // Journal of the Academy of Medical Sciences of Ukraine. - 1995. - V. 1, No. 2. - S. 323–328. 36.Kanep V. Human adaptation in extreme environmental conditions / V. Kanep, D. Slutser, L.M. Saffron. – Riga, 37.Karpin V. A. Foundations of the theory of pathology: philosophical and methodological aspects. Abstract dis. for the competition of scientists. degree of Dr. med. sciences: spec. 09.00.0 "Philosophy of science and technology" / V. A. Karpin. - Novosibirsk. - 2009. - 33 p. 38.Kryzhanovsky G. N. Dysregulatory pathology / G. N. Kryzhanovsky. - M .: Medicine, 2002. - 96 p. 39.Kundiev Yu. I. Fundamental science and wikis of health protection / Yu. I. Kundiev // Journal of the Academy of Medical Sciences of Ukraine. — 2011 . - T. 17, No. 1. - S. 3 -6 p. 40.Kulinichenko VL Modern medicine: transformation of paradigms of theory and practice: philosophical and methodological analysis / VL Kulinichenko. - Kyiv, 2001. - 238 p. 41.Lisobey V.A. Morbidity of transport workers / V. A. Lisobey. - Odessa, 2005. - 260 p. 42.Litvitsky P. F. Pathophysiology vol. 1 / P. F. Litvitsky. - M.: GEOTF-Med, 2002. - 751 p. 43.Meyerson F.Z. Adaptation medicine: the concept of long-term adaptation / F.Z. Meyerson. - M: Delo, 1993. - 138 p. 44.Mechnikov I. I. Etudes of optimism - 2nd ed. / I. I. Mechnikov. - M.: 1990. 45.Moybenko A.A. Endogenous mechanisms of cardioprotection as a basis for pathogenetic therapy of heart diseases / Ed. A.A. Moibenko, V.E. Dosenko, A.N. Parkhomenko. - Kyiv: Naukova Dumka, 2008. - 520 p. 46.Natochin Yu. V. Physical and chemical determinants of physiological evolution: from protocell to man / Yu. V. Natochin // Ros. physiol. Journal them. THEM. Sechenov. - 2006. - T. 92, No. 1, - S. 51-72. 47.Nazarchuk I.A. Human constitution and its role in modern medicine / I.A. Nazarchuk // Medical business. - 2015. - No. 3-4. - S. 25-30. 48.Natochin Yu.V. Physiological evolution of animals: sodium key to resolving contradictions // Bulletin of the Russian Academy of Sciences. - 2007. - T.77. - S. 999-1010. 49.Natochin Yu.V. Evolution of evolutionary physiology // Ros. Physical journal named after I.M. Sechenov. - 2008. - T.94, No. 9. - S. 977-988. 50.Pavlenko S. M. Nosology: textbook / ed. S. M. Pavlenko. - M. : Medicine, 1974. - 63 p. 51.Podvysotsky VV Fundamentals of General Pathology. Guide to the study of the physiology of a sick person / VV Podvysotsky. - St. Petersburg, 1891. (1st ed.). - 413 p. 52.Podvysotsky V. V. On the reserve forces of the body and their significance in the fight against disease / V. V. Podvysotsky. - St. Petersburg, 1901. - 18 p. 53.Popovich I.A. Stress-limiting adaptogenic mechanism of biological and luscious activity of water Naftusya. - Kiev, Computerpress, 2011. - 300 p. 54. Razumov A.N. Health of a healthy person (basics of restorative medicine / A.N. Razumov, V.A. Ponomarenko, V.A. Piskunov. - M .: Medicine, 1996. - 413 p. 55.Serov V. V. General pathological approaches to the knowledge of the disease / V. V. Serov. - M.: Medicine, 1999. - 303 p. 56.Sechenov I. I. On plant acts of animal life / I. I. Sechenov // Med. Bulletin, 1861. - No. 28. - S. 17-22. 57.Selye G. Essays on the adaptation syndrome / G. Selye. - M.: Medicine, 1960. - 254 p. 58.Speransky A.D. Elements of construction of the theory of medicine / A.D. Speransky. - M.: VNIEM, 1937. - 135 p. 59.Sukmansky O.I. Disease: anthropological aspects / O.I. Sukmansky // Integrative Anthropology. - 2016. - No. 2 (28). - S. 45-50. 60.Tverdokhlib V.P. General mechanisms of adaptation and prevention determine the health of a healthy person / V. P. Tverdohlib, D. V. Tverdohlib, Yu.I. Kazakov, F.Z. Meyerson // Bulletin of SUSU. - 2006. - No. 3. - S. 99-102. 61.Trakhtenberg I.M. A book about poisons and poisonings: essays on toxicology. - Kyiv: Naukova Dumka, 2000. - 366 p. 62.Trakhtenberg I.M. The main indicators of the physiological norm in humans. A guide for toxicologists / I. M. Trakhtenberg, V. A. Tychinin, R. E. Sova [and others]; ed. I. M. Trakhtenberg. - K .: Publishing house "Avicenna", 2001. - 371 p. 63.Trakhtenberg I.M. Popular toxicology / Ed. I. M. Trakhtenberg, N. G. Prodanchuk. - Kyiv: VD "Avicena", 2016. - 447 p. 64.Frolkis V. V. Aging, evolution and life extension / V. V. Frolkis, Kh.K. Muradyan. - K .: Naukova Dumka, 1992. - 336 p. 65.Amanda EIChemokine receptors: multifaceted therapeutic targets // Nature Reviews Immunology. - 2002. - No. 2. - P. 106-115. 66.Barley, NTJ The mathematical theory of infectious dis-eases and its applications: 2nd ed. — Hafner Press / MacMillian pub. Co., 1975. - 413 p. 67.Barta AG, Bartb VA, Stelandc A., Zaslavskiya ML Modeling disease dynamics and survivor functions by sanogenesis curves // J. Statist. Planning Inference. - 2005. - 132, No. 1-2. - P. 33-51. 68.Bhopal RS Concepts of epidemiology. An integrated intro-duction to the ideas, theories, principles and methods of epidemiology. - Oxford: Oxford University Press, 2002. - 317 p. 69.Brena RM, Huang TH-M., Plass Ch. Quantitative assessment-ment of DNA methylation: potential applications for disease diagnosis, classification, and prognosis in clinical settings. Review // J. Mol. Med. - 2006. - 84, No. 5. - P. 365-377. 70.Florey ED General pathology. - London: Loyd-Like, 1970. - 1259 p. 71.Gervais P. Allergologie et ecologie. - Paris: Masson, 1976. - 150 p. 72.Goldfain A., Highway B. Adverse events and the ontology for general medical sciences // Adverse Events Work Shop. — July 26, 2011. [Electronic resource]. Access mode: albertgoldfain@gmail.com . 73.Hutchinson M. Genetic basis of common diseases: the general theory of Mendelian recessive genetics // Med. hypotheses. - 2005. - 65, No. 2. - P. 282-286. 74.Kann MGProtein interactions and disease: computational approaches to uncover the etiology of diseases // Bioin-formatics. - 2009. - 25, No. 12. - P. 1536-1542. 75.Kazem S.-Z. The prototype resemblance theory of disease // J. Med. disease. - 2008. - 33. - P. 106-139. 76.Krieger N. Epidemiology and the people's health theory and context. — New York: Oxford University Press, 2011. — 394 p. 77.Rangel AOThe systems theory of living systems and rele-vance to CAM. Part I: Theory // eCAM. - 2005. - 2, No. 1. - P. 13-18. 78.Rangel AOThe systems theory of living systems and rele-vance to CAM. Part II: Theory // eCAM. - 2005. - 2, No. 2. - P. 129-137. 79.Rangel AOThe systems theory of living systems and rele-vance to CAM. Part III: Theory // eCAM. - 2005. - 2, No. 3. - P. 267-275. 80.Rangel AOThe systems theory of living systems and rele-vance to CAM. Part IV: Theory // eCAM. - 2005. - 2, No. 4. - P. 420-439. 81.Reumauxa D., Duthilleula P., Roosb D. Pathogenesis of dis-eases associated with antineutrophil cytoplasm autoanti-bodies // Human Immunol. - 2004. - 65, No. 1. - P. 1-12. 82.Schumacher A., Petron A. Epigenetics of complex diseases: From general theory to experiments laboratory // DNA Methylation: Development, Genetic Disease and Cancer Current Topics in Microbiology and Immunology. - 2006. - 310. - P. 81-115. 83.Selye H. The stress without distress. - New York, 1974. - 171 p. 84.Suzuki J. Ecological model and systems theory [Electronic resource]. Access mode: http://www.hawai.edu/dyson/ Ecological%20model%20web%201-21.01.htm.